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: email@example.com
June 30, 2008
I was mentioning the gamma secretase enzyme around here just the other day as a longstanding target for Alzheimer's therapy. I remember the periodduring the 1990s when the enzyme hadn't been identified yet, and frankly, it was a lot easier to get excited about it then. That's because when it was finally worked out, the protease turned out to be a big multifunctional multiprotein complex, and among its many functions was affecting Notch signaling.
That's worrisome, because a lot of important cellular development pathways go through the Notch receptor, and these are things that you'd really rather not mess with. (Just run the word "notch" through PubMed to see what I mean). Indeed, some of the toxic effects of the earlier gamma secretase inhibitors seem to have been mediated through just those side effects. So for some years now in the gamma secretase field, the hunt has been on for compounds that will shut down beta-amyloid production without messing with the other functions of the enzyme complex.
Myriad Genetics took such a compound of theirs, Flurizan, into the clinic, after licensing it out to the Danish CNS drug company Lundbeck. They claim that these aren't straight inhibitors, but rather change the activity of the protease in some way that relatively less amyloid is produced. The drug showed some effects in Phase II studies - nothing to jump up and down about, but enough for Lundbeck to pony up for Phase III.
They wish now that they hadn't. As of this morning, the drug appears to have missed all its clinical endpoints in the Phase III trial: no improvement in cognition, no improvement in quality of life. There's no way to spin this kind of result, and the company announced at the same time that they're discontinuing any further work on the compound. (Interestingly, this news seems to have actually made some of its investors happier). It's Lundbeck, though, that seems to be left holding the bag, and their stock is getting hammered to multiyear lows. They have a monstrous patent expiration coming up in 2012 (Lexapro, by far their biggest drug ever), which might explain why they took a flier on the Myriad compound in the first place. The whole effort looks like something of a Hail Mary throw on their part - and most of those go down as incomplete. . .
+ TrackBacks (0) | Category: Alzheimer's Disease | Clinical Trials
June 27, 2008
I sketched out a rather small molecule the other day, a perfectly reasonable looking thing, which nonetheless had absolutely no references in Chemical Abstracts. (I’d certainly like to be able to put up a drawing of the structure, but it’s something that I have a work-related interest in, so it has to stay under wraps). But it’s something with only a dozen or so heavy atoms, most of them flat and aromatic – you’d certainly expect something to have been made like it, but apparently not.
This has happened to me many times over the years. Now, you can obviously get into unknown territory immediately if you start looking for bizarre compounds: I don’t happen to have SciFinder access here on the train this morning, but I’m willing to bet that (for example) three-membered rings with one carbon, one boron, and one silicon are pretty wide open for some brave weirdo to explore. Enjoy!
But you don’t have to go that crazy to leave the paved roads behind. Many reasonable low-molecular-weight areas are only very lightly explored. You can get out of the universe of known compounds very quickly, for example, by searching for spirocycles, particularly with an oxygen or nitrogen or two scattered into the rings. Most of these would surely be interesting scaffolds for drug discovery libraries, if there were reasonable chemistry to explore them with. Even some perfectly normal looking substitution patterns of monocyclic compounds haven’t been looked into – I dreamed up a series of oxazole derivatives not long ago that no one’s ever made, and there’s nothing odd about them at all.
As you’d expect, there’s a commercial niche here. Novelty is a key requirement for patentability, so seeing no references turn up around your interesting structure is good news from an IP standpoint. (It may be bad news from a laboratory standpoint, though, because sometimes these things are unknown for a reason). But not always: there are companies that pride themselves on being able to supply such unknown scaffolds and libraries. The perfectly reasonable-looking diazabicyclo compound shown here, for example, has no references in SciFinder, but can be purchased on a multigram scale. (There are about fifty derivatives of that bare scaffold known in the literature, which makes it pretty much uncleared ground compared to the absolutely pulverized IP landscape around, say, piperazine). Next time you're searching for such things, refine your answer set to give only those compounds with no references, and take a look at how many of them are commercially available anyway. . .
+ TrackBacks (0) | Category: Patents and IP | The Scientific Literature
June 26, 2008
Today I have the second part of the guest commentary from Zurich's Dr. Theo Wallimann on research funding in Europe. Today he advances his proposal for a new way of funding young scientists:
The definite proof that European Research Programs (such as the FP-6 and FP-7 Framework Programs) are not the sort that basic scientists regard as most useful is the fact that one has to indicate and list so-called "Deliverables". These are research results or products that one wants to or should achieve in the given time period, e.g. being able to express a protein at high levels in bacteria, (Deliverable 1), to purify it to high purity (Deliverable 2) to characterize it by biochemical and biophysical methods (Deliverable 3) and then try to crystallize this protein in order to produce X-ray compatible protein crystals (Deliverable 4).
One then has to provide yearly reports and let the reviewers know whether the goals set were achieved and met in time and whether one could "deliver" as predicted. If one meets one's own prognosis, one is considered a very good scientist who is able to meet one’s Deliverables. In other words, being able to deliver exactly what was predicted is considered good science, at least by the bureaucrats.
But anyone working in the fields of protein crystallization and X-ray crystal structure solving, for example, knows very well that protein crystallization is still an art which often needs a stroke of luck to get good crystals for X-ray studies. This can literally take years, guided first by brute force screening approaches, and if this does not work by intuition and perseverance. All of a sudden, out of the blue, one may be able to grow crystals once, but they sometimes never come again, even if you repeat the experiment under the very same conditions. In those cases you may find out that something subtle has changed, e.g. the battery of the distilled water apparatus was changed and the water quality was thus somewhat different, etc.
I know of an incident where a long, flexible protein should have been crystallized, but many doctoral students and post-docs could not manage to get crystals. After a year or so, a new post-doc came to the lab and started the project from scratch. However, he realized that his predecessors had left many crystallization trials in multi-well plates in the cold room. They must have stayed there for years, some were murky, even greenish and bacteria or algae must have grown in them. The new post-doc could have gotten rid of these murky old plates, but he was smart and clever enough to take his time to look at them.
Lo and behold, he saw crystals in some of them. He opened the micro-chambers with crystals in them, but saved the mother liquor and the buffer drop in which the crystals had grown. Be honest now, how many of you would have done such a thing? But this turned out to be absolutely crucial, for the bacteria or algae that grew in the protein solution drop and mother liquor produced a protease enzyme, which cut the long protein strand somewhere at its most flexible site. The rest of the protein then crystallized. Although this was a somewhat truncated form of the protein in question, the structure of this core could be solved and years later it was the basis for solving the whole protein structure. Why was it so important to save the supernatant and mother liquor? The post-doc cultivated the bacteria or algae, I don't remember exactly, and purified from them the very protease that was cutting the protein at the specific site, such that it then crystallized.
