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About this Author
DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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July 25, 2014

The Antibiotic Gap: It's All of the Above

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Posted by Derek

Here's a business-section column at the New York Times on the problem of antibiotic drug discovery. To those of us following the industry, the problems of antibiotic drug discovery are big pieces of furniture that we've lived with all our lives; we hardly even notice if we bump into them again. You'd think that readers of the Times or other such outlets would have come across the topic a few times before, too, but there must always be a group for which it's new, no matter how many books and newspaper articles and magazine covers and TV segments are done on it. It's certainly important enough - there's no doubt that we really are going to be in big trouble if we don't keep up the arms race against the bacteria.

This piece takes the tack of "If drug discovery is actually doing OK, where are the new antibiotics?" Here's a key section:

Antibiotics face a daunting proposition. They are not only becoming more difficult to develop, but they are also not obviously profitable. Unlike, say, cancer drugs, which can be spectacularly expensive and may need to be taken for life, antibiotics do not command top dollar from hospitals. What’s more, they tend to be prescribed for only short periods of time.

Importantly, any new breakthrough antibiotic is likely to be jealously guarded by doctors and health officials for as long as possible, and used only as a drug of last resort to prevent bacteria from developing resistance. By the time it became a mass-market drug, companies fear, it could be already off patent and subject to competition from generics that would drive its price down.

Antibiotics are not the only drugs getting the cold shoulder, however. Research on treatments to combat H.I.V./AIDS is also drying up, according to the research at Yale, mostly because the cost and time required for development are increasing. Research into new cardiovascular therapies has mostly stuck to less risky “me too” drugs.

This mixes several different issues, unfortunately, and if a reader doesn't follow the drug industry (or medical research in general), then they may well not realize this. (And that's the most likely sort of reader for this article - people who do follow such things have heard all of this before). The reason that cardiovascular drug research seems to have waned is that we already have a pretty good arsenal of drugs for the most common cardiovascular conditions. There are a huge number of options for managing high blood pressure, for example, and they're mostly generic drugs by now. The same goes for lowering LDL: it's going to be hard to beat the statins, especially generic Lipitor. But there is a new class coming along targeting PCSK9 that is going to try to do just that. This is a very hot area of drug development (as the author of the Times column could have found without much effort), although the only reason it's so big is that PCSK9 is the only pathway known that could actually be more effective at lowering LDL than the statins. (How well it does that in the long term, and what the accompanying safety profile might be, are the subject of ongoing billion-dollar efforts). The point is, the barriers to entry in cardiovascular are, by now, rather high: a lot of good drugs are known that address a lot of the common problems. If you want to go after a new drug in the space, you need a new mechanism, like PCSK9 (and those are thin on the ground), or you need to find something that works against some of the unmet needs that people have already tried to fix and failed (such as stroke, a notorious swamp of drug development which has swallowed many large expeditions without a trace).

To be honest, HIV is a smaller-scale version of the same thing. The existing suite of therapies is large and diverse, and keeps the disease in check in huge numbers of patients. All sorts of other mechanisms have been tried as well, and found wanting in the development stage. If you want to find a new drug for HIV, you have a very high entry barrier again, because pretty most of the reasonable ways to attack the problem have already been tried. The focus now is on trying to "flush out" latent HIV from cells, which might actually lead to a cure. But no one knows yet if that's feasible, how well it will work when it's tried, or what the best way to do it might be. There were headlines on this just the other day.

The barriers to entry in the antibiotic field area similarly high, and that's what this article seems to have missed completely. All the known reasonable routes of antibiotic action have been thoroughly worked over by now. As mentioned here the other day, if you just start screening your million-compound libraries against bacteria to see what kills them, you will find a vast pile of stuff that will kill your own cells, too, which is not what you want, and once you've cleared those out, you will find a still-pretty-vast pile of compounds that work through mechanisms that we already have antibiotics targeting. Needles in haystacks have nothing on this.

In fact, a lot of not-so-reasonable routes have been worked over, too. I keep sending people to this article, which is now seven years old and talks about research efforts even older than that. It's the story of GlaxoSmithKline's exhaustive antibiotics research efforts, and it also tells you how many drugs they got out of it all in the end: zip. Not a thing. From what I can see, the folks who worked on this over the last fifteen or twenty years at AstraZeneca could easily write the same sort of article - they've published all kinds of things against a wide variety of bacterial targets, and I don't think any of it has led to an actual drug.

This brings up another thing mentioned in the Times column. Here's the quote:

This is particularly striking at a time when the pharmaceutical industry is unusually optimistic about the future of medical innovation. Dr. Mikael Dolsten, who oversees worldwide research and development at Pfizer, points out that if progress in the 15 years until 2010 or so looked sluggish, it was just because it takes time to figure out how to turn breakthroughs like the map of the human genome into new drugs.

Ah, but bacterial genomes were sequenced before the human one was (and they're more simple, at that). Keep in mind also that proof-of-concept for new targets can be easier to obtain in bacteria (if you manage to find any chemical matter, that is). I well recall talking with a bunch of people in 1997 who were poring over the sequence data for a human pathogen, fresh off the presses, and their optimism about all the targets that they were going to find in there, and the great new approaches they were going to be able to take. They tried it. None of it worked. Over and over, none of it worked. People had a head start in this area, genomically speaking, with an easier development path than many other therapeutic areas, and still nothing worked.

So while many large drug companies have exited antibiotic research over the years, not all of them did. But the ones that stayed have poured effort and money, over and over, down a large drain. Nothing has come out of the work. There are a number of smaller companies in the space as well, for whom even a small success would mean a lot, but they haven't been having an easy time of it, either.

Now, one thing the Times article gets right is that the financial incentives for new antibiotics are a different thing entirely than the rest of the drug discovery world. Getting one of these new approaches in LDL or HIV to work would at least be highly profitable - the PCSK9 competitors certainly are working on that basis. Alzheimer's is another good example of an area that has yielded no useful drugs whatsoever despite ferocious amounts of effort, but people keep at it because the first company to find a real Alzheimer's drug will be very well rewarded indeed. (The Times article says that this hasn't been researched enough, either, which makes me wonder what areas have been). But any great new antibiotic would be shelved for emergencies, and rightly so.

But that by itself is not enough to explain the shortage of those great new antibiotics. It's everything at once: the traditional approaches are played out and the genomic-revolution stuff has been tried, so the unpromising economics makes the search for yet another approach that much harder.

Note: be sure to see the comments for perspectives from others who've also done antibiotic research, including some who disagree. I don't think we'll find anyone who says it's easy, though, but you never know.

Comments (54) + TrackBacks (0) | Category: Business and Markets | Drug Development | Drug Industry History | Infectious Diseases

July 21, 2014

The Hep C Field Gets Nastier By the Minute

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Posted by Derek

What a mess there is in the hepatitis C world. Gilead is, famously, dominating the market with Sovaldi, whose price has set off all sorts of cost/benefit debates. The companies competing with them are scrambling to claim positions, and the Wall Street Journal says that AbbVie is really pulling out all the stops. Try this strategy on for size:

In a lawsuit filed in February, AbbVie noted it patented the idea of combining two of Gilead's drugs—Sovaldi and an experimental drug called ledipasvir, which Gilead plans to combine into one treatment—and is therefore entitled to monetary damages if Gilead brings the combination pill to market. Legally, AbbVie can't market Sovaldi or ledipasvir because it doesn't have the patents on the underlying compounds. But it is legal for companies to seek and obtain patents describing a particular "method of use" of products that don't belong to them.

Gilead disputes the claims of AbbVie and the other companies. A spokeswoman said Gilead believes it has the sole right to commercialize Sovaldi and products containing Sovaldi's active ingredient, known as sofosbuvir. An AbbVie spokeswoman said the company believes Gilead infringes its patents, and that it stands behind the validity and enforceability of those patents.

You don't see that very often, and it's a good thing. Gilead is, naturally, suing Abbvie over this as well, saying that Abbvie has knowing mispresented to the USPTO that they invented the Gilead therapies. I'm not sure how that's going to play out: Abbvie didn't have to invent the drugs to get a method-of-use patent on them. At the same time, I don't know what sort of enablement Abbvie's patent claims might have behind them, given that these are, well, Gilead's compounds. The company is apparently claiming that a "sophisticated computer model" allows them to make a case that these combinations would be the effective ones, but I really don't know if that's going to cut it (and in fact, I sort of hope it doesn't). But even though I'm not enough of a patent-law guy to say either way, I'm enough of one to say, with great confidence, that this is going to be a very expensive mess to sort out. Gilead's also in court with Merck (and was with Idenix before Merck bought them), and with Roche, and will probably be in court with everyone else before all this is over.

This whole situation reminds me of one of those wildlife documentaries set around a shrinking African watering hole. A lot of lucrative drugs have gone off patent over the last few years, and a lot of them are heading that way soon. So any new therapeutic area with a lot of commercial promise is going to get a lot of attention, and start a lot of fighting. Legal battles aren't cheap on the absolute scale, but on the relative scale of the potential profits, they are. So why not? Claim this, claim that, sue everybody. It might work; you never know. Meanwhile, we have a line forming on the right of ticked-off insurance companies and government health plans, complaining about the Hep C prices, and while they wait they can watch the companies involved throwing buckets of slop on each other and hitting everyone over the head with lawsuits. What a spectacle.

Comments (42) + TrackBacks (0) | Category: Business and Markets | Infectious Diseases | Patents and IP | Why Everyone Loves Us

May 29, 2014

The Price of Sovaldi

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Posted by Derek

John LaMattina has a good post about Gilead, their HCV drug Sovaldi, and the price that the company is charging. Most readers here will be familiar with the situation: Sovaldi has a very high cure rate for hepatitis C, but in the US it costs $84,000 per patient. Insurance companies, in some cases, are pushing back at that price, but LaMattina says to run the numbers, in a question to the head of the insurance trade association:

Sovaldi is a drug that cures hepatitis C. It actually SAVES the healthcare system money in that it will prevent patients from dying from liver cancer, cirrhosis and liver failure. Liver transplants alone can cost $300,000 and then patients must take anti-rejection drugs that cost $40,000 per year for the rest of their lives. The price of Sovaldi, while high now, will drop, first when competitive drugs in late stage development reach the market and then when the drug is generic. Given all of this, what price for Sovaldi would have been acceptable to you – $60,000, $40,000, $10,000? What price are you willing to pay for innovation?

He didn't get an answer to that one, as you can well imagine. But it's a worthwhile question. There are, I'm sure, hepatitis C patients who die of other things before they ever start costing the kinds of money that LaMattina correctly cites for liver transplants. I don't have those figures, but if anyone does, it's the insurance companies, and they may believe that Sovaldi is still not cost-effective. Or (and these are not mutually exclusive explanations) they may be pushing back because that's what they feel they have to do - that otherwise all sorts of companies will push up prices ever more than they do already.

This is just another illustration of the walls that are closing in on the whole drug-discovery business - fewer drugs, higher costs to develop them, higher drug prices, more pushback from the payers. It's been clear for a long time that this can't go on forever, but what might replace it isn't clear (and probably won't be until the situation gets much tighter). I say that because although drug prices are surely going up, the insurance companies are still paying out. They complain, but they pay. We'll know that the real crisis is at hand when a new drug gets flatly rejected for reimbursement by everyone involved. But will that ever happen in quite that way? Keep in mind that drug companies carefully set their own prices according to what they think the market will bear. Gilead surely knew that their price for Sovaldi would be unpopular. But they probably also figured that it would hold.

Pretty much every other industry does this sort of thing, but Health Care Is Different, as always. I had a crack at explaining why I think that is here: in short, we think about health expenses differently than we think about almost any other expense, and I don't think that's ever going to change. But drug prices will continue to test the limits of the insurance companies to write the checks, as long as those checks keep getting written.

Comments (41) + TrackBacks (0) | Category: Drug Prices | Infectious Diseases

May 16, 2014

The Real Numbers on Tamiflu

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Posted by Derek

I've been meaning to cover this controversy about Tamiflu (oseltamivir). The Cochrane group has reviewed all the clinical data obtainable on the drug's efficacy, and has concluded that it doesn't have much. That's in contrast to an earlier review they'd conducted in 2008, which said that, overall, the evidence was slightly positive.

But as Ben Goldacre details in that Guardian piece, a comment left on the Cochrane paper pointed out that the positive conclusions were almost entirely due to one paper. That one summarized ten clinical studies, but only two of the ten had ever appeared in the literature. And this sent the Cochrane Collaboration on a hunt to find the rest of the data, which turned out to be no simple matter:

First, the Cochrane researchers wrote to the authors of the Kaiser paper. By reply, they were told that this team no longer had the files: they should contact Roche. Here the problems began. Roche said it would hand over some information, but the Cochrane reviewers would need to sign a confidentiality agreement. This was tricky: Cochrane reviews are built around showing their working, but Roche's proposed contract would require them to keep the information behind their reasoning secret from readers. More than this, the contract said they were not allowed to discuss the terms of their secrecy agreement, or publicly acknowledge that it even existed. . .Then, in October 2009, the company changed tack. It would like to hand over the data, it explained, but another academic review on Tamiflu was being conducted elsewhere. Roche had given this other group the study reports, so Cochrane couldn't have them.

And so on and very much so on. Roche's conduct here appears shameful, and just the sort of thing that has lowered the public opinion of the entire pharma industry. And not just the public opinion: it's lowered the industry in the eyes of legislators and regulators, who have even more direct power to change the way pharma does business. Over the years, we've been seeing a particularly nasty Tragedy of the Commons - each individual company, when they engage in tactics like this to product an individual drug, lowers the general standing of the industry a bit more, but no one company has the incentive to worry about that common problem. They have more immediate concerns.

So what about Tamiflu? After years of wrangling, the data finally emerged, and they're not all that impressive:

So does Tamiflu work? From the Cochrane analysis – fully public – Tamiflu does not reduce the number of hospitalisations. There wasn't enough data to see if it reduces the number of deaths. It does reduce the number of self-reported, unverified cases of pneumonia, but when you look at the five trials with a detailed diagnostic form for pneumonia, there is no significant benefit. It might help prevent flu symptoms, but not asymptomatic spread, and the evidence here is mixed. It will take a few hours off the duration of your flu symptoms.

I've never considered it much of a drug, personally, and that's without any access to all this hard-to-get data. One of the biggest raps on oseltamivir is that it has always appeared to be most effective if it could be taken after you've been infected, but before you know you're sick. That's not a very useful situation for the real world, since a person can come down with the flu any time at all during the winter. Goldacre again:

Roche has issued a press release saying it contests these conclusions, but giving no reasons: so now we can finally let science begin. It can shoot down the details of the Cochrane review – I hope it will – and we will edge towards the truth. This is what science looks like. Roche also denies being dragged to transparency, and says it simply didn't know how to respond to Cochrane. This, again, speaks to the pace of change. I have no idea why it was withholding information: but I rather suspect it was simply because that's what people have always done, and sharing it was a hassle, requiring new norms to be developed. That's reassuring and depressing at the same time.

That sounds quite likely. No one wants to be the person who sets a new precedent in dealing with clinical data, especially not at a company the size of Roche, so what we might have here is yet another tragedy of the commons: it would have been in the company's best interest to have not gone through this whole affair, but there may have been no one person there who felt as if they were in any position to do something about it. When in doubt, go with the status quo: that's the unwritten rule, and the larger the organization, the stronger it holds. After all, if it's a huge, profitable company, the status quo clearly has a lot going for it, right? It's worked so far - who are you, or that guy over there, to think about rearranging it?

Comments (12) + TrackBacks (0) | Category: Clinical Trials | Infectious Diseases | Why Everyone Loves Us

May 15, 2014

The Daily Show on Finding New Antibiotics

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Posted by Derek

A reader sent along news of this interview on "The Daily Show" with Martin Blaser of NYU. He has a book out, Missing Microbes, on the overuse of antibiotics and the effects on various microbiomes. And I think he's got a lot of good points - we should only be exerting selection pressure where we have to, not (for example) slapping triclosan on every surface because it somehow makes consumers feel "germ-free". And there are (and always have been) too many antibiotics dispensed for what turn out to be viral infections, for which they will, naturally, do no good at all and probably some harm.

But Dr. Blaser, though an expert on bacteria, does not seem to be an expert on discovering drugs to kill bacteria. I've generated a transcript of part of the interview, starting around the five-minute mark, which went like this:

Stewart: Isn't there some way, that, the antibiotics can be used to kill the strep, but there can be some way of rejuvenating the microbiome that was doing all those other jobs?

Blaser: Well, that's what we need to do. We need to make narrow-spectrum antibiotics. We have broad-spectrum, that attack everything, but we have the science that we could develop narrow-spectrum antibiotics that will just target the one organism - maybe it's strep, maybe it's a different organism - but then we need the diagnostics, so that somebody going to the doctor, they say "You have a virus" "You have a bacteria", if you have a bacteria, which one is it?

Stewart: Now isn't this where the genome-type projects are going? Because finding the genetic makeup of these bacteria, won't that allow us to target these things more specifically?

Blaser Yeah. We have so much genomic information - we can harness that to make better medicine. . .

Stewart: Who would do the thing you're talking about, come up with the targeted - is it drug companies, could it, like, only be done through the CDC, who would do that. . .

Blaser: That's what we need taxes for. That's our tax dollars. Just like when we need taxes to build the road that everybody uses, we need to develop the drugs that our kids and our grandkids are going to use so that these epidemics could be stopped.

Stewart: Let's say, could there be a Manhattan Project, since that's the catch-all for these types of "We're going to put us on the moon" - let's say ten years, is that a realistic goal?

Blaser: I think it is. I think it is. We need both diagnostics, we need narrow-spectrum agents, and we have to change the economic base of how we assess illness in kids and how we treat kids and how we pay doctors. . .

First off, from a drug discovery perspective, a narrow-spectrum antibiotic, one that kills only (say) a particular genus of bacterium, has several big problems: it's even harder to discover than a broader-spectrum agent, its market is much smaller, it's much harder to prescribe usefully, and its lifetime as a drug is shorter. (Other than that, it's fine). The reasons for these are as follows:

Most antibiotic targets are enzyme systems peculiar to bacteria (as compared to eukaryotes like us), but such targets are shared across a lot of bacteria. They tend to be aimed at things like membrane synthesis and integrity (bacterial membranes are rather different than those of animals and plants), or target features of DNA handling that are found in different forms due to bacteria having no nuclei, and so on. Killing bacteria with mechanisms that are also found in human cells is possible, but it's a rough way to go: a drug of that kind would be similar to a classic chemotherapy agent, killing the fast-dividing bacteria (in theory) just before killing the patient.

So finding a Streoptococcus-only drug is a very tall order. You'd have to find some target-based difference between those bacteria and all their close relatives, and I can tell you that we don't know enough about bacterial biochemistry to sort things out quite that well. Stewart brings up genomic efforts, and points to him for it, because that's a completely reasonable suggestion. Unfortunately, it's a reasonable suggestion from about 1996. The first complete bacterial genomes became available in the late 1990s, and have singularly failed to produce any new targeted antibiotics whatsoever. The best reference I can send people to is the GSK "Drugs For Bad Bugs" paper, which shows just what happened (and not just at GSK) to the new frontier of new bacterial targets. Update: see also this excellent overview. A lot of companies tried this, and got nowhere. It did indeed seem possible that sequencing bacteria would give us all sorts of new ways to target them, but that's not how it's worked out in practice. Blaser's interview gives the impression that none of this has happened yet, but believe me, it has.

The market for a narrow-spectrum agent would necessarily be smaller, by design, but the cost of finding it would (as mentioned above) be greater, so the final drug would have to cost a great deal per dose - more than health insurance would want to pay, given the availability of broad-spectrum agents at far lower prices. It could not be prescribed without positively identifying the infectious agent - which adds to the cost of treatment, too. Without faster and more accurate ways to do this (which Blaser rightly notes as something we don't have), the barriers to developing such a drug are even higher.

And the development of resistance would surely take such a drug out of usefulness even faster, since the resistance plasmids would only have to spread between very closely related bacteria, who are swapping genes at great speed. I understand why Blaser (and others) would like to have more targeted agents, so as not to plow up the beneficial microbiome every time a patient is treated, but we'd need a lot of them, and we'd need new ones all the time. This in a world where we can't even seem to discover the standard type of antibiotic.

And not for lack of trying, either. There's a persistent explanation for the state of antibiotic therapy that blames drug companies for supposedly walking away from the field. This has the cause and effect turned around. It's true that some of them have given up working in the area (along with quite a few other areas), but they left because nothing was working. The companies that stayed the course have explored, in great detail and at great expense, the problem that nothing much is working. If there ever was a field of drug discovery where the low-hanging fruit has been picked clean, it is antibiotic research. You have to use binoculars to convince yourself that there's any more fruit up there at all. I wish that weren't so, very much. But it is. Bacteria are hard to kill.

So the talk later on in the interview of spending some tax dollars and getting a bunch of great new antibiotics in ten years is, unfortunately, a happy fantasy. For one thing, getting a single new drug onto the market in only ten years from the starting pistol is very close to impossible, in any therapeutic area. The drug industry would be in much better shape if that weren't so, but here we are. In that section, Jon Stewart actually brings to life one of the reasons I have this blog: he doesn't know where drugs come from, and that's no disgrace, because hardly anyone else knows, either.

Comments (58) + TrackBacks (0) | Category: Drug Development | Drug Industry History | Infectious Diseases

March 24, 2014

Google's Big Data Flu Flop

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Posted by Derek

Some of you may remember the "Google Flu" effort, where the company was going to try to track outbreaks of influenza in the US by mining Google queries. There was never much clarification about what terms, exactly, they were going to flag as being indicative of someone coming down with the flu, but the hype (or hope) at the time was pretty strong:

Because the relative frequency of certain queries is highly correlated with the percentage of physician visits in which a patient presents with influenza-like symptoms, we can accurately estimate the current level of weekly influenza activity in each region of the United States, with a reporting lag of about one day. . .

So how'd that work out? Not so well. Despite a 2011 paper that seemed to suggest things were going well, the 2013 epidemic wrong-footed the Google Flu Trends (GFT) algorithms pretty thoroughly.

This article in Science finds that the real-world predictive power has been pretty unimpressive. And the reasons behind this failure are not hard to understand, nor were they hard to predict. Anyone who's ever worked with clinical trial data will see this one coming:

The initial version of GFT was a particularly problematic marriage of big and small data. Essentially, the methodology was to find the best matches among 50 million search terms to fit 1152 data points. The odds of finding search terms that match the propensity of the flu but are structurally unrelated, and so do not predict the future, were quite high. GFT developers, in fact, report weeding out seasonal search terms unrelated to the flu but strongly correlated to the CDC data, such as those regarding high school basketball. This should have been a warning that the big data were overfitting the small number of cases—a standard concern in data analysis. This ad hoc method of throwing out peculiar search terms failed when GFT completely missed the nonseasonal 2009 influenza A–H1N1 pandemic.

The Science authors have a larger point to make as well:

“Big data hubris” is the often implicit assumption that big data are a substitute for, rather than a supplement to, traditional data collection and analysis. Elsewhere, we have asserted that there are enormous scientific possibilities in big data. However, quantity of data does not mean that one can ignore foundational issues of measurement and construct validity and reliability and dependencies among data. The core challenge is that most big data that have received popular attention are not the output of instruments designed to produce valid and reliable data amenable for scientific analysis.

The quality of the data matters very, very, much, and quantity is no substitute. You can make a very large and complex structure out of toothpicks and scraps of wood, because those units are well-defined and solid. You cannot do the same with a pile of cotton balls and dryer lint, not even if you have an entire warehouse full of the stuff. If the individual data points are squishy, adding more of them will not fix your analysis problem; it will make it worse.

Since 2011, GFT has missed (almost invariably on the high side) for 108 out of 111 weeks. As the authors show, even low-tech extrapolation from three-week-lagging CDC data would have done a better job. But then, the CDC data are a lot closer to being real numbers. Something to think about next time someone's trying to sell you on a BIg Data project. Only trust the big data when the little data are trustworthy in turn.

Update: a glass-half-full response in the comments.

Comments (18) + TrackBacks (0) | Category: Biological News | Clinical Trials | Infectious Diseases

March 18, 2014

Another DNA-Barcoded Program From GSK

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Posted by Derek

Two more papers have emerged from GSK using their DNA-encoded library platform. I'm always interested to see how this might be working out. One paper is on compounds for the tuberculosis target InhA, and the other is aimed at a lymphocyte protein-protein target, LFA-1. (I've written about this sort of thing previously here, here, and here).

Both of these have some interesting points - I'll cover the LFA-1 work in another post, though. InhA, for its part, is the target of the well-known tuberculosis drug isoniazid, and it has had (as you'd imagine) a good amount of attention over the years, especially since it's not the cleanest drug in the world (although it sure beats having tuberculosis). It's known to be a prodrug for the real active species, and there are also some nasty resistant strains out there, so there's certainly room for something better.
InhA.png
In this case, the GSK group apparently screened several of their DNA-encoded libraries against the target, but the paper only details what happened with one of them, the aminoproline scaffold shown. That would seem to be a pretty reasonable core, but it was one of 22 diamino acids in the library. R1 was 855 different reactants (amide formation, reductive amination, sulfonamides, ureas), and R2 was 857 of the same sorts of things, giving you, theoretically, a library of over 16 million compounds. (If you totaled up the number across the other DNA-encoded libraries, I wonder how many compounds this target saw in total?) Synthesizing a series of hits from this group off the DNA bar codes seems to have worked well, with one compound hitting in the tens of nanomolar range. (The success rate of this step is one of the things that those of us who haven't tried this technique are very interested in hearing about).
InhA2.png
They even pulled out an InhA crystal structure with the compound shown, which really makes this one sound like a poster-child example of the whole technique (and might well be why we're reading about it in J. Med. Chem.) The main thing not to like about the structure is that it has three amides in it, but this is why one runs PK experiments, to see if having three amides is going to be a problem or not. A look at metabolic stability showed that it probably wasn't a bad starting point. Modifying those three regions gave them a glycine methyl ester at P1, which had better potency in both enzyme and cell assays. When you read through the paper, though, it appears that the team eventually had cause to regret having pursued it. A methyl ester is always under suspicion, and in this case it was justified: it wasn't stable under real-world conditions, and every attempt to modify it led to unacceptable losses in activity. It looks like they spent quite a bit of time trying to hang on to it, only to have to give up on it anyway.

In the end, the aminoproline in the middle was still intact (messing with it turned out to be a bad idea). The benzofuran was still there (nothing else was better). The pyrazole had extended from an N-methyl to an N-ethyl (nothing else was better there, either), and the P1 group was now a plain primary amide. A lot of med-chem programs work out like that - you go all around the barn and through the woods, emerging covered with mud and thorns only to find your best compound about fifteen feet away from where you started.

That compound, 65 in the paper, showed clean preliminary tox, along with good PK, potency, and selectivity. In vitro against the bacteria, it worked about as well as the fluoroquinolone moxifloxacin, which is a good level to hit. Unfortunately, when it was tried out in an actual mouse TB infection model, it did basically nothing at all. This, no doubt, is another reason that we're reading about this in J. Med. Chem.. When you read a paper from an industrial group in that journal, you're either visiting a museum or a mausoleum.

That final assay must have been a nasty moment for everyone, and you get the impression that there's still not an explanation for this major disconnect. It's hard to say if they saw it coming - had other compounds been in before, or did the team just save this assay for last and cross their fingers? But either way, the result isn't the fault of the DNA-encoded assay that provided the starting series - that, in this case, seems to have worked exactly as it was supposed to, and up to the infectious animal model study, everything looked pretty good.

Comments (24) + TrackBacks (0) | Category: Chemical Biology | Drug Assays | Infectious Diseases

March 10, 2014

Repurposing for Cervical Cancer

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Posted by Derek

One of the questions I was asked after my talk at Illinois was about repurposing drugs. I replied that there might be some opportunities there, but I didn't think that there were many big ones that had been missed, unless new biology/target ID turned up. Well, here's a news story that contradicts that view of mine, and I'm welcome to be wrong this time.

Researchers in Manchester have been working on the use of lopinavir (an existing drug for HIV) as a therapy for HPV, the cause of most cervical cancers. There's a vaccine for it now, but that doesn't do much for women who are already diagnosed with probable or confirmed disease. But lopinavir therapy seems to do good, and plenty of it. A preliminary trial in Kenya has apparently shown a very high response rate, and they're now raising money for a larger (up to 1,000 patient) trial. I hope that it works out as it appears to - with any luck, HPV-driven disease will gradually disappear from the world in the coming decades, but there will be plenty of patients in the meantime.

As that Daily Telegraph article shows, it wasn't easy getting this work going, because of availability of the drug in the right formulation. Congratulations to the Manchester group and their collaborators in Kenya for being so persistent.

Comments (6) + TrackBacks (0) | Category: Cancer | Clinical Trials | Infectious Diseases

January 28, 2014

Antivirals: "I Love the Deviousness of It All"

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Posted by Derek

Here's a look at some very interesting research on HIV (and a repurposed compound) that I was unable to comment on here. As for the first line of that post, well, I doubt it, but I like to think of myself as rich in spirit. Or something.

Comments (11) + TrackBacks (0) | Category: Biological News | Infectious Diseases

December 12, 2013

Tiny Details, Not So Tiny

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Posted by Derek

Chemjobber has a good post on a set of papers from Pfizer's process chemists. They're preparing filibuvir, and a key step along the way is a Dieckmann cyclization. Well, no problem, say the folks who've never run one of these things - just hit the diester compound with some base, right?

But which base? The example in CJ's post is a good one to show how much variation you can get in these things. As it turned out, LiHMDS was the base of choice, much better than NaHMDS or KHMDS. Potassium t-butoxide was just awful. But the hexamethyldisilazide was even much better than LDA, and those two are normally pretty close. But there were even finer distinctions to be made: it turned out that the reaction was (reproducibly) slightly better or slightly worse with LiHMDS from different suppliers. The difference came down to two processes used to prepare the reagent - via n-BuLi or via lithium metal, and the Pfizer team still isn't sure what the difference is that's making all the difference (see the link for more details).

That's pure, 100-proof process chemistry for you, chasing down these details. It's a good thing for people who don't do that kind of work at all, though, to read some of these papers, because it'll give you an appreciation of variables that otherwise you might not think of at all. When you get down to it, a lot of our reactions are balancing on some fairly wobbly tightropes strung across the energy-surface landscape, and it doesn't take much of a push to send them sliding off in different directions. Choice of cation, of Lewis acid, of solvent, of temperature, order of addition - these and other factors can be thermodynamic and kinetic game-changers. We really don't know too many details about what happens in our reaction flasks.

And a brief med-chem note, for context: filibuvir, into which all this work was put, was dropped from development earlier this year. Sometimes you have to do all the work just to get to the point where you can drop these things - that's the business.

Comments (8) + TrackBacks (0) | Category: Chemical News | Infectious Diseases

December 4, 2013

More Vaccine Fearmongering

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Posted by Derek

Seth Mnookin's The Panic Virus is an excellent overview of the vaccine/autism arguments that raged for many years (and rage still in the heads of the ignorant - sorry, it's gotten to the point where there's no reason to spare anyone's feelings about this issue). Now in this post at PLOS Blogs, he's alerting people to another round of the same stuff, this time about the HPV vaccine:

Over a period of about a month, (Katie Couric's) producer and I spoke for a period of several hours before she told me that the show was no longer interesting in hearing from me on air. Still, I came away from the interaction somewhat heartened: The producer seemed to have a true grasp of the dangers of declining vaccination rates and she stressed repeatedly that her co-workers, including Couric herself, did not view this as an “on the one hand, on the other hand” issue but one in which facts and evidence clearly lined up on one side — the side that overwhelmingly supports the importance and efficacy of vaccines.

Apparently, that was all a load of crap.

Read on for more. One piece of anecdotal data trumps hundreds of thousands of patients worth of actual data, you know. Especially if it's sad. Especially if it gets ratings.

Comments (57) + TrackBacks (0) | Category: Autism | Infectious Diseases | Snake Oil

November 12, 2013

Leaving Antibiotics: An Interview

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Posted by Derek

Here's the (edited) transcript of an interview that Pfizer's VP of clinical research, Charles Knirsch, gave to PBS's Frontline program. The subject was the rise of resistant bacteria - which is a therapeutic area that Pfizer is no longer active in.

And that's the subject of the interview, or one of its main subjects. I get the impression that the interviewer would very much like to tell a story about how big companies walked away to let people die because they couldn't make enough money off of them:

. . .If you look at the course of a therapeutic to treat pneumonia, OK, … we make something, a macrolide, that does that. It’s now generic, and probably the whole course of therapy could cost $30 or $35. Even when it was a branded antibiotic, it may have been a little bit more than that.

So to cure pneumonia, which in some patient populations, particularly the elderly, has a high mortality, that’s what people are willing to pay for a therapeutic. I think that there are differences across different therapeutic areas, but for some reason, with antibacterials in particular, I think that society doesn’t realize the true value.

And did it become incumbent upon you at some point to make choices about which things would be in your portfolio based on this?

Based on our scientific capabilities and the prudent allocation of capital, we do make these choices across the whole portfolio, not just with antibacterials.

But talk to me about the decision that went into antibacterials. Pfizer made a decision in 2011 and announced the decision. Obviously you were making choices among priorities. You had to answer to your shareholders, as you’ve explained, and you shifted. What went into that decision?

I think that clearly our vaccine platforms are state of the art. Our leadership of the vaccine group are some of the best people in the industry or even across the industry or anywhere really. We believe that we have a higher degree of success in those candidates and programs that we are currently prosecuting.

So it’s a portfolio management decision, and if our vaccine for Clostridium difficile —

A bacteria.

Yeah, a bacteria which is a major cause of both morbidity and mortality of patients in hospitals, the type of thing that I would have been consulted on as an infectious disease physician, that in fact we will prevent that, and we’ll have a huge impact on human health in the hospitals.

But did that mean that you had to close down the antibiotic thing to focus on vaccines? Why couldn’t you do both?

Oh, good question. And it’s not a matter of closing down antibiotics. We were having limited success. We had had antibiotics that we would get pretty far along, and a toxicity would emerge either before we even went into human testing or actually in human testing that would lead to discontinuation of those programs. . .

It's that last part that I think is insufficiently appreciated. Several large companies have left the antibiotic field over the years, but several stayed (GlaxoSmithKline and AstraZeneca come to mind). But the ones who stayed were not exactly rewarded for their efforts. Antibacterial drug discovery, even if you pour a lot of money and effort into it, is very painful. And if you're hoping to introduce a mechanism of action into the field, good luck. It's not impossible, but if it were easy to do, more small companies would have rushed in to do it.

Knirsch doesn't have an enviable task here, because the interviewer pushes him pretty hard. Falling back on the phrase "portfolio management decisions" doesn't help much, though:

In our discussion today, I get the sense that you have to make some very ruthless decisions about where to put the company’s capital, about where to invest, about where to put your emphasis. And there are whole areas where you don’t invest, and I guess the question we’re asking is, do you learn lessons about that? When you pulled out of Gram-negative research like that and shifted to vaccines, do you look back on that and say, “We learned something about this”?

These are not ruthless decisions. These are portfolio decisions about how we can serve medical need in the best way. …We want to stay in the business of providing new therapeutics for the future. Our investors require that of us, I think society wants a Pfizer to be doing what we do in 20 years. We make portfolio management decisions.

But you didn’t stay in this field, right? In Gram negatives you didn’t really stay in that field. You told me you shifted to a new approach.

We were not having scientific success, there was no clear regulatory pathway forward, and the return on any innovation did not appear to be something that would support that program going forward.

Introducing the word "ruthless" was a foul, and I'm glad the whistle was blown. I might have been tempted to ask the interviewer what it meant, ruthless, and see where that discussion went. But someone who gives in to temptations like that probably won't make VP at Pfizer.

Comments (51) + TrackBacks (0) | Category: Drug Development | Drug Industry History | Infectious Diseases

October 16, 2013

Holding Back Experimental Details, With Reason

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Posted by Derek

There's a lot of worry these days about the reproducibility of scientific papers (a topic that's come up here many times). And there's reason to believe that the sharing of data, protocols, and materials is not going so well, either.

. . . authors seem less willing to share these additional details about their study protocols than they have been in the past, according to a survey of 389 authors who published studies in the Annals of Internal Medicine. The findings, presented on 9 September at the International Congress on Peer Review and Biomedical Publication in Chicago, found that over the five years studied the percentage saying they would be willing to do so has dropped from almost 80% to only 60%.

A lack of incentives for sharing might be partly to blame. “There's no recognition, no promotion and no profit for scientists who share more information,” says Steven Goodman, a clinical research expert at Stanford University School of Medicine in California, who was part of the team that evaluated the survey results.

But there are two new papers out that deliberately does not share all the details, and it's not hard to see why. This NPR report has the background, but the abstract from the first paper will be enough for anyone in the field:

Clostridium botulinum strain IBCA10-7060, isolated from a patient with infant botulism, produced botulinum neurotoxin type B (BoNT/B) and another BoNT that, by use of the standard mouse bioassay, could not be neutralized by any of the Centers for Disease Control and Prevention–provided monovalent polyclonal botulinum antitoxins raised against BoNT types A–G.

