About this Author
Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases.
To contact Derek email him directly: derekb.lowe@gmail.com
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Category Archives
April 16, 2008
Posted by Derek
A recent interview in Nature Reviews Drug Discovery with John Powers, formerly of the FDA, points out some problems in designing antibacterial drug trials. Some of these are unique to this area, although others we're stuck with wherever we go.
For one thing, it’s surprisingly hard to make sure, when you’re selecting patients, that the people you’re letting into the trial have the disease that you’re trying to treat. The example used is that some 5% of the patients who present with cough actually have pneumonia. Pneumonia is a very good disease to treat with antibacterial drugs, but you’d better make sure that your patients actually have it. There are some tests available to make sure that a given pathogen is present, although they aren’t available in every case you’d want them to be. If you don’t have such a screen, you risk having a very heterogeneous patient population, which will likely as not obscure the effectiveness of the drug you’re testing.
Then there’s the related difficulty in treating some conditions that you’d think would be clear cases for antibacterials: ear infections, for example. The problem is, it’s surprisingly hard to show benefit for some of these things with existing drugs. The underlying infection may be hard to get to (poor circulation in the infected area), or it may be an intrinsically heterogeneous condition like sinusitis. (That can be the result of umpteen different sorts of bacteria, or it could well be something viral, or several varieties of fungal infection, or allergies, what have you). There’s no point in running a head-to-head with an existing medication in these cases; you should run against placebo. That'll be enough of a challenge.
Another problem is that some of the bacterial diseases progress rather quickly – ahead, in some cases, of our ability to usefully diagnose them. That presents a real challenge for a clinical design, one that is dealt with, in many cases, by not attempting to gather rigorous clinical data under these conditions at all. In this field, diagnostic tools have to be fast if they’re going to be of much use.
There are two sides to all these problems: not only do you want to get the drug to the people who need it (and who will respond to it) the most, you want avoid giving it to people who won’t respond at all. That’s not just for the reasons given above (it’ll mess up your data), although that’s enough all by itself. No, the other problem is that spreading your drug around to inappropriate patient populations will just bring on resistance even faster. That’s going to happen no matter what, of course – the key is to have it happen as slowly as possible.
Comments (5)
+ TrackBacks (0) | Category: Clinical Trials | Infectious Diseases
April 4, 2008
Posted by Derek
This is turning into Cardiovascular Week around the blog, I have to say, and not in a good way. The latest news is the failure of a drug candidate from Takeda, TAK-475 (lapaquistat). They were in the lead in the field of squalene synthase inhibitors for cholesterol lowering (many other companies have taken a crack at this target, and dropped out along the way)., and their compound once had hopes of being a pretty big deal.
Not any more. In retrospect, the bell sounded late last year, when the company had to stop dosing at their highest level. Elevated transaminase levels were being seen in the treatment groups as the dose went up, which is a sure sign of trouble, as in liver damage trouble. Some investors seem to have held out hope for the compound to show enough efficacy at the lower doses, but Takeda has announced that the safety/efficacy ratio doesn’t justify taking the drug forward.
Liver enzymes are definitely one of those things you worry about when you go into man. There are all sorts of assays that are supposed to give you a read on that problem beforehand, and it’s safe to assume that Takeda ran them. But you’re never sure until you hit humans. Animals can react very differently to some compounds, although that can go either way. But if you set off liver enzyme trouble in rats or dogs your compound is probably dead, no matter how it might act in humans. You won’t get the chance to find out, most of the time.
The alternative is to use human liver tissue, but cultured human liver cells rapidly lose their native abilities and become untrustworthy as a model for the real world. Human liver slices are another alternative, but those are rather hard to come by, as you can well imagine, and the data from them have a reputation for being hard to interpret and hard to reproduce. No, for now, there’s no way to really know what will happen in humans without, well, using humans.
The big question that always gets asked in these failures is whether this is a compound-specific effect, a compound class effect, or a mechanistic effect. Most of the time it’s one of the first two. There are particular compounds, and particular structural series, that are known to be Bad News for liver enzymes. There will be some lingering doubt, though, because there’s plenty of squalene synthase activity in the liver, and it’s not impossible that any compound that hits it could cause the same trouble.
There are a number of other inhibitors out there – interestingly enough, they may have other uses besides lowering cholesterol. For some time, it’s been thought that such compounds might be useful antibiotics, since many bacteria need cholesterol synthesis pathways to survive. And there’s a recent report in Science putting this to the test in a particularly relevant system, particularly virulent strains of Staphylococcus aureus.
The “aureus” part of the name refers to the yellow hue that many strains of the bug exhibit, which seems to be correlated with how nasty they are as an infectious agent. The color comes from staphyloxanthin, a pigment that seems to be used as a defense agent by the bacteria by neutralizing reactive oxygen attacks from a host’s immune system. As the current work shows, the first enzyme in the biosynthetic pathway for staphyloxanthin (known as CrtM) has a lot of structural similarities to human squalene synthase. The authors prepared a number of known squalene synthase inhibitors from the literature, and found that one class of them (the phosphonosulfonates) also inhibit CrtM.
They went further, showing that one of these compounds (a BMS clinical candidate from about ten years ago) actually works quite well as an antibiotic in vitro and in an in vivo mouse model. I'm not sure why this compound didn't go further, but perhaps it (and the others in its class) will have a second life in the antiinfectives world. . .
Comments (8)
+ TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Drug Development | Infectious Diseases
April 3, 2008
Posted by Derek
I was having a discussion the other day about which therapeutic areas have the best predictive assays. That is, what diseases can you be reasonably sure of treating before your drug candidate gets into (costly) human trials? As we went on, things settled out roughly like this:
Cardiovascular (circulatory): not so bad. We’ve got a reasonably good handle on the mechanisms of high blood pressure, and the assays for it are pretty predictive, compared to a lot of other fields. (Of course, that’s also now one of the most well-served therapeutic areas in all of medicine). There are some harder problems, like primary pulmonary hypertension, but you could still go into humans with a bit more confidence than usual if you had something that looked good in animals.
Cardiovascular (lipids): deceptive. There aren’t any animals that handle lipids quite the way that humans do, but we’ve learned a lot about how to interpolate animal results. That plus the various transgenic models gives you a reasonable read. The problem is, we don’t really understand human lipidology and its relation to disease as well as we should (or as well as a lot of people think we do), so there are larger long-term problems hanging over everything. But yeah, you can get a new drug with a new mechanism to market. Like Vytorin.
CNS: appalling. That goes for the whole lot – anxiety, depression, Alzheimer’s, schizophrenia, you name it. The animal models are largely voodoo, and the mechanisms for the underlying diseases are usually opaque. The peripheral nervous system isn’t much better, as anyone who’s worked in pain medication will tell you ruefully. And all this is particularly disturbing, because the clinical trials here are so awful that you’d really appreciate some good preclinical pharmacology: patient variability is extreme, the placebo effect can eat you alive, and both the diseases and their treatments tend to progress very, very slowly. Oh, it’s just a nonstop festival of fun over in this slot. Correspondingly, the opportunities are huge.
Anti-infectives: good, by comparison. It’s not like you can’t have clinical failures in this area, but for the most part, if you can stop viruses or kill bugs in a dish, you can do it in an animal, or in a person. The questions are always whether you can do it to the right extent, and just how long it’ll be before you start seeing resistance. With antibacterials that can be, say, "before the end of your clinical trials". There aren’t as many targets here as everyone would like, and none of them is going to be a gigantic blockbuster, but if you find one you can attack it with more confidence than usual.
Diabetes: pretty good, up to a point. There are a number of well-studied animal models here, and if your drug’s mechanism fits their quirks and limitations, then you should be in fairly good shape. Not by coincidence, this is also a pretty well-served area, by current standards. If you’re trying something off the beaten path, though, a route that STZ or db/db rats won’t pick up well, then things get harder. Look out, though, because this disease area starts to intersect with lipids, which (it bears saying again) We Don't Understand Too Well.