With this tool (the peculiar protease) at hand, he could reproduce what he had seen at first, and was rewarded with protein crystals which otherwise would not have seen at all. I think this is a very nice example of a) serendipity but also of b) a smart experimenter who reacted very cleverly and used foresight in formulating hypothesis that he then could prove to be true.
Would you ever state in a EU funding proposal that you plan to grow protein crystals by letting a protein solution stand around in a messy cold room, in hopes that the right bacteria would grow and nibble the protein’s flexible loop off so that the rest of the protein would crystallize? You would blatantly be considered as totally crazy, I would predict. But this episode took place in the 1980s, not back in Marie Curie’s or Pasteur's time, and similar events can and will happen today.
But such considerations are not a concern of the EU functionaries. They want to see the crystals, especially if you told them you would deliver them in a year or two. This is science on deliverables, as one may call it. But it has nothing to do with daily work in a laboratory. Therefore, as some have pointed out, the administrators should be educated scientist themselves, ones who have worked for a few years in a real laboratory environment. I think this would improve things quite a lot.
My proposition for EU research funding would therefore be: give young PhD investigators (after their post-doctoral training and after meeting various quality standards) no-strings-attached research support for 5 years. In this way they can demonstrate their talent and independence by doing what they like to do, as best they can. If after this time their work stands out, support is then generously extended for another 3-5 years.
After that, the tenure decision has to be made, and those not fulfilling the criteria (to be determined) will leave academia. This would give young people an excellent start-up chance – perhaps then there would be fewer people accumulating in academia who were promised promotions that might be delayed and postponed. (In many of these cases, all of a sudden these researchers are then considered "too old" and fall out of the system completely).
This generous scheme is of course risky, for some money will not be spent the best way it could have been. But on the other hand this will allow the really talented young researchers to thrive and take off for their Nobel PriZe ambitions. So, let’s simplify the granting bureaucracy by being much more generous, while trusting in peoples’ ability to self-organize to meet their challenges and perform. In the end it is not bookkeeping that will count, but the really great and innovative research results that bring humanity a step further along. Why shouldn’t we be prepared to take this risk? I am afraid, though, that my scheme would leave thousands and thousands of desktop offenders unemployed. . .
+ TrackBacks (0) | Category: Who Discovers and Why
June 25, 2008
My post a few days ago on research in the EU, quoting a letter to Nature from Dr. Theo Wallimann in Zurich, started off a long comment thread. And now I've heard from Dr. Wallimann himself, who has a wealth of personal experience with research funding, with the EU, and with large consortia of academic groups.
He's sent along a very interesting commentary, which I'm going to post in two parts. Today is on what EU research funding is like, and tomorrow it'll be on what it could (or should) be. So here's Dr. Wallimann with a report from the field:
I did by no means intend to say that important findings can only be made by lone wolf scientists, but wanted to say that if (and I am talking here about basic science, not industrial applied science), small groups are left to work independently, with passion, in the realm of those things that interest them from the inside of their spirit and heart, then the chances of making an unexpected finding are statistically much higher - compared to a granting agency telling you what topics should be worked on in order to qualify for funding.
Once an important finding in basic science has been made, it is relatively easy to find partners and to build up from the bottom a collaborative interdisciplinary team, even up to Manhattan Project-like applications. The latter step is mostly a matter of finances, for one knows what has to be done, since the basic findings and ground-work has been done by the basic scientists.
It is fact that the EU agencies (and probably most of the research funding agencies) want to see such interdisciplinary research networks even before any novel findings have been made. They tend to focus on relevant societal problems, like cancer, obesity, climate change, etc. And this is bloody ridiculous, for this encompasses only (or mostl) those scientists who just happen to work in these areas and who may happen to be excellent or mediocre. But it excludes other groups, mostly younger ones, who may not directly work on such a topic, but whose findings may turn out to be most important for them in the future.
What I would like to stress fervently is that true science is not predictable. If you already know what you want to find out it is no longer truly innovative science: this is exactly what Albert Einstein meant (and explicitly said), and what Albert Szent-Gyorgyi, the archetype of a "Free Radical", said as well. The latter Nobelist (for Vitamin C and on muscle contraction) never received substantial research money from NIH, for he refused to write a 50 page grant proposal exactly delineating and spelling out what he wanted to do during the next 3-5 years. He said, "How can I say what I am going to do in the laboratory in 3-5 years, if I don't even know today what I shall do there tomorrow".
I have been working in an "enforced" consortium of a EU program with a total of 26 laboratories Europe-wide. The sheer size of the consortium, with all of its members focusing on different aspects of the same global question, apparently seems to have been the most convincing argument for the EU administrators The program was substantially funded and we all profited indeed from this financial support, although the administration and book-keeping and report-writing efforts were horrendous. However, as it turned out, when the members met and got acquainted and divided into sub-groups (so-called “work-packages”), one had to realize relatively quickly that one was sitting on a table with competitors who worked on the very same problems as oneself. And example would be wanting to grow crystals of an important enzyme to solve its X-ray structure and from there, to design inhibitors or activators for pharmacological intervention.
So my question now is: how are you going to communicate in such a group? Which of your secrets that would give an advantage to the competitors are you going to spell out? Which hints does your neighbor disclose to you? And so on. This fact led to some rather awkward situations where people were sort of lingering around the real questions and problems and all tried to talk about those results that had just been accepted in a publication and were to be in press very soon. So here is the situation, we were forced to officially "collaborate" by the EU program, in order to get at the EU research financial honey-pot. But once we had the money, we would rather have preferred to work independently again and not share bench data with competitors.
By contrast, if the EU would foster independent smaller groups and if one then made an important finding, they themselves could go out and look for ideal collaboration partners on the spot without any granting agency telling them what to do and whom to consider. This gives a project a real kick-off, since such partners can be specifically selected for mutual compatibility and collaboration. Certainly, they would have to be as passionate as the original about the new finding and call in some other colleagues who would complete a strong team. Finally, such self-organization leads to true potentiation, but desktop planners can definitely not enforce this, I am convinced.
I was participating yet in another consortium program that was overshadowed by its own so-called steering committee. They felt responsible for the success of this program, so they started to strongly interfere and prescribe to us what to do, out of anxiousness that something unpredictable could happen. This simply shut down any possible creative outcome for this program.
As mentioned above, if a basic science program is successful in finding something really novel and important, only then can a "Manhattan Project"-like application of the basic research lead to an applied mega-project.
Many of the commenters here seem to have a misconception about the difference between basic science versus a Manhattan Project. I hope that this helps to clarify some of these issues, and I wish that you could come to work in a basic research laboratory for at least 10 years. You could easily grasp then what I mean to say here, I think. Thanks for your consideration and patience.