That's not good. Until an antitoxin is available, the sequence of this new neurotoxin will not be published, although the fact of its existence is certainly worth knowing. The Journal of Infectious Diseases has two editorial articles on the issues that this work raises:

(The) identification of a novel, eighth botulinum neurotoxin (BoNT) from a patient with botulism expands our understanding of Clostridium botulinum and BoNT diversity, C. botulinum evolution, and the pathogenesis of botulism, but it also reveals a significant public health vulnerability. This new toxin, BoNT/H, cannot be neutralized by any of the currently available antibotulinum antisera, which means that we have no effective treatment for this form of botulism. Until anti-BoNT/H antitoxin can be created, shown to be effective, and deployed, both the strain itself and the sequence of this toxin (with which recombinant protein can be easily made) pose serious risks to public health because of the unusually severe, widespread harm that could result from misuse of either [3]. Thus, the dilemma faced by these authors, and by society, revolves around the question, should all of the information from this and similar studies be fully disseminated, motivated by the desire to realize all possible benefits from the discovery, or should dissemination of some or all of the information be restricted, with the goal of diminishing the probability of misuse?

I think they've made the right call here. (Last year's disputes about publishing work on a new strain of influenza are in just the same category.) Those studying botulin toxins need to know about this discovery, but given the molecular biology tools available to people, publishing the sequence (or making samples of the organism available) would be asking for potentially major trouble. This, unfortunately, seems to me to be an accurate reading of the world that we find ourselves in. There is a point where the value of having the knowledge out there is outweighed by the danger of. . .having the knowledge out there. This is going to be a case-by-case thing, but we should all be ready for some things to land on this side of the line.

Comments (14) + TrackBacks (0) | Category: Infectious Diseases | The Dark Side | The Scientific Literature

August 16, 2013

An HIV Structure Breakthrough? Or "Complete Rubbish"?

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Posted by Derek

Structural biology needs no introduction for people doing drug discovery. This wasn't always so. Drugs were discovered back in the days when people used to argue about whether those "receptor" thingies were real objects (as opposed to useful conceptual shorthand), and before anyone had any idea of what an enzyme's active site might look like. And even today, there are targets, and whole classes of targets, for which we can't get enough structural information to help us out much.

But when you can get it, structure can be a wonderful thing. X-ray crystallography of proteins, and protein-ligand complexes has revealed so much useful information that it's hard to know where to start. It's not the magic wand - you can't look at an empty binding site and just design something right at your desk that'll be a potent ligand right off the bat. And you can't look at a series of ligand-bound structures and say which one is the most potent, not in most situations, anyway. But you still learn things from X-ray structures that you could never have known otherwise.

It's not the only game in town, either. NMR structures are very useful, although the X-ray ones can be easier to get, especially in these days of automated synchroton beamlines and powerful number-crunching. But what if your protein doesn't crystallize? And what if there are things happening in solution that you'd never pick up on from the crystallized form? You're not going to watch your protein rearrange into a new ligand-bound conformation with X-ray crystallography, that's for sure. No, even though NMR structures can be a pain to get, and have to be carefully interpreted, they'll also show you things you'd never had seen.

And there are more exotic methods. Earlier this summer, there was a startling report of a structure of the HIV surface proteins gp120 and gp41 obtained through cryogenic electron microscopy. This is a very important and very challenging field to work in. What you've got there is a membrane-bound protein-protein interaction, which is just the sort of thing that the other major structure-determination techniques can't handle well. At the same time, though, the number of important proteins involved in this sort of thing is almost beyond listing. Cryo-EM, since it observes the native proteins in their natural environment, without tags or stains, has a lot of potential, but it's been extremely hard to get the sort of resolution with it that's needed on such targets.

Joseph Sodroski's group at Harvard, longtime workers in this area, published their 6-angstrom-resolution structure of the protein complex in PNAS. But according to this new article in Science, the work has been an absolute lightning rod ever since it appeared. Many other structural biologists think that the paper is so flawed that it never should have seen print. No, I'm not exaggerating:

Several respected HIV/AIDS researchers are wowed by the work. But others—structural biologists in particular—assert that the paper is too good to be true and is more likely fantasy than fantastic. "That paper is complete rubbish," charges Richard Henderson, an electron microscopy pioneer at the MRC Laboratory of Molecular Biology in Cambridge, U.K. "It has no redeeming features whatsoever."

. . .Most of the structural biologists and HIV/AIDS researchers Science spoke with, including several reviewers, did not want to speak on the record because of their close relations with Sodroski or fear that they'd be seen as competitors griping—and some indeed are competitors. Two main criticisms emerged. Structural biologists are convinced that Sodroski's group, for technical reasons, could not have obtained a 6-Å resolution structure with the type of microscope they used. The second concern is even more disturbing: They solved the structure of a phantom molecule, not the trimer.

Cryo-EM is an art form. You have to freeze your samples in an aqueous system, but without making ice. The crystals of normal ice formation will do unsightly things to biological samples, on both the macro and micro levels, so you have to form "vitreous ice", a glassy amorphous form of frozen water, which is odd enough that until the 1980s many people considered it impossible. Once you've got your protein particles in this matrix, though, you can't just blast away at full power with your electron beam, because that will also tear things up. You have to take a huge number of runs at lower power, and analyze them through statistical techniques. The Sodolski HIV structure, for example, is the product of 670,000 single-particle images.

But its critics say that it's also the product of wishful thinking.:

The essential problem, they contend, is that Sodroski and Mao "aligned" their trimers to lower-resolution images published before, aiming to refine what was known. This is a popular cryo-EM technique but requires convincing evidence that the particles are there in the first place and rigorous tests to ensure that any improvements are real and not the result of simply finding a spurious agreement with random noise. "They should have done lots of controls that they didn't do," (Sriram) Subramaniam asserts. In an oft-cited experiment that aligns 1000 computer-generated images of white noise to a picture of Albert Einstein sticking out his tongue, the resulting image still clearly shows the famous physicist. "You get a beautiful picture of Albert Einstein out of nothing," Henderson says. "That's exactly what Sodroski and Mao have done. They've taken a previously published structure and put atoms in and gone down into a hole." Sodroski and Mao declined to address specific criticisms about their studies.

Well, they decline to answer them in response to a news item in Science. They've indicated a willingness to take on all comers in the peer-reviewed literature, but otherwise, in print, they're doing the we-stand-by-our-results-no-comment thing. Sodroski himself, with his level of experience in the field, seems ready to defend this paper vigorously, but there seem to be plenty of others willing to attack. We'll have to see how this plays out in the coming months - I'll update as things develop.

Comments (34) + TrackBacks (0) | Category: Analytical Chemistry | Biological News | In Silico | Infectious Diseases

July 24, 2013

Stuart Schreiber at the Challenges in Chemical Biology Conference

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Posted by Derek

I'm listening to Stuart Schreiber make his case for diversity-oriented synthesis (DOS) as a way to interrogate biochemistry. I've written about this idea a number of times here, but I'm always glad to hear the pitch right from the source.

Schreiber's team has about 100,000 compounds from DOS now, all of which are searchable at PubChem. He says that they have about 15mg of each of them in the archives, which is a pretty solid collection. They've been trying to maximize the biochemical diversity of their screening (see here and here for examples), and they're also (as noted here) building up a collection of fragments, which he says will be used for high-concentration screening.

He's also updating some efforts with the Gates Foundation to do cell-based antimalarial screening with the DOS compounds. They have 468 compounds that they're now concentrating on, and checking these against resistant strains indicates that some of them may well be working through unusual mechanisms (others, of course, are apparently hitting the known ones). He's showing structures, and they are very DOSsy indeed - macrocycles, spiro rings, chirality all over. But since these assay are done in cells, some large hoops have already been jumped through.

He's also talking about the Broad Institutes efforts to profile small-molecule behavior in numerous tumor cell lines. Here's a new public portal site on this, and there's apparently a paper accepted at Cell on it as well. They have hundreds of cell lines, from all sorts of sources, and are testing those against an "informer set" of small-molecule probes and known drugs. They're trying to make this a collection of very selective compounds, targeting a wide variety of different targets throughout the cell. There are kinase inhibitors, epigenetic compounds, and a long list of known oncology candidates, as well as many other compounds that don't hit obvious cancer targets.

They're finding out a lot of interesting things about target ID with this set. Schreiber says that this work has made him more interested in gene expression profiles than in mutations per se. Here, he says, is an example of what he's talking about. Another example is the recent report of the natural product austocystin, which seems to be activated by CYP metabolism. The Broad platform has identified CYP2J2 as the likely candidate.

There's an awful lot of work on these slides (and an awful lot of funding is apparent, too). I think that the "Cancer Therapeutics Response Portal" mentioned above is well worth checking out - I'll be rooting through it after the meeting.

Comments (23) + TrackBacks (0) | Category: Cancer | Chemical Biology | Infectious Diseases

June 14, 2013

One. . .Million. . .Pounds (For a New Antibiotic?)

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Posted by Derek

Via Stuart Cantrill on Twitter, I see that UK Prime Minister David Cameron is prepared to announce a prize for anyone who can "identify and solve the biggest problem of our time". He's leaving that open, and his examples are apparently ". . .the next penicillin, aeroplane or world wide web".

I like the idea of prizes for research and invention. The thing is, the person who invents the next airplane or World Wide Web will probably do pretty well off it through the normal mechanisms. And it's worth thinking about the very, very different pathways these three inventions took, both in their discovery and their development. While thinking about that, keep in mind the difference between those two.

The Wright's first powered airplane, a huge step in human technology, was good for carrying one person (lying prone) for a few hundred yards in a good wind. Tim Berners-Lee's first Web page, another huge step, was a brief bit of code on one server at CERN, and mostly told people about itself. Penicillin, in its early days, was famously so rare that the urine of the earliest patients was collected and extracted in order not to waste any of the excreted drug. And even that was a long way from Fleming's keen-eyed discovery of the mold's antibacterial activity. A more vivid example than penicillin of the need for huge amounts of development from an early discovery is hard to find.

And how does one assign credit to the winner? Many (most) of these discoveries take a lot of people to realize them - certainly, by the time it's clear that they're great discoveries. Alexander Fleming (very properly) gets a lot of credit for the initial discovery of penicillin, but if the world had depended on him for its supply, it would have been very much out of luck. He had a very hard time getting anything going for nearly ten years after the initial discovery, and not for lack of trying. The phrase "Without Fleming, no Chain; without Chain, no Florey; without Florey, no Heatley; without Heatley, no penicillin" properly assigns credit to a lot of scientists that most people have never heard of.

Those are all points worth thinking about, if you're thinking about Cameron's prize, or if you're David Cameron. But that's not all. Here's the real kicker: he's offering one million pounds for it ($1.56 million as of this morning). This is delusional. The number of great discoveries that can be achieved for that sort of money is, I hate to say, rather small these days. A theoretical result in math or physics might certainly be accomplished in that range, but reducing it to practice is something else entirely. I can speak to the "next penicillin" part of the example, and I can say (without fear of contradiction from anyone who knows the tiniest bit about the subject) that a million pounds could not, under any circumstances, tell you if you had the next penicillin. That's off by a factor of a hundred, if you just want to take something as far as a solid start.

There's another problem with this amount: in general, anything that's worth that much is actually worth a lot more; there's no such thing as a great, world-altering discovery that's worth only a million pounds. I fear that this will be an ornament around the neck of whoever wins it, and little more. If Cameron's committee wants to really offer a prize in line with the worth of such a discovery, they should crank things up to a few hundred million pounds - at least - and see what happens. As it stands, the current idea is like me offering a twenty-dollar bill to anyone who brings me a bar of gold.

Comments (28) + TrackBacks (0) | Category: Current Events | Drug Industry History | Infectious Diseases | Who Discovers and Why

May 29, 2013

Sulfa Side Effects, Decades Later

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Posted by Derek

You'd think that by now we'd know all there is to know about the side effects of sulfa drugs, wouldn't you? These were the top-flight antibiotics about 80 years ago, remember, and they've been in use (in one form or another) ever since. But some people have had pronounced CNS side effects from their use, and it's never been clear why.

Until now, that is. Here's a new paper in Science that shows that this class of drugs inhibits the synthesis of tetrahydrobiopterin, an essential cofactor for a number of hydroxylase and reductase enzymes. And that in turn interferes with neurotransmitter levels, specifically dopamine and serotonin. The specific culprit here seems to be sepiapterin reductase (SPR). Here's a summary at C&E News.

This just goes to show you how much there is to know, even about things that have been around forever (by drug industry standards). And every time something like this comes up, I wonder what else there is that we haven't uncovered yet. . .

Comments (17) + TrackBacks (0) | Category: Infectious Diseases | Toxicology

May 17, 2013

A Little Ranbaxy Example

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Posted by Derek

Compare and contrast. Here we have Krishnan Ramalingam, from Ranbaxy's Corporate Communications department, in 2006:

Being a global pharmaceutical major, Ranbaxy took a deliberate decision to pool its resources to fight neglected disease segments. . .Ranbaxy strongly felt that generic antiretrovirals are essential in fighting the world-wide struggle against HIV/AIDS, and therefore took a conscious decision to embark upon providing high quality affordable generics for patients around the world, specifically for the benefit of Least Developed Countries. . .Since 2001, Ranbaxy has been providing antiretroviral medicines of high quality at affordable prices for HIV/AIDS affected countries for patients who might not otherwise be able to gain access to this therapy.

And here we have them in an advertorial section of the South African Mail and Guardian newspaper, earlier this year:

Ranbaxy has a long standing relationship with Africa. It was the first Indian pharmaceutical company to set up a manufacturing facility in Nigeria, in the late 1970s. Since then, the company has established a strong presence in 44 of the 54 African countries with the aim of providing quality medicines and improving access. . .Ranbaxy is a prominent supplier of Antiretroviral (ARV) products in South Africa through its subsidiary Sonke Pharmaceuticals. It is the second largest supplier of high quality affordable ARV products in South Africa which are also extensively used in government programs providing access to ARV medicine to millions.

Yes, as Ranbaxy says on its own web site: "At Ranbaxy, we believe that Anti-retroviral (ARV) therapy is an essential tool in waging the war against HIV/AIDS. . .We estimate currently close to a million patients worldwide use our ARV products for their daily treatment needs. We have been associated with this cause since 2001 and were among the first generic companies to offer ARVs to various National AIDS treatment programmes in Africa. We were also responsible for making these drugs affordable in order to improve access. . ."

And now we descend from the heights. Here, in a vivid example of revealed preference versus stated preference, is what was really going on, from that Fortune article I linked to yesterday:

. . .as the company prepared to resubmit its ARV data to WHO, the company's HIV project manager reiterated the point of the company's new strategy in an e-mail, cc'ed to CEO Tempest. "We have been reasonably successful in keeping WHO from looking closely at the stability data in the past," the manager wrote, adding, "The last thing we want is to have another inspection at Dewas until we fix all the process and validation issues once and for all."

. . .(Dinesh) Thakur knew the drugs weren't good. They had high impurities, degraded easily, and would be useless at best in hot, humid conditions. They would be taken by the world's poorest patients in sub-Saharan Africa, who had almost no medical infrastructure and no recourse for complaints. The injustice made him livid.

Ranbaxy executives didn't care, says Kathy Spreen, and made little effort to conceal it. In a conference call with a dozen company executives, one brushed aside her fears about the quality of the AIDS medicine Ranbaxy was supplying for Africa. "Who cares?" he said, according to Spreen. "It's just blacks dying."

I have said many vituperative things about HIV hucksters like Matthias Rath, who have told patient in South Africa to throw away their antiviral medications and take his vitamin supplements instead. What, then, can I say about people like this, who callously and intentionally provided junk, labeled as what were supposed to be effective drugs, to people with no other choice and no recourse? If this is not criminal conduct, I'd very much like to know what is.

And why is no one going to jail? I'm suggesting jail as a civilized alternative to a barbaric, but more appealingly direct form of justice: shipping the people who did this off to live in a shack somewhere in southern Africa, infected with HIV, and having them subsist as best they can on the drugs that Ranbaxy found fit for their sort.

Comments (43) + TrackBacks (0) | Category: Infectious Diseases | The Dark Side

May 7, 2013

Another Germ Theory Victory - Back Pain?

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Posted by Derek

The "New Germ Theory" people may have notched up another one: a pair of reports out from a team in Denmark strongly suggest that many cases of chronic low back pain are due to low-grade bacterial infection. They've identified causative agents (Propionibacterium acnes) by isolating them from tissue, and showed impressive success in the clinic by treating back pain patients with a lengthy course of antibiotics. Paul Ewald is surely smiling about this news, although (as mentioned here) he has some ideas about the drug industry that I can't endorse.

So first we find out that stomach ulcers are not due to over-dominant mothers, and now this. What other hard-to-diagnose infections are we missing? Update - such as obesity, maybe?

Comments (25) + TrackBacks (0) | Category: Infectious Diseases

March 14, 2013

Does Baldness Get More Funding Than Malaria?

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Posted by Derek

OK, let's fact-check Bill Gates today, shall we?

Capitalism means that there is much more research into male baldness than there is into diseases such as malaria, which mostly affect poor people, said Bill Gates, speaking at the Royal Academy of Engineering's Global Grand Challenges Summit.

"Our priorities are tilted by marketplace imperatives," he said. "The malaria vaccine in humanist terms is the biggest need. But it gets virtually no funding. But if you are working on male baldness or other things you get an order of magnitude more research funding because of the voice in the marketplace than something like malaria."

Gates' larger point, that tropical diseases are an example of market failure, stands. But I don't think this example does. I have never yet worked on any project in industry that had anything to do with baldness, while I have actually touched on malaria. Looking around the scientific literature, I see many more publications on potential malaria drugs than I see potential baldness drugs (in fact, I'm not sure if I've ever seen anything on the latter, after minoxidil - and its hair-growth effects were discovered by accident during a cardiovascular program). Maybe I'm reading the wrong journals.

But then, Gates also seems to buy into the critical-shortage-of-STEM idea:

With regards to encouraging more students into STEM education, Gates said: "It's kind of surprising that we have such a deficit of people going into those fields. Look at where you can have the most interesting job that pays well and will have impact on society -- all three of those things line up to say science and engineering and yet in most rich countries we see decline. Asia is an exception."

The problem is, there aren't as many of these interesting, well-paying jobs around as there used to be. Any discussion of the STEM education issue that doesn't deal with that angle is (to say the least) incomplete.

Comments (28) + TrackBacks (0) | Category: Drug Development | Drug Industry History | Infectious Diseases

February 28, 2013

IBM's Watson Does Drug Discovery?

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Posted by Derek

I saw this story this morning, about IBM looking for more markets for its Watson information-sifting system (the one that performed so publicly on "Jeopardy". And this caught my eye for sure:

John Baldoni, senior vice president for technology and science at GlaxoSmithKline, got in touch with I.B.M. shortly after watching Watson’s “Jeopardy” triumph. He was struck that Watson frequently had the right answer, he said, “but what really impressed me was that it so quickly sifted out so many wrong answers.”

That is a huge challenge in drug discovery, which amounts to making a high-stakes bet, over years of testing, on the success of a chemical compound. The failure rate is high. Improving the odds, Mr. Baldoni said, could have a huge payoff economically and medically.

Glaxo and I.B.M. researchers put Watson through a test run. They fed it all the literature on malaria, known anti-malarial drugs and other chemical compounds. Watson correctly identified known anti-malarial drugs, and suggested 15 other compounds as potential drugs to combat malaria. The two companies are now discussing other projects.

“It doesn’t just answer questions, it encourages you to think more widely,” said Catherine E. Peishoff, vice president for computational and structural chemistry at Glaxo. “It essentially says, ‘Look over here, think about this.’ That’s one of the exciting things about this technology.”

Now, without seeing some structures and naming some names, it's completely impossible to say how valuable the Watson suggestions were. But I would very much like to know on what basis these other compounds were suggested: structural similarity? Mechanisms in common? Mechanisms that are in the same pathway, but hadn't been specifically looked at for malaria? Something else entirely? Unfortunately, we're probably not going to be able to find out, unless GSK is forthcoming with more details.

Eventually, there's coing to be another, somewhat more disturbing answer to that "what basis?" question. As this Slate article says, we could well get to the point where such systems make discoveries or correlations that are correct, but beyond our ability to figure out. Watson is most certainly not there yet. I don't think anything is, or is really all that close. But that doesn't mean it won't happen.

For a look at what this might be like, see Ted Chiang's story "Catching Crumbs From the Table", which appeared first in Nature, and then in his collection Stories of Your Life and Others, which I highly recommend, as "The Evolution of Human Science".

Comments (32) + TrackBacks (0) | Category: In Silico | Infectious Diseases

February 13, 2013

Mouse Models of Inflammation Are Basically Worthless. Now We Know.

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Posted by Derek

We go through a lot of mice in this business. They're generally the first animal that a potential drug runs up against: in almost every case, you dose mice to check pharmacokinetics (blood levels and duration), and many areas have key disease models that run in mice as well. That's because we know a lot about mouse genetics (compared to other animals), and we have a wide range of natural mutants, engineered gene-knockout animals (difficult or impossible to do with most other species), and chimeric strains with all sorts of human proteins substituted back in. I would not wish to hazard a guess as to how many types of mice have been developed in biomedical labs over the years; it is a large number representing a huge amount of effort.

But are mice always telling us the right thing? I've written about this problem before, and it certainly hasn't gone away. The key things to remember about any animal model is that (1) it's a model, and (2) it's in an animal. Not a human. But it can be surprisingly hard to keep these in mind, because there's no other way for a compound to become a drug other than going through the mice, rats, etc. No regulatory agency on Earth (OK, with the possible exception of North Korea) will let a compound through unless it's been through numerous well-controlled animal studies, for short- and long-term toxicity at the very least.

These thoughts are prompted by an interesting and alarming paper that's come out in PNAS: "Genomic responses in mouse models poorly mimic human inflammatory diseases". And that's the take-away right there, which is demonstrated comprehensively and with attention to detail.

Murine models have been extensively used in recent decades to identify and test drug candidates for subsequent human trials. However, few of these human trials have shown success. The success rate is even worse for those trials in the field of inflammation, a condition present in many human diseases. To date, there have been nearly 150 clinical trials testing candidate agents intended to block the inflammatory response in critically ill patients, and every one of these trials failed. Despite commentaries that question the merit of an overreliance of animal systems to model human immunology, in the absence of systematic evidence, investigators and public regulators assume that results from animal research reflect human disease. To date, there have been no studies to systematically evaluate, on a molecular basis, how well the murine clinical models mimic human inflammatory diseases in patients.

What this large multicenter team has found is that while various inflammation stresses (trauma, burns, endotoxins) in humans tend to go through pretty much the same pathways, the same is not true for mice. Not only do they show very different responses from humans (as measured by gene up- and down-regulation, among other things), they show different responses to each sort of stress. Humans and mice differ in what genes are called on, in their timing and duration of expression, and in what general pathways these gene products are found. Mice are completely inappropriate models for any study of human inflammation.

And there are a lot of potential reasons why this turns out to be so:

There are multiple considerations to our finding that transcriptional response in mouse models reflects human diseases so poorly, including the evolutional distance between mice and humans, the complexity of the human disease, the inbred nature of the mouse model, and often, the use of single mechanistic models. In addition, differences in cellular composition between mouse and human tissues can contribute to the differences seen in the molecular response. Additionally, the different temporal spans of recovery from disease between patients and mouse models are an inherent problem in the use of mouse models. Late events related to the clinical care of the patients (such as fluids, drugs, surgery, and life support) likely alter genomic responses that are not captured in murine models.

But even with all the variables inherent in the human data, our inflammation response seems to be remarkably coherent. It's just not what you see in mice. Mice have had different evolutionary pressures over the years than we have; their heterogeneous response to various sorts of stress is what's served them well, for whatever reasons.

There are several very large and ugly questions raised by this work. All of us who do biomedical research know that mice are not humans (nor are rats, nor are dogs, etc.) But, as mentioned above, it's easy to take this as a truism - sure, sure, knew that - because all our paths to human go through mice and the like. The New York Times article on this paper illustrates the sort of habits that you get into (emphasis below added):

The new study, which took 10 years and involved 39 researchers from across the country, began by studying white blood cells from hundreds of patients with severe burns, trauma or sepsis to see what genes are being used by white blood cells when responding to these danger signals.

The researchers found some interesting patterns and accumulated a large, rigorously collected data set that should help move the field forward, said Ronald W. Davis, a genomics expert at Stanford University and a lead author of the new paper. Some patterns seemed to predict who would survive and who would end up in intensive care, clinging to life and, often, dying.

The group had tried to publish its findings in several papers. One objection, Dr. Davis said, was that the researchers had not shown the same gene response had happened in mice.

“They were so used to doing mouse studies that they thought that was how you validate things,” he said. “They are so ingrained in trying to cure mice that they forget we are trying to cure humans.”

“That started us thinking,” he continued. “Is it the same in the mouse or not?”

What's more, the article says that this paper was rejected from Science and Nature, among other venues. And one of the lead authors says that the reviewers mostly seemed to be saying that the paper had to be wrong. They weren't sure where things had gone wrong, but a paper saying that murine models were just totally inappropriate had to be wrong somehow.

We need to stop being afraid of the obvious, if we can. "Mice aren't humans" is about as obvious a statement as you can get, but the limitations of animal models are taken so much for granted that we actually dislike being told that they're even worse than we thought. We aren't trying to cure mice. We aren't trying to make perfect diseases models and beautiful screening cascades. We aren't trying to perfectly match molecular targets with diseases, and targets with compounds. Not all the time, we aren't. We're trying to find therapies that work, and that goal doesn't always line up with those others. As painful as it is to admit.

Comments (50) + TrackBacks (0) | Category: Animal Testing | Biological News | Drug Assays | Infectious Diseases

January 24, 2013

Three Rings in a Row

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Posted by Derek

GRL.png
Here's a structure that caught me eye, in this paper from Georgia State and Purdue. That's a nice-looking group stuck on the side of their HIV protease inhibitor; I don't think I've ever seen three fused THF rings before, and if I have, it certainly wasn't in a drug candidate. From the X-ray structure, it seems to be making some beneficial interactions out in the P2 site.

This is an analog these are analogs of darunavir, which has two THFs fused in similar fashion. That compound's behavior in vivo is well worked out - most of the metabolism is cleavage of the carbamate. Both with and without that, there's a bunch of scattered hydroxylation and glucuronidation; the bis-THF survives just fine. (That's worth thinking about. Most of us would be suspicious of that group, but it's pretty robust in this case). I'd be interested in seeing if this new structure behaves similarly, or if it's now more sensitive to gastric fluid and the like. No data of that sort is presented in this paper (it's an academic group, after all), but perhaps we'll find out eventually.

Comments (5) + TrackBacks (0) | Category: Infectious Diseases

January 15, 2013

Is Obesity An Infectious Disease?

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Posted by Derek

Like many people, I have a weakness for "We've had it all wrong!" explanations. Here's another one, or part of one: is obesity an infectious disease?

During our clinical studies, we found that Enterobacter, a genus of opportunistic, endotoxin-producing pathogens, made up 35% of the gut bacteria in a morbidly obese volunteer (weight 174.8 kg, body mass index 58.8 kg m−2) suffering from diabetes, hypertension and other serious metabolic deteriorations. . .

. . .After 9 weeks on (a special diet), this Enterobacter population in the volunteer's gut reduced to 1.8%, and became undetectable by the end of the 23-week trial, as shown in the clone library analysis. The serum–endotoxin load, measured as LPS-binding protein, dropped markedly during weight loss, along with substantial improvement of inflammation, decreased level of interleukin-6 and increased adiponectin. Metagenomic sequencing of the volunteer's fecal samples at 0, 9 and 23 weeks on the WTP diet confirmed that during weight loss, the Enterobacteriaceae family was the most significantly reduced population. . .

They went on to do the full Koch workup, by taking an isolated Enterobacter strain from the human patient and introducing it into gnotobiotic (germ-free) mice. These mice are usually somewhat resistant to becoming obese on a high-fat diet, but after being inoculated with the bacterial sample, they put on substantial weight, became insulin resistant, and showed numerous (consistent) alterations in their lipid and glucose handling pathways. Interestingly, the germ-free mice that were inoculated with bacteria and fed normal chow did not show these effects.

The hypothesis is that the endotoxin-producing bacteria are causing a low-grade chronic inflammation in the gut, which is exacerbated to a more systemic form by the handling of excess lipids and fatty acids. The endotoxin itself may be swept up in the chylomicrons and translocated through the gut wall. The summary:

. . .This work suggests that the overgrowth of an endotoxin-producing gut bacterium is a contributing factor to, rather than a consequence of, the metabolic deteriorations in its human host. In fact, this strain B29 is probably not the only contributor to human obesity in vivo, and its relative contribution needs to be assessed. Nevertheless, by following the protocol established in this study, we hope to identify more such obesity-inducing bacteria from various human populations, gain a better understanding of the molecular mechanisms of their interactions with other members of the gut microbiota, diet and host for obesity, and develop new strategies for reducing the devastating epidemic of metabolic diseases.

Considering the bacterial origin of ulcers, I think this is a theory that needs to be taken seriously, and I'm glad to see it getting checked out. We've been hearing a lot the last few years about the interaction between human physiology and our associated bacterial population, but the attention is deserved. The problem is, we're only beginning to understand what these ecosystems are like, how they can be disordered, and what the consequences are. Anyone telling you that they have it figured out at this point is probably trying to sell you something. It's worth the time to figure out, though. . .

Comments (32) + TrackBacks (0) | Category: Biological News | Diabetes and Obesity | Infectious Diseases

October 8, 2012

Nasty Drug Molecules: Amphotericin B

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Posted by Derek

You've probably seen the headlines about fungal meningitis showing up, caused (it appears) by contaminated injectable steroid supplies. As soon as I heard these stories, I wondered what you treat this condition with, and my first thought was "Amphotericin B, most likely". And so it appears.
amphotericin%20jpeg.jpg
That compound still seems to be the usual answer for the nastiest fungal infections, a role it's occupied for decades. That's not by choice. It's an awful compound in many ways, as illustrated by that Wikipedia article linked above:

Amphotericin B is well known for its severe and potentially lethal side-effects. Very often, a serious acute reaction after the infusion (1 to 3 hours later) is noted, consisting of high fever, shaking chills, hypotension, anorexia, nausea, vomiting, headache, dyspnea and tachypnea, drowsiness, and generalized weakness. This reaction sometimes subsides with later applications of the drug, and may in part be due to histamine liberation. An increase in prostaglandin synthesis may also play a role. This nearly universal febrile response necessitates a critical (and diagnostically difficult) professional determination as to whether the onset of high fever is a novel symptom of a fast-progressing disease, or merely the induced effect of the drug.

Organ damage is also distressingly common, and patients who are dying of a systemic fungal infection can suddenly find themselves dying instead of kidney or liver failure. As you'd imagine from that structure, it has to be given intravenously, unless you're treating an oral infection. (Note that it's quite similar to the common topic medicine nystatin). The drug works, as far as anyone can tell, by opening pores in cell membranes, particularly associating with sterols. It seems to have a greater affinity for ergosterol (found in fungi) over cholesterol, which gives it whatever therapeutic window it has.

People have tried for years to replace Amphotericin B, but it remains with us. If you're taking it, you are probably in a bad way.

Comments (22) + TrackBacks (0) | Category: Infectious Diseases

September 4, 2012

A New Malaria Compound

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Posted by Derek

There have been many headlines in recent days about a potential malaria cure. I'm not sure what set these off at this time, since the paper describing the work came out back in the spring, but it's certainly worth a look.

This all came out of the Medicines for Malaria Venture, a nonprofit group that has been working with various industrial and academic groups in many areas of malaria research. This is funded through a wide range of donors (corporations, foundations, international agencies), and work has taken place all over the world. In this case (PDF), things began with a collection of about 36,000 compounds (biased towards kinase inhibitor scaffolds) from BioFocus in the UK. These were screened (high-throughput phenotypic readout) at the Eskitis Institute in Australia, and a series of compounds was identified for structure-activity studies. This phase of the work was a three-way collaboration between a chemistry team at the University of Cape Town (led by Prof. Kelly Chibale), biology assay teams at the Swiss Tropical and Public Health Institute, and pharmacokinetics at the Center for Drug Candidate Optimization at Monash University in Australia.
MMV%20compound%2015.png
An extensive SAR workup on the lead series identified some metabolically labile parts of the molecule over on that left-hand side pyridine. These could fortunately be changed without impairing the efficacy against the malaria parasites. The sulfonyl group seems to be required, as does the aminopyridine. These efforts led to the compound shown, MMV390048, which has good blood levels, passes in vitro safety tests, and is curative in a Plasmodium berghei mouse model at a single dose of 30 mg/kg. That's a very promising compound, from the looks of it, since that's better than the existing antimalarials can do. It's also active against drug-resistant strains, as well it might be (see below). Last month the MMV selected it for clinical development.

So how does this compound work? The medicinal chemists in the audience will have looked at that structure and said "kinase inhibitor", and that has to be where to put your money. That, in fact, appears to have been the entire motivation to screen the BioFocus collection. Kinase targets in Plasmodium have been getting attention for several years now; the parasite has a number of enzymes in this class, and they're different enough from human kinases to make attractive targets. (To that point, I have not been able to find results of this latest compound's profile when run against a panel of human kinases, although you'd think that this has surely been done by now). Importantly, none of the existing antimalarials work through such mechanisms, so the parasites have not had a chance to work up any resistance.

But resistance will come. It always does. The best hope for the kinase-based inhibitors is that they'll hit several malaria enzymes at once, which gives the organisms a bigger evolutionary barrier to jump over. The question is whether you can do that without hitting anything bad in the human kinome, but for the relatively short duration of acute malaria treatment, you should be able to get away with quite a bit. Throwing this compound and the existing antimalarials at the parasites simultaneously will really give them something to occupy themselves.

I'll follow the development of this compound with interest. It's just about to hit the really hard part of drug research - human beings in the clinic. This is where we have our wonderful 90% or so failure rates, although those figures are generally better for anti-infectives, as far as I can tell. Best of luck to everyone involved. I hope it works.

Comments (27) + TrackBacks (0) | Category: Drug Development | Infectious Diseases

May 21, 2012

A New Way to Kill Amoebas, From An Old Drug

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Posted by Derek

Here's a good example of phenotypic screening coming through with something interesting and worthwhile: they screened against Entamoeba histolytica, the protozooan that causes amoebic dysentery and kills tens of thousands of people every year. (Press coverage here).

It wasn't easy. The organism is an anaerobe, which is a bad fit for most robotic equipment, and engineering a decent readout for the assay wasn't straightforward, either. They did have a good positive control, though - the nitroimidazole drug metronidazole, which is the only agent approved currently against the parasite (and to which it's becoming resistant). A screen of nearly a thousand known drugs and bioactive compounds showed eleven hits, of which one (auranofin) was much more active than metronidazole itself.

Auranofin's an old arthritis drug. It's a believable result, because the compound has also been shown to have activity against trypanosomes, Leishmania parasites, and Plasmodium malaria parasites. This broad-spectrum activity makes some sense when you realize that the drug's main function is to serve as a delivery vehicle for elemental gold, whose activity in arthritis is well-documented but largely unexplained. (That activity is also the basis for persistent theories that arthritis may have an infectious-disease component).

The target in this case may well be arsenite-inducible RNA-associated protein (AIRAP), which was strongly induced by drug treatment. The paper notes that arsenite and auranofin are both known inhibitors of thioredoxin reductase, which strongly suggests that this is the mechanistic target here. The organism's anaerobic lifestyle fits in with that; this enzyme would presumably be its main (perhaps only) path for scavenging reactive oxygen species. It has a number of important cysteine residues, which are very plausible candidates for binding to a metal like gold. And sure enough, auranofin (and two analogs) are potent inhibitors of purified form of the amoeba enzyme.

The paper takes the story all the way to animal models, where auranofin completely outperforms metronidazole. The FDA has now given it orphan-drug status for amebiasis, and the way appears clear for a completely new therapeutic option in this disease. Congratulations to all involved; this is excellent work.

Comments (10) + TrackBacks (0) | Category: Academia (vs. Industry) | Drug Assays | Drug Development | Infectious Diseases

A Molecular Craigslist?

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Posted by Derek

Mat Todd at the University of Sydney (whose open-source drug discovery work on schistosomiasis I wrote about here) has an interesting chemical suggestion. His lab is also involved in antimalarial work (here's an update, for those interested, and I hope to post about this effort more specifically). He's wondering about whether there's room for a "Molecular Craigslist" for efforts like these:

Imagine there is a group somewhere with expertise in making these kinds of compounds, and who might want to make some analogs as part of a student project, in return for collaboration and co-authorship? What about a Uni lab which might be interested in making these compounds as part of an undergrad lab course?

Wouldn’t it be good if we could post the structure of a molecule somewhere and have people bid on providing it? i.e. anyone can bid – commercial suppliers, donators, students?

Is there anything like this? Well, databases like Zinc and Pubchem can help in identifying commercial suppliers and papers/patents where groups have made related compounds, but there’s no tendering process where people can post molecules they want. Science Exchange has, I think, commercial suppliers, but not a facility to allow people to donate (I may be wrong), or people to volunteer to make compounds (rather than be listed as generic suppliers. Presumably the same goes for eMolecules, and Molport?

Is there a niche here for a light client that permits the process I’m talking about? Paste your Smiles, post the molecule, specifying a purpose (optional), timeframe, amount, type of analytical data needed, and let the bidding commence?

The closest thing I can think of is Innocentive, which might be pretty close to what he's talking about. It's reasonably chemistry-focused as well. Any thoughts out there?

Comments (19) + TrackBacks (0) | Category: Academia (vs. Industry) | Business and Markets | Drug Development | Infectious Diseases

April 30, 2012

India's First Drug Isn't India's First Drug

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Posted by Derek

There have been a number of headlines the last few days about Ranbaxy's Synriam, an antimalarial that's being touted as the first new drug developed inside the Indian pharma industry (and Ranbaxy as the first Indian company to do it).