Obesity: deceptive in the extreme. There are an endless number of ways to get rats to lose weight. Hardly any of them, though, turn out to be relevant to humans or relevant to something humans would consider paying for. (Relentless vertigo would work to throw the animals off their feed, for example, but would probably be a loser in the marketplace. Although come to think of it, there is Alli, so you never know). And the problem here is always that there are so many overlapping backup redundant pathways for feeding behavior, so the chances for any one compound doing something dramatic are, well, slim. The expectations that a lot of people have for a weight-loss therapy are so high (thanks partly to years of heavily advertised herbal scams and bizarre devices), but the reality is so constrained.
Oncology: horrible, just horrible. No one trusts the main animal models in this area (rat xenografts of tumor lines) as anything more than rough, crude filters on the way to clinical trials. And no one should. Always remember: Iressa, the erstwhile AstraZeneca wonder drug from a few years back, continues to kick over all kinds of xenograft models. It looks great! It doesn’t work in humans! And it's not alone, either. So people take all kinds of stuff into the clinic against cancer, because what else can you do? That leads to a terrifying overall failure rate, and has also led to, if you can believe it, a real shortage of cancer patients for trials in many indications.
OK, those are some that I know about from personal experience. I’d be glad to hear from folks in other areas, like allergy/inflammation, about how their stuff rates. And there are a lot of smaller indications I haven’t mentioned, many of them under the broad heading of immunology (lupus, MS, etc.) whose disease models range from “difficult to run and/or interpret” on the high side all the way down to “furry little random number generators”.
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+ TrackBacks (0) | Category: Animal Testing | Cancer | Cardiovascular Disease | Diabetes and Obesity | Drug Assays | Drug Development | Infectious Diseases | The Central Nervous System
March 5, 2008
Posted by Derek
There’s an interesting article coming out in J. Med. Chem. on antibiotic compounds, which highlights something that’s pretty clear if you spend some time looking at the drugs in that area. We make a big deal (or have made one over the last ten years) about drug-like properties – all that Rule-of-Five stuff and its progeny. Well, take a look at the historically best-selling antibiotic drugs: you’ve never seen such a collection of Rule of Five violators in your life.
That’s partly because a lot of structures in that area have come from natural products, but hey, natural products are drugs, too. Erythromycin, the aminoglycosides, azithromycin, tetracycline: what a crew! But they’ve helped an untold number of people over the years. It’s true that the fluoroquinolones are much more normal-looking, but those are balanced out by weirdo one-shots like fosfomycin. I mean, look at that thing – would you ever believe that that’s a marketed drug? (And with decent bioavailability, too?)
No, you have to be broad-minded if you’re going to beat up on bacteria, and I think some broad-mindedness would do us all good in other therapeutic areas, too. I don’t mean we should ignore what we’ve learned about drug-like properties: our problem is that we tend to make allowances and exceptions on the greasy high-molecular weight end of the scale, since that’s where too many of our compounds end up. It wouldn’t hurt to push things on the other end, because I think that you have a better chance of getting away with too much polarity than you have of getting away with too little.
One reason for that might be that there are a lot of transporter proteins in vivo that are used to dealing with such groups. It’s easy to forget, but a great number of proteins are decorated with carbohydrate residues, and they’re on there for a lot of reasons. And a lot of extremely important small molecules in biochemistry are polar as well – right off the top of my head, I don’t know what the logD or polar surface area of things like ATP or NAD are, but I’ll bet that they’re far off the usual run of drugs. Admittedly, those aren’t going to reach good blood levels if you dose them orally; we’re trying to do something that’s rather unnatural as far as the body’s concerned. But we could still usefully take advantage of some of the transport and handling systems for such molecules.
But that’s not always easy to do. We all talk about making our compounds more polar and more soluble, but we balk at some of the things that will do that for us. Sure, you can slap a couple of methoxyethoxys on your ugly flat molecule, or hang a morpholine off the end of a chain to drag things into the water layer. But slap five or six hydroxyls on your molecule, and you’ll be lucky not to have the security guards show up at your desk.
There are, to be sure, some good reasons why they might. Hydroxyls and such tend to introduce chiral centers, which can make your synthesis difficult and dramatically increase the amount of work needed to fill out the structural possibilities of your lead series. That’s why these things tend to be (or derive from) natural products. Some bacterium or fungus has done most of the heavy lifting already, both in terms of working out the most active isomers and in synthesizing them for you. Erythromycin’s a fine starting material when you can get it by fermentation, but no one would ever, ever consider it if it had to be made by pure total synthesis.
There’s another consideration, which gets you right at the bench level. For an organic chemist, working with charged, water-soluble compounds is no fun. A lot of our lab infrastructure is built for things that would rather dissolve in ethyl acetate than water. A constant run of things with low logD values would mean that we’d all have to learn some new skills (and that we’d all probably have to spend a lot of time on the lyophilizer). Ion-exchange resins, gel chromatography, desalting columns – you might as well be a biochemist if you’re going to work with that stuff. But in the end, perhaps we might be better off, at least part of the time, if we were.
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+ TrackBacks (0) | Category: Drug Industry History | In Silico | Infectious Diseases
October 31, 2007
Posted by Derek
The post here the other day on resistant bacterial infections prompted some readers to wonder why the drug industry isn’t doing more to come up with compounds in this field. It’s not like there’s no money to be made, and it’s not like there’s no history of antibiotic research, after all. But since my industry doesn’t have a history of knowingly leaving money on the table (what industry does?), you’d figure that there’s more to the story.
Money aside, there’s a real problem with finding good targets. For as long as I can remember in the industry, the infectious disease field has suffered from a relatively small target landscape. Almost all the known drugs in the area work through just a handful of basic mechanisms, and adding new ones to the list has been very difficult for at least the last twenty or thirty years.
That was supposed to change, in theory, starting about ten years ago. I interviewed around then at a company that was working in the field, and everyone was quite excited about the bacterial genome sequences that were starting to appear. Surely this would open the sluice gates and let that long-delayed swell of new targets come washing down the flumes. Hasn’t happened. Not yet, anyway.
I have the impression that the same problems that have affected the translation of human genomic data to new drugs have been the problem here as well. In some cases, not as many genes came out as some people were hoping for. And of these, the function of many of them was (to put it mildly) obscure. Of the ones whose use was at least partially known, many of them have proved not to be useful targets for killing the bacteria or limiting their growth. And of the ones that made that cut – and we’re down to an all-too-manageable set by now – screening hasn’t turned up much chemical matter for people like me to work on.
In fact, there’s a persistent feeling among many people in the field that bacterial and fungal proteins have a lower hit rate than you’d assume they would. Even enzymes that are fairly homologous to those in higher organisms, so the story goes, don’t turn up as many hits in the screens as expected. I’m not sure if this is true or not, but as folklore it’s pretty well known. The combination of all these factors with the perceived lack of opportunities for profits (even if you do find something) has made for slow going.
In recent years it’s become clear that the medical need has grown to the point that antibiotic research can indeed be financially worthwhile – but there are any number of financially worthwhile drug outcomes that we haven’t been able to realize. (See obesity, Alzheimer’s, and many other therapeutic areas for examples of multibillion-dollar opportunities waiting for a good idea to come along. Resistant bacteria have their name on one more sword stuck in yet another stone.
Update: there's clearly another reason why developing good antibacterials is hard, and it's the same reason we need more of them. Bacteria are well-stocked with efflux pumps to get rid of molecules they don't like (and with other weapons as well), and they evolve so fast that you can watch them do it. I wrote about efflux on the site a while back - another post is well worth doing soon.