+ TrackBacks (0) | Category: Who Discovers and Why
June 24, 2008
This week was supposed to reveal the FDA's decision on Dai-Ichii Sankyo and Eli Lilly's anticlotting drug prasugrel. That one's in the same chemical class as Plavix (clopidogrel), and works by the same mechanism. Since Plavix did about eight billion dollars of business last year, and the anticlotting area seems to be a limitlessly huge market in general, you can understand why another drug is entering the space.
Both clopidogrel and pasugrel are prodrugs - their structures, as they come out of the bottle, are inactive. But they're converted by cytochrome P450 enzymes in the liver to their active forms, which bind irreversibly to the P2Y12 purinergic receptor on platelets. The clopidogrel link above shows the active form - that thiophene ring gets broken open, and a reactive SH is exposed. The P2Y12 receptor mediates platelet aggregation, so shutting it down extends clotting time.
A few points: for one, you'll note that the structures of the two drugs are very similar indeed. Is pasugrel just a "me-too", then? Well, it certainly is trying to do the same thing by the same mechanism, but as I've said here many times, it's hard to sell a drug unless you can point to some difference. The advantage that prasugrel has is that its metabolic activation takes place through a broader number of liver enzymes, so more of the active metabolite is produced across a wider patient population. And it is indeed about ten times more potent in humans - which may, though, prove to be its downfall.
In the clinic, the large TRITON-TIMI trial ran the two drugs head to head in over 13,000 patients, which is certainly the expensive (and definitive) way to go. The end result was that the prasugrel-treated group had fewer cardiovascular problems of all kinds (good!), but more episodes of severe bleeding (bad!). Overall mortality was the same between the two groups, and that's where the arguing has started. There's a lot of room to break down the numbers more thoroughly to see if there's some real benefit to the drug (or alternatively, to show that it really isn't any more useful than Plavix).
Of course, this is the job of the FDA. And now it seems that they've chosen to punt, delaying their decision by three months. Since the companies don't seem to have been asked to submit any more data, this seems to be an internal wrangle at the agency. I'm not sure what they're going to accomplish by holding their heads and moaning for another quarter, unless the hope is that the numbers can be crunched in some direction which will offer enough of a fingerhold to justify a decision. This is a very, very close call.
If I had to predict - and hey, I write this blog, so I've got a license to do that sort of thing - I'd say that the agency will ultimately approve the drug, but with label restrictions. In the end, they'll turf the problem over to the cardiologists, but with enough warning language on it that no one should be surprised if patients bleed out on occasion. The best outcome would be for some sort of clinical sign to indicate which patients should avoid the drug. The FDA will probably head in that direction, since it appears that the majority of bleeding problems occurred in the oldest and/or lowest-body-weight groups in the trial.
Update: but is that the case? Looking at the NEJM paper, it appears that patients not in these groups did have better efficacy with prasugrel, which improves the numbers. But the hazard ratio for major bleeding was 1.42 in the risky patients (>75 years old, or body weight < 60 kilos, or history of stroke/TIA), but still 1.24 in the ones outside these groups. So it's not at all fair to say that most of the bleeding events were in the risky patients - frankly, it looks like everyone bled, but the healthier cohort just responded better to the drug at the same time. That complicates my guess in the above paragraph, and raises the worst-case chance that the FDA might want to wait until the current trial comes in. What a mess. . .
There's another 10,000 patient study underway which might clarify the situation, or might just emphasize what a tied-up tangle it all is. In the end, I think that the FDA will let the drug be sold until that one finishes up, with the option to revise its opinion when the data come in. The three-month delay will serve to show how seriously they're taking all the safety issues - a big political consideration these days - and to work up the most bulletproof labeling they can come up with.
+ TrackBacks (0) | Category: Cardiovascular Disease
June 23, 2008
If you go to the med-chem or pharmacology literature databases and type "Aurora kinase", you'd better stand back. A geyser of publications will come spraying out, most of them having to do with Aurora A and/or Aurora B as possible targets for cancer therapy. These enzymes are involved in different phases of cell division, among other things, and a lot of evidence points to them as key players in several cancer lines. There are a number of inhibitors compounds known for them as well, in various stages of development, some of which are selective and some of which hit both to different degrees. Attempts to unravel all the functions of the kinases through these compounds, and through various loss/gain of function mutations in cells, have been. . .well, "complex" is a judicious term to use. The functions of the two enzymes may well be tied to each other, so getting a clear look has been hard.
There's a new paper that illustrates just why it hasn't been easy. This one looks at an AstraZeneca compound, ZM447439, which inhibits both Aurora A and Aurora B in enzyme assays, but in cells seems to be the closest match to a clear knockout of B. The authors started with a well-known cancer cell line (HCT-116), and picked out mutants that had acquired resistance to the drug. They turned out, indeed, to have mutated forms of Aurora B in them, and when they introduced those mutant forms into other cells, they also became able to grow in the presence of ZM447439. That's about as good a test of mechanism as you're going to get in the oncology field, and as the commentary on the paper says, "Even had the authors stopped at this point, it would have been an important contribution."
But they kept on digging, and good for them - perhaps they were (rightly) suspicious that everything was working out a bit too neatly. They then chose two other Aurora inhibitors, VX-680 (which hits both forms) and MLN8054, which is known to be selective for Aurora A. When the cells with mutant forms of Aurora B were exposed to the VX compound, they grew anyway - which makes sense from the Aurora B side of things, since they could well have mutated the efficacy away from this compound, in the same way they got away from the AstraZeneca one. But VX-680 definitely seems to hit Aurora A, too - so is that pathway not doing anything at all for efficacy?
Well, when they treated the Aurora B mutant lines with the Aurora-A-selective MLNM compound, they died off, implying that Aurora A inhibition can do the job all by itself, so there's a pretty blatant contradiction here. The authors advance the two hypotheses that have to be looked at: either Aurora A is a good target and the VX compound isn't doing as much against it as everyone thought, or Aurora A inhibition is largely useless (at least in HCT-116 cells!), and the MLNM compound has another target that no one's realized yet. (It's important to realize that this situation could vary from tumor to tumor - here's a suggestion that Aurora A might be the way to go for pancreatic cancer, for example).
And there's another, rather troubling take-home lesson, having to do with the alacrity with which these cells mutated away from sensitivity to the Aurora inhibitors. As the authors put it:
"The rather surprising picture emerging from our studies and from previous studies on Abl and other tyrosine kinases is that the kinase scaffold is very tolerant of mutations in the hinge loop that lines the ATP-binding site. A discouraging consequence of this fact is that these mutations are likely to affect a wide range of ATP-competitive inhibitors—even ones from distinct chemical classes—as most ATP competitors are sensitive to the active site's architecture, to which the mutated residues contribute considerably."
Put simply, the kinases we're targeting have more room to maneuver than we do as medicinal chemists. They can mutate quite a bit and still function, shedding the key binding motifs that our drugs are targeting along the way. We're going to have to work a lot harder to come up with effective combinations.