But that's not quite true, as this post from The Allotrope makes clear. (Its author, Akshat Rathi, found one of my posts when he started digging into the story). Yes, Synriam is a mixture of a known antimalarial (piperaquine) and arterolane. And arterolane was definitely not discovered in India. It was part of a joint effort from the US, UK, Australia, and Switzerland, coordinated by the Swiss-based Medicines for Malaria Venture.

Ranbaxy did take on the late-stage development of this drug combination, after MMV backed out due to no-so-impressive performance in the clinic. As Rathi puts it:

Although Synriam does not qualify as ‘India’s first new drug’ (because none of its active ingredients were wholly developed in India), Ranbaxy deserves credit for being the first Indian pharmaceutical company to launch an NCE before it was launched anywhere else in the world.

And that's something that not many countries have done. I just wish that Ranbaxy were a little more honest about that in their press release.

Comments (8) + TrackBacks (0) | Category: Drug Development | Infectious Diseases

April 25, 2012

DHFR Inhibitors Revisited: A Word From the Authors (and Reviewers)

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Posted by Derek

The other day, I had some uncomplimentary things to say about a recent J. Med. Chem. paper on fragment-based dihydrofolate reductase inhibitors. Well, I know that I don't say these things into a vacuum, by any means, but in this case the lead author has written me about the work, and a reviewer of the paper has showed up in the comments. So perhaps this is a topic worth revisiting?

First, I'll give Prof. Joelle Pelletier of U. Montreal the floor to make the case for the defense. Links added are mine, for background; I take responsibility for those, and I hope they're helpful.

I was informed of your recent blog entitled ‘How do these things get published’. I am corresponding author of that paper. I would like to bring to your attention a crucial point that was incorrectly presented in your analysis: the target enzyme is not that which you think it is, i.e.: it is not a DHFR that is part of ‘a class of enzymes that's been worked on for decades’.

Indeed, it would make no sense to report weak and heavy inhibitors against ‘regular’ DHFRs (known as ‘type I DHFRs’), considering the number of efficient DHFR inhibitors we already know. But this target has no sequence or structural homology with type I DHFRs. It is a completely different protein that offers an alternate path to production of tetrahydrofolate (see top of second page of the article). It has apparently evolved recently, as a bacterial response to trimethoprim being introduced into the environment since the ‘60’s. Because that protein is evolutionarily unrelated to regular DHFRs, it doesn’t bind trimethoprim and is thus intrinsically trimethoprim resistant; it isn’t inhibited by other inhibitors of regular DHFRs either. There have been no efforts to date to inhibit this drug resistance enzyme, despite its increasing prevalence in clinical and veterinary settings, and in food and wastewater (see first page of article). As a result, we know nothing about how to prevent it from providing drug resistance. Our paper is thus the first foray into inhibiting this new target – one which presents both the beauty and the difficulty of complex symmetry.

Regular (type I) DHFRs are monomeric enzymes with an extended active-site cleft. They are chromosomally-encoded in all living cells where they are essential for cellular proliferation. Our target, type II R67 DHFR, is carried on a plasmid, allowing rapid dissemination between bacterial species. It is an unusual homotetrameric, doughnut-style enzyme with the particularity of having a single active site in the doughnut hole. That’s unusual because multimeric enzymes typically have the same number of active sites as they do monomers. The result is that the active site tunnel, shown in Figure 4 a, has 222 symmetry. Thus, the front and back entrances to the active site tunnel are identical. And that’s why designing long symmetrical molecules makes sense: they have the potential of threading through the tunnel, where the symmetry of the inhibitor would match the symmetry of the target. If they don’t string through but fold up into a ‘U”, it still makes sense: the top and bottom of the tunnel are also alike, again allowing a match-up of symmetry. Please note that this symmetry does create a bit of a crystallographer’s nightmare at the center of the tunnel where the axes of symmetry meet; again, it is an unusual system.

You have referred to our ‘small, poorly documented library of fragment compounds’. As for the poor documentation, the point is that we have very little prior information on the ligands of this new target, other than its substrates. We cast as wide a net as we could within a loosely defined chemical class, using the chemicals we have access to. Unfortunately, I don’t have access to a full fragment library, but am open to collaboration.

As a result of extending the fragments, the ligand efficiency does take a beating… so would it have been better not to mention it? No, that would have been dishonest. In addition, it is not a crucial point at this very early stage in discovery: this is a new target, and it IS important to obtain information on tighter binding, even if it comes at the cost of heavier molecules. In no way do we pretend that these molecules are ripe for application; we have presented the first set of crude inhibitors to ‘provide inspiration for the design of the next generation of inhibitors’ (last sentence of the paper).

Your blog is widely read and highly respected. In this case, it appears that your analysis was inaccurate due to a case of mistaken identity. I did appreciate your calm and rational tone, and hope that you will agree that there is redeeming value to the poor ligand efficiency, because of the inherent novelty of this discovery effort. I am appealing to you to reconsider the blog’s content in light of the above information, and respectfully request that you consider revising it.

Well, as for DHFRs, I'm guilty as charged. The bacterial ones really are way off the mammalian ones - it appears that dihydro/tetrahydrofolate metabolism is a problem that's been solved a number of different ways and (as is often the case) the bacteria show all kinds of diversity compared to the rest of the living world. And there really aren't any good D67 DHFR inhibitors out there, not selective ones, anyway, so a molecule of that type would definitely be a very worthwhile tool (as well as a potential antibiotic lead).

But that brings us to the fragments, the chemical matter in the paper. I'm going to stand my my characterization of the fragment library. 100 members is indeed small, and claiming lack of access to a "full fragment collection" doesn't quite cover it. Because of the amount of chemical space that can be covered at these molecular weights, a 200-member library can be significantly more useful than a 100-member one, and so on. (Almost anything is more useful than a 100-member library). There aren't more compounds of fragment size on the shelves at the University of Montreal?

More of a case could be made for libraries this small if they covered chemical space well. Unfortunately, looking over the list of compounds tested (which is indeed in the Supplementary Material), it's not, at first glance, a very good collection. Not at all. There are some serious problems, and in a collection this small, mistakes are magnified. I have to point out, to start with, that compounds #59 and #81 are duplicates, as are compounds #3 and #40, and compounds #7 and #14. (There may be others; I haven't made a complete check).

The collection is heavily biased towards carboxylic acids (which is a problem for several reasons, see below). Nearly half the compounds have a COOH group by my quick count, and it's not a good idea to have any binding motif so heavily represented. I realize that you intentionally biased your screening set, but then, an almost featureless hydrophobic compound like #46 has no business in there. Another problem is that some of the compounds are so small that they're unlikely to be tractable fragment hits - I note succinimide (#102) and propyleneurea (#28) as examples, but there are others. At the other end of the scale, compounds such as the Fmoc derivative #25 are too large (MW 373), and that's not the only offender in the group (nor the only Fmoc derivative). The body of the manuscript mentions the molecular weights of the collections as being from 150 to 250, but there are too many outliers. This isn't a large enough collection for this kind of noise to be in it.

There are a number of reactive compounds in the list, too, and while covalent inhibitors are a very interesting field, this was not mentioned as a focus of your efforts or as a component of the screening set. And even among these, compounds such as carbonyldiimidazole (#26), the isocyanate #82, and disuccinimidylcarbonate (#36) are really pushing it, as far as reactivity and hydrolytic stability. The imine #110 is also very small and likely to have hydrolytic stability problems. Finally, the fragment #101 is HEPES, which is rather odd, since HEPES is the buffer for the enzyme assays. Again, there isn't room for these kinds of mistakes. It's hard for me to imagine that anyone who's ever done fragment screening reviewed this manuscript.

The approach to following up these compounds also still appears inadequate to me. As Dan Erlanson pointed out in a comment to the Practical Fragments post, small carboxylic acids like the ones highlighted are not always legitimate hits. They can, as he says, form aggregates, depending on the assay conditions, and the most straightforward way of testing that is often the addition of a small amount of detergent, if the assay can stand it. The behavior of such compounds is also very pH-dependent, as I've had a chance to see myself on a fragment effort, so you need to make sure that you're as close to physiological conditions as you can get. I actually have seen some of your compounds show up as hits in fragment screening efforts, and they've been sometimes real, sometimes not.

But even if we stipulate that these compounds are actually hits, they need more work than they've been given. The best practice, in most cases when a fragment hit is discovered and confirmed, is to take as many closely related single-atom changes into the assay as possible. Scan a methyl group around the structure, scan a fluoro, make the N-for-C switches - at these molecular weights, these changes can make a big difference, and you may well find an even more ligand-efficient structure to work from.

Now, as for the SAR development that actually was done: I understand the point about the symmetry of the enzyme, and I can see why this led to the idea of making symmetrical dimer-type compounds. But, as you know, this isn't always a good idea. Doing so via flexible alkyl or alkyl ether chains is not a good idea, though, since such compounds will surely pay an entropic penalty in binding.

And here's one of the main things that struck both me and Teddy Z in his post: if the larger compounds were truly taking advantage of the symmetry, their ligand efficiency shouldn't go down. But in this case it does, and steeply. The size of the symmetical inhibitors (and their hydrophobic regions, such as the featureless linking chains, make it unsurprising that this effort found some micromolar activity. Lots of things will no doubt show micromolar activity in such chemical space. The paper notes that it's surprising that the fragment 4c showed no activity when its structural motif was used to build some of the more potent large compounds, but the most likely hypothesis is that this is because the binding modes have nothing to do with each other.

To be fair, compounds 8 and 9 are referred to as "poorly optimized", which is certainly true. But the paper goes on to say that they are starting points to develop potent and selective inhibitors, which they're not. The fragments are starting points, if they're really binding. The large compounds are dead ends. That's why Teddy Z and I have reacted as strongly as we have, because the path this paper takes is (to our eyes) an example of how not to do fragment-based drug discovery.

But still, I have to say that I'm very glad to hear a direct reply to my criticism of this paper. I hope that this exchange has been useful, and that it might be of use for others who read it.

Comments (24) + TrackBacks (0) | Category: Drug Assays | Infectious Diseases | The Scientific Literature

April 18, 2012

How Do These Things Get Published?

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Posted by Derek

Update: I've heard from both the lead author of this paper and one of its reviewers, and I've written a follow-up post on this subject, as well as revising this one where shown below.

I've been saved the trouble of demolishing this J. Med. Chem. paper - the Practical Fragments blog has done it for me. I really hate to say such things, but this appears to be one of the worst papers that journal has published in quite a while.

The authors start out with a small, poorly documented (update: the compounds are, in fact, in the paper's supplementary information, but see the follow-up post) library of fragment compounds. They screen these against dihydrofolate reductase, and get a few possible hits - mind you, there's not much correlation between the numbers and any potency against the enzyme, but these aren't potent compounds, and fragment-level hits don't always perform in high-concentration enzyme assays. But what happens next? The authors string these things together into huge dimeric molecules, apparently because they think that this is a good idea, but they get no data to support this hypothesis at all.

Well, their potency goes from low millimolar to low micromolar, but as Teddy Z at Practical Fragments points out, this actually means taking a terrible beating in ligand efficiency. All that extra molecular weight should buy you a lot more potency than this. There's some hand-waving docking of these structures - which the authors themselves refer to as "poorly optimized" - and some inconclusive attempts at X-ray crystallography, leading to uninterpretable data.

And that's it. That's the paper. This on a class of enzymes that's been worked on for decades, yet. (Update: this characterization is completely wrong on my part - see the follow-up post linked to above for more). Again, I hate to be unkind about this, but I cannot imagine what this is doing in J. Med. Chem., or how it made it through the editorial process. When you submit a scientific manuscript for publication, you open yourself to comments from all comers, and those are mine.

Comments (29) + TrackBacks (0) | Category: Infectious Diseases | The Scientific Literature

March 5, 2012

Trouble With a Boron-Containing Drug Candidate

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Posted by Derek

There have been all kinds of boronic acid-based enzyme inhibitors over the years, but they've been mostly locked in the spacious closet labeled "tool compounds". That's as opposed to drugs. After all these years, Velcade is still the only marketed boron-containing drug that I know of.

There's been a good attempt to change that in antibacterials, with the development of what's commonly referred to as "GSK '052", short for GSK2251052. That's a compound that originally came from Anacor about ten years ago, then was picked up by GlaxoSmithKline, and it's an oxaborole heterocycle that inhibits leucyl tRNA synthetase. (Here's a review on that whole idea, if you're interested).
GSK%20052.png
Unfortunately, last month came word that the Phase II trial of the drug had been suspended. All that anyone's saying is that there's a "microbiological finding", which isn't too informative when it's applied to y'know, an antibacterial trial. (At least it doesn't sound like a general safety or tox problem, at any rate).

Anacor is continuing to exploit boron-containing compounds, although opinion looks divided about their prospects. I always have a sneaking fondness for odd compounds and elements, though, so I'd have to root for them just on that basis.

Comments (19) + TrackBacks (0) | Category: Infectious Diseases | Odd Elements in Drugs

February 17, 2012

Hepatitis C: Reality Intrudes

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Posted by Derek

There's been a big drug development story over the last few months that I've been unable to comment on due to conflicts of interest. That situation continues, but I can point to the latest developments, for those who haven't been following the twists and turns.

Comments (29) + TrackBacks (0) | Category: Infectious Diseases

November 30, 2011

The XMRV Story Is Not Getting Any Saner

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Posted by Derek

Dismissals, accusations, possible data theft, and now an arrest - when a scientific hypothesis (and a scientific career) unravels, it unravels all the way. . .

Comments (6) + TrackBacks (0) | Category: Infectious Diseases | The Dark Side

October 18, 2011

Cyclodextrin's Day in the Sun

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Posted by Derek

Under the "Who'da thought?" category, put this news about cyclodextrin. For those outside the field, that's a ring of glucose molecules, strung end to end like a necklace. (Three-dimensionally, it's a lot more like a thick-cut onion ring - see that link for a picture). The most common form, beta-cyclodextrin, has seven glucoses. That structure gives it some interesting properties - the polar hydroxy groups are mostly around the edges and outside surface, while the inside is more friendly to less water-soluble molecules. It's a longtime additive in drug formulations for just that purpose - there are many, many examples known of molecules that fit into the middle of a cyclodextrin in aqueous solution.

But as this story at the Wall Street Journal shows, it's not inert. A group studying possible therapies for Niemann-Pick C disease (a defect in cholesterol storage and handling) was going about this the usual way - one group of animals was getting the proposed therapy, while the other was just getting the drug vehicle. But this time, the vehicle group showed equivalent improvement to the drug-treatment group.

Now, most of the time that happens when neither of them worked; that'll give you equivalence all right. But in this case, both groups showed real improvement. Further study showed that the cyclodextrin derivative used in the dosing vehicle was the active agent. And that's doubly surprising, since one of the big effects seen was on cholesterol accumulation in the central neurons of the rodents. It's hard to imagine that a molecule as big (and as polar-surfaced) as cyclodextrin could cross into the brain, but it's also hard to see how you could have these effects without that happening. It's still an open question - see that PLoS One paper link for a series of hypotheses. One way or another, this will provide a lot of leads and new understanding in this field:

Although the means by which CD exerts its beneficial effects in NPC disease are not understood, the outcome of CD treatment is clearly remarkable. It leads to delay in onset of clinical signs, a significant increase in lifespan, a reduction in cholesterol and ganglioside accumulation in neurons, reduced neurodegeneration, and normalization of markers for both autophagy and neuro-inflammation. Understanding the mechanism of action for CD will not only provide key insights into the cholesterol and GSL dysregulatory events in NPC disease and related disorders, but may also lead to a better understanding of homeostatic regulation of these molecules within normal neurons. Furthermore, elucidating the role of CD in amelioration of NPC disease will likely assist in development of new therapeutic options for this and other fatal lysosomal disorders.

Meanwhile, the key role of cholesterol in the envelope of HIV has led to the use of cyclodextrin as a possible antiretroviral. This looks like a very fortunate intersection of a wide-ranging, important biomolecule (cholesterol) with a widely studied, well-tolerated complexing agent for it (cyclodextrin). It'll be fun to watch how all this plays out. . .

Comments (16) + TrackBacks (0) | Category: Biological News | Infectious Diseases | The Central Nervous System | Toxicology

October 13, 2011

XMRV - Work Went On

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Posted by Derek

I really hesitate to bring this up again, considering the sorts of comments that came in the last time I mentioned XMRV around here. But I wanted to note a new paper that's come out. The authors reveal the crystal structures of the XMRV protease complexed with a number of known inhibitors. Some of them are what you'd expect from homology with similar enzymes, and some have unusual features.

But the details of the structures aren't the main point here - what's worth noting is that they exist. And they took time, and effort, and money to obtain. What's more, this sort of thing also went in several drug companies with an interest in antiviral research, not that any of that work will ever see the light of day, as opposed to this academic publication. Those people accusing the scientific world of callously ignoring the whole area should sit down with these X-ray structures for a few minutes.

No, XMRV was taken seriously by the medical research community, and a lot of serious effort was put into it. That's why it's such a shame that the whole hypothesis has ended up the way it has.

Comments (17) + TrackBacks (0) | Category: Infectious Diseases

October 4, 2011

XMRV: This Is Not Good

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Posted by Derek

If you haven't seen this XMRV news, then you should. The very day after I wrote my most recent post on the subject came this one from ERV over at Scienceblogs.

There are two key figures in it: one from the original Science paper, showing infected patients expressing XMRV Gag protein (a sign of viral infection). And the other was presented recently by Judy Mikovits at a conference in Ottowa. It shows a different experiment - Gag protein being expressed in some other patients only after treatment with 5-azacytidine. The problem is. . .well. . .I'll let you go see for yourselves what the problem is. It most definitely needs explaining, and the explanations had better be good.

Update: continued unraveling. Mikovits herself has been fired from her research institute, apparently for other causes.

Second update: The Chicago Tribune is on this story, breaking it to a wider public. For a link to the alleged third version of the Mikovits figure, see the comments to this post below.

Comments (88) + TrackBacks (0) | Category: Infectious Diseases

September 29, 2011

XMRV: Over With and Done?

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Posted by Derek

Here's an excellent post-mortem on the whole XMRV chronic-fatigue controversy, which I think almost everyone can agree is now at an end. The latest results are from a large blinded effort to detect the virus across a variety of patient sample (and across a number of labs) - and it's negative. The paper that started all the furor has been partially retracted. As far as I can see, the story is over.

But Judy Mikovits of the Whittemore Peterson Institute for Neuro-Immune Disease (WPI) in Nevada, whose work started all this off, is still a believer. And so, as you might imagine, are many patients:

Mikovits has become something of a savior in the community of people with CFS (also known as myalgic encephalomyelitis, or ME), who for decades have endured charges that the disease is psychosomatic. The 2009 Science paper shouted out that CFS may well have a clear biological cause, and, in turn, raised hopes of effective treatments and even a cure. The new findings give her “great pause,” yet she suspects they're but a speed bump. “I haven't changed my thinking at all,” she says. And she worries that the Blood Working Group conclusions will confuse people with CFS, some of whom got wind of the results early in the blogosphere and contacted her in a panic. “I had 15 suicidal patients call me last week,” she says.

In scientific circles, Mikovits has developed a less flattering reputation. Critics have accused her and her backers of stubbornly wedding themselves to a thesis and moving the goalposts with each study that challenges their conclusions. Even disease advocates who welcome the attention XMRV has brought to CFS believe the time has come to put this line of research to rest. “It's hard to say that this has not received a fair appraisal,” says Kimberly McCleary, president of the CFIDS Association of America, a patient group in Charlotte, North Carolina.

At the worst extreme, you get things like this. Note that that post's comment section filled up with people doubting, very vocally, that any such thing was going on, and sometime hinting at big conspiracies to keep the truth from being heard. I'll be a bit disappointed if some more of that doesn't attach to this post as well.

But while I can see why patients in this area are frustrated beyond words, and desperately hoping for something to help them, they're going to have to deal with what every scientist deals with: the indifference of the universe to what we want it to provide. Blind alleys there are beyond counting, wasted effort there is beyond measuring, in trying to understand a disease. We're used to, as humans, seeing agency and design when something seems so well hidden and so complex - in this case, malevolent design. But just as I reject the intelligent design hypothesis to explain what looks benevolent, I reject it for what sometimes looks like an evil practical joke: the perverse difficulties of biomedical research.

Comments (31) + TrackBacks (0) | Category: Infectious Diseases

September 6, 2011

Chronic Fatigue: Enough Energy Left for Death Threats, Anyway

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Posted by Derek

I've written a bit about the struggles to find the biological causes of chronic fatigue syndrome - but perhaps I should shut up? That seems to be the wiser course, given what's reported in this piece from the UK:

The full extent of the campaign of intimidation, attacks and death threats made against scientists by activists who claim researchers are suppressing the real cause of chronic fatigue syndrome is revealed today by the Observer. According to the police, the militants are now considered to be as dangerous and uncompromising as animal rights extremists.

One researcher told the Observer that a woman protester who had turned up at one of his lectures was found to be carrying a knife. Another scientist had to abandon a collaboration with American doctors after being told she risked being shot, while another was punched in the street. All said they had received death threats and vitriolic abuse.

The crime these people have committed, according to the various unhinged activists, is that they're suggesting that there could perhaps be a psychological component to the condition, or even just that the various proposals put forth for a viral cause don't seem to be holding up well. And we jump from that to death threats, harassment, calls for defunding, and accusations of dark deeds underwritten by Evil Pharmaceutical Companies.

That last one is especially weird, as one of the interviewees in the article makes clear. If there were a definite viral cause for chronic fatigue and allied syndromes, we Evil Pharma Scientists would do what we've done so evilly for HIV, hepatitis, and other diseases: come up with drugs to treat people or (better yet) vaccines to try to keep anyone from ever getting the disease again. Dark stuff indeed.

Comments (38) + TrackBacks (0) | Category: Infectious Diseases | The Dark Side

August 26, 2011

Kibdelomycin, A New Antibiotic. In A Way.

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Posted by Derek

We're going to need new antibiotics. Everyone knows this, and it's not like no one's been trying to do anything about it, either, but. . .we're still going to need more of them than we have. I'm not predicting that we're going to go all the way back to a world where young, healthy people with access to the best medical care die because they decided to play tennis without their socks on, but we're certainly in danger of a much nastier world than we have.

So I'm always interested to hear of new antibiotic discovery programs, and Merck is out with an interesting paper on theirs. They've been digging through the natural products, which have been the fount from which almost all antibiotics have sprung, and they have a new one called kibdelomycin to report. This one was dug out from an organism in a sample from the Central African Republic by a complicated but useful screening protocol, the S. aureus fitness test. This relies on 245 different engineered strains of the bacterium, each with an inducible RNAi pathway to downregulate some essential gene. When you pool these into mixed groups and grow them in the presence of test compounds (or natural product extracts) for 20 generations or so, a check of what strains have moved ahead (and fallen behind) can tell you what pathways you seem to be targeting. A key feature is that you can compare the profile you get with those of known antibiotics, so you don't end up rediscovering something (or discovering something that only duplicates what we already have anyway).
Kibdelomycin.png Now, that's no one's idea of a beautiful structure, although (to be fair) a lot of antibiotics have very weird structures themselves. But it's safe to say that there are some features there that could be trouble in a whole animal, such as that central keto-enol-pyrrolidone ring and the funky unsaturated system next to it. (The dichloropyrrole, though, is interestingly reminiscent of these AstraZeneca gyrase/topoisomerase antibiotic candidates, while both celestramycin and pyoluteorin have a different dichloropyrrole in them).

What kind of activity does kibdelomycin have? Well, this is where my enthusiasm cools off just a bit more. It showed up in screening with a profile similar to the coumarin antibiotics novobiocin and chlorobiocin, and sure enough, it's a topoisomerase II inhibitor. It appears to be active almost entirely on gram-positive organisms. And while there are certainly nasty gram-positive infections that have to be dealt with, I'm more encouraged when I see something that hits gram-negatives as well. They've got more complicated defenses, those guys, and they're harder to kill. It's not easy to get broad-spectrum activity when you're going after gyrase/Topo II, but the fluoroquinolones definitely manage it.

The Merck team makes much out of kibdelomycin being "the first truly novel bacterial type II topoisomerase inhibitor with potent antibacterial activity discovered from natural product sources in more than six decades". And they're right that this is an accomplishment. But the kicker in that sentence is "from natural product sources". Getting gram-positive Topo II inhibitors has actually been one of the areas where synthetic compounds have had the most success. Building off the quinolones themselves has been a reasonably fruitful strategy, and a look through the literature turns up a number of other structural classes with this sort of activity (including some pretty wild ones). Not all of these are going places, but there are certainly a number of possibilities out there.

In short, if kibdelomycin weren't an odd-looking natural product, I wonder how much attention another high-molecular-weight gram-positive-only topoisomerase inhibitor would be getting, especially with only in vitro data behind it. Every little bit helps, and having a new structural class to work from is a worthwhile discovery. But one could still want (and hope) for more.

Comments (14) + TrackBacks (0) | Category: Drug Assays | Infectious Diseases | Natural Products

August 22, 2011

DRACOs: New Antivirals Against Pretty Much Everything?

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Posted by Derek

I've been meaning to write about this paper from the RIder group at MIT's Lincoln Labs, which shows some very interesting approaches to killing off a wide variety of viruses. They've dubbed these new agents DRACOs, for Double-stranded RNA Activated Caspase Oligimerizers, which is certainly one of those acronyms with a lot packed into it.

So now to unpacking it. The first key point is the double-stranded RNA (dsRNA) part. For a long time, that was thought to be a form that isn't wasn't found in human cells (as opposed to single-stranded stuff). We now know that short dsRNAs (up to twenty-odd base pairs) are part of human biology, but viruses produce much longer strands of it during their replication process - or, more accurately, they hijack human cellular machinery to produce it. (Viruses, as a rule, don't do anything for themselves that they don't absolutely have to).

Naturally enough, cells have evolved ways to recognized long dsRNAs as a sign of infection - there's a whole list of proteins that recognize these things and bind to them. Some of them inhibit its downstream processing directly, by just hanging on and gumming up the works, while others set off responses further downstream. One of those is apoptosis, programmed cell death, a brutal but effective fall-on-your-sword pathway that gets initiated by all sorts of unfixable cellular problems. (When a cell's internal controls give a "Fatal Error" message, it's taken literally). And naturally enough, viruses have evolved ways to try to evade these defenses, both by targeting the dsRNA detection proteins and by inhibition of apoptosis pathways. (As a side note, it's always been interesting to untangle these counter-counter-countermeasure situations whenever a new cellular pathway relating to infection is worked out. You find, invariably, that hundreds of millions of years of evolutionary pressure have built up crazily elaborate frameworks around all of them).

This approach tries to speed up the dsRNA-means-apoptosis connection. A DRACO turns out to be a good-sized protein with two functions: one end recognizes and binds to dsRNA, and the second contains a signal to induce apotosis. If multiple copies of the DRACO protein stick to the same viral dsRNA strand, that should be enough to initiate cell death and interrupt the viral replication process. The team tried out a whole range of possibilities for both those functional domains, with the best (so far) using either Protein Kinase R (PKR) or RNAaseL domains to recognize viral RNA and an Apaf caspase recruitment domain for apoptosis signaling. Another key modification was the addition of a PTD (protein transduction domain) tag, which allows large proteins like these entry into cells through active transport. (Cells only take in whole proteins through gatekeeping transport mechanisms; otherwise they just sort of bounce off - this effect was confirmed with DRACOs that lacked the PTD tags).

So, basically, this is the sort of protein that you might expect evolution to stumble onto eventually, but now the connecting line has been drawn by hand instead. It's worth noting at this point, though, that this general idea has occurred to others before: here's a paper from Boston University trying the same sort of strategy. That one was published online in 2009, but didn't make it to print until May of this year, which makes you wonder if that's a typical delay for that journal (FASEB J.) or not. It's also worth noting that, for whatever reason, this new MIT paper does not cite the one from BU.

How did they work? Pretty well. The PTD tags did what they were supposed to, taking the proteins into cells rapidly. Once inside, the DRACOs themselves hung around for several days before being degraded, which is another big hurdle. And they did indeed protect against infection by an impressively wide range of viruses in cell culture: rhinovirus, encephalomyelitis, adenoviruses, arenaviruses, bunyaviruses, flaviviruses, reovirus, and flu. A lot of nasty pathogens fall into those bins.

But that's in cell culture, which is a long way from a living organism. To their credit, the team went on to try out their idea in live mice, and they show some encouraging results. Administering their best DRACO candidates to mice and then exposing them to influenza virus took the survival rate (at ten days) from under 10% in the control groups up to 60-70% survival for the PKR version and up to 100% survival for the RNAaseL version.

It's an impressive graph, but there are some things to note about it. For one, the DRACO proteins were administered by injection - these are probably never going to be feasible as oral medications, since they're large proteins which will just get digested. But again to their credit, the MIT group also tested dosing via intranasal injection (yep, squirting the protein solution up the noses of mice, truly the glamorous end of science). That also showed a strong protective effect after influenza virus exposure, which is a good sign.

Now comes the next concern. You might have already wondered about my mention of the injection route, since we already give millions of people a year injections to combat viral infection: flu shots. Those, though, are vaccines meant to last the whole season (and beyond). DRACO proteins get cleared out in mice on a time scale of days; they wouldn't be expected to have any long-range immune effects. (Of course, their broad antiviral effects, versus the sometimes way-too-specific nature of a vaccine, is a strong point in their favor). But this brings up another issue that's going to have to be addressed: when you look at the graphs of the mice experiments, you note that the DRACOs were given either on Day 0 or Day -1 compared to the exposure to virus.

That's actually a big deal in this field. The problem with antiviral therapies has always been that you don't usually know that you've been infected until, well, after you've been infected. Sometimes that lag time is rather long, and it's always long enough for the virus to get a good running start. Symptoms, after all, don't occur until things are well under way. In the real world, the two opportunities for antiviral therapies are (1) something that you can take long before you're even exposed, and that lasts for a long time (like a vaccine) or (2) something that you can take after you've already realized that you're sick (like an antiviral drug). So far, the DRACO proteins fall in between these two, and the next challenge for these agents is to see if they can stretch into one or the other. The authors, no fools, realize this:

Based on these encouraging initial animal trials, future work should be done to test and optimize antiviral efficacy, pharmacokinetics, and absence of toxicity in vitro and in vivo. Future experiments can further characterize and optimize dsRNA binding, apoptosis induction, cellular transduction, and other DRACO properties. More extensive trials are also needed to determine how long after infection DRACOs can be used successfully, or if DRACOs are useful against chronic viral infections without producing unacceptable levels of cell death in vivo.

It's going to be very interesting to see how this field develops. It's a promising start, for sure, but there are still a lot of ways for things not to work out. Just getting this far along in the "promising start" phase is a real accomplishment, though, and more than many people have ever been able to manage.

Comments (15) + TrackBacks (0) | Category: Infectious Diseases

June 27, 2011

The Evolution of Resistance: Are We Doing It Wrong?

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Posted by Derek

Here's a paper in PNAS that says that we're probably treating infectious disease the wrong way - and perhaps cancer as well. The authors go over the currently accepted doctrines: multiple-mechanism therapies, when possible, and restricted use to patients who really need antibiotics. But there's a third assumption that they say is causing trouble:

A third practice thought to be an effective resistant management strategy is the use of drugs to clear all target pathogens from a patient as fast as possible. We hereafter refer to this practice as “radical pathogen cure.” For a wide variety of infectious diseases, recommended drug doses, interdose intervals, and treatment durations (which together constitute “patient treatment regimens”) are designed to achieve complete pathogen elimination as fast as possible. This is often the basis for physicians exhorting their patients to finish a drug course long after they feel better (long-course chemotherapy). Our claim is that aggressive chemotherapy cannot be assumed to be an effective resistance management strategy a priori. This is because radical pathogen cure necessarily confers the strongest possible evolutionary advantage on the very pathogens that cause drugs to fail.

The harder you hit a population of infectious disease organisms, the harder you're selecting for resistance. The key, they say, is that in many cases there's genetic diversity among these organisms even inside single patients. So you can start off with a population of bacteria, say, that could be managed by less aggressive therapy and the patient's own immune system. But then aggressive treatment ends up killing off the great majority of the bacterial population, which you'd think would be a step forward. But what you're left with are the genotypes that are hardest to kill with antibiotics. They were in a minority, and might well have died out under competition from their less-genetically-burdened cohorts. But killing those off gives the resistant organisms an open field to work in.

The other problem here is a public-heath one. You want to cure the individual patient, and you want to keep their disease from spreading, and you want to keep from encouraging resistance among the infectious organisms. Optimizing for all three at once is probably not possible.

The paper goes into detail with the example of malaria, pointing out that it may well be the norm for people to be infected with several different lineages of malaria parasites at the same time. They seem to be in there competing for nutrients and for red blood cells, and some of them appear to be keeping the others in check. Antimalarial drugs alter the cost/benefit ratio (for the parasites) of carrying resistance genes.

So what should we do? The problem is, they say, that there are probably no general rules that can be recommended:

Thus, aggressive chemotherapy is a double-edged sword for resistance management. It can reduce the chances of high-level resistance arising de novo in an infection. But when an infection does contain resistant parasites, either from de novo mutation or acquired by transmission from other hosts, it gives those parasites the greatest possible evolutionary advantage both within individual hosts and in the population as a whole. How do the opposing evolutionary pressures generated by radical cure combine in different circumstances to determine the useful life span of a drug? There will be circumstances when overwhelming chemical force retards evolution and other times when it drives things very rapidly. We contend that for no infectious disease do we have sufficient theory and empiricism to determine which outcome is more important. It seems unlikely that any general rule will apply even for a single disease, let alone across disease systems.

For more on such ideas as applied to bacterial infections, see here and here. But near the end of this paper, the authors apply similar reasoning to cancer. (That analogy has come up around here before, I should note).

An analogous situation also occurs in cancer therapy, where cell lineages within a tumor compete for access to space and nutrients. There, the argument has recently been made that less aggressive chemotherapy might sustain life better than overwhelming drug treatment, which simply removes the competitively more able susceptible cell lineages, allowing drug-resistant lineages to kill the host. Mouse experiments support this: Conventionally treated mice died of drug-resistant tumors, but less aggressively treated mice survived (95).

So maybe too many of us have been thinking about these questions the wrong way. If we switch over to favoring whatever strategy minimizes resistance, both in individual patients and thus across the population, we could be in better shape. . .

Comments (21) + TrackBacks (0) | Category: Cancer | Infectious Diseases

June 7, 2011

Murine Viruses and Chronic Fatigue: Does the Story Continue

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Posted by Derek

Well, one day after writing an obit for the XMRV story comes this abstract from Retrovirology. The authors, from Cornell and SUNY-Buffalo, say that they've detected other murine retrovirus transcripts from CFS patients (but not in most controls), and that these are more similar to those reported in last year's Lo and Alter paper in PNAS than they are to XMRV itself.

So perhaps the story continues, and what a mess it is at this point. I continue to think that the XMRV hypothesis itself is in serious trouble, but murine retroviruses as a class are still worth following up on. This is tough work, though, because of the twin problems of detection and contamination, and it's going to be easy for people to fool themselves.

Meanwhile, Retraction Watch has more on Science's "Expression of Concern" that I wrote about yesterday. It appears that the journal asked the authors to retract the paper (so says the Wall Street Journal, anyway) but that co-author Judy Mikovits turned them down (as might have been expected from her previous stands in this area). Science released their editorial note early because of the WSJ piece.

Comments (15) + TrackBacks (0) | Category: Infectious Diseases | The Scientific Literature

June 6, 2011

XMRV and Chronic Fatigue: Down For More Than the Third Time

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Posted by Derek

I meant to blog on this late last week, but (in case you haven't seen it) the whole putative link between XMRV and chronic fatigue syndrome seems now to be falling apart. If you want to see the whole saga via my blog posts and the links in them, then here you go: October 2009 - January 2010 - February 2010 - July 2010 - January 2011. At that last check-in, the whole thing was looking more like an artifact.

And now Science is out with a paper that strongly suggests that the entire XMRV virus is an artifact. It looks like something that's produced by the combination of two proviruses during passaging of the cells where it was detected, and the paper suggests that other human-positive samples are the result of contamination. Another paper is (again) unable to replicate detection of XMRV in dozens of samples which had previously been reported as positive, and finds some low levels of murine virus sequences in commercial reagents, which also fits with the contamination hypothesis.

With these results in print, Science has attached an "Editorial Expression of Concern" to the original 2009 XMRV/CFS paper, which touched off this whole controversy. My take: while there are still some studies ongoing, at this point it's going to take a really miraculous result to bring this hypothesis back to life. It certainly looks dead from here.

There will be also be some people who ask whether Science did the world a favor by publishing the original paper in the first place. But on balance, I'd rather have things like this get published than not, although in hindsight it's always easy to say that more experiments should have been done. The same applies to the arsenic-bacteria paper, another one of Science's recent bombshells. I'm not believing that one, either, at this point - not until I see a lot more supporting data - but in the end, I'm not sad that it was published, either. I think we're better off erring a bit on the wild-ideas end of the scale than clamping down too hard. That said, you do have to wonder if Science in particular is pushing things a bit too hard, itself. While I think that these ideas deserve a hearing, it doesn't necessarily have to be there.

Comments (18) + TrackBacks (0) | Category: Infectious Diseases | The Scientific Literature

May 13, 2011

Process Chemistry Makes the Headlines

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Posted by Derek

Not a common occurrence, that. But this Wall Street Journal article goes into details on some efforts to improve the synthetic route to Viread (tenofovir) (or, to be more specific, TDF, the prodrug form of it, which is how it's dosed). This is being funded by former president Bill Clinton's health care foundation:

The chasm between the need for the drugs and the available funding has spurred wide-ranging efforts to bring down the cost of antiretrovirals, from persuading drug makers to share patents of antiretrovirals to conducting trials using lower doses of existing drugs.