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+ TrackBacks (0) | Category: Drug Development | Infectious Diseases
October 29, 2007
Posted by Derek
There’s been a steady stream of reports in the news about methacillin-resistant Staph. aureus. It’s not a new problem, but (like other nasty infections) it does get a lot of press when the media start paying attention. Works in reverse, too – on the viral front, have you noticed the much reduced number of bird-flu-will-kill-us-all stories this year as we head toward winter? This despite the likelihood of bird flu killing us all being as high (or low) as ever, as far as I can tell.
But the resistant bacteria problem is certainly no joke, and there doesn’t seem to be any reason why it won’t gradually get worse over time. It struck me the other day that antiinfectives, as a drug research field, might be moving toward a similar spot to oncology. In both cases, you have a problem with rapidly multiplying cells, giving you a serious medical outcome - often in cancer, and increasingly with infections. The average tumor is a lot more worrisome than the average infection, of course, but that’s something we can only say with confidence in the industrialized world, and we've only been able to say it for the last sixty or seventy years. As cancer gradually becomes more manageable and infections gradually become less so, the two might eventually meet – or even switch places, which would be bad news indeed. (In some genetically bottlenecked species, in fact, the two problems can overlap, which is fortunately extremely unlikely in humans).
There are, of course, a lot of differences between the two fields, not least of which is that you’re fighting human cells in one case and prokaryotes (or worse, viruses) in the other. But many of those differences actually come out making infectious diseases look worse. The transmissibility of bacteria and viruses make them serious contenders for causing havoc, as they have innumerable times in human history, and they can grow more quickly in vivo than any cancer. It’s only the fact that public health measures allow then to be contained, and the fact that we’ve had useful therapies for many of them, that makes people downrate the infectious agents. If either (or both) of those change, we’re going to be rethinking our priorities pretty quickly.
What this means for drug development is that some researchers will have to rethink their attitudes towards antiinfective drugs. For serious infections, we're going to have to think about these projects the way we've traditionally thought of oncology agents - last-ditch therapies for deadly conditions. Anticancer therapies have long had more latitude in their side effects, therapeutic ratios, and dosing regimes, and antibiotics for resistant infections are in the same position. For some years now, there's been a problem that new drugs in this field would perforce have small markets, since they'd be used only when existing agents fail. That market may not be as small as it used to be. . .
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+ TrackBacks (0) | Category: Cancer | Drug Development | Infectious Diseases
July 9, 2007
Posted by Derek
One of the stories I missed while on hiatus has been Roche's recall of antiretroviral Viracept (nelfinavir) tablets. As readers may know, a problem with many batches of the drug became known in June. It's a mesylate (aka methanesulfonate) salt, but some of the tablets turned out to have ethyl mesylate in them as well, which is definitely sonething I'd go out of my way to avoid ingesting. A worldwide recall (except for North America, which is on a different supply chain) has been the result.
Methanesulfonate is a very happy anion, which is one of the reasons why methanesulfonic acid is used to make salts of basic drugs. The ions of these formulations tend to not be too tightly bound or paired, making the salt forms generally easier to dissolve. (The stronger the interactions between the ions, the harder it is for water to break up the party and dissolve them). But the contentedness of the sulfonate anion makes it a good leaving group when it's part of a covalent molecule. It would rather be off floating around with a negative charge on it again than be tied up in a regular bond, so sulfonate esters and the like tend to be pretty reactive.
Alkyl mesylate esters, then, are also pretty toxic. Just how toxic is the question, though. The stuff will react with nucleophiles wherever it finds them, and if that's some protein on the surface of a soon-to-be-shed epithelial cell, then no harm done. But there are many other situations that won't work out so well, going all the way up to DNA damage.
So how did this nasty stuff get in there in the first place? When I heard about the contaminant, my first thought was that someone had been washing out the reactors where the salt was formed with ethanol, and that appears to be exactly the case. Alcohol plus free acid under strong acid catalysis will give you ester, in what's literally one of the oldest reactions in the book. Roche appears to have been able to keep the contaminant down below regulatory levels normally, but someone's mind has been wandering over in Switzerland. In consequence, the fearsome Swiss reputation for purity and consistency takes a torpedo below the water line.
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+ TrackBacks (0) | Category: Infectious Diseases | Why Everyone Loves Us
May 22, 2007
Posted by Derek
As the cost of sequencing goes down, a lot of once-crazy experiments become feasible. There's a good case in point this week in the preprint section of PNAS. A team of researchers looked at a single patient undergoing treatment with vancomycin for a serious infection. (Just saying "vancomycin" makes the "serious infection" part redundant, since it's often the last resort). They periodically isolated Staphylococcus aureus bacteria from the patient's blood during the course of the treatment to look at how resistance to the antibiotic developed.
Fine, fine - except the way they watched the process was to sequence the whole genome of each bacterial isolate. What they found were a total of 35 mutations, which developed sequentially as the treatment continued (and the levels of resistance rose). Here's natural selection, operating in real time, under the strongest magnifying glass available. And it's in the service of a potentially serious problem, since resistant bacteria are no joke. (Reading between the lines of the PNAS abstract, for example, it appears that the patient involved in this study may well not have survived).
The technology involved here is worth thinking about. Even now, this was a rather costly experiment as these things go, and it's worth a paper in a good journal. But a few years ago, needless to say, it would have been a borderline-insane idea, and a few years before that it would have been flatly impossible. A few years from now it'll be routine, and a few years after that it probably won't be done at all, having been superseded by something more elegant that no one's come up with yet. But for now, we're entering the age where wildly sequence-intensive experiments, many of which no one even bothered to think about before, will start to run.
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+ TrackBacks (0) | Category: Infectious Diseases
May 7, 2007
Posted by Derek
Back in 2005, the government of Brazil threatened to break the patent on Abbott's HIV medication Kaletra if the price didn't come down (see here and here). But after a lot of arm-wrestling, a deal was reached. Now it's Merck's turn, with their efavirenz, and this time things went all the way: on Friday, Brazil's president issued a compulsory license to produce the drug outside Merck's patent.
My problem with this, other than the obvious problem I have with expropriation of someone else's property, is that Brazil is trying to have things both ways. The government spends much of its time talking about how the country is an emerging power, with the 12th-largest economy in the world, huge natural resources, its own successful aircraft industry and space program, and so on. But when it comes time to pay for HIV medications, which are important both medically and politically, suddenly they're a poor third-world country being exploited by the evil multinational drugmakers. A look back at the second blog link above, with its quotes from Brazil's Minister of Health on how nationalizing drug patents would help the country's industry, shows that this issue probably has more to do with the first worldview than the second one.
During the Kaletra dispute, I asked a question:
I've known some pretty good Brazilian scientists, but the country isn't up to being able to discover and develop its own new ones. (Very few countries are; you can count them on your fingers.) So I've saved my usual justification for last: if Brazil decides to grab an HIV medication that other people discovered, tested, and won approval for, who's going to make the next one for them?
And now Merck is basically asking Brazil the same thing:
"Research and development-based pharmaceutical companies like Merck simply cannot sustain a situation in which the developed countries alone are expected to bear the cost for essential drugs in both least-developed countries and emerging markets. As such, we believe it is essential to price our medicines according to a country's level of development and HIV burden, thereby ensuring equitable access as well as our ability to invest in future innovative medicines. As the world's 12th largest economy, Brazil has a greater capacity to pay for HIV medicines than countries that are poorer or harder hit by the disease.
This decision by the Government of Brazil will have a negative impact on Brazil's reputation as an industrialized country seeking to attract inward investment, and thus its ability to build world-class research and development."
It should have, anyway. Look, intellectual property law is not pretty, and doesn't give anyone a warm feeling. It's not meant to. But the alternative Jolly-Roger world is even worse, and anything that takes us toward that is a bad move.
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+ TrackBacks (0) | Category: Drug Prices | Infectious Diseases | Patents and IP
April 25, 2007
Posted by Derek
Pfizer got a tiny bit of good news yesterday when an FDA panel recommended their new HIV drug, Maraviroc, for approval. There are several stories that can be told about this news, so let's try a few: The business story is that this is not going to make a lot of difference for the company, because the drug isn't going to be a first-line therapy. They have to hope that it performs well and can expand its use, because a $25 to $50 million/year drug is a roundoff error on the scale of Pfizer's financial concerns. So much for the money.