+ TrackBacks (0) | Category: Cancer
June 19, 2008
There’s been a lot of arguing – has been for many years – about research funding over in the EU. This is above and beyond the usual “not enough” protests, which are the way with funding of pretty much everything, pretty much everywhere, pretty much all the time.
A word on that: in my last 25 years of hearing academic researchers talk about grant money, never once have I heard that the situation is good. It’s always bad, worse, getting worse, tight, terrible, year in and year out. That’s not to say that sometimes those adjectives haven’t been accurate, but it’s hard to imagine that they’ve applied without letup. Some years ago, I realized that asking a professor about research grants is exactly like asking a farmer about rain. I did grow up on the Mississippi Delta, which actually comes in handy once in a while.
But the latest EU discussion is only partially about the amount of money involved; it’s also about how it’s to be used. There was an editorial in Nature not long ago from a fellow who wanted to make sure that it was spent wisely. “Wisely”, in his view, was to make sure that it goes to “problems society recognizes as central”, and the way to do this, naturally, was to have large research collaborations and consortia. These would presumably be put together by committees, commissions, and various far-seeing agencies staffed by the sorts of experts who spring up whenever the money starts to sprinkle down. I can just hear the Third Organization Meeting of the Steering Committee starting up right now, the chairman reminding everyone that they have a very full schedule today, please take your seats for our first speaker on "The Challenges and Opportunities of Interdisciplinary Research Management in a Multipolar World". . .
I grit my teeth when I think about this sort of thing; it's enough to make a man wish he'd gone to truck-driving school instead. So I particularly enjoyed a letter that the journal printed in response, from Theo Wallimann at the ETH in Zurich. He points out that nearly every single significant discovery in the history of science has come outside the framework of such top-down research consortia. Single researchers or small groups pursuing their own ideas have been the source of the good stuff, and half the time these breakthroughs haven’t even been what people were looking for in the first place. Says Wallimann about the big multicenter operations:
“. . . These mostly involve laboratories that have already established their name and fame, and are now often comfortably operating on well-worn tracks or working opportunistically on headline-grabbing problems or fashionable topics.
Science and innovation are chaotic, stochastic processes that cannot be governed and controlled by desk-bound planners and politicians, whatever their intentions. Good scientists are by definition anarchists,”
I can only cheer him on, because I couldn’t do a better job of summing up what I believe about science myself. In tribute, I’m going to go out to my lab and try something anarchic: an experiment that’s very interesting, but has very little chance of succeeding. If the EU really wants to tell its scientists what to do, they would be better off mandating six months of the same.
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June 18, 2008
I’ve done a fair amount of work against drug targets for metabolic disorders, so a recent letter in Nature caught my eye. The authors have used an ingenious technique to determine the number and age of the adipocytes (fat cells) that an individual has, and have tracked that cell population year by year.
One thing that comes out is confirmation of the fact that people basically set their number of fat cells during childhood and/or adolescence, and that number is then constant through their adult life. Several subjects in this study put on or took off weight during it, but that made no real difference to their number of adipocytes. And though liposuction does reduce the number of fat cells (by brute force!), they’re back to their original count after three years or so. So weight changes, as other studies have also indicated, are almost entirely due to individual fat cells becoming larger and smaller.
But that doesn’t mean that you’ve got the same fat cells all the way through. Most interestingly, this study found that about 8% of the adipocyte population turns over every year, which is a higher fraction than anyone realized. Half the fat cells in the body, then, have been replaced after about eight years have gone by. That also means that the stable total number results from a balance between adipocyte death and new cell formation, and it would certainly be interesting to know how these are tied together so well. The authors suggest that this relatively high turnover could be a potential target for weight loss drugs. If we could figure out how, say, to keep the fat cell population from being renewed so exactly, their numbers might naturally decrease. (On the other hand, perhaps the rate at which they die would drop to keep the balance – no one knows yet).
So, how do you tell how old a fat cell is, anyway? That’s the ingenious part I mentioned above, and it involves the same sort of techniques used in radiocarbon dating. The amount of carbon-14 in the atmosphere is relatively constant, with a few minor variations over the last fifty thousand years or so. Well, relatively constant except for the 1950s and 1960s, when we as a species reset the counter but good by atmospheric testing of atomic and nuclear weapons. Those tests released a much larger than usual amount of 14C into the world - in 1963 the count had doubled over normal background - and that's since cycled into the biosphere through uptake by plants and other living creatures.
That process has sent the atmospheric levels of radioactive carbon down steeply over the years, but there’s plenty of signal to detect, and we know just how much it’s gone down every year. In effect, every year of the last 50 or 60 has an anomalous carbon-14 reading, and each one is unique and vintage-dated. We take up the carbon through our food, and as a cell is formed, the particular carbon isotope signature of your body at the time is in all its parts. Many of these are recycled constantly – but the DNA isn’t. Extracting the DNA from cells and looking at the carbon-14 levels through mass spectrometry gives you a “production date” stamp for when that cell was born. (See here for a longer discussion of carbon isotope mass spectrometry as it relates to detection of banned steroid hormone use, specifically in the Floyd Landis case. That post, by the way, led to the longest comment thread ever seen on this blog). The same technique is being used for other cell populations as well.
The confirmation that the number of fat cells seems to be set before adulthood also ties in with the obesity trends seen in the general population. The great majority of obese adults were also obese as children, and the great majority of non-obese children do not become obese as adults. What factors set this adipocyte count in a person’s early life, and how many of them are environmental and could be modified, will be very useful to know. . .
+ TrackBacks (0) | Category: Diabetes and Obesity
June 17, 2008
Let’s start from first principles: most drugs mess something up. More elegantly, most drugs inhibit some enzyme’s activity or block some receptor’s binding site. Proteins are generally pretty well optimized at what they do, so it’s a lot easier to block their activities than it is to speed them up. (There are rare exceptions).
And if you’re going to target an enzyme with a small molecule inhibitor, you’ll do just that – find a small molecule that fits into the active site of the enzyme and gums up the works. In a few cases, we know of drugs that bind to other sites on the protein and mess up the active site indirectly, by altering the whole conformation of the protein, but most inhibitors are in or near the site where the natural substrates bind.
This background is what makes a paper in the latest Nature so odd. A large multicenter academic team has been studying inhibition of beta-amyloid formation by some known anti-inflammatory drugs. Beta-amyloid is cleaved out of a larger protein called APP, and the proteases that do the chopping have long been drug discovery targets. (Mind you, when I was working on Alzheimer’s disease in the early 1990s, we still didn’t know which enzymes those were, which made things rather difficult).
The key enzymes in that process are known as beta-secretase (or BACE) and gamma-secretase. The effect of the various known drugs has seemed to be more tied to the latter, although no one’s been sure just what the mechanism is, since none of them seem to be actual gamma-secretase inhibitors when you study them in isolated systems. The current work has turned some of these drugs into photoaffinity probes to try to find out what they’re really targeting.