Beginning in 2005, the Clinton team saw a possible path in the laboratory to lowering the price of the drugs. Mr. Clinton's foundation had brokered discounts on first-line AIDS drugs, many of which were older and used relatively simple chemistry. Newer drugs, with advantages such as fewer side effects, were more complex and costly to make. . .A particularly difficult step in the manufacture of the antiretroviral drug tenofovir comes near the end. The mixture at that point is "like oatmeal, making it very difficult to stir," explained Prof. Fortunak. That slows the next reaction, a problem because the substance that will become the drug is highly unstable and decomposing, sharply lowering the yield.

Fortunak himself is a former Abbott researcher, now at Howard University. One of his students does seem to have improved that step, thinning out the reaction mixture (which was gunking up with triethylammonium salts) and improving the stability of the compound in it. (Here's the publication on this work, which highlights that step, formation of a phosphate ester, which is greatly enhanced with addition of tetrabutylammonium bromide). This review has more on production of TDF and other antiretrovirals.

This is a pure, 100% real-world process chemistry problem, as the readers here who do it for a living will confirm, and it's very nice to see this kind of work get the publicity that it deserves. People who've never synthesized or (especially) manufactured a drug generally don't realize what a tricky business it can be. The chemistry has to work on large scale (above all!), and do so reproducibly, hitting the mark every time using the least hazardous reagents possible, which have to be reliably sourced at reasonable prices. And physically, the route has to avoid extremes of temperature or pressure, with mixtures that can be stirred, pumped from reactor to reactor, filtered, and purified without recourse to the expensive techniques that those of us in the discovery labs use routinely. Oh, and the whole process has to produce the least objectionable waste stream that you can come up with, too, in case you've got all those other factors worked out already. Not an easy problem, in most cases, and I wish that some of those people who think that drug companies don't do any research of their own would come down and see how it's done.

To give you an example of these problems, the paper on this tenofovir work mentions that the phosphate alkylation seems to work best with magnesium t-butoxide, but that the yield varies from batch to batch, depending on the supplier. And in the workup to that reaction, you can lose product in the cake of magnesium salts that have to be filtered out, a problem that needs attention on scale.

According to the article, an Indian generic company is using the Howard route for tenofovir that's being sold in South Africa. (Tenofovir is not under patent protection in India). Interestingly, two of the big generic outfits (Mylan and Cipla) say that they'd already made their own improvements to the process, but the question of why that didn't bring down the price already is not explored. Did the Clinton foundation improve a published Gilead route that someone else had already fixed? Cipla apparently does the same phosphate alkylation (PDF), but the only patent filing of theirs that I can find that addresses tenofovir production is this one, on its crystalline form. Trade secret?

Comments (21) + TrackBacks (0) | Category: Chemical News | Drug Development | Drug Prices | Infectious Diseases

April 15, 2011

Selenium In a Drug Structure: Why Not?

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Posted by Derek

You don't see too many drugs with selenium in them, that's for sure. It's one of those elements that can be used to illustrate the Paracelsian doctrine that the dose makes the poison: selenium is an essential element that's also toxic. There's no doubt at all about either of those properties; it all depends on how much of it you get.

And that's the problem with using the element in a drug molecule - the dose of many pharmaceuticals would then exceed the safe amount of selenium that a person could take in. That's especially true for whopping-dose areas like antibiotics (Home of the Horse Pill reads the sign over the door). So it's especially interesting to see that Achillion has spent some time and effort developing just that: a new antibiotic candidate whose essential feature is a selenium substitution.

No, they're not idiots. In fact, I have to salute them for having the nerve to go down this path. The key here is that the selenium in tied up in a heterocycle, a selenophene (analogous to thiophene, and not a heterocycle that very many chemists will have seen.) This keeps the element from being bioavailable, as is apparently the case with the even stranger heterocycle ebselen.
selenophene%2Cjpg.jpg
And going from a thiophene to a selenophene is not a neutral switch - in this case, it seems to have been quite helpful. The structures are in a family of topoisomerase/gyrase inhibitors that have shown a lot of promise, but have dropped out of development due to potential cardiac side effects. It's the dreaded hERG channel again, which has sunk many a development program. Binding to that ion channel can lead to long QT syndrome in some patients, and you really don't want that risk. (Neither do the regulatory agencies, which require testing of any new drug candidate for just this reason).

Switching to selenophene gave the cleanest hERG profile for Achillion's entire series of compounds, while still retaining antibacterial activity. So these selenium heterocycles are, for the adventurous, probably worth a look - they can be similar to thiophene in some situations, and not so similar in others. People are going to look at you funny if you make them, but you should never let that slow you down.

Comments (30) + TrackBacks (0) | Category: Infectious Diseases | Odd Elements in Drugs

March 16, 2011

Pfizer Moves Antibacterials to Shanghai

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Posted by Derek

So Pfizer has announced that their antibacterial research is moving to the Shanghai site. Is this the first example of a large/traditional therapeutic area moving to China? And if it is, should we care? After all, there are Swiss, German, British, and Japanese companies, among others, with multinational research sites. Some programs run at one facility, and some at another. When you add China to that list, though, something happens for a lot of people.

That's because the Chinese sites got their start as the inexpensive way to offshore work, for one thing. But Shanghai's not as cheap as it used to be - it's still less expensive than doing the work in the US or western Europe, but the cost advantage is eroding. Another factor is that you don't see companies expanding into new therapeutic areas these days, so much as moving the existing ones around. In that zero-sum game, expanding one site means contracting another.

Here's something to think about, though: does Pfizer's choice here represent a calculation about some future opportunity in China, should they be able to develop any drugs? Would the "discovered and developed in Shanghai" factor help with the regulatory authorities there?

Comments (37) + TrackBacks (0) | Category: Business and Markets | Infectious Diseases

January 11, 2011

XMRV: It's Ugly, But That's Science

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Posted by Derek

How's the XMRV / chronic fatigue syndrome connection holding up? Not real well. Science has a roundup of the latest news in the area, and none of it looks encouraging. There are four studies that have come out in the journal Retrovirology that strongly suggest that earlier positive test results for the virus in CFS samples are just artifacts.

For one thing, when you look closely, it turns out that the sequences from cell-cultured XMRV samples are quite a bit more diverse than the ones taken from widely separated patients at different times. And that's just not right for an infectious agent; it's the opposite of what you should see. A number of supposedly XMRV-specific primers that have been used in such assays also appear to amplify other murine viral sequences as well, and samples that show positive for XMRV also appear to have some mouse DNA in them. Finally, there's reason to believe that some common sources of PCR reagents may have murine viral contaminants that blow up this particular assay.

Taken together, these latest results really have to make you cautious in assigning any role at all to XMRV based on the published data. You can't be sure that any of the numbers are what they're supposed to be, and the most parsimonious explanation is that the whole thing has been a mistake. To illustrate the state of things, you may remember an effort to have several labs (on both sides of the issue) test the same set of samples. Well, according to Science. . .

Some had hoped that a project in which several U.S. labs are testing for XMRV in the same samples would clear up the picture. But so far this effort has been inconclusive. Four CFS patients' blood initially tested positive for XMRV at WPI and the U.S. Centers for Disease Control and Prevention but not at an NCI lab. When all three labs tested new samples from the same patients, none found XMRV—for reasons that aren't yet clear, says Coffin. The group now plans to test blood from several dozen CFS patients and controls.

No, this isn't looking good at all. It's pretty typical, though, of how things are out at the frontiers in this business. There are always more variables than you think, and more reasons to be wrong than you've counted. A theory doesn't hold up until everyone who wants to has had a chance to take some big piñata-shattering swings at it, with weapons of their choice. So, to people outside of research: you're not seeing evidence of bad faith, conspiracy, or stupidity here. You're seeing exactly how science gets done. It isn't pretty, but it gets results in the end. Circumspice.

Comments (70) + TrackBacks (0) | Category: Analytical Chemistry | Infectious Diseases

December 15, 2010

Chiral What? Chiral How?

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Posted by Derek

Thanks to an email from a reader, I can bring you this very weird paper from Tetrahedron. The authors claim to have extracted a local plant and isolated nevirapine, (sold as Viramune by Boehringer Ingleheim as a reverse transcriptase inhibitor for HIV).
nevirapine.png
That's kind of odd. I'm no natural products expert, but I've sure seen a lot of them over the years, and that framework (and the N-cyclopropyl) don't look so likely to me. But hey, plants do odd things. That's not what's really puzzling about this paper. No, what's had me staring at it this morning is the claim that, in contrast to the marketed drug, this stuff is optically active nevirapine.

Say what? Try as I might, I can't see any plausible way that that's a chiral compound. The authors seem to think it is, though. They claim optical rotation, somehow, and then say that "The detailed structure and stereochemistry of compound 1 was established unambiguously by single crystal X-ray crystallography." But hold on - that's not as easy as it sounds. Getting absolute configurations from the X-ray data of light-atom-only molecules takes special efforts, and I don't see any being taken (molybdenum X-rays, direct methods, no talk of anomalous dispersion, etc.)

I'm just not willing to see that nitrogen atom as a source of chirality - if it were, shouldn't that be the focus of this whole paper? Instead, the authors just blithely tell us how neat it is that they've isolated the chiral material. In fact, they find it so neat that they tell us two times in a row:

This is a very interesting discovery that naturally occurring optically active nevirapine has been biosynthesized in the seeds of C.viscosa and the optically inactive nevirapine was designed as a selective non-nucleoside inhibitor of HIV-1 reverse transcriptase. It is also a remarkable finding that the seed of C.viscosa is the source of optically active nevirapine, which was also designed and synthesized before its isolation from natural source.

This sounds like some sort of lunatic patent-busting exercise, to be honest. And it sounds as if someone doesn't know what a chiral compound is. And that whoever reviewed this for Tetrahedron was incompetent. And that the editor who let it through should be a least a little bit ashamed. Well?

Comments (73) + TrackBacks (0) | Category: Infectious Diseases | Natural Products | The Scientific Literature

December 2, 2010

HIV Therapies: A Thank-You

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Posted by Derek

A rare op-ed note of appreciation for the drug industry: who would have predicted, 20 years ago, that the viral disease for which we have the widest range of effective therapies would be HIV?

Comments (20) + TrackBacks (0) | Category: Infectious Diseases

November 3, 2010

TRIM21: A Cure For the Common Cold? Maybe Not. . .

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Posted by Derek

This article is getting the "cure for the common cold" push in a number of newspaper headlines and blog posts. I'm always alert for those, because, as a medicinal chemist, I can tell you that finding a c-for-the-c-c is actually very hard. So how does this one look?

I'd say that this falls into the "interesting discovery, confused reporting" category, which is a broad one. The Cambridge team whose work is getting all the press has actually found something that's very much worth knowing: that antibodies actually work inside human cells. Turns out that when antibody-tagged viral particles are taken up into cells, they mark the viruses for destruction in the proteosome, an organelle that's been accurately compared to an industrial crushing machine at a recycling center. No one knew this up until now - the thought had been that once a virus succeeds in entering the cell, that the game was pretty much up. But now we know that there is a last line of defense.

Some of the press coverage makes it sound as if this is some new process, a trick that cells have now been taught to perform. But the point is that they've been doing it all along (at least to nonenveloped viruses with antibodies on them), and that we've just now caught on. Unfortunately, that means that all our viral epidemics take place in the face of this mechanism (although they'd presumably be even worse without it). So where does this "cure for the common cold" stuff come in?

That looks like confusion over the mechanism to me. Let's go to the real paper, which is open-access in PNAS. The key protein in this process has been identified as tripartite-motif 21 (TRIM21), which recognized immunoglobin G and binds (extremely tightly, sub-nanomolar) to antibodies. This same group identified this protein a few years ago, and found that it's highly conserved across many species, and binds an antibody region that never changes - strong clues that it's up to something important.

Another region of TRIM21 suggested what that might be. It has a domain that's associated with ubiquitin ligase activity, and tagging something inside the cell with ubiquitin is like slapping a waste-disposal tag on it. Ubiquinated proteins tend to either get consumed where they stand or dragged off to the proteosome. And sure enough, a compound that's known to inhibit the action of the proteosome also wiped out the TRIM21-based activity. A number of other tests (for levels of ubiquitination, localization within the cell, and so on) all point in the same direction, so this looks pretty solid.

But how do you turn this into a therapy, then? The newspaper articles have suggested it as a nasal spray, which raises some interesting questions. (Giving it orally is a nonstarter, I'd think: with rare exceptions, we tend to just digest every protein that gets into the gut, so all a TRIM21 pill would do is provide you with a tiny (and expensive) protein supplement). Remember, this is an intracellular mechanism; there's presumably not much of a role for TRIM21 outside the cell. Would a virus/antibody/TRIM21 complex even get inside the cell to be degraded? On the other hand, if that kept the virus from even entering the cell, that would be an effective therapy all its own, albeit through a different mechanism than ever intended.

But hold on: there must be some reason why this mechanism doesn't always work perfectly - otherwise, no nonenveloped virus would have much of a chance. My guess is that the TRIM21 pathway is pretty efficient, but that enough viral particles miss getting labeled by antibodies to keep it from always triggering. If that's true, then TRIM21 isn't the limiting factor here - it's antibody response. If that's true, then it could be tough to rev up this pathway.

Still, these are early days. I'm very happy to see this work, because it shows us (again) how much we don't know about some very important cellular processes. Until this week, no one ever realized that there was such a thing as an intracellular antibody response. What else don't we know?

Comments (12) + TrackBacks (0) | Category: Biological News | Infectious Diseases

August 24, 2010

XMRV? Or Umpteen Other Viruses? Or What?

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Posted by Derek

The long-delayed PNAS paper on the chronic fatigue/XMRV results has finally come out. It's not going to stop the arguing.

From what I can see, this team didn't find "canonical" XMRV in the samples from CFS patients. But what they did find was a whole slew of similar-looking traces of murine leukemia viruses (MLVs). (The samples do not appear to have been contaminated, which is the first thing you'd wonder about).

So now we're back to more head-scratching. Is XMRV a culprit at all, or is it some other related MLV? Or is it, instead, several of them at the same time? How many people without symptoms show the same MLV signs anyway? And so on. It's clear that this story is nowhere near over. It's only barely starting. . .

Here's the PNAS commentary on the article, which adds some clarity. But no one's got enough clarity on hand for this subject yet.

Comments (13) + TrackBacks (0) | Category: Infectious Diseases

August 3, 2010

Know How to Make Praziquantel? Tell The World.

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Posted by Derek

One of the people I met this past weekend was Matt Todd, chemistry professor at the University of Sydney. We talked about a project his lab is working on, and I wanted to help call attention to it.

They're working on praziquantel, also known as PZQ or Biltricide, which is used to cure schistosomiasis in the tropics. It's on the WHO's list of essential medicines for this reason. But PZQ is used now as a racemate, and this is one of those cases where everyone would be better off with a single enantiomer - not least, because the active enantiomer is significantly easier for patients to stand than the racemic mixture. Problem is, there's no cheap enantioselective synthesis or resolution.

So what Todd's group has done is crowdsourced the problem. Here's the page to start with, where they lay out the current synthetic difficulties - right now, those include enantioselective Pictet-Spengler catalysts and help with the resolution of a key intermediate. They were in need of chiral HPLC conditions, but that problem has recently been solved. I'd like to ask the chemists in the crowd here to take a look, because it wouldn't surprise me if one of us had some ideas that could help. Don't leave your suggestions here, though; do it over at their pages so it's all in one place.

This sort of thing is an excellent fit with open-source models for doing science: it's all pro bono, and the more eyes that take a look at the situation, the better the chance that a solution will emerge. I don't think it's getting the publicity it deserves. And no, in case anyone's wondering, I don't think that this is how we're all going to end up discovering drugs. Figuring out how to do this for large commercial projects tends to bring on frantic hand-waving. But in cases like this - specific problems where there's no chance for profit to push things along - I think it can work well. It makes a lot more sense than that stuff I was linking to last week!

Comments (22) + TrackBacks (0) | Category: Business and Markets | Chemical News | General Scientific News | Infectious Diseases

July 7, 2010

XMRV and Chronic Fatigue: You Thought You Were Confused Before

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Posted by Derek

Time to revisit the chronic fatigue/XMRV controversy, because it's become even crazier. To catch up, there was a 2009 report in Science that this little-known virus correlated strongly with patients showing the clinical syndrome. Criticism was immediate, with several technical comments and rebuttals coming out in the journal. Then researchers from the UK and Holland strongly challenged the original paper's data and said that they could not reproduce anything like it.

Recently I (and a lot of other people who write about science) received an e-mail claiming that a paper was about to come out from a group at the NIH that confirmed the first report. I let that one go by, since I thought I'd wait for, you know, the actual paper (for one thing, that would let me be sure that there really was one). Now Science reports that yes, there is such a manuscript. But. . .

Science has learned that a paper describing the new findings, already accepted by the Proceedings of the National Academy of Sciences (PNAS), has been put on hold because it directly contradicts another as-yet-unpublished study by a third government agency, the U.S. Centers for Disease Control and Prevention (CDC). That paper, a retrovirus scientist says, has been submitted to Retrovirology and is also on hold; it fails to find a link between the xenotropic murine leukemia virus-related virus (XMRV) and CFS. The contradiction has caused "nervousness" both at PNAS and among senior officials within the Department of Health and Human Services, of which all three agencies are part, says one scientist with inside knowledge.

I'll bet it has! It looks like the positive findings are from Harvey Alter at NIH, and the negative ones are from William Switzer at the CDC. Having two separate government labs blatantly contradict each other - simultaneously, yet - is what everyone seems to be trying to avoid. Sounds to me like each lab is going to have to try the other's protocols before this one gets ironed out. I wouldn't be expecting either paper to appear any time soon, if that's the case.

Update: Well, as it turns out, the Retrovirology paper has been published - so what's holding up PNAS? Might as well get them both out so everyone can compare. . .

Comments (36) + TrackBacks (0) | Category: Biological News | Infectious Diseases

May 10, 2010

Unlovely Polyphenols

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Posted by Derek

Here's a new paper from the folks at the Burnham Institute and UCSD on a new target for vaccinia virus. They're going after a virulence factor (N1L) through computational screening, which is a challenge, since this is a protein-protein interaction.

They pulled out a number of structures, which have some modest activity in cell infection assays. In addition, they showed through calorimetry that the compounds do appear to be affecting the target protein, specifically its equilibrium between monomeric and oligomeric forms. But the structures of their best hits. . .well, here's the table. You can ignore compounds 6 and 8; they show up as cytotoxic. But the whole list is pretty ghastly, at least to my eyes.

These sorts of highly aromatic polyphenol structures have two long traditions in medicinal chemistry: showing activity in assays, for the first part, and not being realizable as actual drugs, for the second. There's no doubt that they can do a lot of things; it's just that getting them to do them in a real-world situation is not trivial. Part of the problem is specificity (and associated toxicity) and part of it is pharmacokinetics. As you'd imagine, these compounds can have rather funky clearance behavior, what with all those phenols.

So I'd regard these as proof-of-concept compounds that validate N1L as a target. I think that we'll need to wait for someone to format up an assay for high-throughput (non-virtual) screening to see if something more tractable comes up. Either that, or rework the virtual screens on the basis that we've seen enough polyphenols come up on this target already. . .

Note: readers of the paper will note that our old friend resveratrol turns up as an active compound as well. It's very much in the polyphenol tradition; make of that what you will.

Comments (25) + TrackBacks (0) | Category: In Silico | Infectious Diseases | Pharmacokinetics

April 30, 2010

Rosetta@Home

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Posted by Derek

Many readers will have heard of Rosetta@Home. It's a distributed-computing approach to protein folding problems, which is certainly an area that can absorb all the floating-point operations you can throw at it. It's run from David Baker's lab at the University of Washington, and has users all over the world contributing.

A reader sends along news that recently the project seems to have come across a good hit in one of their areas, proteins designed to bind to the surface of influenza viruses. It looks like they have one with tight binding to an area of the virus associated with cell entry, so the next step will be to see if this actually prevents viral infection in a cell assay.

At that point, though, I have to step in as a medicinal chemist and ask what the next step after that could be. It won't be easy to turn that into any sort of therapy, as Prof. Baker makes clear himself:

Being able to rapidly design proteins which bind to and neutralize viruses and other pathogens would definitely be a significant step towards being able to control future epidemics. However, in itself it is not a complete solution because there is a problem in making enough of the designed proteins to give to people--each person would need a lot of protein and there are lots of people!

We are also working on designing new vaccines, but the flu virus binder is not a vaccine, it is a virus blocker. Vaccines work by mimicking the virus so your body makes antibodies in advance that can then neutralize the virus if you get infected later. the designed protein, if you had enough of it, should block the flu virus from getting into your cells after you had been exposed; a vaccine cannot do this.

One additional problem is that the designed protein may elicit an antibody response from people who are treated with it. in this case, it could be a one time treatment but not used chronically.

The immune response is definitely a concern, but that phrase "If you had enough of it" is probably the big sticking point. Most proteins don't fare so well when dosed systemically, and infectious disease therapies are notorious for needing whopping blood levels to be effective. At the same time, there's Fuzeon (enfuvirtide), a good-sized peptide drug (26 amino acids) against HIV cell entry. It was no picnic to develop, and its manufacturing was such an undertaking that it may have changed the whole industry, but it is out there.

My guess is that Rosetta@Home is more likely to make a contribution to our knowledge of protein folding, which could be broadly useful. More specifically, I'd think that vaccine design would be a more specific place that the project could come up with something of clinical interest. These sorts of proteins, though, probably have the lowest probability of success. The best I can see coming out of them is more insight into protein-protein interfaces - which is not trivial, for sure, but it's not the next thing to an active drug, either.

Comments (9) + TrackBacks (0) | Category: Biological News | Drug Development | Infectious Diseases

April 16, 2010

A Landmark In Clinical Trial Data Interpretation

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Posted by Derek

You know, let's just declare this "Sketchy Biotech Day" around here. A reader sends along this intriguing news item from Maryland regarding Rexahn Pharmaceuticals. They recently reported clinical data on their lead compound, Serdaxin,:

On Tuesday, the Rockville company reported the drug performed well in a phase 2a clinical trial for treating patients with one such ailment: major depressive disorder. But the announcement also said "the overall study did not achieve statistical significance," worrying investors and sending Rexahn's stock price tumbling from $3.53 to $1.76 that day.

Wednesday morning, executives felt compelled to issue a follow-up statement, offering "additional commentary, clarifications and insights" to allay investors' concerns. That apparently did the trick — at least somewhat. By the end of trading on Wednesday, the price had rebounded to $2.15. By Thursday morning, shares had climbed to $2.51; they were trading at $2.47 Thursday afternoon.

In its initial statement, Rexahn said that results from the trial, which enrolled 77 patients at several sites in the U.S., "are compelling and warrant further study in a larger phase 2 trial."

Well, to me, "compelling" clinical trial numbers are a hard thing to sell without the statistics to back them up. But that's not slowing these folks down. Here I offer you what is perhaps the most breathtaking rationalization I have yet heard about drug development - and mind you, that is saying a lot. Says Rexahn's CEO:

"Based on the feedback and reaction from our shareholders, stakeholders and other market participants, it is clear that neither the purpose of the Serdaxin trial or its results were well understood.

"The purpose of the Serdaxin Phase IIa trial was to establish, as a proof of concept, that Serdaxin can work as an antidepressant drug for patients suffering from Major Depressive Disorder," Ahn said. "I am happy to say that this is exactly what the study accomplished. The trial results unambiguously reach the conclusion that patients, especially those suffering from severe depression, respond positively to Serdaxin.

"Some market participants have asked us why our overall trial results were not statistically significant," he said. "The answer is simply that the Serdaxin study was never designed to achieve statistical significance as a primary objective, but rather to establish a positive signal among treated patients. This is exactly what the trial succeeded in accomplishing."

So here you have it: a clinical trial that was, apparently, not designed to show statistical significance. And it didn't! Champagne for everyone! Think of how many other drugs have had results just this compelling, but we've all just been too stupid to realize what we had. Throw open the pharma mausoleums and let the dead compounds come forth!

Perhaps some day we'll all look back on this event as the Day the Drug Industry Changed Forever. Or perhaps it's time to ask just what Serdaxin is. . .well, you'll never guess. It's clavulanic acid. (See, I told you that you wouldn't get it). Yep, the beta-lactamase inhibitor that's given as part of Augmentin, to overcome resistant strains of bacteria. Weirdly, it does seem to penetrate the blood-brain barrier, which is not something I would have guessed. And the Rexahn people have done some animal studies that suggest it has anxiolytic effects (as well as effects on sexual arousal, which they're not ignoring: that, friends, is the drug development candidate Zoraxel on their web site. Still clavulanic acid, though, but a rose by any other name. . .).

But none of that means a thing unless you achieve results in humans. And though I hate to contradict such a visionary mind as Dr. Ahn's, I'm afraid I'm going to have to hold out for statistical significance. And wonder, in the meantime, if any of the zillions of people who've taken clavulanate before ever noticed any elevation in their mood. Never happened to me, that's for sure. . .

Comments (53) + TrackBacks (0) | Category: Clinical Trials | Drug Development | Infectious Diseases | The Central Nervous System

April 9, 2010

Dundee's NMT Inhibitors for Sleeping Sickness: An Update

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Posted by Derek

I've had some follow-up with the people at Dundee who reported those compounds for sleeping sickness recently. As mentioned, one of the key points in making these a viable therapy will be brain penetration, since trypanosomes in the central nervous system are a hallmark of the most serious phase of the disease.

The group has a patent application out (WO2010026365), and you can see from it that they've been addressing this problem. Their Table 5 has blood and brain concentrations after dosing in mice, and there's a compound on it (DDD73490) with a brain/blood ratio of 6. That one, as the med-chem audience will have no trouble believing, has an N-methyl on the sulfonamide - getting NH sulfonamides into the brain is often a losing battle. And there are a number of other compounds on the list with fluorinated N-alkyl groups on the sulfonamide, which suggests that the plain N-methyl solved one problem but created another. The tables in the patent also suggest some other therapeutic areas that these NMT inhibitors could be used in, and I'm sure that these are being investigated as we speak.

Stephen Brand at Dundee tells me that they're definitely in the market for something else that can provide the "cis kink" that the sulfonamide gives their structures, so if anyone has any ideas, please feel free to suggest them. My thoughts turn to seeing if a fragment-based approach might work here - perhaps there's a ligand-efficient piece to these compounds that could be used as a new starting point to build out to something with a lower molecular weight and better properties?

Antitrypanosome compounds are never going to make anyone rich, but if they work out, they could relieve a tremendous amount of pain and suffering in the tropics. They're being developed in partnership with the Drugs for Neglected Diseases Initiative, and the group is also looking into partnering opportunities to go after Chagas Disease. That'll be harder, but well worth a look.

Comments (14) + TrackBacks (0) | Category: Infectious Diseases

April 1, 2010

Good News Versus Sleeping Sickness

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Posted by Derek

Nature has a very encouraging paper out today on some potential treatments for trypanosomiasis (sleeping sickness). The mechanism is protein N-myristoylation (catalyzed by an enzyme abbreviated as NMT) which is a process that's important for membrane targeting and trafficking. NMT has been shown to be essential for trypanosome survival by siRNA experiments, so it's a pretty well-validated target.

And now there's some chemical evidence for that idea. This groups screened a compound library, found some micromolar-level hits, and optimized these through good old-fashioned medicinal chemistry down to nanomolar-level compounds. The compounds aren't that bad - they're all pyrazole sulfonamides, a bit bulky and aromatic, but everyone who's done med-chem has seen a lot uglier compounds than these. Here's an X-ray structure of the lead bound to the target enzyme.

And more to the point, that lead compound actually works. In two models of sleeping sickness infection in rats, it cured every single animal in the test group. There's a lot of evidence presented that the compound is working on-target; it certainly convinces me. It's also good news that it doesn't seem to be showing toxicity, because human cells use NMT of their own. All in all, this compound is an excellent start, and may well be a drug candidate all by itself.

But if it is, it's only going to be useful in the earlier stages of the infection. The nastiest part of the disease is when the parasites make it into the central nervous system, but these compounds don't seem to penetrate into the brain. The paper mentions that further optimization is underway to try to address this, and I wish them good luck, and quickly. And I hope that this report stimulates other people to look through their own compound collections for NMT inhibitors that might do the same thing.

Comments (22) + TrackBacks (0) | Category: Infectious Diseases

March 5, 2010

Your Own Personal Bacteria

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Posted by Derek

There's a report in Nature on the bacteria found in the human gut that's getting a lot of press today (especially for a paper about, well, bacteria in the human gut). A team at the Beijing Genomics Institute, with many collaborators, has done a large shotgun sequencing effort on gut flora and identified perhaps one thousand different species.

I can well believe it. The book I recommended the other day on bacteria field marks has something to say about that, pointing out that if you're just counting cells, that the cells of our body are far outnumbered by the bacteria we're carrying with us. Of course, the bacteria have an advantage, being a thousand times smaller (or more) than our eukaryotic cells, but there's no doubt that we're never alone. In case you're wondering, the average European subject of the study probably carries between 150 and 200 different types of bacteria, so there's quite a bit of person-to-person variability. Still, a few species (mostly Bacteroides varieties) were common to all 124 patients in the study, while the poster child for gut bacteria (E. coli) is only about halfway down the list of the 75 most common organisms. We have some Archaea, too, but they're outnumbered about 100 to 1.

What's getting all the press is that idea that particular mixtures of intestinal bacteria might be contributing to obesity, cancer, Crohn's disease and other conditions. This isn't a new idea, although the new study does provide more data to shore it up (which was its whole purpose, I should add). It's very plausible, too: we already know of an association between Helicobacter and stomach cancer, and it would be surprising indeed if gut bacteria weren't involved with conditions like irritable bowel syndrome or Crohn's. This paper confirms earlier work that such patients do indeed have distinctive microbiota, although it certainly doesn't solve the cause-or-effect tangle that such results always generate.

The connection with obesity is perhaps more of a stretch. You can't argue with thermodynamics. Clearly, people are obese because they're taking in a lot more calories than they're using up, and doing that over a long period. So what do bacteria have to do with that? The only thing I can think of is perhaps setting off inappropriate food cravings. We're going to have to be careful with that cause and effect question here, too.

One problem I have with this work, though, is the attitude of the lead author on the paper, Wang Jun. In an interview with Reuters, he makes a very common mistake for an academic: assuming that drug discovery and treatment is the easy part. After all, the tough work of discovery has been done, right?

"If you just tackle these bacteria, it is easier than treating the human body itself. If you find that a certain bug is responsible for a certain disease and you kill it, then you kill the disease," Wang said

For someone who's just helped sequence a thousand of them, Wang doesn't have much respect for bacteria. But those of us who've tried to discover drugs against them know better. Where are these antibiotics that kill single species of bacteria? No such thing exists, to my knowledge. To be sure, we mostly haven't looked, since the need is for various broader-spectrum agents, but it's hard to imagine finding a compound that would kill off one Clostridium species out of a bunch. And anyway, bacteria are tough. Even killing them off wholesale in a human patient can be very difficult.

Even if we magically could do such things, there's the other problem that we have no idea of which bacterial strains we'd want to adjust up or down. The Nature paper itself is pretty good on this topic, emphasizing that we really don't know what a lot of these bacteria are doing inside us and how they fit into what is clearly a very complex and variable ecosystem. A look at the genes present in the samples shows the usual common pathways, then a list that seem to be useful for survival in the gut (adhesion proteins, specific nutrient uptake), and then a massive long tail of genes that do we know not what nor why. Not only do we not know what's happening on other planets, or at the bottom of our own oceans, we don't even know what's going on in our own large intestines. It's humbling.

Dr. Wang surely realizes this; I just wish he'd sound as if he does.

Comments (25) + TrackBacks (0) | Category: Biological News | Diabetes and Obesity | Infectious Diseases

February 26, 2010

A Friday Book Recommendation

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Posted by Derek

This isn't exactly med-chem, but its focus probably overlaps with the interests of a number of readers around here. I recently came across a copy of A Field Guide to Bacteria and enjoyed it very much. I don't think there's another book quite like it available: it describes where you're likely to find different varieties of bacteria (from hot springs to your fridge), how they behave in a natural environment (as opposed to a culture dish) and how to identify them by field marks, if possible. It's not written for microbiologists, but it can provide a different perspective even if you work in the field (since many people that do focus on pathogens - really a very small subset of bacteria, when you get down to it).

I'm already inspired to set up some Winogradsky columns with my kids, perhaps with some unusual chemical additives to see what happens. If we discover anything, I'll report back. . .

Comments (11) + TrackBacks (0) | Category: Book Recommendations | General Scientific News | Infectious Diseases

February 16, 2010

XMRV and Chronic Fatigue Syndrome: More Negative Data

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Posted by Derek

Update: fixed formatting problems with the post. Not sure what happened!

The wrangling over this issue has been fierce, and now it's even more so. Here's another paper from the UK, just coming out today, that has found no association between patients diagnosed with Chronic Fatigue Syndrome and xenotropic murine leukaemia virus-related virus. The bottom line:

In summary, we have studied 299 DNA samples and 565 serum samples for evidence of XMRV infection. We have not identified XMRV DNA in any samples by PCR, however, some serum samples were able to neutralise XMRV reactivity in our assay. Only one of these positive sera came from a CFS patient, implying that there is no association between XMRV infection and CFS.

I have, as they say, no dog in this fight, so I'm going to sit back while things get sorted out. But something clearly needs to get sorted, because there are claims in this area that seem to be completely irreconcilable.

Comments (11) + TrackBacks (0) | Category: Infectious Diseases

February 2, 2010

A Pile of Malaria Leads For the Taking

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Posted by Derek

I kept meaning to write last week about GlaxoSmithKline's decision to open up a database of possible lead compounds against malaria. These were hits from a larger screen that the company ran, and been made unusually public. (Here's the press release as a PDF). There are about 13,500 structures, apparently. The company is to be commended for doing this, naturally, but I wish that the press coverage would emphasize a few things that it hasn't so far.

For one, these are not antimalarial compounds, at least not to a medicinal chemist. Some of them might be, but for now, they're all potential antimalarials, with a long, long way to go. This is all in what most drug discovery organizations call the "hit to lead" stage. Some of these compounds may well be screening artifacts. Others will turn out to work through mechanisms that won't be useful - they'll kill malaria parasites, but they'll kill lots of other things, too. Some of them will hit other targets that aren't quite as severe, but will still be enough to make them undesirabel. And many others will be too weak to be useful as they are, and turn out, after investigation, to have no clear path forward to making them more potent. And so on.

The most interesting compounds still have a long road ahead. What are their blood levels after various sorts of dosing? Which of those dosage forms are the best - the most reliable, the easiest to make, the most stable on storage? What metabolites do the compounds form in vivo, and what do those do? What long-term toxic effects might they have? How susceptible are they to resistance on the part of the parasites? On top of all these questions are the big ones, about how well these potential drugs knock down malaria under real-world conditions.

This, in short, is what drug development is all about, and it would be good to see some of this brought out in the press coverage. This is what I (and many of the readers of this site) do for a living, and it's enough to occupy all our time with plenty left over. If you can do this sort of thing, you're a drug company, and I'm always looking for opportunities to tell people just what it is that drug companies do and to move people past the evil-pharma versus saintly-university mindset. Nature has it right in their editorial:

Meanwhile, universities and other academic institutions should do more to support and reward the sort of translational research required to develop drug leads such as those offered by GSK — even though that work usually does not result in high-profile, breakthrough research papers. In addition, such translational activities provide a means for universities to contribute to public–private partnerships such as the MMV, the Drugs for Neglected Diseases Initiative and the Institute for OneWorld Health.

Universities also have another part to play. Their often aggressive intellectual-property policies can stymie research and development in neglected diseases — they should ensure that their licensing deals with companies make exceptions for royalty-free use of technologies for good causes. That change, too, is beginning to happen — although, when it comes to hogging intellectual property, academics and their institutions are often among the worst offenders. . .

Comments (16) + TrackBacks (0) | Category: Academia (vs. Industry) | Infectious Diseases

January 13, 2010

Two Doses of Crazy

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Posted by Derek

I'd like to take the time this morning to deal with two conspiracy theorists, and I'll take them in order of increasing foil-hat thickness. First up is Joe Collier, an emeritus professor who writes a blog for the British Medical Journal. He notes the recent study that suggested that cell phone emissions could have a beneficial effect in rodent models of Alzheimer's. I didn't give that any play on this blog - too many other things going on, and I don't find any rodent models of Alzheimer's particularly trustworthy to start with. But the study also showed (apparently beneficial) effects on normal rodents, and is certainly worth following up on.

But Collier takes this result and runs with it:

So what happens next? Faced with the prospect, albeit remote, of losing a lucrative market, I predict that the industry will want to quash the electromagnetic treatment theory as soon as possible. To this end, I would expect that the industry propaganda machine will go into overdrive in an attempt to undermine the credibility and findings of Arendash, and to overwhelm the decision makers (ultimately the funders) so that the use of drugs is maintained. The power of industry as an information generator and distributor is unmatched, and industry will use all its persuasive skills. . .

And so on, and so on. The problem (well, one problem) with this line of reasoning is that it could also be extended to other new drugs for Alzheimer's. If the industry wanted to keep selling the existing Alzheimer's drugs at all cost, why would we go to the trouble of trying to develop better ones? We are, you know - I have no idea how much money has vanished down that particular pipe, but it sure has been a lot, and I've helped flush some of it through myself. But we're not the monolithic "drug industry" over here. We're a bunch of companies climbing all over each other trying to make money, take each others' market share, and get to the clinic faster than the other guys down the road. That's what keeps things moving - everyone who's done industrial drug discovery has read a new press release or seen a new patent filing and heard the footsteps coming up from behind.