The drug development story is that this will be the first CCR5 inhibitor to reach the market. That's a useful benchmark by the standards of this blog, because back in 2002, in my second month of blogging, I wrote about this class of drugs. The first CCR5 inhibitors had already made it into human patients by that time, and here we are, five years later, and one of them is just about to make it to market. Patience is supposed to be a virtue, but in the drug business, it's a case of making that virtue out of necessity.
And the big philosophical story is how the world has changed in the last twenty years. Here's a new HIV medication, one with a new mechanism, and it makes the second business page of the paper if it makes it at all. A completely new drug for a dreaded disease is coming, and no one thinks it'll do all that well, because of all the competition, y'know. It'll be given to people who've failed courses of treatment with all the other HIV drugs out there, and unless you're paying attention it's hard to keep up with all of them.
For people who remember the 1980s, all this still feels strange - imagine a message from the future popping up in 1985, saying: "In twenty years, the viral disease with by far the most crowded market, the largest number of possible therapeutic options and the widest variety of drug mechanisms will be. . .HIV". Actually, that would have scared everyone even more than they already were, because it would sounded like the worst predictions from that era had come true. In reality, HIV isn't even in the top 15 causes of death in the US, with the most recent figures I can find putting its contribution to the death rate a bit below that of aortic aneurysm. (Some other parts of the world are a different story, of course, although the 1980s predictions for them were even more apocalyptic.) But all in all, I'm fine with living in a world where new drugs against deadly diseases aren't necessarily front-page news. . .
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+ TrackBacks (0) | Category: Infectious Diseases
April 13, 2007
Posted by Derek
I've been out of the research labs for over two months now, and you know what I miss the most? No, not the safety meetings (hah!) or the smell of the solvents - what I miss is getting fresh data on experiments. Waiting for results on something crucial is hard to take, but it's also exciting, and there's nothing I've found outside of science that compares.
I've sat at my desk holding a warm printout from an LC/MS, or with a newly arrived e-mail from the biologists, and I swear, I've closed my eyes for a moment before I've looked at them. That's the last moment of not knowing; after that you're living in the new world that the experiment made. I don't know what I'd do with a job that didn't have that feeling in it, and honestly, that's one reason I'm still looking.
It occurs at all sorts of levels - checking the NMR to see if your reaction worked or not, waiting for the PK results to see if your idea raised the blood levels, holding your breath when the compound goes into two-week tox testing. And beyond that things get really terrifying, when human data start coming in from the clinic.
Ask Vertex. I wrote here about their antiviral compound (telaprevir, VX-950) for hepatitis. It's a huge market that really needs a better drug, and a lot of people have taken swings at it. Well, on Saturday night in Barcelona, the company is presenting their latest clinical data, and investors are checking their heart rates. The drug's success would be the biggest event in the history of the company (and a huge advance in hepatitis therapy), and failure (the antiviral norm, unfortunately) would be very, very hard to take.
The company's top clinicians already know the answer, of course, because a person's got to have time to make slides. They've had the experience I was talking about, on a scale that few people have ever felt. You click a button, turn a page, and the future writes itself out there in front of you. . .
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+ TrackBacks (0) | Category: Clinical Trials | Infectious Diseases | Who Discovers and Why
February 7, 2007
Posted by Derek
Antiviral drugs are one of those big unmet medical needs that we talk about in the drug industry. The reason we talk about them is, of course, that from a business standpoint - and this is a business, for sure - "unmet need" is equivalent to "unmade profit".
The problem is, the reason that some of these big opportunities are unclaimed is that they're not easy to address. As I've said here before, one big problem with antivirals is that there are a very limited number of good targets for drugs. After all, viruses are pretty stripped-down to start with: they do a limited number of things, but they do them very well indeed. Compared to a relatively target-rich therapeutic area like cancer, infectious disease is a desert.
One well-known oasis, though, contains the viral proteases. Many viruses carry these as a key part of their machinery, to help "unpack" necessary proteins from larger precursors. Famously, that's how many of the anti-HIV drugs work, and the same general strategy should be applicable to several other viral types.
Hepatitis C has been one of the big targets for many years now. Various development programs have come and gone, but no one has been able to really nail this one. Vertex is now in the middle of trying to, and as Adam Feuerstein points out, they're really betting a large part of the company on the attempt. Over the next few months, results should start coming out for their PROVE trials of telaprevir (VX-950), and for Vertex's sake, the drug had better work. A herd of competitors, probably led by Schering-Plough, is ready to take over should anything slip.
"Work" is defined as "work well enough so that people don't have to take injections of interferon". That'll depend, as always, on the balance of efficacy and toxicity, and it's the side effect profile that everyone will be watching, since it's widely assumed that the drug will in fact do some good against the disease. The nerve-wracking thing about working for a small-to-medium sized company has always been that your future ends up depending on single events like this, and I wish everyone at Vertex good luck. (Of course, as people at Pfizer will tell you, your future even at a gigantic company can end up depending on the results of one clinical trial - this industry is getting altogether too exciting for a lot of people to take).
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+ TrackBacks (0) | Category: Clinical Trials | Infectious Diseases
October 18, 2006
Posted by Derek
There's a curious paper (subscriber-only link) in the latest Nature that's getting some attention, titled "A linguistic model for the rational design of antimicrobial peptides". For non-subscribers, here's a synopsis of the work from the magazine's news site.
A group at MIT headed by Gregory Stephanopolous has been studying various antimicrobial peptides, which are secreted by all kinds of organisms as antibiotics. Taking the amino acid sequences of several hundred of these and feeding them into a linguistic pattern-analysing program suggested some common features, which they then used to synthesize 42 new unnatural candidates. The hit rate for these was about 50%, which is far, far more than you'd expect if you weren't tuning in to some sort of useful rules.
It's the concept of "peptide grammar" that seems to be the news hook here. But I'm quite puzzled by all the fuss, because looking for homology among protein sequences is one of the basic bioinformatics tools. I have to wonder what the MIT group found with their linguistics program that they wouldn't have found with biology software. What they're doing is good old structure-activity relationship work, the lifeblood of every medicinal chemist. Well, it's perhaps better described as sequence-activity relationships, but sequence is just a code for structure. There's nothing here that any drug company's bioinformatics people wouldn't be able to do for you, as far as I can see.
So why haven't they? Well, despite the article's mention of a potential 50,000 further peptides of this type, the reason is probably because not many people care. After all, we're talking about small peptides here, of the sort that are typically just awful candidates for real-world drugs. And I'm not just babbling theory here - many people have actually tried for many years now to commercialize various antimicrobial peptides and landed flat on their faces.
You won't see a mention of that history in the Nature news story, unfortunately. They do, to their credit, mention (albeit in the fourth paragraph from the end) that peptides are troublesome development candidates. That's where it also says that there are reports that bacteria can become resistant even to these proteins, which prompts me to remind everyone that bacteria can become resistant to everything short of freshly extruded magma. It's in the very last paragraph of the story, though, that Robert Hancock of UBC in Vancouver says just what I was thinking when I started reading:
(Hancock) questions how different the linguistics technique is from other computational methods used to find similarities between protein sequences. "What's new is the catchy title," he says.
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+ TrackBacks (0) | Category: Biological News | Drug Development | Infectious Diseases
September 11, 2006
Posted by Derek
It's been a while since I wrote about the neuraminidase inhibitors (Tamiflu and Relenza, oseltamavir and zanamivir). As we start to head into fall, though, I'm sure that avian flu will invade the headlines again, if nothing else (and I hope it's nothing else).