(For those outside the field, photoaffinity probes are derivatives of some compound of interest, where some special UV-light-absorbing group has been attached off the back end. These photoaffinity groups are innocuous under normal conditions, but they turn into crazily reactive intermediates when they’re irradiated, and will then form a bond with the first thing they see. The idea is that you let your photoaffinity-modified compound find its usual protein targets, then you turn on the ultraviolet lamp. The reactive group does its werewolf thing and forms a permanent bond to the protein its next to. You can then search for the strangely labeled proteins, and you’ve found what the drug of interest was binding to. When it works, it works, although it’s a lot harder than I’ve made it sound).
When they labeled various gamma-secretase systems, all the way up to whole cell extracts, they found that the anti-inflammatories did not actually seem to bind to gamma-secretase at all: it wasn’t labeled. Based on earlier enzyme studies, that’s probably what they expected. But what was labeled was a real surprise: the APP protein, the substrate of the enzyme. Looking more closely, it appears that the compounds bind right to the part of APP that gets cleaved into beta-amyloid, and inhibit the enzyme’s action that way.
That, as far as I know, is pretty much a first. Update: the closest thing might be the mechanism of the antibiotic vancomycin, which binds to the weird D-Ala-D-Ala section of two of the components of the gram-positive bacterial cell wall and prevents them from being used.). This isn’t something that most drug discovery programs would try a priori, that’s for sure. For one thing, we have a hard time getting small molecule to bind to protein surfaces. Active sites inside proteins are our usual speed, because those are more defined cavities which are optimized to hold reasonably small substrates. But sticking to some outer part of a protein, while it does happen, is very hard to do in a targeted fashion. (We’d love to learn the trick, if there’s a trick to be learned – inhibiting protein-protein interactions with small molecules would open up a whole new world of drug targets).
Another reason that no one targets substrates instead of enzymes is that there’s generally a whole lot more substrate floating around than there is enzyme. Imagine someone throwing a hungry piranha into a pond full of goldfish. Which is the more efficient way to defuse the situation - armoring each goldfish, or disabling the piranha? That metaphor just occurred to me, and while a bit weird, it’s actually reasonably close to the situation you have with a protease enzyme and its substrates - if you want to get fancy, you can imagine that the piranha only likes certain types of goldfish, and only bites them in select spots.
But on the other side, there's also a reason why protecting the substrate might actually help out in some situations. Proteases tend to have multiple targets, so inhibiting them can also disrupt pathways that you didn't want to touch. Binding to the one substrate you care about might give you a much cleaner profile, compared to shutting down everything.
So you have to wonder what this result means. Have we been missing a whole range of potential enzyme inhibitors by ignoring things that bind to the substrates? I'm not convinced of that yet, but I am interested. I still have a hard time believing that we can do a good job targeting particular protein surfaces, at least at present, and I can't help wondering if there's something odd about that beta-amyloid sequence that makes it more likely to pick up small molecule interactions. (It certainly excels at picking up interactions with itself if it gets a chance, which is the whole problem). It's still going to be a lot easier to inhibit enzymes directly rather than bind to their targets, but it's worth exploring. We need all the ideas we can get.
+ TrackBacks (0) | Category: Alzheimer's Disease
June 16, 2008
About a year ago, I wrote about GSK's attempt to sell the lipase inhibitor orlistat over the counter as Alli:
"So my forecast for Alli is strong sales - for a while. Then it takes a dive, never to scale those heights again, as the word gets out. And the demand continues to grow for a weight-loss drug that works. . ."
Thanks to Pharmalot, this week we find this AP story which seems to confirm that suspicion. Sales for Alli aren't up to GSK's hopes, and the company is declining to say how much repeat business there is after people have tried it out, which says all that needs to be said. And this after one of their biggest marketing campaigns ever.
What still throws me is that an analyst quoted in the piece still talks about it as a drug that should, in theory, be a big seller. As that post from last summer makes clear, I've never once understood that, since Roche never could make it a huge seller as Xenical. You'll never be able to get around the unpleasant side effects of a pancreatic lipase inhibitor, as far as I can see, and you'll never be able to advertise one without mentioning them.
I think that the new, slimmed-down GSK organization is wasting money on this whole idea. But hey, Marketing thinks it's a great opportunity. . .
+ TrackBacks (0) | Category: Business and Markets | Diabetes and Obesity
June 13, 2008
The long-running saga of Elan's attempt to come up with a vaccine for Alzheimer's disease continues. There have been bold attempts, setbacks, rethinks, more setbacks, and now they're starting up again. Dosing of the latest version of their vaccine against the beta-amyloid protein, known as ACC-001, was suddenly halted in April when one patient came down with a skin lesion which was thought to be possibly autoimmune-linked vasculitis.
Biopsy results didn't confirm that, though, and the Elan/Wyeth partnership is resuming clinical studies. I'm not sure what that couple of months has done to their trial design; I assume that they've just started enrolling new patients and will continue with them, while continuing to monitor the former dosage groups. Maybe, though, there's a way to continue with some of those people and not lose all the time, effort, and data.
The idea of an amyloid vaccine has always excited and alarmed me in equal measure. But that's how I feel about the immune system in general, come to think of it. We have enough cellular firepower to completely destroy ourselves from the inside out - keeping that on a leash to where it (mostly) only goes after what it's supposed to is extremely impressive.
Now, I think that the usual sorts of vaccines are one of the great public health advances of civilization, but they work so well because they're targeted to outside agents (viral coat proteins and the like). Even so, there's a disturbingly large part of the population that remain suspicious of all vaccinations - I say "disturbing" not least because if that population gets too large, the efficacy of vaccination in general could be crippled. But what will these people think about a vaccine that's targeted to an endogenous protein? My immunology may need brushing up, but I can't think of any other example of such.
One thing that may keep this from becoming a huge issue, though, is that an amyloid vaccine, if it succeeds, will be targeted at the elderly rather than at children. And it'll be something that will have an effect against a disease that everyone can see right in front of them, rather than preventing diseases that most people have only read about in books. We'll be back at the situation that prevailed when the polio vaccine was introduced: no one had much doubt that the vaccine was better than the disease.
But even a vaccine fan like me still has room to admire, from a distance, the nerve of this approach. The brain is a special case, immunologically, and letting slip the dogs of war in there is not an intrinsically safe idea. But Alzheimer's is an intrinsically nasty disease. . .
+ TrackBacks (0) | Category: Alzheimer's Disease
June 12, 2008
Well, this is turning into GlaxoSmithKline week around here, but with good reason. I’ve had a lot of mail from people who have been affected by this week’s cutbacks, and others who left the company before the latest round. And that leads to these thoughts for today:
1. The company is being rather coy when they describe the current layoffs as only involving 2% of the work force. The recent cuts were focused on the Centers for Excellence in Drug Discovery (CEDDS), which is where the great bulk of discovery medicinal chemists are. To be more specific, this one seems to have hit the Metabolic Pathways group especially hard, and there’s thought that the other CEDDS will be going through similar contractions.