So I have a counterprediction for Collier. The South Florida study will, in fact, be followed up on. It's interesting enough. And if there's something to it, someone will find a way to optimize the effect and make money off it. And the drug industry will not mobilize to squash it, either - honestly, we have enough to do trying to get our own stuff to work. I haven't seen a single statement from a drug company about this study so far myself, and if Joe Collier has, I'd invite him to produce it.

Next! OK, now we move on to something that seems to be getting some more headlines in the past week or two, and that people have been e-mailing me about. One Wolfgang Wodarg, a German doctor and SPD politician, has been telling everyone that the handling of the H1N1 flu epidemic should be investigated because, he says, it's all a "fake pandemic" whipped up by the drug companies. (You can get all the Wodarg you need, and more, at his web site). Stories in the more excitable press make him sound like the head of all the health agencies of Europe, but people are confusing the Council of Europe (where Wodarg heads a subcommittee) with the EU, among other things they're mixing up.

The World Health Organization is now fielding questions about whether they oversold the epidemic, but it's a sure bet that (if it taken off more drastically) they'd be fielding even more about why they weren't prepared for it. At any rate, if you think that the Monolithic Drug Industry can simultaneously push around the WHO, the CDC, and the public health agencies of every other country in the world, I invite you to think again. If we could do all that, we'd at least be in good enough financial shape that we wouldn't be laying thousands of people off and doing ridiculous mergers out of desperation.

Wodarg, for his part, seems to have been sounding all kinds of alarms for a long time now. Back in the fall, he was telling everyone that the vaccine was going to give them cancer, for example. In case anyone's wondering, I treat his suggestions with the contempt that they appear to richly deserve.

Comments (34) + TrackBacks (0) | Category: Alzheimer's Disease | Infectious Diseases | Snake Oil | Why Everyone Loves Us

January 7, 2010

Is XMRV the Cause of Chronic Fatigue Syndrome? Or Anything?

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Posted by Derek

Last fall it was reported that a large proportion of patients suffering from chronic fatigue syndrome also showed positive for a little-understood retrovirus (XMRV). This created a lot of understandable excitement for sufferers of a conditions that (although often ill-defined) seems to have some puzzling biology buried in it somewhere.

Well, let the fighting begin: a new paper in PLoS One has challenged this correlation. Groups from Imperial College and King's College have failed to detect any XMRV in a similar patient population:

. . .Unlike the study of Lombardi et al., we have failed to detect XMRV or closely related MRV proviral DNA sequences in any sample from CFS cases. . .Based on our molecular data, we do not share the conviction that XMRV may be a contributory factor in the pathogenesis of CFS, at least in the U.K.

Interestingly, XMRV has also been reported in tissue from prostate cancer patients, but recent studies in Germany and Ireland failed to replicate these results. Could we be looking at a geographic coincidence, a retroviral infection that's found in North America but not in Europe, and one whose connection with these diseases is either complex or nonexistent?

Note: as per a comment on this post, the Whittemore Peterson Institute is firing back, claiming that their original work is valid and that the London study has many significant differences. PDF of their release here.

Comments (94) + TrackBacks (0) | Category: Biological News | Cancer | Infectious Diseases

November 23, 2009

Ozonides As Drugs: What Will They Think of Next?

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Posted by Derek

You know, I often think that I have too narrow a view of what kinds of structures can go into drug molecules. (That may come as worrisome statement for some past and present colleagues of mine, who feel that my tolerances are already set a bit too wide!) But I do have limits; there are some structures that I just wouldn't make on purpose, and which I wouldn't submit for testing even if I made them by accident.

Surely ozonides fall into this category. But when I put the "Things I Won't Work With" stamp on them, at least as far as making them on scale and actually isolating them, some readers pointed out that people were investigating them for antimalarial activity. And here we are, with a new paper in J. Med. Chem. on their activity and properties.

Arterolane is the lead compound, which is in Phase III trials as a combination therapy. And it has to be one of the funkier structures ever to make it as far as Phase III, for sure, with both an ozonide and an adamantane in it. Those two, in fact, sort of cancel each other out - the steric hindrance of the adamantane is surely one of the things that makes the ozonide decide not to explode, as its smaller and more footloose chemical relatives would. You get blood levels of the stuff after oral dosing, a useful (although not especially long) half-life, and no show-stopping toxicity.
arterolane.jpg
Endoperoxides are already known as antimalarials, thanks to the natural product arteminisin, which has led to two synthetic derivatives used as antimalarials. So the step to ozonides was, structurally, a small one, but must have been rather larger psychologically. And that's definitely not something to discount. I probably wouldn't have made compounds of this sort, and it's unnerving (even to me) that arterolane has gone further into the clinic than anything I've ever made. I have to congratulate the people who had the imagination to pursue these things.

Comments (18) + TrackBacks (0) | Category: Drug Development | Infectious Diseases | Odd Elements in Drugs

October 13, 2009

Chronic Fatigue - Retroviruses to Blame, or Not?

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Posted by Derek

Chronic fatigue syndrome has long been controversial and mysterious. Is the mystery clearing up, or getting deeper? There have been diagnoses of something like CFS for a long time, under a lot of different names. The common sign is persistent fatigue with no obvious physical cause, often accompanied by joint pain, disrupted sleep, and other symptoms. It's more common in women than in men - but then, so are a lot of autoimmune disorders, which has made some sort of immune syndrome a popular explanation. All sorts of contradictory data have been generated around that idea, but nothing convincing has emerged.

There's a preprint in Science from teams at the National Cancer Institute, the Cleveland Clinic, and Whittemore Peterson Institute that's attracting a lot of interest. It presents evidence for a viral infection which is far more common in patients diagnosed with CFS. What's even more intriguing is that the virus (XMRV, a mouse retrovirus) is already one that's suspected of involvement in some cases of prostate cancer, as shown by analysis of biopsy samples. (Commentary on that work here). About two-thirds of the CFS patients were found to be positive for the virus, as opposed to about three per cent of the control group. The WPI people are now saying that since the manuscript went in that further work has shown 98% of a 300-CFS-patient sample as positive for XMRV. More on that below.

In the case of the prostate patients, there seems to be a link with a deficiency in the RNAse L pathway, which is part of the interferon-induced antiviral response. It may be that patients with this immune system vulnerability are more susceptible to infection by XMRV, which then goes on to cause (or exacerbate) prostate cancer. There may be a link between RNAse L function and a diagnosis of CFS as well. It makes a neat story, and I hope that it's true.

But we're not quite there yet. No one's seen the data yet on that 300-patient cohort mentioned above, and it's not clear if a different diagnostic method was used on them compared to the group in the Science paper. And that paper itself doesn't have enough details on the patients to satisfy some readers - a specialist at the CDC complained about this to the New York Times, and said that his team would try to reproduce the results, but that he wasn't hopeful. (Working on chronic fatigue has not been the sort of thing that breeds a hopeful outlook, to be sure). Other researchers in the field have voiced their doubts to Science (who, to be sure, did accept the original paper).

One of the problems in this area has been defining who's a patient and who isn't. It's a bit of a catch-all diagnosis, or can be, so there's always the suspicion that even if there's a solid underlying cause that the data are hard to dig out of a heterogeneous patient sample. And there's the whole psychological-or-physical question, too, which is a sure route to raised voices and waving fists. My thinking is that there are very likely a number of people with other issues (which I will leave undefined) piled into this area, and that the necessary attempts to draw boundaries will be sure to leave someone upset.

As for this retrovirus angle, there are a number of other steps that need to be taken. Looking over historical blood and tissue samples will be very interesting - could you find that a person showed no sign of the virus when younger, then went positive before showing signs of the disease? Or does it stay latent for a longer period before finally breaking through? Are there animals that are susceptible to infection, and do they show similar symptoms to humans? Can we at least demonstrate infection of cultured cells in vitro? (Update: I see that they've shown that, which is a very good step). Do any of the existing antiretroviral drugs have any effect on either of those processes, and if so, what happens when you give them to patients with CFS? What about the 3% or so of the population that seems to be positive for XMRV but shows no sign of either prostate cancer or CFS - what's different about them, if anything? And so on.

The Whittemore Peterson Institute people are way out in front on these questions, for better or worse. You may have said, as I did, "Who they?", but it turns out that they've only been around since 2004. The institute was set up by the parents of a CFS patient to do research in the field, and they've apparently been quite busy. Their web site gives the impression that the question of CFS as a retroviral infection is basically settled, but I'm not there yet. I have a lot of sympathy for the unidentified-infectious-agent line of thinking, and I believe that there are probably several things out there that will eventually fit into this category, but it can be a hard thing to prove. Let's hope this one is solid, so we can get to work.

Comments (17) + TrackBacks (0) | Category: Infectious Diseases | The Central Nervous System

October 7, 2009

A Nobel for Ribosome Structure

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Posted by Derek

This was another Biology-for-Chemistry year for the Nobel Committee. Venkatraman Ramakrishnan (Cambridge), Thomas Steitz (Yale) and Ada Yonath (Weizmann Inst.) have won for X-ray crystallographic studies of the ribosome.

Ribosomes are indeed significant, to put it lightly. For those outside the field, these are the complex machines that ratchet along a strand of messenger RNA, reading off its three-letter codons, matching these with the appropriate transfer RNA that's bringing in an amino acid, then attaching that amino acid to the growing protein chain that emerges from the other side. This is where the cell biology rubber hits the road, where the process moves from nucleic acids (DNA going to RNA) and into the world of proteins, the fundamental working units of a day-to-day living cell.

The ribosome has a lot of work to do, and it does it spectacularly quickly and well. It's been obvious for decades that there was a lot of finely balanced stuff going on there. Some of the three-letter codons (and some of the tRNAs) look very much like some of the others, so the accuracy of the whole process is very impressive. If more proofs were needed, it turned out that several antibiotics worked by disrupting the process in bacteria, which showed that a relatively small molecule could throw a wrench into this much larger machinery.

Ribosomes are made out of smaller subunits. A huge amount of work in the earlier days of molecular biology showed that the smaller subunit (known as 30S for how it spun down in a centrifuge tube) seemed to be involved in reading the mRNA, and the larger subunit (50S) was where the protein synthesis was taking place. Most of this work was done on bacterial ribosomes, which are relatively easy to get ahold of. They work in the same fashion as those in higher organisms, but have enough key differences to make them of interest by themselves (see below).

During the 1980s and early 1990s, Yonath and her collaborators turned out the first X-ray structures of any of the ribosomal subunits. Fuzzy and primitive by today's standards, those first data sets got better year by year, thanks in part to techniques that her group worked out first. (The use of CCD detectors for X-ray crystallography, a technology that was behind part of Tuesday's Nobel in Physics, was another big help, as was the development of much brighter and more focused X-ray sources). Later in the 1990s, Steitz and Ramakrishnan both led teams that produced much higher-resolution structures of various ribosomal subunits, and solved what's known as the "phase problem" for these. That's a key to really reconstructing the structure of a complex molecule from X-ray data, and it is very much nontrivial as you start heading into territory like this. (If you want more on the phase problem, here's a thorough and comprehensive teaching site on X-ray crystallography from Cambridge itself).
Ribosomal%20structures.jpg
By the early 2000s, all three groups were turning out ever-sharper X-ray structures of different ribosomal subunits from various organisms. The illustration above, courtesy of the Nobel folks, shows the 50S subunit at 9-angstrom (1998), 5-angstrom (1999) and 2.4-angstrom (2000) resolution, and shows you how quickly this field was advancing. Ramakrishnan's group teased out many of the fine details of codon recognition, and showed how some antibiotics known to cause the ribosome to start bungling the process were able to to work. It turned out that the opening and closing behavior of the 30S piece was a key for this whole process, with error-inducing antibiotics causing it to go out of synch. And here's a place where the differences between bacterial ribosomes and eukaryotic ones really show up. The same antibiotics can't quite bind to mammalian ribosomes, fortunately. Having the protein synthesis machinery jerkily crank out garbled products is just what you'd wish for the bacteria that are infecting you, but isn't something that you'd want happening in your own cells.

At the same time, Steitz's group was turning out better and better structures of the 50S subunit, and helping to explain how it worked. One surprise was that there was a highly ordered set of water molecules and hydrogen bonds involved - in fact, protein synthesis seems to be driven (energetically) almost entirely by changes in entropy, rather than enthalpy. Both his group and Ramakrishnan's have been actively turning out structures of the ribosome subunits in complex with various proteins that are known to be key parts of the process, and those mechanisms of action are still being unraveled as we speak.

The Nobel citation makes reference to the implications of all this for drug design. I'm of two minds on that. It's certainly true that many important antibiotics work at the ribosomal level, and understanding how they do that has been a major advance. But we're not quite to the point where we can design new drugs to slide right in there and do what we want. I personally don't think we're really at that stage with most drug targets of any type, and trying to do it against structures with a lot of nucleic acid character is particularly hard. The computational methods for those are at an earlier stage than the ones we have for proteins.

One other note: every time a Nobel is awarded, the thoughts go to the people who worked in the same area, but missed out on the citation. The three-recipients-max stipulation makes this a perpetual problem. This is outside my area of specialization, but if I had to list some people that just missed out here, I'd have to cite Harry Noller of UC-Santa Cruz and Marina Rodnina of Göttingen. Update: add Peter Moore of Yale as well. All of them work in this exact same area, and have made many real contributions to it - and I'm sure that there are others who could go on this list as well.

One last note: five Chemistry awards out of the last seven, by my count, have gone to fundamental discoveries in cell or protein biology. That's probably a reasonable reflection of the real world, but it does rather cut down on the number of chemists who can expect to have their accomplishments recognized. The arguing about this issue is not be expected to cease any time soon.

Comments (45) + TrackBacks (0) | Category: Analytical Chemistry | Biological News | Current Events | Infectious Diseases

June 2, 2009

A Deuterium Deal

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Posted by Derek

Well, there's someone who certainly believes in the deuterated-drug idea! GlaxoSmithKline has announced today that they've signed a deal with Concert Pharmaceuticals to develop these. There's a $35 million payment upfront, which I'm sure will be welcome in this climate, and various milestone and royalty arrangements from there on out. I know that the press story says that it's a "potential billion dollar deal", but you have to make a useless number of assumptions to arrive at that figure. Let's just say that the amount will be somewhere between that billion-dollar figure and. . .well, the $35 million that Glaxo's just put up.

Where things will eventually land inside that rather wide range is impossible to say. No one's taken such a compound all the way through development, and every one of them is going to be different. (Deuterium might be a good idea, but it ain't magic.) It looks like the first compound up for evaluation will be an HIV protease inhibitor, CTP-518, which is a deuterated version of someone's existing compound - Concert has filed paten applications on deuterated versions of both darunavir (WO2009055006) and atazanavir (WO2008156632). The hope is that CTP-518 will have an improved enough metabolic profile to eliminate the need to add ritonavir into the drug cocktail.

The company is also providing deuterated versions of three of GSK's own pipeline compounds for evaluation, which is interesting, since that's the sort of thing that Glaxo could do itself. In fact, that's one of the key points to the whole deuterated-compound idea: the window of opportunity. Deuteration isn't difficult chemistry, and the applications for it in improving PK and tox profiles are pretty obvious (see below). It's a good bet that drug company patent applications will hencrforth include claims (and exemplified compounds) to make sure that deuterated versions of drug candidates can't be poached away by someone else. This strategy has a limited shelf life, but it's long enough to be potentially very profitable indeed.

One more note about that word "obvious". Now that people are raising all kinds of money and interest with the idea, sure, it looks obvious. And I'm sure that it's a thought that many people have had before - and then said "Nah, that's too funny-sounding. Might not work. And besides, you might not be able to patent it. And besides, if it were that good an idea, someone else would have already done it. There must be a good reason why no one's done it, you know". Getting up the nerve to try these things, that's the hard part. Roger Tung and Concert (and the other players in this field) deserve congratulations for not being afraid of the obvious.

Comments (25) + TrackBacks (0) | Category: Business and Markets | Drug Development | Infectious Diseases | Pharmacokinetics | Who Discovers and Why

May 8, 2009

Altermune - Real Stuff or Not?

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Posted by Derek

Kary Mullis is an outlier among Nobel Prize winners. Attendees some of his invited talks in the years after his award will know what I’m talking about. These were famously random affairs, with the audience never knowing quite what to expect when the next slide came up on the screen. And his own book, Dancing Naked in the Mind Field, will give you about as much flakiness as you can stand.

But although he's been way off base about a lot of things, he may not be that way about everything. I notice (h/t Biotechniques) that he gave a lecture recently at San Jose State, and instead of hearing about the discovery of PCR, the students got an update on Mullis’s company Altermune, whose website website is intertwined with Mullis's own. The site is worth a look. Mullis has a vigorous writing style, and the rest of the front page is his pitch for his company’s approach to immunotherapy for infectious disease:

We have been slowly developing chemistry- the art of dealing, using instruments we devise, with things that are much too small for us to see. They have plus and minus charges on them that we can't feel; they have oily places on them much too tiny for us to notice oil and they have water-loving patches too small for us to see oil droplets beading up on the water. Microbes need all of these things, specific types of them, in fact, to survive, and none of them are beyond the scope of our instruments and our synthetic tools. That's our advantage. Just in this last century we have come to know these things the way we used to know javelins and swords.

How can we help our immune system? Altermune has a shot at it.

Give its antibodies - its workhorse molecules - bionic arms. That's right, little chemical extensions that allow an old antibody to do new tricks. Altermune, LLC, in collaboration with Biosearch in Novato, CA, this summer, fitted up some antibodies whose job used to be binding to something called galactose-alpha-1,3-galactosyl-beta-1,4-N-acetyl glucosamine, with new bionic arms, synthesized on an Applied Biosystems ABI 3900, arms that can tightly sieze an influenza virion, shake it a little bit for emphasis, and turn it over to a hungry human macrophage for further processing. The change was accomplished with a swallowed drug. No need to send the antibodies back to the factory. Viruses never saw the ABI 3900 coming.

It looks like he’s using DNA aptamers as recognition elements for specific pathogens, which are used to bring on a response from the ubiquitous antibodies that target 1,3-Gal-Gal antigens. Here's the patent on the technique. And I have to say, that’s not necessarily a crazy idea at all. That epitope has been suggested before as a way to boost immune response, and marrying that to an aptamer could work. (Other aptamer conjugates are under investigation). Of course, the problem (as with all nucleic-acid based things) is, how do you dose it (and how long does it hang around once you do?)

Mullis seems to be talking about oral delivery, which is a real challenge. But that makes me wonder about a report from a company called RXi, which claims to be having some success in delivering their RNAi therapy to macrophages through the gut. They're packaging things in beta-glucan particles and taking advantage of a transport system (and of the fact that there are macrophages in the gut wall waiting for whatever comes out of the food supply). Perhaps something like this would do the trick for a immunological approach like Altermune's?

The immune system scares me, to be honest. I think that evolutionarily we've always walked a narrow path between "strong enough to fight off threats" and "touchy enough to get you killed". Versions of the machinery that threw their hosts into anaphylactic shock too easily have been weeded out by strong selection pressure - you probably wouldn't live long enough to pass that blueprint on. But it's still a tricky thing to mess with (ask TeGenaro). Using existing antibodies might be the most sensible way to do it. . .

Comments (13) + TrackBacks (0) | Category: General Scientific News | Infectious Diseases

April 27, 2009

Don't Hit The Bunkers Just Yet

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Posted by Derek

Swine flu: is it time to panic yet? Actually, it never is, and this is a particularly useless time to start running in circles, despite the apparent non-stop coverage on the cable news channels. I had some exposure to those during my recent vacation, which only confirmed the complete ban on the damned things in my own house.

I’m reminded of a line from Michael Lewis’s article on New Orleans in the immediate aftermath of Hurricane Katrina. He described a neighbor as suffering from a severe information handicap: his TV was on. But I can’t get all superior about the Internet, either, since Drudge and others are running piled-up red headlines in the same manner. What’s the real situation?

As far as I can make out, it’s this: over the past many weeks, about one thousand cases of influenza have been reported in Mexico, with about seventy of them fatal. Travelers returned from Mexico have shown up ill in several other locations. But none of them have died – in fact, many of them don’t seem to be all that sick, and appear to be recovering without incident. This flu seems to have spread human-to-human in Mexico, but I’m not aware of any reports of that happening in other locations yet.

And here’s what we don’t know: the number of people actually infected in Mexico is unclear and will remain so. Seventy deaths in a thousand cases of flu is a very alarming figure, and that’s what’s driving all the attention. But we don’t know if that number should really be five thousand, or even ten. And we don’t know if all of those seventy patients even had influenza (or this strain of it) at all – the great majority of them don’t appear to have been serotyped.

So no, it’s not time to sound the sirens just yet. Odds are that this will wind down, just like many other outbreaks of influenza do. But we don’t know that for sure. If I had a nonessential trip to Mexico City scheduled, I’d postpone it. (Not that I’m looking to spend a lot of time in the city in general: one factor in the apparently high fatality rate there might be the awful air quality).

One thing an outbreak like this does, though, is to remind everyone that viral epidemics are potentially a real problem. I don’t think that this one is the Pandemic We’ve Been Waiting For, but that one might well be out there, and there’s no way to know when it might appear. If and when it does, we may not have many pharmacological weapons against it, for the reasons I’ve outlined here. For now, keep an eye on whether any of the cases outside Mexico develop into anything more serious than a day or two in bed, and whether any of these transmit to people around them. And don't watch any cable news. Here's the CDC's page on the outbreak, and here's the WHO.

Comments (34) + TrackBacks (0) | Category: Current Events | Infectious Diseases

April 13, 2009

An HIV Drug. Or A Gout Drug? Or Both. . .

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Posted by Derek

We get a lot of surprises in this business, most of them not so good. That's understandable, since there are lot more ways for drugs and their mechanisms to go wrong than there are for them to go right. But once in a while, you do see something that's unexpectedly good news.

That may be what's happened to a small San Diego outfit, Ardea. As Xconomy details, the company (formed out of the remnants of IntraBiotics and Valeant) was testing an HIV compound in the clinic when they noticed significant declines in blood levels of uric acid.

That rang a bell: something that decreases uric acid levels would be useful for gout, and there's only been one new gout drug approved in the last 40 years. Follow-up work showed that the effect seemed to be coming from a metabolite of the original drug, and thanks to the HIV trial data, they already had good hopes for that compound's safety. The new compound, RDEA594, has made it through Phase I and is headed for Phase II, and the trials look to be manageable affairs that the company can afford to run. The market is there: more people have gout in the US than are HIV-positive (although the two diseases clearly aren't comparable in other respects!). But the state of HIV research now means, weirdly, that the serious medical needs in that population are actually being met more completely than those in many other disease areas. (Ardea's HIV compound is progressing as well).

So good luck to them, on both fronts. It's a reminder to always look through all your data, and to be alert for whatever opportunities might be hiding in there. We don't get as many as we'd like, so we can't let any of them slip away.

Comments (11) + TrackBacks (0) | Category: Drug Development | Infectious Diseases

March 25, 2009

Two! Two! Two Drugs in One!

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Posted by Derek

There's an idea that shows up in the antibiotic field that seems a bit crazy by the standards of other therapeutic areas. Since bacteria develop resistance to single agents, why not take two different classes of antibiotic molecule and, y'know, string 'em together somehow? How about that, eh?

Well, it's the sort of thought that occurs either to people who don't know much about drug discovery, or to those who know an awful lot. In between, you're probably going to dismiss that one as something of an eye-roller. But while it's got some problems, it's not quite as much of a bozo move as it appears. Here's an example that just showed up in J. Med. Chem., where a group tied Cipro (ciprofloxacin) to neomycin.

The first objection is "Why don't you just give people two pills, instead of trying to make them all into one molecule?" (Here's a review that talks about both options). Well, one answer is that two different agents are going to have different absorption and PK, whereas a conjugate drug will be coming on all at the same time, which could be an advantage. But a more compelling answer is that the new conjugate is going to be a different creature at both of its drug targets, and might well be different enough at both to qualify as a new agent to the resistant strains.

The molecules described in that paper above are, depending on your point of view, fluoroquinolones with a lot of sugars hanging off of them - most unusual as far as traditional quinolone SAR - or neomycin oligosaccharides with some odd heterocycles hanging off of them in turn, which is also not the sort of thing that's usually tried on that scaffold. So if you can still hit both targets, you may well be able to hit them with something they haven't seen before (and may not yet know how to deal with). Importantly, in the case of those quinolone/neomycin thingies, some evidence is shown in the paper that bacteria have a harder time developing resistance to the new compounds. (In order to completely evade them, the bacteria will have to mutate out of both targets, too, but that advantage mostly holds with two separate pills as well).

But all this brings up the second objection: how do you think you're going to get away with hanging all that stuff off an active compound? Well, that's why this trick is usually done with known antibiotics. The SAR of these things has been well worked out by now, and that includes the parts of the molecule that don't seem to have much effect on things. Those will be the preferred positions to attach your linking groups, they're the nonessential region(s) of the molecule that can be messed with.

There's a potential show-stopper in all this, though, and it can be seen on display in the J. Med. Chem. paper. Sticking two drug molecules together, no matter how you do it, is going to make a rather large entity. Neomycin, for its part, didn't start out very small, and the linkers used in this paper aren't the tiniest things on the shelf, either (although I do like the use of the triazole click reaction, mentioned yesterday as well). It turns out that the resulting double-barreled compounds are better than plain neomycin, but worse than plain Cipro. And this happens in spite of the fact that when you assay them against the fluorquinolone target enzymes (DNA gyrase and topoisomerase IV), the new compounds are actually more potent than the original drug. So what's the problem?

Well, the problem, almost certainly, is that these things are probably just too huge. The disconnect between enzyme and bacterial potency here may well reflect trouble getting into the bacteria (although that doesn't seem to be hurting the neomycin end of the activity so much). Larger molecules are trouble when dosed orally, too, and I'd expect compounds like the ones shown to be difficult to develop as traditional pills. (That said, there's a real need for IV-based antibiotics for nasty hospital-derived infections, so something like this could still fly, as long as it showed activity against real bacteria).

So this idea is hard to realize, but it's not necessarily crazy. It keeps showing up in the antibiotic world, and here's an account of the same concept being applied to malaria therapy. Eventually someone's going to get this to work.

Comments (19) + TrackBacks (0) | Category: Drug Development | Infectious Diseases

March 13, 2009

Drugs For Bacteria: Really That Hard, Or Not?

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Posted by Derek

A few readers have told me that I’m being too hard on antibacterial drug discovery, at least on target-based efforts in the field. The other day I asked if anyone could name a single antibacterial drug on the market that had been developed from a target, rather than by screening or modification of existing drugs and natural products, and the consensus was that there’s nothing to point to yet.

The objections are that antibacterials are an old field, and that for many years these natural products (and variations thereof) were pretty much all that anyone needed. Even when target-based drug discovery got going in earnest (gathering momentum from the 1970s through the 1980s), the antibacterial field was in general thought to be pretty well taken care of, so correspondingly less effort was put into it. Even now, there’s still a lot of potential in modifying older compounds to evade resistance, which is not something that a lot of other drug discovery areas have the option of doing.

And I have to say, these points have something to them. It’s true that antibacterials are something of a world apart; this was the first field of modern pharmaceutical discovery, and the struggle against living, adapting organisms makes it different than most other therapeutic areas even today. The lack of target-driven successes is surely due in part to historical factors. (The relative success of the later-blooming antiviral therapeutic targets is evidence in favor of this, too).

That said, I think that it’s not generally realized how few target-based drugs there are in the field (approximately none), so I did want to highlight that. And it does seem to be the case that working up from targets in the area is a hard row to hoe. There’s a rather disturbing review from GlaxoSmithKline that makes that case:

"From the 70 HTS campaigns run between 1995–2001 (67 target based, 3 whole cell), only 5 leads were delivered, so that, on average, it took 14 HTS runs to discover one lead. Based on GSK screening metrics, the success rate from antibacterial HTS was four- to five-fold lower than for targets from other therapeutic areas at this time. To be sure, this was a disappointing and financially unsustainable outcome, especially in view of the length of time devoted to this experiment and considering that costs per HTS campaign were around US$1 million. Furthermore, multiple high-quality leads are needed given the attrition involved in the lead optimization and clinical development processes required to create a novel antibiotic.

GSK was not the only company that had difficulty finding antibacterial leads from HTS. A review of the literature between 1996 and 2004 shows that >125 antibacterial screens on 60 different antibacterial targets were run by 34 different companies25. That none of these screens resulted in credible development candidates is clear from the lack of novel mechanism molecules in the industrial antibacterial pipeline. We are only aware of two compounds targeting a novel antibacterial enzyme (PDF) that have actually progressed as far as Phase I clinical trials, and technically speaking PDF was identified as an antibacterial target well before the genome era."

So although the history is a mitigating factor, the field does seem to have its. . .special character. The GSK authors discuss some of the possible reasons for this, but those can be the topic of another post or two; they're worth it.

Comments (3) + TrackBacks (0) | Category: Drug Assays | Drug Industry History | Infectious Diseases

March 11, 2009

A Quick Quiz (Re: Antibacterials)

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Posted by Derek

Just as an addendum to this morning's post, a quick question: can anyone name an antibiotic that was brought up through a target-driven approach? That is, not one that's a variation on an existing class, or has its origins in a hey-that-killed-bugs assay. I mean, one that started off with people saying "OK, XYZase looks to be essential in bacteria, and higher organisms don't have it. Nothing's on the market that works that way, but it looks to be a good target, so let's go after it".

Off the top of my head, I can't think of one. There may be an example somewhere, but just the fact that I'm having to rack my brain about it says something. Doesn't it?

Comments (31) + TrackBacks (0) | Category: Infectious Diseases

Bacteria: Respect Must Be Paid

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Posted by Derek

I’ve had the opportunity to learn more about antibacterial drug discovery in the last year or so – that was one of the few therapeutic areas I hadn’t worked in, actually. And although I already knew that it was no picnic in the park (I’d heard the complaints), doing it myself has given me a new respect for the nasty resilience of bacteria.

I’ve been used to having my compounds go into cell assays, where a good number of them fail. That’s expected – every medicinal chemist knows that some of the potent compounds in the primary assay (against the purified protein target) are going to wipe out when they go up against cells. Cells have membranes, for one thing, and they have bailing pumps built into them to spit out molecules that they don’t recognize. I’ve seen compounds, as has everyone who does drug discovery, that bounce right off the cell assay while closely related analogs work just fine. That’s why you run the assay, to weed those guys out – you may not every understand what specifically went wrong, but you at least get a chance to try to avoid it as you go on.

But bacteria are different beasts. Their independent, free-living nature makes them nastier than even tumor cell lines. Cancer cells, aggressive creatures though they are, still expect to get their food delivered (and their garbage hauled) by the bloodstream. (That’s what makes angiogenesis a drug target in oncology). But bacteria have to search out their own meals, fighting it out with every other bacterium in the area while doing so. Their membranes are like armor plate compared to a lot of higher-organism cell lines, with the gram-negative organisms taking the trophy. Or is it the mycobacteria? (They're both awful, and the proportion of compounds that fail when you move past the pure-protein stage is thus far higher). They react to threats, communicate with each other, and reproduce like crazy. It’s like dealing with a swarm of tiny, self-replicating attack submarines.

So yes, finding an effective new antibacterial drug is a real triumph, and it’s not a triumph that’s been happening very often in recent years. This gets mentioned a lot in the popular press, when they feel like running a Coming of the Superbugs piece, and one of the usual explanations is that drug companies got out of the area years ago because they thought the problem wasn’t big enough to worry about. That’s part of the explanation – or was, quite a while ago. And the finances are different in this space, true. You’re never going to have a multibillion dollar blockbuster, because a new agent is going to be reserved just for infections that are unresponsive to the older drugs. But it’ll still sell.

No, there are plenty of companies working in the area now, and many that never left. And the need for new agents is clear, and has been for quite a while now. The real reason that we don’t have lots of new antibacterial drugs is that it’s really hard to find them, for one thing, and the the bacterial are more than capable of fighting back when we try.

Update: for more on the topic, see here.

Comments (25) + TrackBacks (0) | Category: Infectious Diseases

February 13, 2009

A Cure for the Common Cold? Don't. . .Ah, Hold Your Breath

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Posted by Derek

If you want a good example of the way that the popular media handle a drug discovery story, take a look at all the headlines this morning on the news of the sequencing of the common-cold rhinoviruses.

There are a couple of "Cure For the Common Cold Unlikely" ones, but most of the others seem to regard this as a big step forward. "Cure May Be Found", "Getting Closer" , "May Lead to Cure", "Could Help to Cure" - that's the sort of thing. The problem is, how many viral diseases can we cure? I mean, really cure with drugs after a person's been infected, wipe out and make go away? Right. Do I hear a zero? Viral diseases can be very difficult to get a handle on, because there aren't many moving parts in there. If none of them are amenable to small-molecule drug approaches, people like me are pretty well out of the game.

The best chance you have with a viral infection is with a vaccine. But what this genomics work is telling us, actually, is that a vaccine is going to be rather hard to come by. This paper sequenced ninety-nine different rhinovirus strains, and if there are that many, there are surely that many more. Or there will be, after the next cold season - just wait. These things are mutating all the time - which is, of course, why we get colds year after year. The team working on this project was able to bin the viral genomes into fifteen different classes, but what are we going to do, develop fifteen different (and simultaneous) vaccines? Against a scurrying, hopping, moving target like this one?

No, this is very interesting work, and it'll tell us a lot about how viruses do their nasty viral business out in the real world. But I wouldn't start throwing around the "C" word. All that can do is disappoint people, I'm afraid.

UpdateOK, so who's giving the wrong impression here? As per the comments to this post, here's one of the article's co-authors, Dr. Steve Liggett, as quoted in the New York Times:

"We are now quite certain that we see the Achilles' heel, and that a very effective treatment for the common cold is at hand," said Dr. Stephen Liggett, an asthma expert at the University of Maryland and co-author of the finding.

Say what? That's just a bizarre thing to say. But perhaps he was misquoted, because you can also find this, which seems to be a lot more grounded in reality:

There is hope that a careful study of the viral genomes will reveal one central point of attack that could be exploited by drug makers. "What we would like is a single Achilles' heel for all the viruses that we have found so far, and we could attack in that direction," Liggett said.

But the viruses are found to have impressive powers of change. The study shows that some human rhinoviruses result from the exchange of genetic material from two separate strains infecting the same person. Such recombination had not been thought possible for rhinoviruses.

That recombination is one reason why a vaccine against the common cold appears to be impossible, said Ann C. Palmenberg, director of the Institute for Molecular Virology at the University of Wisconsin, and lead author of the sequencing effort. The viruses just keep changing too much.

Comments (24) + TrackBacks (0) | Category: Infectious Diseases

February 9, 2009

Maribavir, Ouch

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Posted by Derek

Viropharma has announced that their Phase III trial of maribavir, a compound targeting cytomegalovirus, failed big-time. Well, they didn't used the term "big-time", but they might as well have. The treatment group (patients with recent bone marrow transplants) showed no difference in CMV infection rates compared to placebo. This is especially disappointing, considering that the compound looked pretty good in Phase II. That's a useful lesson in the difference between Phase II and the real world.

The company has been through this before. Back in the late 1990s, they were working on another antiviral, Pleconaril, that in those heady days caused their stock to shoot up well over $50/share. Some people had gotten it into their heads that the stuff was going to cure the common cold and who knows what else besides. In the spring of 2000, the bad news came in that the drug would do nothing of the kind. I was short the stock at that point, and I've long wished that I had a videotape of me trying to call my broker after I saw the stock quote that morning. I kept missing the buttons on the phone; it was pretty entertaining.

Maribavir isn't one of VPHM's own creations, actually - they licensed it from GSK, and it's a good ol' nucleoside analog in the tradition of many antivirals. But that's a tough area to work in, and today's bad news is just more proof.

Comments (12) + TrackBacks (0) | Category: Clinical Trials | Infectious Diseases

April 16, 2008

Fun With Bacteria

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Posted by Derek

A recent interview in Nature Reviews Drug Discovery with John Powers, formerly of the FDA, points out some problems in designing antibacterial drug trials. Some of these are unique to this area, although others we're stuck with wherever we go.

For one thing, it’s surprisingly hard to make sure, when you’re selecting patients, that the people you’re letting into the trial have the disease that you’re trying to treat. The example used is that some 5% of the patients who present with cough actually have pneumonia. Pneumonia is a very good disease to treat with antibacterial drugs, but you’d better make sure that your patients actually have it. There are some tests available to make sure that a given pathogen is present, although they aren’t available in every case you’d want them to be. If you don’t have such a screen, you risk having a very heterogeneous patient population, which will likely as not obscure the effectiveness of the drug you’re testing.

Then there’s the related difficulty in treating some conditions that you’d think would be clear cases for antibacterials: ear infections, for example. The problem is, it’s surprisingly hard to show benefit for some of these things with existing drugs. The underlying infection may be hard to get to (poor circulation in the infected area), or it may be an intrinsically heterogeneous condition like sinusitis. (That can be the result of umpteen different sorts of bacteria, or it could well be something viral, or several varieties of fungal infection, or allergies, what have you). There’s no point in running a head-to-head with an existing medication in these cases; you should run against placebo. That'll be enough of a challenge.

Another problem is that some of the bacterial diseases progress rather quickly – ahead, in some cases, of our ability to usefully diagnose them. That presents a real challenge for a clinical design, one that is dealt with, in many cases, by not attempting to gather rigorous clinical data under these conditions at all. In this field, diagnostic tools have to be fast if they’re going to be of much use.