There's an interesting report in Nature (subscriber link) on how these drugs work. Bird flu is a Type A influenza, but there are two broad groups inside that class, which are defined by what variety of neuraminidase enzyme they express. (There are actually nine enzyme variants known, but four of them fall into one group and five into the other).
The drugs were developed against group-2 enzymes, but they're also effective against group-1 influenzas. Since the X-ray crystal structures showed the the drugs bound in the same way to all the group-2 neuraminidases, and since the active sites of all the subtypes across the two groups are extremely similar, no one ever thought that their binding modes would be different. Well, until last month, anyway, when the X-ray crystallographic data came in.
And what it showed was that the active sites of the group-1 enzymes, sequence homology be damned, have a much different structure than the group-2s. As it turns out, though, they can adopt a similar shape when an inhibitor binds to them, which is why the marketed inhibitors still work on them, but they're fundamentally quite different.
I can't resist the urge to use this example to illustrate some of the real problems in our current state of the art for computation and modeling. The differences between these two enzymes are due to their different amino acid residues far away from the active site, which makes modeling them much, much more difficult (and makes the error bars much, much wider when you do). That's why no one realized how far off the group-1 and group-2 neuraminidases were until the X-ray structure was available: modeling couldn't tell you. Any modeling efforts that tried would probably have decided, incorrectly, that the two groups were nearly identical. Why shouldn't they be?
But if we'd had that X-ray data from the start, modeling would very likely have told you, incorrectly, that there was little chance that either Relenza or Tamiflu would work on the group-1 enzyme variants. Why should they? The "induced fit" binding modes, where the enzyme changes shape significantly as the ligand binds, are understandably very difficult to model. There are just too many possibilities, too many of which are within each other's computational error bars.
Now, it's true that this latest work isn't based on molecular modeling at all. (You have to wonder how close these guys got, though). But plenty of projects that are using it are just as much in the dark as a neuraminidase team would have been, and they may not even realize it. Most molecular modelers are well aware of these limitations, but not all of them - or all of the managers over them - are willing to accept them. And when you get out to investors or the general public, it's all too easy for modelers or managers to act as if things are perfectly under control, when in reality they're lurching around in the dark. Like the rest of us. . .
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+ TrackBacks (0) | Category: In Silico | Infectious Diseases
July 19, 2006
Posted by Derek
I wrote some time ago (Ay! Four years ago - have I been doing this for that long?) about the Roche/Trimeris HIV drug Fuzeon (T-20, enfuvirtide), and its costly manufacturing process. Roche built a factory in Colorado just to make the drug, which is a 26-amino acid peptide. And instead of doing it recombinantly, they're producing it the good old chemical way, by peptide coupling. (Here's a not incredibly competent collection of whiz-bang photos of the place, which at least have no purple spotlights in them)
Back in 2002, I had some thought that Roche had perhaps lost its corporate mind. But as this article from Chemical and Engineering News points out (subscriber-only, I think), they've actually done everyone a favor, whether by losing their minds or not. Their decision to go fully synthetic, and the massive investment that followed, has lowered the cost of all sorts of peptide synthesis reagents, starting materials, and equipment, to the point that it's now become enough of an industry to attract a lot more production interest. (And one of the big players in the contract business is. . .Roche's Colorado facility!)
As the article points out, recombinant technology (producing the peptide in engineered cells) is a wonderful thing, but only when it's working perfectly. And getting it to that point can be a long, expensive task. There are a lot of potential cell lines to choose from, each with its own advantages and disadvantages, and uncountable ways to engineer them and culture them. Even then, the purification of the target protein can be a whole new nightmare - as one chemist interviewed by C&EN says, at least synthesis doesn't give you back ten times as many different things as you put into it.
Peptides still aren't anyone's first choice for development when there's a small-molecule alternative. But for the targets that no small molecule is going to hit, they're worth looking at. Recent years have seen improvements in metabolic stability and duration of action, as people come up with all sorts of nifty delivery systems and conjugate polymers. You could do a lot worse.
But perhaps Roche could have done better. There were all sorts of glowing forecasts about Fuzeon when it was first approved, and all sorts of grumbling from people who took the optimistic numbers and calculated that Roche would be making its money back in two or three years at the prices they'd set. Well, that hasn't happened yet, since the drug isn't selling nearly as well as had been hoped.
Another two or three years should do it, if nothing better comes along to cut into Fuzeon sales. And stipulating that (which is no sure bet) Roche might be selling it for a long time to come, since the barrier to generic manufacture is going to be rather high. So, even after that wild factory in Colorado, they're still probably going to go into the black on Fuzeon, but it does make you wonder how the return compares to some of the other drugs in Roche's portfolio.
But that's their problem. In the meantime, it looks like they've helped everyone else in the business by making industrial peptide synthesis more affordable. Adam Smith's invisible hand strikes again. . .
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+ TrackBacks (0) | Category: Drug Development | Drug Prices | Infectious Diseases
May 10, 2006
Posted by Derek
There's been a lot of press coverage the last week or so about two new routes to Tamiflu (oseltamavir). Roche famously starts from shikimic acid, most of which they get from Chinese star anise, and the new syntheses are attempts to get around that bottleneck.
E. J. Corey's getting more attention than Masakatsu Shibasaki, partly because he's a Nobel winner and partly because he's made a point of placing his synthesis in the public domain. (Shibasaki's applied for a patent). It's nice to see organic synthesis make the headlines, but unfortunately, a lot of the coverage has been of the "Nobel Prize Winner Solves Tamiflu Problem" sort. I've also seen several stories that suggest that Corey's route opens the door (at last, right?) to mass production.
Not so fast. Roche has already been producing rather large amounts of oseltamavir, although they'd be glad to find a better route. And it's not like they haven't been trying themselves, as this PDF will make clear. And it's far from clear that Corey's route will be of commercial value, even though his overall yield, as given, is about 27%, which news articles are saying is roughly twice the yield from shikimic acid. (Note, though, that that Roche PDF claims a higher yield than Corey's - I'm not sure who's right).
Let's get technical and take a look at the chemistry. First off, the repeated claim that Corey's route starts from two of the cheapest feedstocks available - butadiene and acrylic acid - is only partly true. The key Diels-Alder reaction actually uses trifluoroethyl acrylate, which is substantially more expensive than acrylic acid, although admittedly ten times cheaper than the same amount of shikimic acid from the same source. Moving on, there are eleven steps, and according to the supplementary material for the paper (where the full experimentals are), steps 1, 3, 4, 5, 6, and 8 have chromatography in their workup. The others are run through a plug of silica or are taken on crude, which tells me that Corey's students probably tried to do the same with the remaining steps but took a hit on the yields. Every chromatographic purification adds a great deal to the cost of a process route, needless to say.
There are other wrinkles. Steps 1 and 2 start at -78 degrees before coming up to more process-friendly temperatures. Step 8 is a slow addition at -40, and step 9 is an inverse addition at -20. Low-temperature reactions are certainly doable on scale, but again, they'll add to the cost and complexity. Those last two steps involve an acylaziridine intermediate, whose thermal stability would need to be checked out, and could partially negate the advantage of not using azide in the route.
The scale of the reactions in this paper is in the ten-gram range, which is fine, until you get to steps 8 and 9. Those low-temperature reactions are shown on 300 and 160 milligrams, respectively. That tenfold drop in scale indicates another area that would need to be checked out; there can be a huge difference between something that works on a couple of hundred mgs and a useful process, especially in the cold.
All this isn't to say that Corey's route doesn't work, or that it can't work on scale. But it's important to keep in mind that the kind of chemistry done in his lab is about as far from industrial scale as you can get. It may be that the more interesting features of his route (the catalyzed Diels-Alder, for example) could be combined with some of Roche's own process ideas and turned into something feasible. But for now, this is an interesting route that's a long way from solving anyone's Tamiflu shortage.