And there have been other cutbacks over the last few months, though, and there are surely more to come. With such a smaller head count in the CEDDS, everyone seems to be expecting the related groups to be next in line – IT, chemical development, more of the in-house biology, and so on. If the company is doing more research on the outside, then some of these folks will presumably not be needed. GSK looks to be shrinking for many months to come.
That makes a person wonder about whether these cutbacks are meant to send some big signal to the investors or not. You'd think that you'd make a bigger deal out of them if that were the case, rather than minimizing them for the public, as the company seems to be doing.
2. It’s going to be interesting to watch to see if the new style the company is trying will work. They’re breaking down the CEDDS into even smaller teams, from what I hear, turning the discovery organization into who-knows-how-many smaller competing units. It’s been described as the “if only we were a bunch of startups” philosophy, and there are several points to consider about that.
For one thing, startups may not be as wonderful as they appear statistically, because of survivorship bias: a number of them disappear with people having hardly been aware that they were around in the first place. Even if that’s a desirable state of affairs, will a large company be able to replicate it in-house? And even if it can be done, will it happen in this case, or will the teams be either too large to be nimble or too small to work? I’ve no idea. Neither does anyone else, and it'll be years before we know.
3. There have been a lot of comments, both here and at other news sites, about how this is another evil deed of the MBA folks, and if they’d only turn things over to the scientists and get back to the science, the company wouldn’t be in this position. Hmmm.
What I'm about to say feels strange to me, because I’m a scientist through-and-through, and I’ve done my share of complaining about ridiculous business attitudes. For that matter, I've found myself laid off though what I thought was a mistaken site closure. But all that said, there’s a case to be made that GSK partly got themselves into this fix by letting the scientists free to do science. That’s how I see, for example, the huge effort the company had for years in nuclear receptors. A massive amount of fundamental work was done, but (because it’s such a horrendously difficult area) little or nothing ever came out the far end to make anyone any money. I'm willing to be corrected on those points, but that's how I see it now.
And it’s not like the company’s productivity has been one of the wonders of the world overall. One correspondent, an ex-GSK researcher, pointed out to me in an e-mail that one of the sites hit hard this week had taken one drug to market in twenty-five years. Some of that is surely bad luck, but that explanation can only take you so far.
It’s interesting to hear people talk about the good old days in the industry. The other day I saw a comment about getting things back to the good productive days of the mid-to-late 1990s, which (I can tell you) didn’t seem to flippin’ productive at the time. But there are stories beyond counting of the days when Company XYZ Really Had Their Act Together, when the scientists were happy and management was wise and stayed out of their way, and the clinical candidates flowed like a free bar at an ACS meeting.
I used to feel bad, hearing these tales, sorry that I’d missed such days. But then I noted their similarity to the myths of Golden Ages that you see everywhere, and began to wonder. The drug industry was definitely a different place back when. Screening cascades weren’t so rigorous, animal models ruled the day (and actually, in some cases, steered projects right more quickly than their replacements), and there were more good targets that hadn’t been exploited yet. I’m willing to stipulate all that; it was a different world.
But most of us, I think, date the Real Good Old Days of the industry to a period before we joined – no matter when that was. Listening to people talk about when things were good is like listening to the guys down at the lake tell you that you should have been around last week when the fish were biting. There were any number of severe problems back in any Golden Era, but those sort of disappear into the glowing mist.
4. So GSK’s upper management is doing what upper management does: they’re trying to get a better return on their money – for which, read “the money of the shareholders”. Looking over the last ten years or so, they’ve decided that what the company has been doing has not been working. The loss of Avandia (whose discovery goes back further than that period) made the problems unignorable. So they’re trying something different. It’s hard to make the case that something different wasn’t needed.
We can all argue about whether this particular something is the right idea, or whether it’s being implemented in the right way. But no one should be surprised that a company with GSK’s current issues and cost structure is being shaken up. These cutbacks may be the work of people who are mistaken; they may even be the work of fools. But it's not the work of greedy sociopaths bent on destroying the drug industry. I’d give up on that line of thought and switch to something more useful.
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June 11, 2008
Thoughts on the GSK cutbacks, whose size, interestingly, is reported by Reuters this morning as (only) 350 jobs (i.e. 2%) worldwide, a figure which does not jibe with what I've been hearing from various people on the ground:
1. If the company seriously expects external collaborations to run at the same level of detail and efficiency as their internal research, they’re kidding themselves. I think – or hope – that they’re smarter than that, and that they’re planning to mostly just buy these things outright, as with Sirtris, rather than strike collaborative deals for them. Of course, they now have fewer people to prosecute the fruits of those acquisitions, but someone appears to think the numbers add up.
2. Doesn’t a statement that you’re going to emphasize external research rather than internal stand as an indictment of upper management? After all, who set the priorities and funded the programs? They surely won’t let individual project leaders or area heads explain lack of progress as “just one of those things, you know how it goes”, so how to explain what is apparently a catastrophic lack of progress across the board? And what does this say about the whole “Centers of Excellence” framework for drug discovery, erected some years ago at great cost of time and money?
3. Still, if you’re going to do such as thing as cut half your research staff, it’s probably better to go ahead and
do it the way that GSK did. Update: see the comments. This has actually dragged on for a while, and productivity appears to have gone where it goes in the sentence after next. Get it over with in one day rather than spread it out over time, department by department. The latter method sends productivity straight to hell. The death-of-a-thousand-cuts routine tends to terrify and dismay everyone, even in areas that are left untouched, and it sends a lot of good people out the door on their own.
4. But it’s not that productivity is going to be anything wonderful at GSK now. The people that are left will feel (will have felt?) a brief interval of relief that they still have jobs. But that’s followed by the employment equivalent of survivor guilt as they watch longtime colleagues go out the door, and on the heels of that comes the realization that nothing in particular holds the company back from doing the same thing to them, whenever it sees fit. That brings on (rightly) a feeling that you owe your company exactly as much loyalty as it seems to owe you. Many good people will be looking for the door themselves, and will be gone as soon as an opportunity presents itself.
+ TrackBacks (0) | Category: Business and Markets
June 10, 2008
Update: GSK is indeed wielding the ax today and tomorrow. I'm hearing that that the smallest cuts are around 40% of the entire research staff at the various sites. This is big, and it's bad. . .
GlaxoSmithKline has been going through some sort of mid-life crisis recently. Their chairman, Jean-Pierre Garnier, just retired amidst the mutter of angry shareholders, for one thing. And the company has been splashing out on some very flashy acquisitions, such as the Sirtris deal which has just now completed. This is all going on against the backdrop of the Avandia disaster, and a perceived drought of current clinical successes.