There are two sides to all these problems: not only do you want to get the drug to the people who need it (and who will respond to it) the most, you want avoid giving it to people who won’t respond at all. That’s not just for the reasons given above (it’ll mess up your data), although that’s enough all by itself. No, the other problem is that spreading your drug around to inappropriate patient populations will just bring on resistance even faster. That’s going to happen no matter what, of course – the key is to have it happen as slowly as possible.

Comments (5) + TrackBacks (0) | Category: Clinical Trials | Infectious Diseases

April 4, 2008

Another Cholesterol Medication Goes Down (Or Does It)?

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Posted by Derek

This is turning into Cardiovascular Week around the blog, I have to say, and not in a good way. The latest news is the failure of a drug candidate from Takeda, TAK-475 (lapaquistat). They were in the lead in the field of squalene synthase inhibitors for cholesterol lowering (many other companies have taken a crack at this target, and dropped out along the way)., and their compound once had hopes of being a pretty big deal.

Not any more. In retrospect, the bell sounded late last year, when the company had to stop dosing at their highest level. Elevated transaminase levels were being seen in the treatment groups as the dose went up, which is a sure sign of trouble, as in liver damage trouble. Some investors seem to have held out hope for the compound to show enough efficacy at the lower doses, but Takeda has announced that the safety/efficacy ratio doesn’t justify taking the drug forward.

Liver enzymes are definitely one of those things you worry about when you go into man. There are all sorts of assays that are supposed to give you a read on that problem beforehand, and it’s safe to assume that Takeda ran them. But you’re never sure until you hit humans. Animals can react very differently to some compounds, although that can go either way. But if you set off liver enzyme trouble in rats or dogs your compound is probably dead, no matter how it might act in humans. You won’t get the chance to find out, most of the time.

The alternative is to use human liver tissue, but cultured human liver cells rapidly lose their native abilities and become untrustworthy as a model for the real world. Human liver slices are another alternative, but those are rather hard to come by, as you can well imagine, and the data from them have a reputation for being hard to interpret and hard to reproduce. No, for now, there’s no way to really know what will happen in humans without, well, using humans.

The big question that always gets asked in these failures is whether this is a compound-specific effect, a compound class effect, or a mechanistic effect. Most of the time it’s one of the first two. There are particular compounds, and particular structural series, that are known to be Bad News for liver enzymes. There will be some lingering doubt, though, because there’s plenty of squalene synthase activity in the liver, and it’s not impossible that any compound that hits it could cause the same trouble.

There are a number of other inhibitors out there – interestingly enough, they may have other uses besides lowering cholesterol. For some time, it’s been thought that such compounds might be useful antibiotics, since many bacteria need cholesterol synthesis pathways to survive. And there’s a recent report in Science putting this to the test in a particularly relevant system, particularly virulent strains of Staphylococcus aureus.

The “aureus” part of the name refers to the yellow hue that many strains of the bug exhibit, which seems to be correlated with how nasty they are as an infectious agent. The color comes from staphyloxanthin, a pigment that seems to be used as a defense agent by the bacteria by neutralizing reactive oxygen attacks from a host’s immune system. As the current work shows, the first enzyme in the biosynthetic pathway for staphyloxanthin (known as CrtM) has a lot of structural similarities to human squalene synthase. The authors prepared a number of known squalene synthase inhibitors from the literature, and found that one class of them (the phosphonosulfonates) also inhibit CrtM.

They went further, showing that one of these compounds (a BMS clinical candidate from about ten years ago) actually works quite well as an antibiotic in vitro and in an in vivo mouse model. I'm not sure why this compound didn't go further, but perhaps it (and the others in its class) will have a second life in the antiinfectives world. . .

Comments (8) + TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Drug Development | Infectious Diseases

April 3, 2008

Whose Guess Is Better?

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Posted by Derek

I was having a discussion the other day about which therapeutic areas have the best predictive assays. That is, what diseases can you be reasonably sure of treating before your drug candidate gets into (costly) human trials? As we went on, things settled out roughly like this:

Cardiovascular (circulatory): not so bad. We’ve got a reasonably good handle on the mechanisms of high blood pressure, and the assays for it are pretty predictive, compared to a lot of other fields. (Of course, that’s also now one of the most well-served therapeutic areas in all of medicine). There are some harder problems, like primary pulmonary hypertension, but you could still go into humans with a bit more confidence than usual if you had something that looked good in animals.

Cardiovascular (lipids): deceptive. There aren’t any animals that handle lipids quite the way that humans do, but we’ve learned a lot about how to interpolate animal results. That plus the various transgenic models gives you a reasonable read. The problem is, we don’t really understand human lipidology and its relation to disease as well as we should (or as well as a lot of people think we do), so there are larger long-term problems hanging over everything. But yeah, you can get a new drug with a new mechanism to market. Like Vytorin.

CNS: appalling. That goes for the whole lot – anxiety, depression, Alzheimer’s, schizophrenia, you name it. The animal models are largely voodoo, and the mechanisms for the underlying diseases are usually opaque. The peripheral nervous system isn’t much better, as anyone who’s worked in pain medication will tell you ruefully. And all this is particularly disturbing, because the clinical trials here are so awful that you’d really appreciate some good preclinical pharmacology: patient variability is extreme, the placebo effect can eat you alive, and both the diseases and their treatments tend to progress very, very slowly. Oh, it’s just a nonstop festival of fun over in this slot. Correspondingly, the opportunities are huge.

Anti-infectives: good, by comparison. It’s not like you can’t have clinical failures in this area, but for the most part, if you can stop viruses or kill bugs in a dish, you can do it in an animal, or in a person. The questions are always whether you can do it to the right extent, and just how long it’ll be before you start seeing resistance. With antibacterials that can be, say, "before the end of your clinical trials". There aren’t as many targets here as everyone would like, and none of them is going to be a gigantic blockbuster, but if you find one you can attack it with more confidence than usual.

Diabetes: pretty good, up to a point. There are a number of well-studied animal models here, and if your drug’s mechanism fits their quirks and limitations, then you should be in fairly good shape. Not by coincidence, this is also a pretty well-served area, by current standards. If you’re trying something off the beaten path, though, a route that STZ or db/db rats won’t pick up well, then things get harder. Look out, though, because this disease area starts to intersect with lipids, which (it bears saying again) We Don't Understand Too Well.

Obesity: deceptive in the extreme. There are an endless number of ways to get rats to lose weight. Hardly any of them, though, turn out to be relevant to humans or relevant to something humans would consider paying for. (Relentless vertigo would work to throw the animals off their feed, for example, but would probably be a loser in the marketplace. Although come to think of it, there is Alli, so you never know). And the problem here is always that there are so many overlapping backup redundant pathways for feeding behavior, so the chances for any one compound doing something dramatic are, well, slim. The expectations that a lot of people have for a weight-loss therapy are so high (thanks partly to years of heavily advertised herbal scams and bizarre devices), but the reality is so constrained.

Oncology: horrible, just horrible. No one trusts the main animal models in this area (rat xenografts of tumor lines) as anything more than rough, crude filters on the way to clinical trials. And no one should. Always remember: Iressa, the erstwhile AstraZeneca wonder drug from a few years back, continues to kick over all kinds of xenograft models. It looks great! It doesn’t work in humans! And it's not alone, either. So people take all kinds of stuff into the clinic against cancer, because what else can you do? That leads to a terrifying overall failure rate, and has also led to, if you can believe it, a real shortage of cancer patients for trials in many indications.

OK, those are some that I know about from personal experience. I’d be glad to hear from folks in other areas, like allergy/inflammation, about how their stuff rates. And there are a lot of smaller indications I haven’t mentioned, many of them under the broad heading of immunology (lupus, MS, etc.) whose disease models range from “difficult to run and/or interpret” on the high side all the way down to “furry little random number generators”.

Comments (9) + TrackBacks (0) | Category: Animal Testing | Cancer | Cardiovascular Disease | Diabetes and Obesity | Drug Assays | Drug Development | Infectious Diseases | The Central Nervous System

March 5, 2008

Smaller, Wetter, Harder to Work With

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Posted by Derek

There’s an interesting article coming out in J. Med. Chem. on antibiotic compounds, which highlights something that’s pretty clear if you spend some time looking at the drugs in that area. We make a big deal (or have made one over the last ten years) about drug-like properties – all that Rule-of-Five stuff and its progeny. Well, take a look at the historically best-selling antibiotic drugs: you’ve never seen such a collection of Rule of Five violators in your life.

That’s partly because a lot of structures in that area have come from natural products, but hey, natural products are drugs, too. Erythromycin, the aminoglycosides, azithromycin, tetracycline: what a crew! But they’ve helped an untold number of people over the years. It’s true that the fluoroquinolones are much more normal-looking, but those are balanced out by weirdo one-shots like fosfomycin. I mean, look at that thing – would you ever believe that that’s a marketed drug? (And with decent bioavailability, too?)

No, you have to be broad-minded if you’re going to beat up on bacteria, and I think some broad-mindedness would do us all good in other therapeutic areas, too. I don’t mean we should ignore what we’ve learned about drug-like properties: our problem is that we tend to make allowances and exceptions on the greasy high-molecular weight end of the scale, since that’s where too many of our compounds end up. It wouldn’t hurt to push things on the other end, because I think that you have a better chance of getting away with too much polarity than you have of getting away with too little.

One reason for that might be that there are a lot of transporter proteins in vivo that are used to dealing with such groups. It’s easy to forget, but a great number of proteins are decorated with carbohydrate residues, and they’re on there for a lot of reasons. And a lot of extremely important small molecules in biochemistry are polar as well – right off the top of my head, I don’t know what the logD or polar surface area of things like ATP or NAD are, but I’ll bet that they’re far off the usual run of drugs. Admittedly, those aren’t going to reach good blood levels if you dose them orally; we’re trying to do something that’s rather unnatural as far as the body’s concerned. But we could still usefully take advantage of some of the transport and handling systems for such molecules.

But that’s not always easy to do. We all talk about making our compounds more polar and more soluble, but we balk at some of the things that will do that for us. Sure, you can slap a couple of methoxyethoxys on your ugly flat molecule, or hang a morpholine off the end of a chain to drag things into the water layer. But slap five or six hydroxyls on your molecule, and you’ll be lucky not to have the security guards show up at your desk.

There are, to be sure, some good reasons why they might. Hydroxyls and such tend to introduce chiral centers, which can make your synthesis difficult and dramatically increase the amount of work needed to fill out the structural possibilities of your lead series. That’s why these things tend to be (or derive from) natural products. Some bacterium or fungus has done most of the heavy lifting already, both in terms of working out the most active isomers and in synthesizing them for you. Erythromycin’s a fine starting material when you can get it by fermentation, but no one would ever, ever consider it if it had to be made by pure total synthesis.

There’s another consideration, which gets you right at the bench level. For an organic chemist, working with charged, water-soluble compounds is no fun. A lot of our lab infrastructure is built for things that would rather dissolve in ethyl acetate than water. A constant run of things with low logD values would mean that we’d all have to learn some new skills (and that we’d all probably have to spend a lot of time on the lyophilizer). Ion-exchange resins, gel chromatography, desalting columns – you might as well be a biochemist if you’re going to work with that stuff. But in the end, perhaps we might be better off, at least part of the time, if we were.

Comments (13) + TrackBacks (0) | Category: Drug Industry History | In Silico | Infectious Diseases

October 31, 2007

Resistant Little Creatures

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Posted by Derek

The post here the other day on resistant bacterial infections prompted some readers to wonder why the drug industry isn’t doing more to come up with compounds in this field. It’s not like there’s no money to be made, and it’s not like there’s no history of antibiotic research, after all. But since my industry doesn’t have a history of knowingly leaving money on the table (what industry does?), you’d figure that there’s more to the story.

Money aside, there’s a real problem with finding good targets. For as long as I can remember in the industry, the infectious disease field has suffered from a relatively small target landscape. Almost all the known drugs in the area work through just a handful of basic mechanisms, and adding new ones to the list has been very difficult for at least the last twenty or thirty years.

That was supposed to change, in theory, starting about ten years ago. I interviewed around then at a company that was working in the field, and everyone was quite excited about the bacterial genome sequences that were starting to appear. Surely this would open the sluice gates and let that long-delayed swell of new targets come washing down the flumes. Hasn’t happened. Not yet, anyway.

I have the impression that the same problems that have affected the translation of human genomic data to new drugs have been the problem here as well. In some cases, not as many genes came out as some people were hoping for. And of these, the function of many of them was (to put it mildly) obscure. Of the ones whose use was at least partially known, many of them have proved not to be useful targets for killing the bacteria or limiting their growth. And of the ones that made that cut – and we’re down to an all-too-manageable set by now – screening hasn’t turned up much chemical matter for people like me to work on.

In fact, there’s a persistent feeling among many people in the field that bacterial and fungal proteins have a lower hit rate than you’d assume they would. Even enzymes that are fairly homologous to those in higher organisms, so the story goes, don’t turn up as many hits in the screens as expected. I’m not sure if this is true or not, but as folklore it’s pretty well known. The combination of all these factors with the perceived lack of opportunities for profits (even if you do find something) has made for slow going.

In recent years it’s become clear that the medical need has grown to the point that antibiotic research can indeed be financially worthwhile – but there are any number of financially worthwhile drug outcomes that we haven’t been able to realize. (See obesity, Alzheimer’s, and many other therapeutic areas for examples of multibillion-dollar opportunities waiting for a good idea to come along. Resistant bacteria have their name on one more sword stuck in yet another stone.

Update: there's clearly another reason why developing good antibacterials is hard, and it's the same reason we need more of them. Bacteria are well-stocked with efflux pumps to get rid of molecules they don't like (and with other weapons as well), and they evolve so fast that you can watch them do it. I wrote about efflux on the site a while back - another post is well worth doing soon.

Comments (15) + TrackBacks (0) | Category: Drug Development | Infectious Diseases

October 29, 2007

Bacterial Infection: Better Or Worse Than Cancer?

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Posted by Derek

There’s been a steady stream of reports in the news about methacillin-resistant Staph. aureus. It’s not a new problem, but (like other nasty infections) it does get a lot of press when the media start paying attention. Works in reverse, too – on the viral front, have you noticed the much reduced number of bird-flu-will-kill-us-all stories this year as we head toward winter? This despite the likelihood of bird flu killing us all being as high (or low) as ever, as far as I can tell.

But the resistant bacteria problem is certainly no joke, and there doesn’t seem to be any reason why it won’t gradually get worse over time. It struck me the other day that antiinfectives, as a drug research field, might be moving toward a similar spot to oncology. In both cases, you have a problem with rapidly multiplying cells, giving you a serious medical outcome - often in cancer, and increasingly with infections. The average tumor is a lot more worrisome than the average infection, of course, but that’s something we can only say with confidence in the industrialized world, and we've only been able to say it for the last sixty or seventy years. As cancer gradually becomes more manageable and infections gradually become less so, the two might eventually meet – or even switch places, which would be bad news indeed. (In some genetically bottlenecked species, in fact, the two problems can overlap, which is fortunately extremely unlikely in humans).

There are, of course, a lot of differences between the two fields, not least of which is that you’re fighting human cells in one case and prokaryotes (or worse, viruses) in the other. But many of those differences actually come out making infectious diseases look worse. The transmissibility of bacteria and viruses make them serious contenders for causing havoc, as they have innumerable times in human history, and they can grow more quickly in vivo than any cancer. It’s only the fact that public health measures allow then to be contained, and the fact that we’ve had useful therapies for many of them, that makes people downrate the infectious agents. If either (or both) of those change, we’re going to be rethinking our priorities pretty quickly.

What this means for drug development is that some researchers will have to rethink their attitudes towards antiinfective drugs. For serious infections, we're going to have to think about these projects the way we've traditionally thought of oncology agents - last-ditch therapies for deadly conditions. Anticancer therapies have long had more latitude in their side effects, therapeutic ratios, and dosing regimes, and antibiotics for resistant infections are in the same position. For some years now, there's been a problem that new drugs in this field would perforce have small markets, since they'd be used only when existing agents fail. That market may not be as small as it used to be. . .

Comments (13) + TrackBacks (0) | Category: Cancer | Drug Development | Infectious Diseases

July 9, 2007

Now With Ethyl Mesylate!

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Posted by Derek

One of the stories I missed while on hiatus has been Roche's recall of antiretroviral Viracept (nelfinavir) tablets. As readers may know, a problem with many batches of the drug became known in June. It's a mesylate (aka methanesulfonate) salt, but some of the tablets turned out to have ethyl mesylate in them as well, which is definitely sonething I'd go out of my way to avoid ingesting. A worldwide recall (except for North America, which is on a different supply chain) has been the result.

Methanesulfonate is a very happy anion, which is one of the reasons why methanesulfonic acid is used to make salts of basic drugs. The ions of these formulations tend to not be too tightly bound or paired, making the salt forms generally easier to dissolve. (The stronger the interactions between the ions, the harder it is for water to break up the party and dissolve them). But the contentedness of the sulfonate anion makes it a good leaving group when it's part of a covalent molecule. It would rather be off floating around with a negative charge on it again than be tied up in a regular bond, so sulfonate esters and the like tend to be pretty reactive.

Alkyl mesylate esters, then, are also pretty toxic. Just how toxic is the question, though. The stuff will react with nucleophiles wherever it finds them, and if that's some protein on the surface of a soon-to-be-shed epithelial cell, then no harm done. But there are many other situations that won't work out so well, going all the way up to DNA damage.

So how did this nasty stuff get in there in the first place? When I heard about the contaminant, my first thought was that someone had been washing out the reactors where the salt was formed with ethanol, and that appears to be exactly the case. Alcohol plus free acid under strong acid catalysis will give you ester, in what's literally one of the oldest reactions in the book. Roche appears to have been able to keep the contaminant down below regulatory levels normally, but someone's mind has been wandering over in Switzerland. In consequence, the fearsome Swiss reputation for purity and consistency takes a torpedo below the water line.

Comments (6) + TrackBacks (0) | Category: Infectious Diseases | Why Everyone Loves Us

May 22, 2007

Evolution In Action

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Posted by Derek

As the cost of sequencing goes down, a lot of once-crazy experiments become feasible. There's a good case in point this week in the preprint section of PNAS. A team of researchers looked at a single patient undergoing treatment with vancomycin for a serious infection. (Just saying "vancomycin" makes the "serious infection" part redundant, since it's often the last resort). They periodically isolated Staphylococcus aureus bacteria from the patient's blood during the course of the treatment to look at how resistance to the antibiotic developed.

Fine, fine - except the way they watched the process was to sequence the whole genome of each bacterial isolate. What they found were a total of 35 mutations, which developed sequentially as the treatment continued (and the levels of resistance rose). Here's natural selection, operating in real time, under the strongest magnifying glass available. And it's in the service of a potentially serious problem, since resistant bacteria are no joke. (Reading between the lines of the PNAS abstract, for example, it appears that the patient involved in this study may well not have survived).

The technology involved here is worth thinking about. Even now, this was a rather costly experiment as these things go, and it's worth a paper in a good journal. But a few years ago, needless to say, it would have been a borderline-insane idea, and a few years before that it would have been flatly impossible. A few years from now it'll be routine, and a few years after that it probably won't be done at all, having been superseded by something more elegant that no one's come up with yet. But for now, we're entering the age where wildly sequence-intensive experiments, many of which no one even bothered to think about before, will start to run.

Comments (34) + TrackBacks (0) | Category: Infectious Diseases

May 7, 2007

Brazil Raises The Pirate Flag

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Posted by Derek

Back in 2005, the government of Brazil threatened to break the patent on Abbott's HIV medication Kaletra if the price didn't come down (see here and here). But after a lot of arm-wrestling, a deal was reached. Now it's Merck's turn, with their efavirenz, and this time things went all the way: on Friday, Brazil's president issued a compulsory license to produce the drug outside Merck's patent.

My problem with this, other than the obvious problem I have with expropriation of someone else's property, is that Brazil is trying to have things both ways. The government spends much of its time talking about how the country is an emerging power, with the 12th-largest economy in the world, huge natural resources, its own successful aircraft industry and space program, and so on. But when it comes time to pay for HIV medications, which are important both medically and politically, suddenly they're a poor third-world country being exploited by the evil multinational drugmakers. A look back at the second blog link above, with its quotes from Brazil's Minister of Health on how nationalizing drug patents would help the country's industry, shows that this issue probably has more to do with the first worldview than the second one.

During the Kaletra dispute, I asked a question:

I've known some pretty good Brazilian scientists, but the country isn't up to being able to discover and develop its own new ones. (Very few countries are; you can count them on your fingers.) So I've saved my usual justification for last: if Brazil decides to grab an HIV medication that other people discovered, tested, and won approval for, who's going to make the next one for them?

And now Merck is basically asking Brazil the same thing:

"Research and development-based pharmaceutical companies like Merck simply cannot sustain a situation in which the developed countries alone are expected to bear the cost for essential drugs in both least-developed countries and emerging markets. As such, we believe it is essential to price our medicines according to a country's level of development and HIV burden, thereby ensuring equitable access as well as our ability to invest in future innovative medicines. As the world's 12th largest economy, Brazil has a greater capacity to pay for HIV medicines than countries that are poorer or harder hit by the disease.

This decision by the Government of Brazil will have a negative impact on Brazil's reputation as an industrialized country seeking to attract inward investment, and thus its ability to build world-class research and development."

It should have, anyway. Look, intellectual property law is not pretty, and doesn't give anyone a warm feeling. It's not meant to. But the alternative Jolly-Roger world is even worse, and anything that takes us toward that is a bad move.

Comments (44) + TrackBacks (0) | Category: Drug Prices | Infectious Diseases | Patents and IP

April 25, 2007

A New HIV Therapy. Yawn?

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Posted by Derek

Pfizer got a tiny bit of good news yesterday when an FDA panel recommended their new HIV drug, Maraviroc, for approval. There are several stories that can be told about this news, so let's try a few: The business story is that this is not going to make a lot of difference for the company, because the drug isn't going to be a first-line therapy. They have to hope that it performs well and can expand its use, because a $25 to $50 million/year drug is a roundoff error on the scale of Pfizer's financial concerns. So much for the money.

The drug development story is that this will be the first CCR5 inhibitor to reach the market. That's a useful benchmark by the standards of this blog, because back in 2002, in my second month of blogging, I wrote about this class of drugs. The first CCR5 inhibitors had already made it into human patients by that time, and here we are, five years later, and one of them is just about to make it to market. Patience is supposed to be a virtue, but in the drug business, it's a case of making that virtue out of necessity.

And the big philosophical story is how the world has changed in the last twenty years. Here's a new HIV medication, one with a new mechanism, and it makes the second business page of the paper if it makes it at all. A completely new drug for a dreaded disease is coming, and no one thinks it'll do all that well, because of all the competition, y'know. It'll be given to people who've failed courses of treatment with all the other HIV drugs out there, and unless you're paying attention it's hard to keep up with all of them.

For people who remember the 1980s, all this still feels strange - imagine a message from the future popping up in 1985, saying: "In twenty years, the viral disease with by far the most crowded market, the largest number of possible therapeutic options and the widest variety of drug mechanisms will be. . .HIV". Actually, that would have scared everyone even more than they already were, because it would sounded like the worst predictions from that era had come true. In reality, HIV isn't even in the top 15 causes of death in the US, with the most recent figures I can find putting its contribution to the death rate a bit below that of aortic aneurysm. (Some other parts of the world are a different story, of course, although the 1980s predictions for them were even more apocalyptic.) But all in all, I'm fine with living in a world where new drugs against deadly diseases aren't necessarily front-page news. . .

Comments (12) + TrackBacks (0) | Category: Infectious Diseases

April 13, 2007

Deep Breaths

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Posted by Derek

I've been out of the research labs for over two months now, and you know what I miss the most? No, not the safety meetings (hah!) or the smell of the solvents - what I miss is getting fresh data on experiments. Waiting for results on something crucial is hard to take, but it's also exciting, and there's nothing I've found outside of science that compares.

I've sat at my desk holding a warm printout from an LC/MS, or with a newly arrived e-mail from the biologists, and I swear, I've closed my eyes for a moment before I've looked at them. That's the last moment of not knowing; after that you're living in the new world that the experiment made. I don't know what I'd do with a job that didn't have that feeling in it, and honestly, that's one reason I'm still looking.

It occurs at all sorts of levels - checking the NMR to see if your reaction worked or not, waiting for the PK results to see if your idea raised the blood levels, holding your breath when the compound goes into two-week tox testing. And beyond that things get really terrifying, when human data start coming in from the clinic.

Ask Vertex. I wrote here about their antiviral compound (telaprevir, VX-950) for hepatitis. It's a huge market that really needs a better drug, and a lot of people have taken swings at it. Well, on Saturday night in Barcelona, the company is presenting their latest clinical data, and investors are checking their heart rates. The drug's success would be the biggest event in the history of the company (and a huge advance in hepatitis therapy), and failure (the antiviral norm, unfortunately) would be very, very hard to take.

The company's top clinicians already know the answer, of course, because a person's got to have time to make slides. They've had the experience I was talking about, on a scale that few people have ever felt. You click a button, turn a page, and the future writes itself out there in front of you. . .

Comments (10) + TrackBacks (0) | Category: Clinical Trials | Infectious Diseases | Who Discovers and Why

February 7, 2007

Vertex, Hepatitis, and Gripping the Arms of Your Chair

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Posted by Derek

Antiviral drugs are one of those big unmet medical needs that we talk about in the drug industry. The reason we talk about them is, of course, that from a business standpoint - and this is a business, for sure - "unmet need" is equivalent to "unmade profit".

The problem is, the reason that some of these big opportunities are unclaimed is that they're not easy to address. As I've said here before, one big problem with antivirals is that there are a very limited number of good targets for drugs. After all, viruses are pretty stripped-down to start with: they do a limited number of things, but they do them very well indeed. Compared to a relatively target-rich therapeutic area like cancer, infectious disease is a desert.

One well-known oasis, though, contains the viral proteases. Many viruses carry these as a key part of their machinery, to help "unpack" necessary proteins from larger precursors. Famously, that's how many of the anti-HIV drugs work, and the same general strategy should be applicable to several other viral types.

Hepatitis C has been one of the big targets for many years now. Various development programs have come and gone, but no one has been able to really nail this one. Vertex is now in the middle of trying to, and as Adam Feuerstein points out, they're really betting a large part of the company on the attempt. Over the next few months, results should start coming out for their PROVE trials of telaprevir (VX-950), and for Vertex's sake, the drug had better work. A herd of competitors, probably led by Schering-Plough, is ready to take over should anything slip.

"Work" is defined as "work well enough so that people don't have to take injections of interferon". That'll depend, as always, on the balance of efficacy and toxicity, and it's the side effect profile that everyone will be watching, since it's widely assumed that the drug will in fact do some good against the disease. The nerve-wracking thing about working for a small-to-medium sized company has always been that your future ends up depending on single events like this, and I wish everyone at Vertex good luck. (Of course, as people at Pfizer will tell you, your future even at a gigantic company can end up depending on the results of one clinical trial - this industry is getting altogether too exciting for a lot of people to take).

Comments (12) + TrackBacks (0) | Category: Clinical Trials | Infectious Diseases

October 18, 2006

Peptides as Texts

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Posted by Derek

There's a curious paper (subscriber-only link) in the latest Nature that's getting some attention, titled "A linguistic model for the rational design of antimicrobial peptides". For non-subscribers, here's a synopsis of the work from the magazine's news site.

A group at MIT headed by Gregory Stephanopolous has been studying various antimicrobial peptides, which are secreted by all kinds of organisms as antibiotics. Taking the amino acid sequences of several hundred of these and feeding them into a linguistic pattern-analysing program suggested some common features, which they then used to synthesize 42 new unnatural candidates. The hit rate for these was about 50%, which is far, far more than you'd expect if you weren't tuning in to some sort of useful rules.

It's the concept of "peptide grammar" that seems to be the news hook here. But I'm quite puzzled by all the fuss, because looking for homology among protein sequences is one of the basic bioinformatics tools. I have to wonder what the MIT group found with their linguistics program that they wouldn't have found with biology software. What they're doing is good old structure-activity relationship work, the lifeblood of every medicinal chemist. Well, it's perhaps better described as sequence-activity relationships, but sequence is just a code for structure. There's nothing here that any drug company's bioinformatics people wouldn't be able to do for you, as far as I can see.

So why haven't they? Well, despite the article's mention of a potential 50,000 further peptides of this type, the reason is probably because not many people care. After all, we're talking about small peptides here, of the sort that are typically just awful candidates for real-world drugs. And I'm not just babbling theory here - many people have actually tried for many years now to commercialize various antimicrobial peptides and landed flat on their faces.

You won't see a mention of that history in the Nature news story, unfortunately. They do, to their credit, mention (albeit in the fourth paragraph from the end) that peptides are troublesome development candidates. That's where it also says that there are reports that bacteria can become resistant even to these proteins, which prompts me to remind everyone that bacteria can become resistant to everything short of freshly extruded magma. It's in the very last paragraph of the story, though, that Robert Hancock of UBC in Vancouver says just what I was thinking when I started reading:

(Hancock) questions how different the linguistics technique is from other computational methods used to find similarities between protein sequences. "What's new is the catchy title," he says.

Comments (10) + TrackBacks (0) | Category: Biological News | Drug Development | Infectious Diseases

September 11, 2006

Enzymes Do Whatever They Want To

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Posted by Derek

It's been a while since I wrote about the neuraminidase inhibitors (Tamiflu and Relenza, oseltamavir and zanamivir). As we start to head into fall, though, I'm sure that avian flu will invade the headlines again, if nothing else (and I hope it's nothing else).

There's an interesting report in Nature (subscriber link) on how these drugs work. Bird flu is a Type A influenza, but there are two broad groups inside that class, which are defined by what variety of neuraminidase enzyme they express. (There are actually nine enzyme variants known, but four of them fall into one group and five into the other).

The drugs were developed against group-2 enzymes, but they're also effective against group-1 influenzas. Since the X-ray crystal structures showed the the drugs bound in the same way to all the group-2 neuraminidases, and since the active sites of all the subtypes across the two groups are extremely similar, no one ever thought that their binding modes would be different. Well, until last month, anyway, when the X-ray crystallographic data came in.

And what it showed was that the active sites of the group-1 enzymes, sequence homology be damned, have a much different structure than the group-2s. As it turns out, though, they can adopt a similar shape when an inhibitor binds to them, which is why the marketed inhibitors still work on them, but they're fundamentally quite different.

I can't resist the urge to use this example to illustrate some of the real problems in our current state of the art for computation and modeling. The differences between these two enzymes are due to their different amino acid residues far away from the active site, which makes modeling them much, much more difficult (and makes the error bars much, much wider when you do). That's why no one realized how far off the group-1 and group-2 neuraminidases were until the X-ray structure was available: modeling couldn't tell you. Any modeling efforts that tried would probably have decided, incorrectly, that the two groups were nearly identical. Why shouldn't they be?

But if we'd had that X-ray data from the start, modeling would very likely have told you, incorrectly, that there was little chance that either Relenza or Tamiflu would work on the group-1 enzyme variants. Why should they? The "induced fit" binding modes, where the enzyme changes shape significantly as the ligand binds, are understandably very difficult to model. There are just too many possibilities, too many of which are within each other's computational error bars.

Now, it's true that this latest work isn't based on molecular modeling at all. (You have to wonder how close these guys got, though). But plenty of projects that are using it are just as much in the dark as a neuraminidase team would have been, and they may not even realize it. Most molecular modelers are well aware of these limitations, but not all of them - or all of the managers over them - are willing to accept them. And when you get out to investors or the general public, it's all too easy for modelers or managers to act as if things are perfectly under control, when in reality they're lurching around in the dark. Like the rest of us. . .

Comments (11) + TrackBacks (0) | Category: In Silico | Infectious Diseases

July 19, 2006

Fuzeon's Fallout

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Posted by Derek

I wrote some time ago (Ay! Four years ago - have I been doing this for that long?) about the Roche/Trimeris HIV drug Fuzeon (T-20, enfuvirtide), and its costly manufacturing process. Roche built a factory in Colorado just to make the drug, which is a 26-amino acid peptide. And instead of doing it recombinantly, they're producing it the good old chemical way, by peptide coupling. (Here's a not incredibly competent collection of whiz-bang photos of the place, which at least have no purple spotlights in them)

Back in 2002, I had some thought that Roche had perhaps lost its corporate mind. But as this article from Chemical and Engineering News points out (subscriber-only, I think), they've actually done everyone a favor, whether by losing their minds or not. Their decision to go fully synthetic, and the massive investment that followed, has lowered the cost of all sorts of peptide synthesis reagents, starting materials, and equipment, to the point that it's now become enough of an industry to attract a lot more production interest. (And one of the big players in the contract business is. . .Roche's Colorado facility!)

As the article points out, recombinant technology (producing the peptide in engineered cells) is a wonderful thing, but only when it's working perfectly. And getting it to that point can be a long, expensive task. There are a lot of potential cell lines to choose from, each with its own advantages and disadvantages, and uncountable ways to engineer them and culture them. Even then, the purification of the target protein can be a whole new nightmare - as one chemist interviewed by C&EN says, at least synthesis doesn't give you back ten times as many different things as you put into it.

Peptides still aren't anyone's first choice for development when there's a small-molecule alternative. But for the targets that no small molecule is going to hit, they're worth looking at. Recent years have seen improvements in metabolic stability and duration of action, as people come up with all sorts of nifty delivery systems and conjugate polymers. You could do a lot worse.

But perhaps Roche could have done better. There were all sorts of glowing forecasts about Fuzeon when it was first approved, and all sorts of grumbling from people who took the optimistic numbers and calculated that Roche would be making its money back in two or three years at the prices they'd set. Well, that hasn't happened yet, since the drug isn't selling nearly as well as had been hoped.

Another two or three years should do it, if nothing better comes along to cut into Fuzeon sales. And stipulating that (which is no sure bet) Roche might be selling it for a long time to come, since the barrier to generic manufacture is going to be rather high. So, even after that wild factory in Colorado, they're still probably going to go into the black on Fuzeon, but it does make you wonder how the return compares to some of the other drugs in Roche's portfolio.

But that's their problem. In the meantime, it looks like they've helped everyone else in the business by making industrial peptide synthesis more affordable. Adam Smith's invisible hand strikes again. . .

Comments (11) + TrackBacks (0) | Category: Drug Development | Drug Prices | Infectious Diseases

May 10, 2006

A New Route to Tamiflu?

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Posted by Derek

There's been a lot of press coverage the last week or so about two new routes to Tamiflu (oseltamavir). Roche famously starts from shikimic acid, most of which they get from Chinese star anise, and the new syntheses are attempts to get around that bottleneck.

E. J. Corey's getting more attention than Masakatsu Shibasaki, partly because he's a Nobel winner and partly because he's made a point of placing his synthesis in the public domain. (Shibasaki's applied for a patent). It's nice to see organic synthesis make the headlines, but unfortunately, a lot of the coverage has been of the "Nobel Prize Winner Solves Tamiflu Problem" sort. I've also seen several stories that suggest that Corey's route opens the door (at last, right?) to mass production.

Not so fast. Roche has already been producing rather large amounts of oseltamavir, although they'd be glad to find a better route. And it's not like they haven't been trying themselves, as this PDF will make clear. And it's far from clear that Corey's route will be of commercial value, even though his overall yield, as given, is about 27%, which news articles are saying is roughly twice the yield from shikimic acid. (Note, though, that that Roche PDF claims a higher yield than Corey's - I'm not sure who's right).

Let's get technical and take a look at the chemistry. First off, the repeated claim that Corey's route starts from two of the cheapest feedstocks available - butadiene and acrylic acid - is only partly true. The key Diels-Alder reaction actually uses trifluoroethyl acrylate, which is substantially more expensive than acrylic acid, although admittedly ten times cheaper than the same amount of shikimic acid from the same source. Moving on, there are eleven steps, and according to the supplementary material for the paper (where the full experimentals are), steps 1, 3, 4, 5, 6, and 8 have chromatography in their workup. The others are run through a plug of silica or are taken on crude, which tells me that Corey's students probably tried to do the same with the remaining steps but took a hit on the yields. Every chromatographic purification adds a great deal to the cost of a process route, needless to say.

There are other wrinkles. Steps 1 and 2 start at -78 degrees before coming up to more process-friendly temperatures. Step 8 is a slow addition at -40, and step 9 is an inverse addition at -20. Low-temperature reactions are certainly doable on scale, but again, they'll add to the cost and complexity. Those last two steps involve an acylaziridine intermediate, whose thermal stability would need to be checked out, and could partially negate the advantage of not using azide in the route.

The scale of the reactions in this paper is in the ten-gram range, which is fine, until you get to steps 8 and 9. Those low-temperature reactions are shown on 300 and 160 milligrams, respectively. That tenfold drop in scale indicates another area that would need to be checked out; there can be a huge difference between something that works on a couple of hundred mgs and a useful process, especially in the cold.

All this isn't to say that Corey's route doesn't work, or that it can't work on scale. But it's important to keep in mind that the kind of chemistry done in his lab is about as far from industrial scale as you can get. It may be that the more interesting features of his route (the catalyzed Diels-Alder, for example) could be combined with some of Roche's own process ideas and turned into something feasible. But for now, this is an interesting route that's a long way from solving anyone's Tamiflu shortage.

To be fair, Corey himself isn't responsible for some of the hype, except I wish he wouldn't let himself be quoted as saying that the thinks that the Tamiflu production problems are "solved". Headline writers know nothing about organic chemistry or drug development, and they run with what's in the press releases. Of course, there's the larger question hanging over all of this: will Tamiflu even do anyone any good if there is a human outbreak of avian flu? And that, nobody knows.