To be fair, Corey himself isn't responsible for some of the hype, except I wish he wouldn't let himself be quoted as saying that the thinks that the Tamiflu production problems are "solved". Headline writers know nothing about organic chemistry or drug development, and they run with what's in the press releases. Of course, there's the larger question hanging over all of this: will Tamiflu even do anyone any good if there is a human outbreak of avian flu? And that, nobody knows.
Comments (19)
+ TrackBacks (1) | Category: Chemical News | Infectious Diseases
January 19, 2006
Posted by Derek
So, are the neuraminidase inhibitors (Tamiflu and Relenza, oseltamivir and zanamivir) going to be of any use against bird flu? The press coverage is a mass of confusion. Headlines range from stuff like "Newer Flu Drugs Work Better" to "Don't Use Older Flu Drugs, Experts Warn" to "Tamiflu Not Effective Against Bird Flu". The problem is, we're looking at two different classes of drugs, and two different sorts of flu.
A few days ago the CDC issued a warning that the prevalent H3N2 flu strains this year have mutations that make the older class of flu antivirals (the aminoadamantanes) ineffective. But I'm not sure how many people even get these any more, since they were never very impressive to start with. I don't think anyone has seriously proposed them as a defense against H5N1 avian influenza, should that ever take off.
But Tamiflu and Relenza are a different story; a blizzard of hype has surrounded their possible use. Lost in the bird-flu noise is their use against "regular" influenza, a market where they've never performed up to expectations - no doubt they're selling rather better so far this season - and the CDC recommended their use for this purpose.
Comes now a report in The Lancet from a group in Rome (available to subscribers here), looking over all the published studies on the various drugs. They also recommend that that adamantanes be retired, and they aren't very positive on the use of the NA inhibitors against the standard forms of flu, which I'd say is in line with the clinical experience. And they found no evidence that either Tamiflu or Relenza is effective against bird flu, which leads to all the jumpy headlines.
But this isn't really a surprising finding, since there hasn't been (to my knowledge) any published study on the use of the drugs against avian influenza in humans. (Cell culture, yes, but that's a long way from the real world). There hasn't been enough time (and there haven't been enough patients, fortunately). A better headline would have been "Tamiflu's Effectiveness Against Bird Flu Unknown", but we already knew that. Didn't we?.
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+ TrackBacks (0) | Category: Infectious Diseases
November 14, 2005
Posted by Derek
Andrew Stimpson isn't a scientist. If he were, he might have heard the line about extraordinary claims requiring extraordinary evidence. And his claim is indeed extraordinary - he says that he has managed to clear HIV from his system without therapy. Well, other than vitamins, don't you know - and if he says that he got them from Matthias Rath, I'm going to have to go lie down for a while.
This story has generated all sorts of irresponsibly breathless headlines, but when you read the stories underneath them you find that there's not much behind it. Stimpson received a positive HIV diagnosis on the basis of two antibody tests in 2002. Near the end of 2003, he was found to be negative, and was asked to repeat the test to confirm it. He refused, and sued the British health trust that did the testing.
Update: Press reports disagree about this. Some have the story as above, and others say that Stimpson tested negative on several occasions during 2002 and 2003. His initial postive tests showed what is being described as "an extremely low viral load."
Here's where things get messy. Stimpson appears to have sued because he felt that the original tests were in error. (The agency naturally stood by both its positive results). When no money was forthcoming, he then seems to have gone to a couple of the British tabloids with his miracle recovery story: ". . .I am just one person who managed to control (HIV), to survive from it and to get rid of it from my body", he's quoted as saying, which is an interesting statement from someone who was previously claiming not to be infected at all. Update: Stimpson eventually received a letter from the National Health Service calling his HIV-negative status "exceptional and medically remarkable", so he at least didn't come by his miracle-recovery story alone.
Stimpson hasn't been tested again, and doesn't seem to be available at the moment. I am not inclined to believe any claim such as his, to put it mildly, until he's been poked and prodded from every angle - to put it mildly. You would think that he might wish to help other HIV sufferers if he really has reversed the disease, wouldn't you? The article link above quotes the head of a charity in England as saying "The answer may turn out to be very complex. We must not jump to conclusions." Actually, I'm close to jumping to the conclusion that the answer might be rather simple.
Update: Press reports also disagree - markedly - about Stimpson's willingness to undergo further tests. My final sentence isn't meant to suggest some complex biochemical rationale. I'm thinking that the chances are best that the first positive results were in error - after all, their false-positive rate is surely much higher than the spontaneous-clearance-of-HIV rate. The health agency that tested him, though, might well prefer to treat this as an amazing medical anomaly rather than as a botched test. And given that he wasn't able to collect damages, it became in Andrew Stimpson's financial interest to go with that explanation as well, selling his story to the British tabloids for an undisclosed amount.
In the end, I agree with this quote, from the Nature.com news item on this story: ""If it is real, it's very interesting," says Jonathan Weber, an expert on infectious diseases at Imperial College London. But he cautions that the most likely scenario based on the current evidence is "either a false positive [in 2002], or he's still infected".
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+ TrackBacks (2) | Category: Infectious Diseases
November 9, 2005
Posted by Derek
While the Wall Street Journal is opening its site for free this week, may I recommend this excellent article on the vaccine and antibiotic markets? It's a clear-eyed look at why drug companies haven't put more time and money into these areas over the years. The headline makes it sound as if it's going to be a pharma-bashing-festival, but the authors (Scott Hensley and Bernard Wysocki) lay out the facts, which are just as I understand them from my vantage point, too.
The second article in the series is also up here. It's an equally good overview of the possible incentives that are being discussed to encourage work in vaccines and anti-infectives. I'm glad to see the idea of incentives being discussed, because as it stands, the market isn't necessarily going to give us what we need in the time we need it. New antibiotics are generally reserved for use in resistant cases only, so you can't make your money back there. And new vaccines can end up costing too much in liability suits (many - most - of which aren't particularly well justified). But put some incentives in there, and perhaps the numbers can work out. The article goes into detail on some of the proposals - straight cash, guaranteed purchases, extra product exclusivity, and so on.
I know that some people will hear these ideas and wonder why the government doesn't just do the research itself, rather than cough up money to the drug companies. The biggest reason is that the drug companies are better at it, and faster as well. We stay on our toes competing against each other. The biggest pitfall in these incentive plans, as far as I'm concerned, is that it might end up with companies that have no one breathing down their neck. Better to have two or three organizations racing each other and throwing elbows to grab the prize, than to have someone ambling over to pick it up.
Comments (5)
+ TrackBacks (0) | Category: Infectious Diseases
November 2, 2005
Posted by Derek
In the first post below, I said that we would be in big trouble if we had to rely on a vaccine for all of our protection against a flu pandemic. The problem is, if we're relying on antiviral drugs, we're in even worse shape. (See my post on this from last March.)
Right now, the only drugs likely to do much of anything against an influenza pandemic are the neuraminidase inhibitors like Tamiflu and Relenza. But the problem is, these drugs really have to be taken early in the course of the infection to be most effective. By the time many people realize that they have the flu, it may be too late to do much about it.
One way to get around that problem would be to take the drugs prophylactically, but that has two serious disadvantages. For one thing, this route might well lead to a quicker development of resistant viral strains, which is something that we already know can happen. And for another, it would burn through huge amounts of drug, and we don't happen to have huge amounts of either one.
Why is that? Well, for one thing, neither compound was selling very well until recently. The companies involved have never had to ramp up production to the levels that people are talking about now. It's doable, but it won't be fun. The ten-step Roche synthetic route to Tamiflu uses some azide chemistry, which is potentially toxic and explosive, but it's nothing that a good bunch of industrial chemists can't handle. (It helps, for example, that India's Cipla already has experience making AZT, because that relies on similar chemistry). But any ten-step route is not going to be trivial to implement if you've never done it before, azide or no azide.