Now the company is cutting their own head count in research, to what sounds like a pretty serious degree. There have been substantial cuts at their sites in Italy and the UK, and the Research Triangle and Pennsylvania sites are getting it even harder, from what I'm hearing. Some chemistry areas are losing more than half their people. I believe that today is the day that a lot of people are hearing whether they stay or go, and I feel bad just hearing it from a distance, having seen that stuff close up a few times myself.
The proximate cause of all this turmoil is probably the loss of all that Avandia revenue, although that may have just advanced the timetable on some decisions that the eompany was going to make eventually no matter what. Many GSK scientists are (understandably) feeling as if they’re being ditched in favor of a bunch of people whose main advantage is that upper management isn’t so familiar with them yet.
Whether that’s true or not, it’s a tough one to refute. There is a persistent “grass is greener” mentality in the drug industry. Perhaps that’s partly because, on an individual basis, the grass really is often greener. The best way to work your way up in the industry, for the majority of scientists, is to jump ship once in a while, which keeps you from being pigeonholed or taken for granted in your current company. (A less charitable view, accurate in a few cases, is that it’s in some people’s best interest to leave before everyone else catches on to them).
And on a company-wide level, it’s hard not to think of everyone else as being at least a little more competent than your own shop is. That’s because you see the inevitable bozo mistakes of your own workplace up close, whereas you don’t get such good seats for the ones happening elsewhere. And the side that all drug companies show to their competition is a bristling pile of patents and confident press releases about their mighty drug pipelines. You know, looking at your own company’s public face, how much of it is real and how much is bravado or wishful thinking. But it’s hard to keep in mind that the same goes for everyone else, too.
I don’t know how much this effect is contributing to what’s going on at GSK. After all, some of the deals that the company’s making are for specific development compounds that they didn’t have in house. But I’m pretty sure that there are researchers over there who are thinking about whether they could have gotten a sirtuin program off the ground a few years ago, like the one they just bought. Or what would have happened to them if they'd tried. . .
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June 9, 2008
Time for just a brief piece this morning, about a topic I've mentioned before which is getting more noticeable all the time. If you follow the papers coming out in the Journal of the American Chemical Society (known as "Jay-ay-cee-ess" or just plain "Jacks" to the working chemist), you've been seeing an awful lot of nano-scale work. Nanorods, nanoprisms, nanoarrays of nanocrystals. The percentage of these things has, to my eye, just been rising steadily. Try the ASAP section and see what you think.
And what's interesting about these papers, completely apart from their subject matter, is that they're surely headed for obscurity in almost every case. That's not because nanoscience is going nowhere (quite the contrary, I think). It's because things are in such an early stage still. There are so many small steps to be made, many of which will turn out to have been in the wrong direction. Even the work that leads to something will be cited for its historical interest (". . .the first report of nanoscale battleaxes, now a crucial part of the world economy, came as early as 2008. . .").
This is the era when this work can be published. Much earlier and we wouldn't have been able to characterize these structures, and much later it'll seem trivial. (I know, some of it seems trivial on arrival - there are still a lot of chemists who roll their eyes and groan when they see this stuff). And boy, are people taking advantage of this window of opportunity. It has to be a good thing, in general, that there's so much work going on in so many different directions. I'm just glad that I don't have to figure out which of these seeds are going to bloom. . .
+ TrackBacks (0) | Category: Chemical News
June 6, 2008
Since it’s a favorite topic of mine, I really have to point out this study in PLoS ONE on resveratrol. A large collaboration looked at the gene transcription effects of dosing the compound in mice, compared to a normal diet and to a calorie-restricted one. I can’t do better than the first paragraph of the paper does at setting the scene:
” Caloric restriction (CR) retards several aspects of the aging process in mammals, including age-related mortality, tumorigenesis, physiological decline and the establishment of age-related transcriptional profiles. The wide scope of these actions, and the profound metabolic and hormonal shifts induced by CR has led to efforts at identifying natural or synthetic compounds that mimic the effects of CR in the absence of overt metabolic and endocrine disturbances or reduced caloric intake. Because most age-related diseases are likely to be secondary to the aging process itself, the discovery of such compounds could have a profound public health impact by reducing disease incidence and possibly extending the quality and length of the human lifespan.”
That’s a fine list of things that everyone would like to avoid: cancer, decline, and death. And the last sentence makes a key point, that the age-related diseases are not inevitable, but can be attacked as a group by attacking aging itself. A few years back, that statement might not have made it into a scientific paper at this level, but it can now.
This study had three groups of male mice (in a hybrid strain derived from C57 black): a control group getting 84 kcal/mouse/week of food, a calorie-restricted group getting 25% less chow, and a group getting the first diet plus 4.9 mg/kg of resveratrol, both experimental diets starting at mouse middle age (14 months). This same group had already reported that starting CR at that point in that mouse strain leads to about a 13% increase in lifespan.
As a baseline, they checked the transcriptional changes in young versus old mice on the control diet. There were, for example, about a thousand genes in heart tissue (out of twenty thousand checked) with a highly significant change in their profile. Comparing old heart tissue from the controls to the old tissue from the CR group, 536 genes showed a highly significant difference due to caloric restriction. The resveratrol-treated group, meanwhile, showed the same level of change in 522 genes, from basically the same list.
They also looked at skeletal muscle and brain (neocortex) and found similar but definitely less dramatic effects. In muscle, CR only affected about a quarter of the age-related genes (as opposed to half in the heart), and resveratrol was very similar. In the brain tissue, CR was able to reverse the aging profile in only 19% of age-related genes, and resveratrol lagged with 13%. The take-home message there is that aging can be a different process in different tissues, and attempts to alter it are going to vary across those tissues as well. (Here's the figure covering all these).
Another interesting question is whether CR (or resveratrol) affect other genes that aren’t in the age-related group. The answer is “Oh, yes indeed”, with over seven hundred genes whose profile was altered by CR but are not directly altered by age alone. (Compare that to the thousand age-altered genes, five hundred of which are reversed by CR, and you can see that this could be a source of significant effects). Resveratrol treatment did an extraordinary job of mimicking this profile, affecting 745 of the same 747 genes. The same thing was found in the other tissues – 1164 non-age-related transcription changes were found in skeletal muscle from the CR mice, and resveratrol treatment affected all 1164 of them.
So resveratrol appears to be a pretty close mimic of caloric restriction – but it’s closest in the non-age-related genes, which is interesting. The thing is, there’s no guarantee that all these transcriptional changes are good – presumably a lot of the ones that reverse age-related changes are beneficial (although we don’t know that for sure), but the ones that aren’t involved in aging could be more of a mixed bag. The net effect of CR does seem to be beneficial, but there are a lot of ways to arrive at that end point, and resveratrol could be mimicking the bad as well as the good. Here’s an attempt at figuring out the functions of the various genes involved in each group.