Comments (19) + TrackBacks (1) | Category: Chemical News | Infectious Diseases

January 19, 2006

Tamiflu: Good For Anything, Or Not?

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Posted by Derek

So, are the neuraminidase inhibitors (Tamiflu and Relenza, oseltamivir and zanamivir) going to be of any use against bird flu? The press coverage is a mass of confusion. Headlines range from stuff like "Newer Flu Drugs Work Better" to "Don't Use Older Flu Drugs, Experts Warn" to "Tamiflu Not Effective Against Bird Flu". The problem is, we're looking at two different classes of drugs, and two different sorts of flu.

A few days ago the CDC issued a warning that the prevalent H3N2 flu strains this year have mutations that make the older class of flu antivirals (the aminoadamantanes) ineffective. But I'm not sure how many people even get these any more, since they were never very impressive to start with. I don't think anyone has seriously proposed them as a defense against H5N1 avian influenza, should that ever take off.

But Tamiflu and Relenza are a different story; a blizzard of hype has surrounded their possible use. Lost in the bird-flu noise is their use against "regular" influenza, a market where they've never performed up to expectations - no doubt they're selling rather better so far this season - and the CDC recommended their use for this purpose.

Comes now a report in The Lancet from a group in Rome (available to subscribers here), looking over all the published studies on the various drugs. They also recommend that that adamantanes be retired, and they aren't very positive on the use of the NA inhibitors against the standard forms of flu, which I'd say is in line with the clinical experience. And they found no evidence that either Tamiflu or Relenza is effective against bird flu, which leads to all the jumpy headlines.

But this isn't really a surprising finding, since there hasn't been (to my knowledge) any published study on the use of the drugs against avian influenza in humans. (Cell culture, yes, but that's a long way from the real world). There hasn't been enough time (and there haven't been enough patients, fortunately). A better headline would have been "Tamiflu's Effectiveness Against Bird Flu Unknown", but we already knew that. Didn't we?.

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November 14, 2005

One Darn Miracle After Another

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Posted by Derek

Andrew Stimpson isn't a scientist. If he were, he might have heard the line about extraordinary claims requiring extraordinary evidence. And his claim is indeed extraordinary - he says that he has managed to clear HIV from his system without therapy. Well, other than vitamins, don't you know - and if he says that he got them from Matthias Rath, I'm going to have to go lie down for a while.

This story has generated all sorts of irresponsibly breathless headlines, but when you read the stories underneath them you find that there's not much behind it. Stimpson received a positive HIV diagnosis on the basis of two antibody tests in 2002. Near the end of 2003, he was found to be negative, and was asked to repeat the test to confirm it. He refused, and sued the British health trust that did the testing.

Update: Press reports disagree about this. Some have the story as above, and others say that Stimpson tested negative on several occasions during 2002 and 2003. His initial postive tests showed what is being described as "an extremely low viral load."

Here's where things get messy. Stimpson appears to have sued because he felt that the original tests were in error. (The agency naturally stood by both its positive results). When no money was forthcoming, he then seems to have gone to a couple of the British tabloids with his miracle recovery story: ". . .I am just one person who managed to control (HIV), to survive from it and to get rid of it from my body", he's quoted as saying, which is an interesting statement from someone who was previously claiming not to be infected at all. Update: Stimpson eventually received a letter from the National Health Service calling his HIV-negative status "exceptional and medically remarkable", so he at least didn't come by his miracle-recovery story alone.

Stimpson hasn't been tested again, and doesn't seem to be available at the moment. I am not inclined to believe any claim such as his, to put it mildly, until he's been poked and prodded from every angle - to put it mildly. You would think that he might wish to help other HIV sufferers if he really has reversed the disease, wouldn't you? The article link above quotes the head of a charity in England as saying "The answer may turn out to be very complex. We must not jump to conclusions." Actually, I'm close to jumping to the conclusion that the answer might be rather simple.

Update: Press reports also disagree - markedly - about Stimpson's willingness to undergo further tests. My final sentence isn't meant to suggest some complex biochemical rationale. I'm thinking that the chances are best that the first positive results were in error - after all, their false-positive rate is surely much higher than the spontaneous-clearance-of-HIV rate. The health agency that tested him, though, might well prefer to treat this as an amazing medical anomaly rather than as a botched test. And given that he wasn't able to collect damages, it became in Andrew Stimpson's financial interest to go with that explanation as well, selling his story to the British tabloids for an undisclosed amount.

In the end, I agree with this quote, from the Nature.com news item on this story: ""If it is real, it's very interesting," says Jonathan Weber, an expert on infectious diseases at Imperial College London. But he cautions that the most likely scenario based on the current evidence is "either a false positive [in 2002], or he's still infected".

Comments (10) + TrackBacks (2) | Category: Infectious Diseases

November 9, 2005

Cash For Vaccines

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Posted by Derek

While the Wall Street Journal is opening its site for free this week, may I recommend this excellent article on the vaccine and antibiotic markets? It's a clear-eyed look at why drug companies haven't put more time and money into these areas over the years. The headline makes it sound as if it's going to be a pharma-bashing-festival, but the authors (Scott Hensley and Bernard Wysocki) lay out the facts, which are just as I understand them from my vantage point, too.

The second article in the series is also up here. It's an equally good overview of the possible incentives that are being discussed to encourage work in vaccines and anti-infectives. I'm glad to see the idea of incentives being discussed, because as it stands, the market isn't necessarily going to give us what we need in the time we need it. New antibiotics are generally reserved for use in resistant cases only, so you can't make your money back there. And new vaccines can end up costing too much in liability suits (many - most - of which aren't particularly well justified). But put some incentives in there, and perhaps the numbers can work out. The article goes into detail on some of the proposals - straight cash, guaranteed purchases, extra product exclusivity, and so on.

I know that some people will hear these ideas and wonder why the government doesn't just do the research itself, rather than cough up money to the drug companies. The biggest reason is that the drug companies are better at it, and faster as well. We stay on our toes competing against each other. The biggest pitfall in these incentive plans, as far as I'm concerned, is that it might end up with companies that have no one breathing down their neck. Better to have two or three organizations racing each other and throwing elbows to grab the prize, than to have someone ambling over to pick it up.

Comments (5) + TrackBacks (0) | Category: Infectious Diseases

November 2, 2005

The Flu Plan, Part Two: Antiviral Drugs

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Posted by Derek

In the first post below, I said that we would be in big trouble if we had to rely on a vaccine for all of our protection against a flu pandemic. The problem is, if we're relying on antiviral drugs, we're in even worse shape. (See my post on this from last March.)

Right now, the only drugs likely to do much of anything against an influenza pandemic are the neuraminidase inhibitors like Tamiflu and Relenza. But the problem is, these drugs really have to be taken early in the course of the infection to be most effective. By the time many people realize that they have the flu, it may be too late to do much about it.

One way to get around that problem would be to take the drugs prophylactically, but that has two serious disadvantages. For one thing, this route might well lead to a quicker development of resistant viral strains, which is something that we already know can happen. And for another, it would burn through huge amounts of drug, and we don't happen to have huge amounts of either one.

Why is that? Well, for one thing, neither compound was selling very well until recently. The companies involved have never had to ramp up production to the levels that people are talking about now. It's doable, but it won't be fun. The ten-step Roche synthetic route to Tamiflu uses some azide chemistry, which is potentially toxic and explosive, but it's nothing that a good bunch of industrial chemists can't handle. (It helps, for example, that India's Cipla already has experience making AZT, because that relies on similar chemistry). But any ten-step route is not going to be trivial to implement if you've never done it before, azide or no azide.

A bigger problem is that these drugs have syntheses from a starting material called shikimic acid. That's a component of an important metabolic pathway in plants. (It's important enough that the well-known herbicide Roundup works by shutting it down). Shikimic acid is found in small quantities in a lot of plant species, but star anise, a spice used in Chinese cooking, has a lot of it. (If you'd like to extract some from any star anise you have in your kitchen, here's how). Roche already has a network of suppliers in China, and the generic companies who plan to produce the drug are having a hard time sourcing the shikimate. It can also be produced by fermentation, which Roche uses for some of its supply, but that's an even more specialized process.

All in all, I think it's prudent to stockpile these drugs, although I'm not sure, for the reasons given above, where the US government is going to find the quantities it's looking for. But even if we can pile the stuff up to the rafters, we have to be ready for the possibility that these drugs may or may not do us much good. I see that I've ended both of these posts on the same note. . .

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The Flu Plan, Part One: Vaccines

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Posted by Derek

The government's proposed plan for dealing with a flu pandemic is worth some comment, although it's going to undergo mutations just as surely as the viruses do. It's hard to argue with the overall approach, but there are some details that need explaining.

For example, there's a proposed boost for research into vaccine production through cell culture techniques (as opposed to the famous chicken-egg methods), and I think that this is a fine idea. Unfortunately, it was just as fine an idea two or three years ago, and we'd probably be in better shape now if this idea had been pushed back then. Money doesn't convert to time quite as easily in basic research as it does in some other areas (although it doesn't hurt, true). Some of the companies that do work in this area are pointing this out today, in rather testy tones of voice:

. . .so far the government has not backed development of three cell-based vaccines that have received or are close to receiving regulatory approval in the United States and Europe - including one developed by a Meriden (CT) biotechnology company. Instead, the Department of Health and Human Services last April funded only one cell-based flu vaccine - $97 million for a vaccine that has not yet been tested in animals or humans.
"I don't know what the hell they are thinking about," said Dan Adams, president and chief executive officer of Protein Sciences. . ."

This is the voice of a man whose company missed out on a $97 million dollar contract, so that has to be taken into account. But it does appear that HHS and the FDA have been overly cautious about moving to cell-culture based vaccines.

But "caution" is a popular word in the vaccine field, in the financial, medical, and legal senses. and that brings up another provision in the President's proposal that I haven't seen anyone else comment on yet: liability protection for vaccine producers. As you might figure, I think that this is on principle a good idea, but the trial lawyers (and some others) will think differently. This will be an interesting fight, but it might take place largely out of sight. "Fight for your right to sue the people who are trying to protect you from bird flu" isn't a very catchy slogan.

My last comment on vaccines in this context is to point out that - cell culture or no cell culture - if we get to the point that we're relying on a vaccine to save people from a pandemic, then we could be in big trouble. There's an inevitable delay in vaccine development and production - months and months and months of delay, and that's when things are really zipping along. Viruses can mutate in the time it takes to fight their previous versions. If we're lucky, the vaccines that are being developed now will have enough protective effect against whatever flu strain might cause a pandemic. But they might well not, and we need to realize that.

Comments (4) + TrackBacks (1) | Category: Infectious Diseases

October 13, 2005

Buy! It's More Expensive Than Usual!

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Posted by Derek

Note: This post has a follow-up with Jim Cramer's reaction to it here.

The small-pharma flavor of the month seems to be Biocryst Pharmaceuticals, but it's not one of their current development projects that has everyone jumping up and down. It's a drug that failed its Phase III trials two years ago. Despite the best efforts of various stock newsletters and of multimedia stock tout Jim Cramer, though, I'm managing to resist the company's stock.

The words "avian influenza" are the missing piece to this puzzle. The drug, peramivir, is a neuraminidase inhibitor developed as a flu treatment, which is the same mechanism as the marketed drugs Relenza and Tamiflu. With the current worries about a possible pandemic, antivirals of all sorts are getting a second look.

In this case, you have to go back a few years for the first look. Peramivir was in Phase II trials during the late 1990s, and in 1999 the results were announced: not too bad. Their endpoint was reduction of viral titer, the blood marker of flu virus infection, and they hit it. On to Phase III, then, to see if that effect was worth anything in the real world.

There were some rough patches. Biocryst's development partner, Johnson & Johnson, pulled out of the deal before the Phase III trials got properly off the ground. (So much for the Valentine-card sentiment about them being the "ideal partner" at the end of that 1999 press release). J&J seems to have taken a look at the market performance of the other neuraminidase inhibitors and concluded that they had better places to put their money.

They were probably right about that. Tamiflu and Relenza were supposed to be much more successful than they've turned out to be. I wrote about this a couple of weeks ago in the context of a Canadian effort to develop new antivirals. The Canadians make an appearance in at least one article on Biocryst, from the New York Times, which also talks about the unhappiness of the smaller companies (Gilead, Biota) that first discovered Tamiflu and Relenza:

Tamiflu's inventor, Gilead Sciences, a California biotechnology company, told Roche in June that it wanted to take back the rights to the drug, accusing Roche of a "consistent record of inactivity and neglect" since the medicine was approved by the F.D.A. in 1999.

A Roche spokesman, Terence J. Hurley, said the company had fulfilled all its obligations to Gilead to promote and manufacture the drug and the dispute was in arbitration. . .

Biota, which is based in Australia, filed a lawsuit there against Glaxo last year, saying it did not adequately try to market Relenza. After the drug's first year on sale, "essentially all promotion was stopped," Mr. Molloy said.
Biota is seeking about $300 million in royalties it says it would have earned if Glaxo had done an adequate job. (Biota has now teamed up with Sankyo to move Sankyo's version of Relenza forward under a $5.6 million grant from the National Institutes of Health in the United States.) Glaxo denies Biota's accusations in the case, which is headed toward arbitration later this year.

"We lost a lot of money, quite frankly, promoting it, and the demand wasn't there," said David Stout, Glaxo's president for pharmaceutical operations.

I especially like that last quote, since I thought that the drug industry was always supposed to be stampeding people into buying stuff that they didn't need. Maybe Glaxo could hire Marcia Angell as a consultant to show them how it's done. Just thinking out loud here. . .ah, what a match it would be. . .

OK, where were we? Ah, back in early 2000, as Biocryst was preparing to go it alone in their Phase III effort. They did manage to get things off the ground, but the results were very disappointing. The endpoint this time wasn't just reducing viral load, but reducing flu symptoms. And the drug managed to decrease the time to improvement of symptoms by. . .about half a day, with no statistical significance, and this at doses up to 800 mg/day. They dropped the compound immediately, and rightly so.

Although that press release doesn't go into the details, Biocryst has told the press that one reason that peramivir might have failed was poor blood levels after oral dosing. I'm going to reserve judgment on that explanation, because the blood levels were certainly high enough to go through Phase II and Phase III trials – blaming them now sounds a bit ex post facto. Injected versions of the drug seem to perform well in rodent models of avian flu infection, and they're looking to get a human trial going via the same route. (This was an option before, too, of course, but the drug had no commercial chance as an injectable versus two non-injectable compounds as competition). And in all the noise about injectable peramivir, I haven't heard anyone say how it performs versus injections of Tamiflu or Relenza, either. Surely they can be formulated for it.

The prospect of a flu pandemic has changed things, but the problem is, it's too soon to say if people are now being more realistic or just more hysterical. In the last few weeks, though, I think things have tipped toward the latter. Avian flu, if it crossed over into some highly infectious human form, could be very bad news. But we're not seeing that happen (yet) with the current bird flu. It's worth remembering that flu viruses of this type have already crossed over into humans in recent years without taking off around the world. That doesn't mean that it can't happen, but it does mean that it's not inevitable.

So, no one knows how likely a pandemic is, when it might occur, and how it might behave. It's prudent to take a look at marginal compounds like peramivir, whose possible use against avian flu was being spoken about years ago. But it's not prudent to buy, or urge others to buy Biocryst's stock after it's already tripled in price. Looking at that price and the implied value of peramivir, The Biotech Stock Blog says:

"An NPV of $350 million, for example, implies $900 million of sales next year at a 50% gross profit and discounting back 15%. If you assume there is risk associated with the company realizing future cash flow from peramivir, then the implied future cash flow is considerably larger. For example, handicapping the likelihood of BioCryst winning a government contract and selling product next year at 50%, implies BioCryst sells $1.8 billion worth of peramivir next year!

Any way you slice it, the expectations for BioCryst are wildly optimistic based on the current stock price. This is not to say that peramivir does not ultimately become a successful drug or that there isn't money to be made on BioCryst. Ultimately, however, reality will come back to the stock and the fast money will go elsewhere. When the music stops, you don't want to be the one without a chair."

(Link via The Stalwart). I agree with this analysis completely. Would Jim Cramer, in between shouting into the microphone and waving his arms, care to comment on these numbers? Or are we going to have a historial re-enactment of 1999, with Biocryst playing the part of Viropharma and Cramer taking on the role of Tokyo Joe? Since his analysis of BCRX so far includes the phrase "Trading is all about the buzz", that's just what we might be in for.

I made a lot of money shorting VPHM back then, and (although I haven't yet) I'm tempted to go short BCRX now. I wonder if there are any shares left to borrow?

Comments (4) + TrackBacks (1) | Category: Infectious Diseases

October 3, 2005

Well Deserved

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Posted by Derek

The Medicine/Physiology Nobel for Barry Marshall and Robin Warren is a fine thing. It's important to realize just how odd it seemed that ulcers could be caused by bacterial infection, when Everyone Knew that they were due to excess stomach acid, no doubt caused by stress and such things. (Check out the retrospectively insane passage from 1967 cited here in an excellent review of the H. pylori discovery. It's a respectable review article with authoritative research showing that over-dominant mothers were responsible for most ulcers. Sigmund Freud has a hell of a lot to answer for.)

H. pylori is the source of almost all ulcers, and is involved in many stomach cancers as well. Infectious agents are now suspected to play a role in many other chronic conditions. The germ theory of disease has become more important than ever in the last twenty years, and these are two of the scientists most responsible.

Marshall and Warren pursued their line of research despite raised eyebrows and dismissive head-shaking, even to the point of ingesting a culture of bacteria to show that it could infect the stomach lining. And they were absolutely correct, as the scientific world came to realize. An important (and encouraging) part of the story is how they were able to prove their case and completely change medical opinion within just a few years. It's good to think about that when people start going on about Dogmatic Intolerant Scientists and Science As A New Religion and so on.

Crazy ideas won't necessarily get you tossed out of the club. Crazy ideas with nothing to back them up will. But just come back with the evidence, and they won't be crazy any more. Show me the religion that takes its heretics and makes them bishops, won't you?

Comments (11) + TrackBacks (1) | Category: Infectious Diseases

September 26, 2005

Antivirals "Gathering Dust"?

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Posted by Derek

The CBC has an article claiming that:

"Formulas for new, inexpensive influenza drugs that could expand the world's tiny arsenal of weapons against pandemic flu are gathering dust because the pharmaceutical industry isn't interested in developing them, scientists say.

They believe governments should fund the testing and development of the drugs, side-stepping big pharma and bringing them to market as cheap generic medications.

And they point to the story of Relenza - one of only four flu drugs currently sold - as evidence public-sector involvement will be needed if crucial new flu drugs are ever going to hit pharmacy shelves. . ."

Which scientists say these things? Well, one of them is Mark von Itzstein, of Griffith University in Australia, who is quoted as saying that he has "three compounds that are ready to be tested in animals and could be available on a commercial basis in three to five years for about $10 a treatment course". You have to get to the end of the article to get to some of the problems with that statement, and some of them never make it to the surface at all.

For one thing, having three compounds that are ready to be tested in animals is not as big a number as it might sound. I've been on projects where many more compounds than that - about ten times more, in some cases - went into animal testing, and nothing still came out the other end. It's good to have compounds that you believe in, but Prof. von Itzstein (who helped discover the drug now sold as Relenza) surely knows, you usually need a lot more shots on goal than that.

Another little detail is that going from this unspecified "animal testing" (efficacy model? two-week toxicity?) to "available on a commercial basis" in under five years is rather unlikely. That's a very, very short time for drug development, and I don't see how all the regulatory requirements could be met so quickly. And having a cost estimate in hand makes it seem as if there's already a bulk synthesis of the compounds, but why would you do that before you've even come close to going into animals?

This all has to do with a Worthwhile Candian Initiative called ICAV, which aims to get more antiviral drugs on the market. I certainly can support that idea, but I think that the people involved will soon find out one reason why there aren't more of them already: antiviral drug development is very hard. There are a lot of disparaging references in that CBC article about the profit-driven drug companies ignoring all these worthy drugs, but then there's this:

"ICAV is trying to get buy-in from governments around the world, starting with Canada. It has asked the federal government for $70 million over seven years to promote development of antiviral drugs for a number of diseases, including influenza, HIV and hepatitis C."

You know, I could have sworn that those indications could all support profitable drugs - if of course, they, like, work and everything. One of the problems with neuraminidase inhibitors like Relenza is that they have to be administered rather soon in the disease's progression, or they're basically useless. That's one reason that they haven't caught on, together with their often less-than-compelling efficacy. But getting antivirals with compelling efficacy is, as mentioned, hard. Those of us over in the profit-driven drug industry can only agree with Prof. von Itzstein wholeheartedly when he's quoted as saying "We need new antivirals." The only thing I would add is just a "good" in the middle of that sentence.

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July 25, 2005

The Check Shows Up in the Mail. Really.

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Posted by Derek

In the drug industry, we tend to look down a bit at academia's attempts at pharmaceutical research. We don't go out of our way to hire people with university degrees in medicinal chemistry, for example, which you'd think would be a perfect fit. (Here's why.) And we're always insinuating that the professoriat just doesn't understand what it takes to develop a drug, and what kind of timelines have to be met. I've made a number of comments like that here, and I'll surely make some more.

But I have to admit that it's not always true. There are a few drugs that have come out of academic research, although in all the cases I'm aware of, much of the expensive heavy lifting was done after signing a deal with a pharma or biotech company. (Scroll down to the September 2004 posts herefor more ranting than you may need on the "all drugs come from academic research anyway, right?" position.)

One notable success story has been the antiretroviral Emtriva (emtricitabine), a nucleoside mimic that acts as a reverse transcriptase inhibitor. It was discovered in a longstanding program to find new antiviral agents at Emory, with the chemistry coming from Prof. Dennis Liotta and his group. (Personal disclosure: I nearly went to Emory for grad school to work in Liotta's group, and was strongly considering doing a post-doc with him afterwards. And I've attended his Gulf Coast Chemistry Conference a couple of times as well.)

I mention all these connections, I guess, because word comes now that Emory has cut a deal cashing in all future royalties for a record-setting $525 million dollars. They're selling 65% of the royalty stream to Gilead, the company that markets Emtriva (the orginal deal was done with Triangle Pharmaceutical, a firm of Burroughs Wellcome refugees later bought by Gilead), and 35% to VC firm Royalty Pharma. And the deal provides that the University itself gets 60% of that, with the rest to be split between Liotta, Raymond Shinazi (on the medical side), and former Emory researcher Woo-Baeg-Choi.

That is 210 million dollars to be split between the three of them. My heartiest congratulations, from down here on the floor where I'm fanning myself. I can tell you that if I come up with a winning drug here in industry, I'll likely get promoted, and may well even see a bonus. But I will most definitely not see any seventy million dollars. Maybe this academic model for drug discovery has something to it after all. . .

Comments (0) + TrackBacks (0) | Category: Business and Markets | Infectious Diseases

July 17, 2005

And It Goes Like This

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Posted by Derek

It's no wonder that there's still so much argument over autism and vaccines. Paranoia is an endlessly renewable resource - big glowing hunks of it are always being dug out of the ground and put to use. For an unfortunately typical example, take a look at this piece from the New York Times. Some fifteen years ago, studies were carried out in New York to determine the safety and efficacy of pediatric doses of the existing HIV medications:

The controversy extends back to a bleak period in New York City history when well over a hundred children a year were dying of AIDS, most under the age of 5. As many as one in every five children infected with H.I.V. were dead by 2, doctors now say; up to 50 percent were dead by 4.

There were no AIDS drugs approved for children in those years. The first AIDS drug, AZT, was approved for adults in 1987. Babies were being abandoned in hospitals, their mothers unable to care for them and with no foster homes available. About 40 percent of the children with H.I.V. were in foster care.

As a result, pediatricians began pressing pharmaceutical companies to let them try drugs shown to work in adults. . .

. . .One center that took part in the trials was a small boarding home for H.I.V.-infected foster children called Incarnation Children's Center, the brainchild of Dr. Stephen W. Nicholas, now director of pediatrics at Harlem Hospital Center. With as many as 24 infected children abandoned in the hospital in 1988, the idea of finding them a home outside the hospital came to him after a young patient greeted him with, "Hi, Daddy."

Working with Columbia University and the Catholic Archdiocese of New York, Dr. Nicholas became the medical director of Incarnation, on Audubon Avenue in Washington Heights, which opened in 1989 and added an outpatient clinic in 1992. Foster children there and elsewhere were enrolled in trials - at first, trials of single drugs like AZT, and later, of multiple-drug cocktails and protease inhibitors, which by 1996 were helping turn AIDS into a manageable, if still chronic, disease.

For his trouble, Dr. Nicholas became the focus of attention from one Liam Scheff, who published a screed 18 months ago on Indymedia (and didn't I groan when I saw that phrase in the article) accusing the Incarnacion facility of forcing poisonous drugs down the throats of innocent children, killing who knows how many in the process, et cetera, et cetera. I should mention that Scheff doesn't think that HIV is likely to be the cause of AIDS, doesn't think that the drugs against it necessarily have done any good, and so on - just so you all know where he's coming from.

Witness now how avalanches start: That Indymedia piece set off a group called the Alliance for Human Research Protection, whose publicity got the New York Post going, which led to a BBC-financed film ("The New York Experiment - Guinea Pig Kids"), which ignited the activists at a Brooklyn-based group that seeks reparations for slavery and whose leader claims (with no apparent evidence) that many of the children didn't even have HIV:

What we know already," he said, "is that 98 percent of the children experimented on were black and Latino and that the fundamental basis of why they chose those kids was racism. They have the arrogance to say it was for their own good, but we know it was racism."

That brought a couple of city councilmen into camera range, and things have continued to deteriorate. At this point, what really happened in the late 1980s doesn't seem to matter much, but for the record:

"Pediatricians involved in the trials say they are mystified by the onslaught. While powerful drugs do have side effects, many said, they remembered no fatal reactions. At Incarnation, Dr. Nicholas said, no child had died of a reaction and "no child ever had an unexpected side effect."

He said that, with one exception, no children had been included in the trials without "absolute proof" by advanced testing methods that they were infected and not simply carrying their mother's antibodies. He said the exception was a trial that proved that by giving AZT to pregnant, infected women and then to their newborns in the first six weeks of life it was possible to sharply reduce the rate of H.I.V. transmission from mother to child. He called that study "the most important clinical trial in the history of AIDS."

Well, yeah, fine - but what about the secret experiments? Evil corporations and secretive government agencies? Racist plots and toxic drugs administered by sinister doctors? What about the good stuff? Hasn't Dr. Nicholas watched any TV, seen any hit movies? Doesn't he know how this country really works?

My heart goes out to him, actually. From all I can tell, he has done the world a real service, and saved more children than could we can count from awful, lingering deaths. For this, he and his co-workers get the Mengele/Tuskegee treatment from publicity hounds and people who've rotted their brains reading Indymedia. What a reward.

Comments (9) + TrackBacks (0) | Category: Infectious Diseases | Press Coverage

July 7, 2005

More on Brazil and Kaletra

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Posted by Derek

I didn't plan on becoming the defender of Abbott's pricing decisions, particularly after that Norvir business in 2004, which I though reflected poorly on them. But these are special circumstances. Since we're on the subject of Brazil and its compulsory licensing threat, I thought it would be worth going to the source. Here, then, is the statement of Brazil's Minister of Health on the matter, dated June 27th. There are some interesting features in it that I'd like to highlight (emphasis added):

"This stage may come to represent the first step for introducing a new phase in our local ARV production. An additional target is to support our national manufacturing industry in this respect, as we are totally committed in maintaining high quality in the medicines available in the public health services.

The Brazilian law allows compulsory licensing in cases of public interest or emergency situations. These are related to issues that involve health, nutrition, protecting the environment, and the technological or sociological development of the country."

Now, much of the rest of Dr. Humberto Costa's statement emphasizes pricing. But I find the industrial-policy aspects rather troubling. How much of this decision is predicated on economic nationalism? We can argue about to what extent Abbott should forgo Kaletra profits in order to help poor Brazilians who are infected with HIV. But should they forgo profits in order to develop the Brazilian generics industry? Here's some more from Dr. Costa:

"In spite of being successful in reducing prices over the period, Brazil still pays exorbitant and unacceptable prices even from the point of view of the full application of capitalist principles."

Wow, even from the point of view of capitalism and everything. . .we've gone about as far as we can go, I guess. How annoying that the antiretroviral drugs have pretty much all come from people who hoped to earn back the immense cost of their development. All I can say to Dr. Costa is: if you think the prices you're paying are unacceptable, you should see what other people have to pay to make up for yours.

And here comes some more capitalism, so get braced: if you go ahead and confiscate someone else's intellectual property, companies will have to factor the chance of that happening again into their future development costs and pricing decisions. And no, in case you're wondering, that will not make prices go down, and it will not make people eager to do more business in Brazil. Not to worry, though: if countries around the world follow your example and seize whatever drugs suit them, eventually there won't be many drugs to seize.

Comments (34) + TrackBacks (0) | Category: Infectious Diseases

July 6, 2005

Brazil Pulls Out the Pin

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Posted by Derek

Just how much should an anti-HIV drug cost? What if you're selling it in a place where most of the patients can't afford it? These questions have been fought out in Africa and other parts of the developing world over the last few years (and the stagnating world, too, unfortunately.) Now Brazil may be making good on a threat of outright patent confiscation.

The Brazilian government is unhappy with the price of Abbott's combination therapy, Kaletra (PDF), which they already pay just over $100 million per year for. Mind you, that's the lowest price in the world outside Africa. Online pharmacies claim that the average US retail for Kaletra tablets is about $4.06 each, and they offer it at about $3.60. Brazil's paying $1.17, and they're saying that they'll issue a compulsory license if the price doesn't come down to 68 cents.

They've threatened to do this before, but have never come this close to following through. The worry for Abbott is that once the Brazilian generic companies start making the stuff, it'll end up all over the rest of the world at a base of $0.68/tablet. And where do you think demand for it will be strongest? In the countries where it's already the most expensive, which Abbott is counting on for their profits.

Opinions vary a bit, as you'd figure. You can find no shortage of activists cheering the Brazilians on. To wit, from the AP article linked above:

"We are the hostages of these companies, and compulsory licensing is a defense against the abuse of monopolies," said Jorge Beloqui, the leader of a Sao Paulo-based AIDS support group.
Beloqui, a university math professor, has taken 30,000 anti-AIDS pills provided free by the government since 1991. If Brazil breaks the patent, he says, activists will pressure Brazilian politicians to go a step further and let its generic drug makers produce much more of Abbott's drug so it can be shipped around the world to needy patients.
"These medicines are essential to the world, and I think Brazil should sell them," he said.

Actually, Prof. Beloqui is the hostage of a retrovirus, but his comments seem pretty representative of the "stick it to The Man!" point of view. Well, speaking for The Man (to crib a line from Tom Wolfe), I have to say that Brazil seems to be playing to the galleries here. There are accusations that the country is spending less on anti-HIV medications than it did five years ago, and they turned down $40 million in US money not so long ago. There's another problem, too. Brazil is acting according to WTO language about breaking patents in case of a public health crisis. But you have to wonder

Allowing Brazil to use the "public health crisis" justification creates a dangerous and perverse incentive for governments of the developing world: if you as a government are responsible and work hard to uphold a fiscally manageable public health program, then you will be punished by having to pay for expensive drugs, but if you fail or simply ignore the problem and cry "crisis," then you will be rewarded with permission to trample on intellectual property rights.

I've known some pretty good Brazilian scientists, but the country isn't up to being able to discover and develop its own new ones. (Very few countries are; you can count them on your fingers.) So I've saved my usual justification for last: if Brazil decides to grab an HIV medication that other people discovered, tested, and won approval for, who's going to make the next one for them?

Comments (43) + TrackBacks (0) | Category: Drug Prices | Infectious Diseases | Patents and IP

June 30, 2005

Where's the Combo?

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Posted by Derek

Gruntdoc wonders about why a particular combination therapy isn't available yet. Skin infections with methacillin-resistant staphylococcus aureus (MRSA), which I hope I never come any closer to experiencing, are treated with one of several antibiotic combinations, but they're all administered as separate drugs.

The answer is what you might suspect: the FDA would want clinical trials of the single-dose combination, just to make sure that things work the way that they're supposed to. Any company developing the combo would have to recoup those costs, not to mention the costs of then beating the drum for the idea that the new combination is a better idea. But the antibiotics in question are generics, which means that there could be some real cost-containment issues over the use of a more expensive combination.

But we have a rather close example at hand: the recently approve BiDil. (Here's the package insert, in PDF format.) That's a combination of two generics, too, which (famously) shows far better effects in the black population than it did in general clinical trials. Nitromed, the developer of the therapy, had to run some pretty reasonable-sized ones, and they spent a lot of money in the process.

They started by establishing that the blood levels of the two drugs were reasonable when given in combination, and went on to a group of 186 male patients. That trial (with 273 in the placebo group) didn't show a benefit, but hinted at one in the black subjects. The company also ran an 804-patient trial against enalapril, and saw the same trend, which led to the definitive 18-month trial in 518 black patients (with a roughly equal number in the placebo arm.) Keep in mind, this is all for two drugs whose individual efficacy was well-studied.

Note added after original post: Nitromed was after something more than the individual efficacy of each drug. Their hypothesis was that the combination would make the blood-pressure-lowering effect much more pronounced, and that this would translate into clinical benefit as seen in eventual mortality. Why this only seems to be the case in the black population is a head-scratcher. The situation for combination antibiotics would be simpler. So. . .

A combination antibiotic trial wouldn't be as long, or as expensive. But it wouldn't be negligible, either, and it's likely that some companies have run the numbers and decided that the investment would be unlikely to pay off.

Comments (3) + TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Infectious Diseases

June 22, 2005

Fan Mail

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Posted by Derek

This is the first one of these I've had since I started blogging. It's in response to this recent post, and I thought I'd celebrate by sharing it with everyone:

"You are a shameful individual Mr. Lowe - to make a living in the pharmaceutical industry, whether past or present and then turn around and cast Dr. Rath, who presented clear evidence that his formulations work not only with AIDS but also cancer, as some greedy vitamin pusher when contrasted with the pharmaceutical industry which makes profits over and above 20,000 times the cost of drugs is beyond absurd - it is a baseless slander scheme. You guys may believe you can hide the truth from people, and maybe you might, God will have done what God sees fit to allow, but the day will come when you and your cohorts will have to answer for your lies, deceptions and greed-driven undermining of the health and welfare of many nations - on that Day justice will be served."

Dr. Rath's clinical trials were conducted where, exactly? By whom? With what sorts of controls and in what patient population? And reached what sort of statistical significance against which endpoints? The governments of Switzerland, England, and South Africa disagree with him for what reasons?

Your figure of "20,000 times the cost of drugs" comes from where? Arrived at by what measure? If a drug makes ten billion dollars of profit over its patented lifespan (a mighty fine number, one that most never reach), does that mean, if we divide it out, that the "cost" of that drug was. . .$500,000? On whose planet?

And Dr. Rath's profit margins are. . .what, exactly? The money for his international operation and his high-profile advertisements comes from. . .where?

I'll take my chances with God if and when the time comes, as will Matthias Rath. At least I won't have to explain why I urged thousands of people to forsake the medications that could keep them alive. I can, if I choose to, show my face in South Africa without fear of arrest. Can Dr. Rath?

Comments (38) + TrackBacks (0) | Category: Infectious Diseases

June 16, 2005

Pfizer Opens Their Wallet - Again

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Posted by Derek

Well, as a comment to Tuesday's post mentioned, no sooner do I talk about the antifungal market than Pfizer turns around and buys a company with a promising antifungal drug. Vicuron has concentrated on antiinfectives in general, which has been a rough place to be over the last ten years or so. Good ideas are hard to find, and if you come up with an amazing new antibiotic, you can expect to see its use restricted as much as possible. And rightly so, in hopes of delaying the onset of resistance. That's good medical practice, but it does tend to put a kink in the sales figures.

Pfizer's deal makes a lot of sense. Their last big new antibiotic ran into trouble a few years ago over side effects: Trovan (alatrofloxacin), another fluoroquinolone. They acquired Zyvox (linezolid), the first oxazolidinone antibiotic, when they purchased Pharmacia/Upjohn, and they still sell an awful lot of Zithromax (azithromycin). But I don't believe that there was much coming along in their antiinfectives portfolio, and they have immediate problems to be fixed. Last summer, Pfizer lost patent protection for Diflucan (fluconazole, which I mentioned the other day), and the patent for azithromycin expires later this year.

The Pfizer deal-makers have been on hiatus recently, but they'll probably keep busy for a while now, because the company is facing even more patent expirations over the next few years. As the clock keeps ticking, Pfizer will probably be forced to go out and buy things before their mighty marketing machine starts sucking air. They're already talking about cutting costs and head count, and I've heard from inside the company that some people there are uneasy about the future. And perhaps they should be - no one's ever tried to have a drug company as big as Pfizer before, and it's not for sure that it's such a great idea. Not everything scales up. Research productivity, for example, may actually have a negative correlation with size.

I've wondered, loudly, for years how they're going to manage. Nothing's made me change my mind. An antibiotic and an antifungal will help, but Pfizer's going to need a lot, lot more.

Comments (3) + TrackBacks (0) | Category: Business and Markets | Infectious Diseases

June 14, 2005

Fungal Problems

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Posted by Derek

You want a tough therapeutic area to work in? Try antifungals. There are plenty of problems that conspire to make it a real headache.