A bigger problem is that these drugs have syntheses from a starting material called shikimic acid. That's a component of an important metabolic pathway in plants. (It's important enough that the well-known herbicide Roundup works by shutting it down). Shikimic acid is found in small quantities in a lot of plant species, but star anise, a spice used in Chinese cooking, has a lot of it. (If you'd like to extract some from any star anise you have in your kitchen, here's how). Roche already has a network of suppliers in China, and the generic companies who plan to produce the drug are having a hard time sourcing the shikimate. It can also be produced by fermentation, which Roche uses for some of its supply, but that's an even more specialized process.
All in all, I think it's prudent to stockpile these drugs, although I'm not sure, for the reasons given above, where the US government is going to find the quantities it's looking for. But even if we can pile the stuff up to the rafters, we have to be ready for the possibility that these drugs may or may not do us much good. I see that I've ended both of these posts on the same note. . .
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+ TrackBacks (1) | Category: Infectious Diseases
Posted by Derek
The government's proposed plan for dealing with a flu pandemic is worth some comment, although it's going to undergo mutations just as surely as the viruses do. It's hard to argue with the overall approach, but there are some details that need explaining.
For example, there's a proposed boost for research into vaccine production through cell culture techniques (as opposed to the famous chicken-egg methods), and I think that this is a fine idea. Unfortunately, it was just as fine an idea two or three years ago, and we'd probably be in better shape now if this idea had been pushed back then. Money doesn't convert to time quite as easily in basic research as it does in some other areas (although it doesn't hurt, true). Some of the companies that do work in this area are pointing this out today, in rather testy tones of voice:
. . .so far the government has not backed development of three cell-based vaccines that have received or are close to receiving regulatory approval in the United States and Europe - including one developed by a Meriden (CT) biotechnology company. Instead, the Department of Health and Human Services last April funded only one cell-based flu vaccine - $97 million for a vaccine that has not yet been tested in animals or humans.
"I don't know what the hell they are thinking about," said Dan Adams, president and chief executive officer of Protein Sciences. . ."
This is the voice of a man whose company missed out on a $97 million dollar contract, so that has to be taken into account. But it does appear that HHS and the FDA have been overly cautious about moving to cell-culture based vaccines.
But "caution" is a popular word in the vaccine field, in the financial, medical, and legal senses. and that brings up another provision in the President's proposal that I haven't seen anyone else comment on yet: liability protection for vaccine producers. As you might figure, I think that this is on principle a good idea, but the trial lawyers (and some others) will think differently. This will be an interesting fight, but it might take place largely out of sight. "Fight for your right to sue the people who are trying to protect you from bird flu" isn't a very catchy slogan.
My last comment on vaccines in this context is to point out that - cell culture or no cell culture - if we get to the point that we're relying on a vaccine to save people from a pandemic, then we could be in big trouble. There's an inevitable delay in vaccine development and production - months and months and months of delay, and that's when things are really zipping along. Viruses can mutate in the time it takes to fight their previous versions. If we're lucky, the vaccines that are being developed now will have enough protective effect against whatever flu strain might cause a pandemic. But they might well not, and we need to realize that.
Comments (4)
+ TrackBacks (1) | Category: Infectious Diseases
October 13, 2005
Posted by Derek
Note: This post has a follow-up with Jim Cramer's reaction to it here.
The small-pharma flavor of the month seems to be Biocryst Pharmaceuticals, but it's not one of their current development projects that has everyone jumping up and down. It's a drug that failed its Phase III trials two years ago. Despite the best efforts of various stock newsletters and of multimedia stock tout Jim Cramer, though, I'm managing to resist the company's stock.
The words "avian influenza" are the missing piece to this puzzle. The drug, peramivir, is a neuraminidase inhibitor developed as a flu treatment, which is the same mechanism as the marketed drugs Relenza and Tamiflu. With the current worries about a possible pandemic, antivirals of all sorts are getting a second look.
In this case, you have to go back a few years for the first look. Peramivir was in Phase II trials during the late 1990s, and in 1999 the results were announced: not too bad. Their endpoint was reduction of viral titer, the blood marker of flu virus infection, and they hit it. On to Phase III, then, to see if that effect was worth anything in the real world.
There were some rough patches. Biocryst's development partner, Johnson & Johnson, pulled out of the deal before the Phase III trials got properly off the ground. (So much for the Valentine-card sentiment about them being the "ideal partner" at the end of that 1999 press release). J&J seems to have taken a look at the market performance of the other neuraminidase inhibitors and concluded that they had better places to put their money.
They were probably right about that. Tamiflu and Relenza were supposed to be much more successful than they've turned out to be. I wrote about this a couple of weeks ago in the context of a Canadian effort to develop new antivirals. The Canadians make an appearance in at least one article on Biocryst, from the New York Times, which also talks about the unhappiness of the smaller companies (Gilead, Biota) that first discovered Tamiflu and Relenza:
Tamiflu's inventor, Gilead Sciences, a California biotechnology company, told Roche in June that it wanted to take back the rights to the drug, accusing Roche of a "consistent record of inactivity and neglect" since the medicine was approved by the F.D.A. in 1999.
A Roche spokesman, Terence J. Hurley, said the company had fulfilled all its obligations to Gilead to promote and manufacture the drug and the dispute was in arbitration. . .
Biota, which is based in Australia, filed a lawsuit there against Glaxo last year, saying it did not adequately try to market Relenza. After the drug's first year on sale, "essentially all promotion was stopped," Mr. Molloy said.
Biota is seeking about $300 million in royalties it says it would have earned if Glaxo had done an adequate job. (Biota has now teamed up with Sankyo to move Sankyo's version of Relenza forward under a $5.6 million grant from the National Institutes of Health in the United States.) Glaxo denies Biota's accusations in the case, which is headed toward arbitration later this year.
"We lost a lot of money, quite frankly, promoting it, and the demand wasn't there," said David Stout, Glaxo's president for pharmaceutical operations.
I especially like that last quote, since I thought that the drug industry was always supposed to be stampeding people into buying stuff that they didn't need. Maybe Glaxo could hire Marcia Angell as a consultant to show them how it's done. Just thinking out loud here. . .ah, what a match it would be. . .
OK, where were we? Ah, back in early 2000, as Biocryst was preparing to go it alone in their Phase III effort. They did manage to get things off the ground, but the results were very disappointing. The endpoint this time wasn't just reducing viral load, but reducing flu symptoms. And the drug managed to decrease the time to improvement of symptoms by. . .about half a day, with no statistical significance, and this at doses up to 800 mg/day. They dropped the compound immediately, and rightly so.
Although that press release doesn't go into the details, Biocryst has told the press that one reason that peramivir might have failed was poor blood levels after oral dosing. I'm going to reserve judgment on that explanation, because the blood levels were certainly high enough to go through Phase II and Phase III trials – blaming them now sounds a bit ex post facto. Injected versions of the drug seem to perform well in rodent models of avian flu infection, and they're looking to get a human trial going via the same route. (This was an option before, too, of course, but the drug had no commercial chance as an injectable versus two non-injectable compounds as competition). And in all the noise about injectable peramivir, I haven't heard anyone say how it performs versus injections of Tamiflu or Relenza, either. Surely they can be formulated for it.
The prospect of a flu pandemic has changed things, but the problem is, it's too soon to say if people are now being more realistic or just more hysterical. In the last few weeks, though, I think things have tipped toward the latter. Avian flu, if it crossed over into some highly infectious human form, could be very bad news. But we're not seeing that happen (yet) with the current bird flu. It's worth remembering that flu viruses of this type have already crossed over into humans in recent years without taking off around the world. That doesn't mean that it can't happen, but it does mean that it's not inevitable.
