About this Author
College chemistry, 1983
The 2002 Model
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: firstname.lastname@example.org
July 25, 2014
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.
+ TrackBacks (0) | Category: Business and Markets | Drug Development | Drug Industry History | Infectious Diseases
July 21, 2014
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.
+ TrackBacks (0) | Category: Business and Markets | Infectious Diseases | Patents and IP | Why Everyone Loves Us
May 29, 2014
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.
+ TrackBacks (0) | Category: Drug Prices | Infectious Diseases
May 16, 2014
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?
+ TrackBacks (0) | Category: Clinical Trials | Infectious Diseases | Why Everyone Loves Us
May 15, 2014
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.
+ TrackBacks (0) | Category: Drug Development | Drug Industry History | Infectious Diseases
March 24, 2014
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.
+ TrackBacks (0) | Category: Biological News | Clinical Trials | Infectious Diseases
March 18, 2014
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.
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).
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.
+ TrackBacks (0) | Category: Chemical Biology | Drug Assays | Infectious Diseases
March 10, 2014
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.
+ TrackBacks (0) | Category: Cancer | Clinical Trials | Infectious Diseases
January 28, 2014
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.
+ TrackBacks (0) | Category: Biological News | Infectious Diseases
December 12, 2013
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.
+ TrackBacks (0) | Category: Chemical News | Infectious Diseases
December 4, 2013
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.
+ TrackBacks (0) | Category: Autism | Infectious Diseases | Snake Oil
November 12, 2013
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 —
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.
+ TrackBacks (0) | Category: Drug Development | Drug Industry History | Infectious Diseases
October 16, 2013
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 . 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.
+ TrackBacks (0) | Category: Infectious Diseases | The Dark Side | The Scientific Literature
August 16, 2013
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.
+ TrackBacks (0) | Category: Analytical Chemistry | Biological News | In Silico | Infectious Diseases
July 24, 2013
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.
+ TrackBacks (0) | Category: Cancer | Chemical Biology | Infectious Diseases
June 14, 2013
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.
+ TrackBacks (0) | Category: Current Events | Drug Industry History | Infectious Diseases | Who Discovers and Why
May 29, 2013
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. . .
+ TrackBacks (0) | Category: Infectious Diseases | Toxicology
May 17, 2013
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.
+ TrackBacks (0) | Category: Infectious Diseases | The Dark Side
May 7, 2013
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?
+ TrackBacks (0) | Category: Infectious Diseases
March 14, 2013
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.
+ TrackBacks (0) | Category: Drug Development | Drug Industry History | Infectious Diseases
February 28, 2013
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".
+ TrackBacks (0) | Category: In Silico | Infectious Diseases
February 13, 2013
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.
+ TrackBacks (0) | Category: Animal Testing | Biological News | Drug Assays | Infectious Diseases
January 24, 2013
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.
+ TrackBacks (0) | Category: Infectious Diseases
January 15, 2013
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. . .
+ TrackBacks (0) | Category: Biological News | Diabetes and Obesity | Infectious Diseases
October 8, 2012
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.
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.
+ TrackBacks (0) | Category: Infectious Diseases
September 4, 2012
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.
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.
+ TrackBacks (0) | Category: Drug Development | Infectious Diseases
May 21, 2012
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.
+ TrackBacks (0) | Category: Academia (vs. Industry) | Drug Assays | Drug Development | Infectious Diseases
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?
+ TrackBacks (0) | Category: Academia (vs. Industry) | Business and Markets | Drug Development | Infectious Diseases
April 30, 2012
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