For one, fungal infections have a way of binning themselves into two categories, marked "pretty trivial" and "pretty life-threatening." Athlete's foot is a good example of the first one, and coccidioidomycosis is a good example of the second. Actually, that disease shows another form of the trivial/deadly dichotomy. Many people with coccidioidomycosis never realize that they had it, or that they had anything at all. It shows up as a mild cough or cold, and then disappears. But in some people, most especially HIV sufferers or other immune-comprimised patients, it's extremely bad news indeed.

So there are large markets where people aren't willing to pay much to be treated, and a number of much smaller, very desperate markets scattered all over the place. That's a tough situation, and the best thing would be to find a real blunderbuss antifungal that would pitch in for all of them.

And there actually is one, but it's a pretty nasty drug. For the worst systemic fungal infections, though, amphotericin B is basically all there is. It's given intravenously, and you have to keep a close watch on the side effects, which run to things like high fever, vomiting, and kidney damage. A less vicious, orally available drug that works as effectively would be a real advance.

It's not like people haven't tried. Fluconazole and Itraconazole are worthy attempts, but they suffer from their own side effect problems. Check out the general information here, and note, for example, the number of drug interactions. The "conazoles" are notorious for interacting with some key drug-metabolizing enzymes, particularly CYP 3A4, and thus sending the blood levels of other medicines all over the place.

And to top it all off, there aren't that many good drug targets in this area, or at least, not any more. There are companies that have bailed out of the whole field for lack of anything reasonable to do. There's some hope that the sequencing of fungal genomes might lead to some new targets, but that hasn't worked out too well with other organisms, and I include humans in that list. We can always hope.

Comments (6) + TrackBacks (0) | Category: Infectious Diseases

June 9, 2005

Dr. Rath Does What He Can

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Posted by Derek

There's a doctor named Matthias Rath who for some years has been taking out big ads in the New York Times and the International Herald Tribune. Rath is a big proponent of megavitamin therapy for just about everything, and by some cosmic coincidence he also has a line of vitamins for sale. No doubt he has a web site and a half, but damned if I'll link to it.

His ads are thunderous, paranoid denunciations of the pharmaceutical industry, the likes of which I haven't seen since the Church of Scientology took off after Eli Lilly and Prozac in the early 1990s. If you want some Instant Rath, take those and add some Lyndon Larouche-level conspiracy theories (for a while there, Rath was all but blaming drug companies for 9/11), and mix well. Season to taste, but if you've really got a taste for this stuff stuff, there's no hope for you.

His latest manifestos have been targeted to South Africa, and they're just what that country doesn't need. Rath rants about antiretroviral drugs being sinister poisons, while apparently everyone could be cured of HIV if they'd just guzzle his multivitamins without pause. The South African activist groups demanding free retroviral drugs are, according to him, tools of the "international drug cartel" that exists in the fevered reaches of his head.

It's hard to know how to answer such otherworldly accusations. Try, for example, the idea of drug companies funding groups who are screaming for their patents to be abrogated and their profits confiscated. I'm having a hard time making the connection. All in all, I'd rather be stuck in an elevator for three days with a dozen Intelligent Design advocates than spend five minutes with Matthias Rath.

South Africa's attitudes and policies toward HIV are enough of a mess already, as those who remember former president Mbeki's handling of the epidemic know. According to an article in Nature Medicine, the South African Traditional Healer's Association has sided with Rath, and a recent press conference from health minister Manto Tshabalala-Msimang featured one of her many endorsements of garlic, lemon peel, and beets instead of antiretrovirals. Meanwhile Rath is lobbying South Africa's parliament directly, amid accusations that he's planning to set up a factory to sell his own vitamin pills.

And meanwhile, at least 20% of South Africa's adult population is infected with HIV. What could be a great nation is threatened with an ugly slide back into the third world, while wastes of good carbon like Matthias Rath spend their time fighting the only known treatments. It makes you wish you could just avert your eyes.

Comments (8) + TrackBacks (0) | Category: Infectious Diseases | Snake Oil

May 18, 2005

Vertex Turns Over a Winner

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Posted by Derek

Vertex announced some impressive clinical data against hepatitis C the other day, which has been a fine thing for their stock price. It looks to be a fine thing for people infected with hepatitis as well, with better results than the current interferon therapy in a much shorter time.

I'd have to guess that the side effects are lower, too, interferons being rather powerful things. Schering-Plough and Roche have been beating each other silly in that market for years now - these results point to a future where they might each end up with a much lower market share. (If Vertex's drug works even better in combination with them, though, everyone might still do just fine.)

Other things being equal, or even in the neighborhood of equal, a small organic molecule is going to beat a biotech protein every time. They're easier and cheaper to make, and easier to store and dispense. And as for dosing, well, you can get orally active small molecules (like Vertex's) - try getting an orally active protein, and get back to me when you do. Mind you, it looks like Vertex's compound really has to be taken in mighty quantities (750 mg t.i.d., that is, three times a day), but anti-infectives often have to be hammered in like this. It's still surely going to be cheaper than interferon therapy.

Vertex being Vertex, I'm sure that there's a nice presentation about all the contributions that molecular modeling made to this compound's development. But I've no doubt that their large bunch of capable medicinal chemists made their mark on it, too. Congratulations to the lot of them!

Comments (2) + TrackBacks (0) | Category: Infectious Diseases

April 13, 2005

Do It Again

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Posted by Derek

This is the 50th anniversary year of the announcement of Jonas Salk's polio vaccine, as you've probably been noticing. There a new book out on the discovery, and plenty of newspaper and magazine articles.

I'll save comment on the vaccine (and Salk himself) for another time. What got me thinking was an incident during the late phases of of the research (which was recounted in a recent article in Smithsonian magazine, taken from the book mentioned above.)

Salk and his team were injecting patients who had already had polio with their vaccine candidates, hoping to show a fresh antibody response. Blood samples were taken after a few days, and the corresponding blood serum was added to a cell culture along with fresh virus and a dye, Phenol Red. If the cells lived - that is, if there were enough antibodies in the serum to inactivate the virus - they would clear the dye color to yellow as the medium became more acidic. If they died, the red color would remain. (This was an assay developed by Julius Youngner. You can see the two colors of Phenol Red here.)

On the morning that the test results were ready for their most promising vaccine candidate, the rack of cell culture tubes showed up completely yellow. There was much celebrating, but Salk finally turned to everyone and said "OK, now let's make sure that we can do it again."

Good for him, I thought when I read that. My fellow researchers will recognize Salk's comment as that of someone who knew his way around a lab. Some of the best scientific advice that you can get is don't trust anything until you've done it at least twice. All kinds of ridiculous stuff happens sporadically, and you'll go crazy if you react to all of it. I've been kicked around like a soccer ball by "N of one" data too many times myself. Nope, don't break out the party hats until the second experiment works, and don't despair until the second one fails.

Comments (5) + TrackBacks (0) | Category: Infectious Diseases

February 22, 2005

An Antiviral Example

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Posted by Derek

I mentioned yesterday that sometimes you can find an antiviral target that doesn't depend on what the virus itself has to offer. As fate would have it, there are a few drugs coming along that use just such a mechanism against HIV.

They're based on their affinity toward a protein called CCR5, which sits straddling the outer membrane of some types of cells. It's one type of receptor protein, whose lot in life is to latch onto specific other molecules if and when they come by. Our lot in life in the drug industry is to make small molecules that bind to them - the various kinds of receptors are hugely important drug targets. (For those outside the field, briefly, part of a receptor stays on the outside of the cell membrane, and part of it loops to the inside. When a molecule binds to the outside loops, that binding event changes the shape of the whole protein and sets off a signaling cascade in the cell, which signals can be tied into just about every cell process you can think of.)

In the mid-1990s, studies on patients who appeared more naturally resistant to HIV showed that they had a mutated form of CCR5. It turned out that the receptor is one of the things that the virus uses to get into blood cells and infect them, but the mutated form didn't let HIV bind to it very well. That immediately led to the idea of blocking a normal patient's CCR5 with some small drug molecule - if the receptor were stopped up with that, maybe HIV wouldn't be able to bind to it, either.

This receptor-blocking idea is a favorite in drug research. It's usually a lot easier to gum up a receptor than it is to mimic the specific thing that turns it on. That's why everyone jumped on this idea so quickly. But "quick" is a relative term in the drug development world. I think that the relevant chemical series were found to bind to CCR5 somewhere around 1996 or 1997. The projects at the different companies took off from there - and here it is 2005, and we're starting to begin to talk about something getting close to being submitted for the FDA's consideration. The thing is, that's not a slow calendar at all. It's normal to fast, unfortunately for all of us.

Schering-Plough (whose preclinical research team included several former colleagues of mine), GSK, and Pfizer are in the lead in this area, with several other companies also taking a crack at it. Early clinical results were promising, and we should be hearing more soon. Here's hoping that they all work.

Comments (1) + TrackBacks (0) | Category: Infectious Diseases

February 21, 2005

Can Med-Chem Help With Bird Flu?

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Posted by Derek

If avian flu does gain a foothold in humans, what can drug companies do about it? (This should give you the latest headlines on the disease.) It's definitely something to worry about. There hasn't been a real rampager of a flu epidemic in a long time, and a pessimist would say that we're overdue.

The answer to my question is "Work on a vaccine!" Because if you rephrase it and ask "What can people like this Derek Lowe guy and his hotshot medicinal chemistry buddies do?", the answer is "Not much." It's not a widely appreciated fact among the public, but we have hardly any drugs that affect viral diseases. The disease with by far the largest number of therapeutic options is HIV infection, and if you find that an unnerving thought, you should.

The problem, as I've mentioned before, is that viruses don't give you much to work with. They have very small genomes, and thus code for a bare-bones set of proteins. Since those are generally what we'd attack, we're often at a loss to find a good drug target. Sometimes you can find a target in the human cells that the virus attacks, but that takes a lot of basic research into the infection process.

And even if we find a target, we're years away from a drug. Getting a chemical lead structure, optimizing it, making sure that it actually does some good (and doesn't do a corresponding amount of harm!) - it's a terribly slow process. And it's remained that way despite hundreds of millions of dollars waiting to be picked up off the ground by the first company that can shorten it. The incentives are there; the technology isn't.

That time scale probably won't be much use if we get into an epidemic one of these years. The virus will outrun us. The best thing we can be doing now is learning everything we can about the whole class of H5N1 influenza viruses and how to make broadly active vaccines against them and their combinations with human agents. Prevention, monitoring, and immunology are going to have to save us if we get into trouble. Because though it pains me to say it, people like me aren't going to be able to help.

Comments (7) + TrackBacks (0) | Category: Infectious Diseases

August 19, 2004

Empty Shelves

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Posted by Derek

Yesterday I was writing about a proposal to encourage new antibiotics, partly by not putting so much effort into discouraging the use of the current ones. The economist who's advocating this, Paul Rubin, also would like for the FDA to consider accelerating the approval process (and at the very least, not making it even harder than for other classes of drugs.)

I like the sound of that part, as you'd guess, though always with a nervous look up in the sky for the circling silhouettes of the product-liability attorneys, whose razory talons were the subject of yesterday's post. But there's another problem with just stepping out of the way of the new antibiotics: there aren't very many coming through.

Many companies have been scaling back their anti-infectives research over the last few years, and I don't think that the regulatory environment is the main reason. The whole therapeutic area is rather target-poor. We've exploited the obvious vulnerabilities of bacteria, thus the -cillins and -sporins, the fluoroquinolones and the erythromycins. Extended searching hasn't turned up many more modes of attack, at least not of that quality. The most recent new class of antibiotics that I can think of are the oxazolidinones, but resistance to the first one is already showing up.

Here's a rundown of newer antibiotics (the situation hasn't changed much since this appeared.) Note that most of the things on this list have been known for a long time and are being re-examined, or are improved versions of things we already have.

I know where Rubin is coming from - drug resistance wouldn't be as much of a problem if we had a steadier stream of new antibiotics with new mechanisms of action. But I don't know if we can hold up our end. Providing incentives by loosening regulatory requirements could persuade some companies to get into the hunt (or stay in it), but the hunt itself is the real limiting factor. It's not a good situation, and I think that we in the industry are kind of at a loss as to what to do about it. . .

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August 18, 2004

Resistance to Resistance

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Posted by Derek

Forbes has an article on some recent work of Paul Rubin, an economist at Emory. He's looking at the situation in approvals of new antibiotic drugs, which isn't an encouraging sight.

He's of the opinion that too much government effort has gone into cutting overuse of the existing drugs (to try to slow down the development of resistant bacteria) and not enough has been done to make new drugs easier to bring to market. The use of antibiotics in general is being discouraged, and at the same time the FDA has made the regulatory environment for new submissions tougher. A quote:

". . .the FDA policy of requiring additional testing for antibiotics is a fairly bizarre policy and makes no sense. . .A much more cost-effective alternative would be to approve the drug in the normal manner (or even provide an accelerated approval) and spend additional resources on...post-approval surveillance."

He's probably right about this, but (and here's the usual problem) it makes sense only if you ignore the tort lawyers. If your new antibiotic goes out and causes trouble in some subset of the patient population, it's no use telling the attorneys that, hey, the FDA approved it. They're not going to get money out of the FDA; they're going to get it out of you. Nope, it was your willful, stupid, perverse, dare I say evil negligence that led to this completely avoidable tragedy, and. . .aargh, you can write the rest as well as I can.

That's the thing: the FDA requires that we show safety and efficacy. We can prove the presence of efficacy, but safety is merely the absence of harm. No one can prove a trial lawyer's definition of safety. A clinical trial can tell us that in the population that participated in the trial, X adverse events took place. Whether X is a greater or lesser number than we'd expect in the general population is a question that can be answered statistically, but whether our drug caused those X events isn't a question that can usually be answered at all.

In such cases, our best chance is to see if the affected patients had something in common, or if the problem increased in proportion to the dose. Often enough, neither is the case - does that make the compound safe, or not? Even if there weren't any signs during the trials, what will happen when our drugs hit the orders-of-magnitude larger population of paying customers? We don't know. We can rule out what our clinical trials were powerful enough to see, but we will never see the one-in-fifty-thousand kinds of trouble. Not until the lawsuits start flying.

There's yet another problem with Rubin's argument, scientific rather than regulatory, which I'll address tomorrow. . .

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April 13, 2004

It's a Bacterial Planet, You Know

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Posted by Derek

You've probably heard of the hypothesis that a reasonable amount of dirt is good for you, especially in childhood. (My kids are certainly taking no chances.) The idea is that the immune system needs a certain amount of challenge to develop properly, so trying to live too antiseptic a life is a mistake. I think that this is very likely correct, and it turns out that it's especially correct if you're a zebrafish.

Not many of my readers are zebrafish, at least as far as I can tell from my referral logs, but they're an influential demographic. Danio rerio isn't as well known outside biology as say, the fruit fly, but it's a workhorse model organism for vertebrate development. Zebrafish are small, fast-growing, and the embryos are nearly transparent in their earlier stages. (Xenopus frogs share these characteristics, and have their partisans, too.)

The March 30th issue of the Proceedings of the National Academy of Sciences, with a Warholian zebrafish cover, features a study from Washington U. where the fish were raised under strictly aseptic (gnotobiotic) conditions. That's not easy to do, but if you make absolutely sure that no bacteria are present, it turns out that the embryos don't even develop properly. The defects are in the gut, which makes a lot of sense.

It turns out that colonization by normal intestinal flora is vital - zebrafish and their bacteria have become evolutionarily entangled. The bacteria actually induce some crucial gene expression by their presence, and the developmental program just doesn't have an aseptic default setting. There hasn't been an aseptic zebrafish since the beginning of biological time.

OK, these guys swim around in tropical pools, floating in a bacterial soup. But we're floating in one, too, just at a slightly lower density. Every part of a human body that can be easily (benignly) colonized by bacteria already is. Are there similar developmental effects in man? It wouldn't surprise me at all. No one's going to be running that exact embryo experiment, needless to say, but there are probably ways to sneak up on the answer using cell cultures. There's never been an aseptic human baby, either. . .although this is enough to make a person wonder about situations where a pregnant mother has had to take a long course of powerful antibiotics.

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March 7, 2004

They Will Do Such Things. . .

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Posted by Derek

I see that Steven den Beste linked to me as a general source of med-chem info, which was good of him. He was discussing resistance in treatment of tuberculosis (on the way to a broader point about current events), so I thought I'd say a few words about antiinfective drugs.

As I've mentioned in the past, it's not an easy area. At least, not any more. This was one of the first frontiers for medicinal chemistry (think Salversan for syphilis, sulfa drugs, penecillin and so on.) But it's clear that no one realized the long-term consequences of the free use of those early drugs. And even if they had, I doubt if much would have changed. There wasn't much incentive for restraint, not when people who were marked for death suddenly getting up and walking around.

It's easy to forget how serious infectious disease was back then. People are horrified now when there's a death like, say, Jim Henson's: a rampaging septic reaction that kills within a few days. But go back a hundred years, and that sort of thing happened all the time. Earaches could kill you, things that we'd consider bad colds might end up killing you. A toothache could signal that the end of your life was a week or two away. No, once drugs came around that could fight this sort of thing, no one felt like holding back.

But now we've burned out a lot of the easy targets. There are, broadly, two classes of drug targets against bacteria and other infectious agents. The first are enzymes and pathways unique to the pathogen, and those are naturally the best. Penecillin and all the related drugs fall into this category. They mess up the synthesis of the bacterial cell wall, leaving the affected organisms naked to the world and thus easy prey for the immune response. Cells of higher organisms don't make such walls, so you can beat on that pathway all day long without much risk.

The second group are targets that are present in humans as well, but with enough variation in the protein that you can hope for a selective compound. This takes more work, most of the time, and sometimes you can't separate the activity enough to be useful. Many bacterial enzymes are distant cousins of their human equivalents, but many others are too close to work against.


And with either class of drug, you have resistance. That's what they didn't appreciate in the early decades - and if they did, they underestimated it. Bacteria have such short life cycles, and there are so many of them. They're an ideal laboratory for evolution, and when humans came in and put the selection pedal down, the changes started and haven't stopped.

One common mechanism is for the target protein to end up mutating. There's a good amount of genetic variation in the bacterial population, and some of the group you're trying to hit might have a form of the protein that doesn't bind your drug. Given enough bacteria or enough time, there are bound to be some. So you treat with the drug, everyone else dies, these naturally resistant organisms have the whole field to themselves, and they run wild.

Sometimes the bacteria whip out another protein to take care of your drug all by itself. That's what happened to penicillin. Some bacteria turned out to have an enzyme to defend against such compounds (which are, after all, found in nature as antibiotics.) The enzyme, beta-lactamase, cleaves the crucial four-membered ring at the heart of the whole drug class. Naturally enough, this enzyme is all over the place now. (Thus the drug Augmentin, which contains a penicillin derivative and another drug, clavulinic acid, which inactivates beta-lactamase. But as you could guess, organisms have appeared whose beta-lactamase isn't affected by it.)

Yet another resistance mechanism is an active-transport pump. These are membrane-spanning proteins that physically expel the drug molecule once it enters the bacterium, pumping it right back out before it can do its job. (Cancer cells do the same thing, by the way.) What makes all of these such a problem is the habit many bacteria have of swapping DNA segments like trading cards. It's hard to measure, but I'm sure that over the years we've selected for accelerated DNA transfer. Under stress, the active traders have an edge, since they have a better chance of swapping in some DNA to code for the necessary inactivating enzyme or pump.

It's a battle. And from all appearances, it's never going to end. We're fighting tenacious, adaptable organisms that pull out all the stops all the time. They don't sit around fretting about the younger generation and their DNA-swapping ways, or worry that they're losing their essential staphylococcusness by taking on all these new characteristics. There are no spirochetes grousing that an arginine at that position was good enough for their granddads, and it's good enough for them. No, they'll do whatever it takes. It's life or death for them. Just like it is for us.

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September 2, 2002

A Last-Ditch Effort - Or Is It?

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Posted by Derek

There's a rather weird legal fight going on between Glaxo SmithKline and the rest of the world. Like everyone else, GSK is fighting to hold on to profitable drugs that are losing patent protection. A lot of. . .creative. . .arguments are being deployed in these efforts, and I can't figure out if this is one of them or not.

The drug is Augmentin, which is actually two drugs in one. (For those readers old enough to remember it, you can now cue up the voice-over to the old Certs ad.) The antibiotic ingredient is plain old amoxicillin, a beta-lactam warhorse that's been generic for a long time now. Unfortunately, plenty of bacteria can chew right through amoxicillin and others of that era. I mean that literally: they use an enzyme called beta-lactamase to break open the four-membered ring at the core of all the penicillins.

That's where the second ingredient comes in, clavulinic acid (actually, its potassium salt.) It's a natural product that has a roughly similar structure, similar enough to fit into the active site of the beta-lactamase enzyme and gum up the works. Using the enzyme inhibitor leaves the amoxicillin free to do its work, and the combination is quite effective.

Well, amoxicillin you can order by the drum. But clavulinic acid is another matter. It's not economical to synthesize, not from the ground up (and neither are the beta-lactam antibiotics themselves, for that matter.) All these compounds are made (at least partially) by fermentation, which is just short of being a black art. You have to find strains of organisms (fungi for the 'cillins, bacteria for clavulinate) that produce unusually high amounts of the material, and you have to make them do it reproducibly. That means keeping them happy, but not so happy that they decide to give up the hard biochemical work of synthesizing your compound. And you have to find a good way to purify your stuff from the reeking fermentation broth - ideally in a continuous-feed mode so you don't have to run batch after batch. It's not trivial.

Perhaps you can guess where this is heading. GSK claims that they spent a lot of time and money developing a particular bacterial strain that produced clavulinic acid better than anything else known. And they're now claiming that some of these bacteria walked out of their facilities and are being used by their competitors (specifically Novartis as well as the generic companies Ranbaxy and Teva.) They seem to have a particular employee in mind, and a particular transaction history for the theft.

Problem is, that all happened starting in 1988. You wonder why GSK sat back for this long if they knew all this. . .and there are generic Augmentin formulations in Europe which don't figure into the suit. How'd they make their clavulinic acid? You do have to wonder if this isn't a desperation move.

On the other hand, this sort of theft isn't unknown. About twelve years ago, a New Jersey drug company had a former employee walk out with some of their engineered bacteria, which he later tried to sell to at least one small biotech outfit. They went to the Feds. The employee was caught on tape, thinking that he was selling the material to a Middle Eastern government, when he was really selling it to the FBI on two camera angles.

So GSK could be on to something, too. It'll be fun to watch.

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August 8, 2002

Better Them Than Me

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Posted by Derek

Roche and their partner, Trimeris are developing an anti-HIV compound (called T-20) that has some remarkable features. It's the first to target a cell protein (gp-41) that is a key binding step in HIV's mode of infection, for one thing. But to be more precise, it has 106 more interesting things about it - that's the total number of synthetic steps in the manufacturing process.

My synthetic-organic readers are probably saying just what everyone in the field does when they first hear about that one - it's usually a variation of "no (procreating) way," followed by laughter. Those of us who've done natural product synthesis get the shivers, remembering those 20- or 30-step build-the-pyramids projects from our pasts. Trying to extrapolate those experiences up the asymptotic curve of awfulness to 106 steps is a scary exercise.

Fortunately, the compound is a peptide (36 amino acids,) which means that the chemistry is well-established and can be done largely by machine. It also means that you don't do all 106 steps in a row. Well, you could try, if you had a good excuse like having had a big recent dose of LSD or something, but it's not recommended.

For starters, it probably wouldn't work. Peptide synthesizers work by hanging one end of the chain off a solid resin support. As the molecule gets longer and snakier, it tends to ball up on you. Eventually, the far end, the one that is getting new amino acids added to it, isn't sticking out into the solution any more, but is tucked back into its own folds. End of synthesis, by default. The second problem with having that many linear steps is a mathematical one. A to-the-hundredth-power term in an equation is a bomb waiting to go off, and if your synthetic yields aren't just about perfect, you're going to be in bad shape.

For example, if every step works in 95% yield (which would be a mighty fine result across 106 steps,) then you're going to come staggering across the finish line with a 0.4% overall yield. What if you average an 85% yield? Admittedly, a peptide synthesizer will beat that, but it had damn well better, because that pace will leave you with 3-millionths of a percent yield. Ugly things, those exponents.

Roche, not being a gang of idiots, will certainly be making T-20 in small chunks, then stitching those together. The tricky part is figuring out where to break up a molecule that size. What combination of fragment assembly schemes has the best chance of high reproducible yields? The life expectancies of humans being what they are, you can't try all the permutations and pick the best. Some educating guessing using known pitfalls of protein design has apparently given them a route that works.

But it's going to be a honker of a synthesis, no matter how well it goes, because it's going to have to be done on monstrous scale. Peptides, as I never tire of pointing out, have every chance of making crappy drugs, and this is worse than most. You can't take a 36 amino-acid peptide orally and expect much to happen; your digestive tract will rip it to shreds like it does every other protein. T-20 has to be injected, twice a day, 100 mg per shot. Roche is going to have to make thousands of kilos of this stuff, which should handily break any records for peptide synthesis. It already looks like it'll be tough, at least at first.

While T-20 works quite well, it's going to be extremely costly to produce. Roche has reportedly already spent nearly $500 million on the manufacturing facility in Colorado. T-20, then, is also going to be extremely costly to take. There's room to doubt how long it'll take to pay off, especially for Trimeris. If resistance to the drug shows up ahead of expectations, it could never pay off at all. (The companies are developing some related peptides that might get around this problem, which is a good strategy.)

I'm still in awe of the decision to go ahead with this drug. It's a major risk, and I can only hope that it has major rewards for both the patients and the companies. And I can also be glad that I'm not having to keep those peptide synthesizers out in Boulder stocked with solvents!

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July 17, 2002

A Twisty Road

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Posted by Derek

The business news has been on top of the science news recently, that's for sure. Maybe we can go a week or so without accounting issues, mergers, and whatnot.

I wanted to call people's attention to a good article in July 8 issue of The Scientist (free, but registration required.) It's a history of a recently developed vaccine for the common bacterium Staphylococcus aureus, a common cause of adventitious infections and septic shock. "Recently developed" isn't too accurate, though, since the research has been going on since the mid-1960s.

I won't go into all the twists and turns of the story, but there are plenty of them. At every step, there were good reasons to think that the entire idea wasn't going to work. Some of these were: Staph aureus doesn't have a polysaccharide capsule, need for a vaccine - wrong. The ones that people cultured didn't have much of one, but the real-world organisms do, of a tricky and complex kind. You can't raise good immunity to that kind of polysaccharide, then - wrong. It took some doing, but an antibody response was seen. OK, but they won't be protective, because people have them already - right, but wrong, for various intricate reasons.

The end result was reported earlier this year in the New England Journal of Medicine, showing a statistically significant decline in S. aureus infections in dialysis patients who received the vaccine. It wasn't a knockout blow, but it was pretty effective for something that was long thought impossible. More trials are underway.

I'm not beating the drum for the vaccine (although I wish it, and its licensee, a company called Nabi, well.) I am beating the drum for sticking with projects through bad patches, as long as there are experiments to run that can get you out of them. There's no point in flogging a project that's come to a dead end, of course, and there's always some useless thing you can think of to try to keep working. But I'm talking about definitive experiments. You should never give up until you've run the best make-or-break tests you can think of.

It's a truism in the pharmaceutical industry that every great drug project has come close to dying at some point. This vaccine effort faced termination more than once, but stayed alive because it passed crucial tests at the crucial times. Maybe having near-death research experiences is actually helpful. They concentrates the mind on key data and key experiments, on the stuff that could be the most convincing evidence to keep things going.

Many projects come to those points and fail, of course. But the projects that I'd mourn are the ones that got killed off before they even got a chance to redeem themselves. Most of them would have failed, as well. Most projects do. But some of them could have been contenders.

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July 11, 2002

New! Viruses So Potent, You'd Swear They Were Homemade!

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Posted by Derek

The big science story at the moment seems to be the SUNY-Stonybrook polio virus synthesis.

To tell the truth, I thought this sort of experiment had already been done. I'm not at all surprised that it worked, and only a bit surprised that it worked as well as it appears to have. Viruses (especially the smaller ones) are rather simple things. Synthesizing the needed genetic material isn't a big obstacle (easier, again, for the smaller viruses.) The Stony Brook team worked out a good system to go from the naked RNA of the polio virus to functioning viruses themselves, and that step is to me the main novelty.

Anyone who uses this as a platform to rant about creation of life is going to have to defend the notion that viruses are alive. And that's a tough one - how can something that doesn't eat, doesn't excrete, and can be disassembled and reconstituted count as alive? A virus is a little von Neumann machine, emphasis on machine.

Using this as a platform to rant about bioweapons is a bit more excusable. The sequence of polio virus has been a matter of public record for a long time now, though, and the road to this experiment could have been taken by any number of competent researchers. Here is a report from 1997 pointing out that very thing. The report (from Columbia U) stated:

"Even if total virus destruction could be accomplished, the small size of the poliovirus genome, whose sequence is known and whose complementary DNA is infectious, would make it possible for a terrorist to synthesize a new stock."

That's five years ago, folks, which is a long time in molecular biology. If this experiment serves to show people how hard containment of knowledge is, then the lesson has been worthwhile. Since genies don't go back into their bottles, it's better if we find out all we can about the ones that are running around.

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March 20, 2002

If It Were Easy. . .

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Posted by Derek

As I mentioned yesterday, Viropharma's compound Picovir (pleconaril) was turned down unanimously by an FDA panel. This could be the end for an interesting compound that's been kicking around for many years, going back to the days (1990 or so) when Sterling-Winthrop still existed as a drug company.

Kodak took over Sterling in 1988, looking to get into the high-margin drug industry (they already had a chemicals business, the Eastman side of things.) As it turned out, you couldn't have paid a gang of saboteurs to do a worse job running Sterling, and the whole deal was a costly disaster that lasted some six years. The pieces of Sterling were sold off (at a mighty loss) to the French firm Sanofi, among others. During the chaos, some of the Sterling people left to form Viropharma, negotiating with Sanofi for the rights to pleconaril.

It's an interesting compound, with a mechanism that (to my knowledge) isn't shared by any other antiviral candidate. It binds to a site on the surface of the virus, keeping it from infecting cells. Viropharma kept plugging away at it, trying it out for meningitis and respiratory infections, but without notable success.

The last couple of years were a particularly wild ride. If you go back and look at the stock chart, you can see a huge run-up, followed by an equally hair-frizzing decline. What happened was some media reports in December of 1999 convinced various clueless investors that VPHM had, yes, the cure for the common cold. That was indeed what Viropharma had started trying pleconaril against, the meningitis data having proven unimpressive. The compound was far from a miracle cure.

But try telling that to the notorious stock promoter Tokyo Joe. Remember Joe? Viropharma stock was one of his calls during this period, and his people piled into it hugely, followed by a swarm of tag-along momentum players. They had a real fiesta for a while there, but NASDAQ was in all-fiesta mode back then, anyway.

Momentum investing means, of course, buying stocks just because other people are buying them. It's the Bigger-Fool theory in action, and it's always struck me as similar to the way some jackrabbits dart in front of 18-wheel trucks. (This is coming from someone who shorted Imclone at what turned out to be their low point, so I'm no stranger to risk.) In this case, the 18-wheeler appeared in the form of new clinical data showing that pleconaril wasn't particularly effective against colds, which led to the roll-off-the-table section of the stock chart.

I'm happy to say that I was short VPHM when that happened. Of course, I'd shorted them at about 50 and promptly watched the stock jump like it had been hit with a cattle prod, right up over 100, and mighty quickly, too. Swallowing hard, I shorted some more. I just couldn't see the drug working that well based on the clinical data the company had already shown. Meanwhile, Tokyo Joe's people on the stock message boards were already making VPHM out to be the next Pfizer. That's a quote from some guy - another table-pounder kept going on about how you'd have liked to have bought into penicillin in 1940, wouldn't you? Right? Here's the chance of a lifetime, again! Some other maniac saw the compound as basically the savior of the human race. Then the bad news hit. I'd like to have a videotape of me trying to dial my broker right after I saw the stock quote that morning (down 43 5/8 or something like that.) I kept missing the buttons on my phone; it took three tries before I successfully dialed my broker to take my profits.

The data that came out of those studies helped keep the compound from being recommended yesterday. Pleconaril, taken three times a day, starting very early in the course of a cold, reduces the duration of cold symptoms by a day or two. And that's about it, and that's just not enough. That's an awful lot of drug to load your system with for a relatively minor disease, and it would presumably involve spending a fair amount of money that an HMO might not be keen on reimbursing.

Viropharma kept making their case, of course. One point was that dosing with the drug reduced what's descriptively called "virus shedding," which could make you less infectious to others. To the best of my knowledge, no clinical data was ever collected to put that idea to the test, though. They got a big company to buy into the compound, namely Aventis (known to longtime pharmaceutical people by its heritage, as Hoechst-Marion-Merrel Dow-Roussel-Rhone-Poulenc-Rohrer, which sounds like a white-shoe law firm.)

But, in the end, the combination of lackluster efficacy with some extra safety concerns (possible interactions with the menstrual cycle in a few women, for example) doomed the compound. The effects they saw would have meant nothing for a compound that treated, say, pancreatic cancer, which is otherwise a death sentence. But for a cold?

To their credit, you can see that Viropharma realized all this. That's why they started trials on viral meningitis. When that didn't work out, they went to serious respiratory infections. No dice. Finally, they were left with colds. They did the best with what they had, but it wasn't enough.

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February 26, 2002

New Drugs for HIV

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Posted by Derek

Megan McArdle points out the recent news (which has shown up in Tuesday's NY Times and other outlets as well) about new HIV treatments with possibly fewer side effects. She asks if the same technique can be applied to other diseases, and I thought for the benefit of the non-pharma audience that I'd go into some detail on that.

Actually, there's no particular new technique involved - just good ol' drug development. These compounds work by different mechanism than the stuff we've had so far. Here's a (fairly) quick explanation, centering around one of the therapies highlighted in the press reports, the one from Schering-Plough.

The specific target of that compound is a protein called CCR5, which sits straddling the outer membrane of some types of cells. Part on the outside, part loops to the inside. It's one of a huge class of proteins called receptors, whose lot in life is to latch onto specific other molecules if and when they come by. When they do, that binding event sends a signal into the cell, and these signals can be tied into just about every cell process you can think of. This is one general way that you can enable some molecule floating outside the cells to set off changes inside them.

The subject, like most molecular pharmacology, rapidly reveals its career-worthy godawfulness on closer inspection. All those things in the above paragraph vary hugely and interrelatedly. To give you an idea, various receptors are a key step in the actions of things as important (and as unrelated) as insulin, cocaine, growth hormone, and caffeine. They're still counting up how many different receptors there are from the human gene sequences, but it's probably going to be in the low thousands when the dust settles.

In the mid-1990s, studies on patients who appeared more naturally resistant to HIV showed that they had a mutated form of CCR5. It turned out that the receptor is one of the things that the virus uses to get into blood cells and infect them, but the mutated form didn't let HIV bind to it very well. That immediately led to the idea of blocking a normal patient's CCR5 with some small drug molecule - if the receptor were stopped up with that, maybe HIV wouldn't be able to bind to it, either.

This receptor-blocking idea is a favorite in drug research. It's usually a lot easier to gum up a receptor than it is to mimic the specific thing that turns it on. That's why everyone jumped on this idea so quickly. So far, it seems to work, and congratulations to the Schering-Plough team for it. Although I haven't talked to them about it - not that they'd tell me anything, either - I know several of the chemists who worked on this project. They and their biology colleagues deserve the success.

But will this lead to a marketed HIV drug? Good question. It's obviously made it through the animal toxicity testing I spoke about the other day, because the compound has shown efficacy in humans. Those are both big steps. Now come more studies, with more patients, to make the case to the FDA. It's not an early-stage drug any more, and the odds are fairly good that it'll make it, but there are still several places where it could banana-peel and slip off the tightrope.

If it does, will it have fewer side effects than the protease inhibitor cocktails? Another good question. Right now the only thing you can be sure of is that the side effects will be different. All drugs, every single one of 'em, have side effects. Some are major, some are minor, and some are minor only relative to the disease that's being treated. Since this doesn't work on HIV protease, it presumably will avoid the problems of those drugs, which is good news. But there could always be others out there waiting.

There could mechanism-based tox, for example. We really won't know until larger, longer trials are conducted what might happen when you block CCR5 for an extended period, what happens when you block it while you're taking other drugs at the same time, or if there's some subset of the patient population that will react unusually.

Or there could be non-mechanism-based tox, which is what happened with the protease inhibitors: keep in mind that (when the research began) no one expected the body-fat remodeling and the other side effects of that class. Those seem to have nothing to do with blocking HIV protease, and arguments rage as we speak about what causes them. Is there some other protease that you can't avoid hitting when you go after the one in HIV? Could be. Is there some totally unrelated thing with (by sheer bad luck) a similar-looking binding site, so that most anything that binds HIV protease will hit it, too? Can't rule it out.

None of these arguments are specific to the HIV therapy field, of course. Investigative drugs go down the tubes all the time for just these sorts of reasons. And sometimes even the large trials aren't enough to catch bad side effects that occur at very low frequency, and you get the serious bad news after the stuff has gone to market. That seems to be what happened with the diabetes drug Rezulin (troglitazone,) and it's not the only example. When that happens, so many lawsuits start flying that it looks like it's snowing.

Am I a gloomy researcher or what? Nah, just realistic. I'm actually fairly perky most of the time, so I'll end on an optimistic note:. What we have now are some new ways to treat a terrible disease. The more routes of attack we have, the better. Along the way, we're learning a lot that can help out in other fields as well. The great thing about drug discovery, about science in general, is that nothing's ever really in vain, and no good work is ever really wasted. It all adds up, and keeps adding up. And what we're building, I truly believe, is the greatest work of the human race.

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