So, no one knows how likely a pandemic is, when it might occur, and how it might behave. It's prudent to take a look at marginal compounds like peramivir, whose possible use against avian flu was being spoken about years ago. But it's not prudent to buy, or urge others to buy Biocryst's stock after it's already tripled in price. Looking at that price and the implied value of peramivir, The Biotech Stock Blog says:
"An NPV of $350 million, for example, implies $900 million of sales next year at a 50% gross profit and discounting back 15%. If you assume there is risk associated with the company realizing future cash flow from peramivir, then the implied future cash flow is considerably larger. For example, handicapping the likelihood of BioCryst winning a government contract and selling product next year at 50%, implies BioCryst sells $1.8 billion worth of peramivir next year!
Any way you slice it, the expectations for BioCryst are wildly optimistic based on the current stock price. This is not to say that peramivir does not ultimately become a successful drug or that there isn't money to be made on BioCryst. Ultimately, however, reality will come back to the stock and the fast money will go elsewhere. When the music stops, you don't want to be the one without a chair."
(Link via The Stalwart). I agree with this analysis completely. Would Jim Cramer, in between shouting into the microphone and waving his arms, care to comment on these numbers? Or are we going to have a historial re-enactment of 1999, with Biocryst playing the part of Viropharma and Cramer taking on the role of Tokyo Joe? Since his analysis of BCRX so far includes the phrase "Trading is all about the buzz", that's just what we might be in for.
I made a lot of money shorting VPHM back then, and (although I haven't yet) I'm tempted to go short BCRX now. I wonder if there are any shares left to borrow?
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+ TrackBacks (1) | Category: Infectious Diseases
October 3, 2005
Posted by Derek
The Medicine/Physiology Nobel for Barry Marshall and Robin Warren is a fine thing. It's important to realize just how odd it seemed that ulcers could be caused by bacterial infection, when Everyone Knew that they were due to excess stomach acid, no doubt caused by stress and such things. (Check out the retrospectively insane passage from 1967 cited here in an excellent review of the H. pylori discovery. It's a respectable review article with authoritative research showing that over-dominant mothers were responsible for most ulcers. Sigmund Freud has a hell of a lot to answer for.)
H. pylori is the source of almost all ulcers, and is involved in many stomach cancers as well. Infectious agents are now suspected to play a role in many other chronic conditions. The germ theory of disease has become more important than ever in the last twenty years, and these are two of the scientists most responsible.
Marshall and Warren pursued their line of research despite raised eyebrows and dismissive head-shaking, even to the point of ingesting a culture of bacteria to show that it could infect the stomach lining. And they were absolutely correct, as the scientific world came to realize. An important (and encouraging) part of the story is how they were able to prove their case and completely change medical opinion within just a few years. It's good to think about that when people start going on about Dogmatic Intolerant Scientists and Science As A New Religion and so on.
Crazy ideas won't necessarily get you tossed out of the club. Crazy ideas with nothing to back them up will. But just come back with the evidence, and they won't be crazy any more. Show me the religion that takes its heretics and makes them bishops, won't you?
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+ TrackBacks (1) | Category: Infectious Diseases
September 26, 2005
Posted by Derek
The CBC has an article claiming that:
"Formulas for new, inexpensive influenza drugs that could expand the world's tiny arsenal of weapons against pandemic flu are gathering dust because the pharmaceutical industry isn't interested in developing them, scientists say.
They believe governments should fund the testing and development of the drugs, side-stepping big pharma and bringing them to market as cheap generic medications.
And they point to the story of Relenza - one of only four flu drugs currently sold - as evidence public-sector involvement will be needed if crucial new flu drugs are ever going to hit pharmacy shelves. . ."
Which scientists say these things? Well, one of them is Mark von Itzstein, of Griffith University in Australia, who is quoted as saying that he has "three compounds that are ready to be tested in animals and could be available on a commercial basis in three to five years for about $10 a treatment course". You have to get to the end of the article to get to some of the problems with that statement, and some of them never make it to the surface at all.
For one thing, having three compounds that are ready to be tested in animals is not as big a number as it might sound. I've been on projects where many more compounds than that - about ten times more, in some cases - went into animal testing, and nothing still came out the other end. It's good to have compounds that you believe in, but Prof. von Itzstein (who helped discover the drug now sold as Relenza) surely knows, you usually need a lot more shots on goal than that.
Another little detail is that going from this unspecified "animal testing" (efficacy model? two-week toxicity?) to "available on a commercial basis" in under five years is rather unlikely. That's a very, very short time for drug development, and I don't see how all the regulatory requirements could be met so quickly. And having a cost estimate in hand makes it seem as if there's already a bulk synthesis of the compounds, but why would you do that before you've even come close to going into animals?
This all has to do with a Worthwhile Candian Initiative called ICAV, which aims to get more antiviral drugs on the market. I certainly can support that idea, but I think that the people involved will soon find out one reason why there aren't more of them already: antiviral drug development is very hard. There are a lot of disparaging references in that CBC article about the profit-driven drug companies ignoring all these worthy drugs, but then there's this:
"ICAV is trying to get buy-in from governments around the world, starting with Canada. It has asked the federal government for $70 million over seven years to promote development of antiviral drugs for a number of diseases, including influenza, HIV and hepatitis C."
You know, I could have sworn that those indications could all support profitable drugs - if of course, they, like, work and everything. One of the problems with neuraminidase inhibitors like Relenza is that they have to be administered rather soon in the disease's progression, or they're basically useless. That's one reason that they haven't caught on, together with their often less-than-compelling efficacy. But getting antivirals with compelling efficacy is, as mentioned, hard. Those of us over in the profit-driven drug industry can only agree with Prof. von Itzstein wholeheartedly when he's quoted as saying "We need new antivirals." The only thing I would add is just a "good" in the middle of that sentence.
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+ TrackBacks (1) | Category: Infectious Diseases
July 25, 2005
Posted by Derek
In the drug industry, we tend to look down a bit at academia's attempts at pharmaceutical research. We don't go out of our way to hire people with university degrees in medicinal chemistry, for example, which you'd think would be a perfect fit. (Here's why.) And we're always insinuating that the professoriat just doesn't understand what it takes to develop a drug, and what kind of timelines have to be met. I've made a number of comments like that here, and I'll surely make some more.
But I have to admit that it's not always true. There are a few drugs that have come out of academic research, although in all the cases I'm aware of, much of the expensive heavy lifting was done after signing a deal with a pharma or biotech company. (Scroll down to the September 2004 posts herefor more ranting than you may need on the "all drugs come from academic research anyway, right?" position.)
One notable success story has been the antiretroviral Emtriva (emtricitabine), a nucleoside mimic that acts as a reverse transcriptase inhibitor. It was discovered in a longstanding program to find new antiviral agents at Emory, with the chemistry coming from Prof. Dennis Liotta and his group. (Personal disclosure: I nearly went to Emory for grad school to work in Liotta's group, and was strongly considering doing a post-doc with him afterwards. And I've attended his Gulf Coast Chemistry Conference a couple of times as well.)
I mention all these connections, I guess, because word comes now that Emory has cut a deal cashing in all future royalties for a record-setting $525 million dollars. They're selling 65% of the royalty stream to Gilead, the company that markets Emtriva (the orginal deal was done with Triangle Pharmaceutical, a firm of Burroughs Wellcome refugees later bought by Gilead), and 35% to VC firm Royalty Pharma. And the deal provides that the University itself gets 60% of that, with the rest to be split between Liotta, Raymond Shinazi (on the medical side), and former Emory researcher Woo-Baeg-Choi.
That is 210 million dollars to be split between the three of them. My heartiest congratulations, from down here on the floor where I'm fanning myself. I can tell you that if I come up with a winning drug here in industry, I'll likely get promoted, and may well even see a bonus. But I will most definitely not see any seventy million dollars. Maybe this academic model for drug discovery has something to it after all. . .
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+ TrackBacks (0) | Category: Business and Markets | Infectious Diseases
July 17, 2005
Posted by Derek
It's no wonder that there's still so much argument over autism and vaccines. Paranoia is an endlessly renewable resource - big glowing hunks of it are always being dug out of the ground and put to use. For an unfortunately typical example, take a look at |