Of course, a much more relevant measure of benefit is how the animals themselves are doing under these treatments. The paper looks at some measures of cardiac function in young and old control mice, as well as in the treatment groups, and find that both CR and resveratrol seem to protect against decline. That chart also shows some other physiological readouts, at least one of which is rather surprising.
There's a huge insulin-signaling component in this whole field of study - the putative target of resveratrol (the sirtuins) are thoroughly tangled up in insulin and insulin-related growth factor (IGF) pathways. Genetic manipulation of several genes in those areas has also shown powerful effects on lifespan and aging in model organisms. So one of the oddities here is that the CR diet showed an effect on IGF-1, but resveratrol didn't. And while both treatment groups showed increased insulin sensitivity, several markers of that (glucose transporters, for example) showed the expected changes in the CR group but not the resveratrol group.
So if resveratrol treatment really does increase lifespan in the same way that caloric restriction does, it could mean that the insulin signaling axis isn't as important in CR as people thought. That's a difficult conclusion to come to, given the other data in the field, so a more reasonable one might be that resveratrol is hitting those same pathways, but not in the same way that CR does. (The similar increase in insulin sensitivity in the two groups argues for that view). Supporting this view, the transcription factor Pgc-1alpha, which is known to be very important for a range of genes in insulin sensitivity, was upregulated in muscle in the CR group but untouched in the resveratrol group.
The weirdest thing about this whole study, though, to my mind was the finding that levels of the prototype sirtuin, SIRT1, were not elevated in either group. That's in direct contrast to results seen in rats and humans under caloric restriction. In fact, in this case SIRT1 levels actually went down in the CR mice. There are several potential conclusions, all of which will keep people busy for a good while: perhaps some (or most?) of the anti-aging benefits of either CR or resveratrol in all species are coming from something else other than the effect on SIRT1. That would sow confusion, for sure. Or perhaps this is only true in mice, but not in rats (or people), and the sirtuin pathway really is the answer in the other species - in that case, you have to wonder what's so special about mice, and just what those different pathways are that kick in with them.
No, this is a very interesting study, and a very hopeful one, but it also points out just how much we don't know. I'm sure many more surprises like this are on the way, both positive and negative ones. But the overall point is made: aging and its effects can be altered. We don't understand quite how it's happening, and there are a lot of things to be worked out, but we can do it. If we can get the details worked out, human history is going to go through the biggest inflection point since fire and agriculture.
+ TrackBacks (0) | Category: Aging and Lifespan
June 5, 2008
You may or may not have noticed, but slowly and quietly, Merck has been getting many of the large Vioxx judgments against it overturned on appeal. These cases made huge headlines when they were first tried, but the articles that tell the end of the story have not, for the most part, made the front page.
This is one reason that the company was finally able to settle a huge number of pending lawsuits for much less than many people thought likely. Merck seemed to like its chances, considering the cases they’d won and the way things looked in the appeals courts, and the amount of money they were able to settle for finally became a better deal for them than the alternative of fighting out every case. Of course, now people are starting to wonder if the company settled too soon - opinions differ.
It's important to note, though, that some of these reversals have been less than total victories for Merck. The first Texas case falls into that category, but the New Jersey punitive damages were thrown out based on the idea of pre-emption. A state jury, the appeals court ruled, can't decide if Merck defrauded the federal government when it got Vioxx approved. (We'll be revisiting that part of the argument when Wyeth v. Levine and Warner-Lamber v. Kent get decided).
But in the end, what looked for a while like an avalanche that might sweep the company away has come down to . . .what? Twenty cases went to juries, and Merck has now prevailed, to a large degree, in 17 of them, including all the largest awards. The Vioxx affair has still been a big financial hit, and it’s definitely had effects on Merck, but it hasn’t been quite the disaster it looked like being. Well, not financially - the company's reputation has taken a fearsome beating, and the drug industry as a whole hasn't come out of the business looking any better, either.
I can’t claim to have kept a cool head through the thing. There really was a period where the entire Vioxx affair could have taken a different turn – if Merck had lost a string of jury trials at the start, a settlement would have been much harder to arrange, and would have cost (naturally) a huge amount more. But fighting the first wave of cases to an expensive draw and appealing every verdict that went against them turned out to be the right strategy. Of course, any rational observer would have wished for a world where the whole business never would have taken place, but that's not where we find ourselves.
But, as you’ll have noticed, the preceding paragraphs are written from a point of view that’s pretty sympathetic to Merck. Zooming out to a more neutral view, what do we have? Vioxx certainly did some people a great deal of harm. The clinical data that led to its withdrawal make it extremely likely that some people experienced heart attacks, fatal in some cases, because they took the drug. Where the arguing starts is when you start pinning numbers to that last sentence. Vioxx’s bad effects, though real, were also small compared to the number of people who took it. (And the arguing continues when you try to balance its bad effects with the good that it did for the patients who really needed it, who were surely, though, a small subset of the people who actually were on the drug).
Those last two sentences point to some of the problem. If Merck had not tried to make Vioxx the pain drug for everyone in the world with any kind of inflammation pain, it’s quite possible that its cardiovascular effects would never have been noticed. And it’s worth remembering that they were noticed during a trial for a completely different indication, the possibility that COX-2 inhibitors might have a protective effect against colon cancer. Only after that trial flashed an unmistakable statistical warning did everyone go back to Merck’s earlier data and start arguing about what could or should have been noticed before.
The problem is that many other drugs have data that, in retrospect, look like trouble. It’s just that in many cases, the trouble never appears, either because it never rises to the level of being noticed, or it never was really there to begin with. There are drug candidates that cause bad effects in one out of every ten people who take them, and those never make it out of the clinic. (Most of the ones causing trouble at that level don’t even make it into the clinic in the first place). The ones that cause trouble at one in a hundred get weeded out, too, if that trouble is bad enough. The one in a thousand, one in ten thousand, one in a hundred thousand levels are where the difficulty is, because clinical trials have an increasingly difficult time picking up those problems. They’ll show up, if they do, after a drug comes to market.
But why stop there? There’s no reason not to believe that there are drugs that also cause direct harm, but only to one out of every million patients. Or ten million, or hundred million. Some unlikely combination of genetic and environmental factors comes up – we really don’t know enough to rule that sort of thing at all. We call those drugs “safe”, but “safe” means “causing harm at too low a level to see”. Every single drug in the world has bad side effects, from the bottom of the scale (hideous old last-ditch chemotherapy drugs that are one step away from World War One battlefield agents), all the way up to the top. It's just a question of how often they turn up.
+ TrackBacks (0) | Category: Cardiovascular Disease | Toxicology
June 4, 2008
I was talking with a colleague recently about the different cultures that have grown up in different drug companies where lab associates are concerned. For those outside the industry, those are non-PhD-holding scientists, who (for the most part) do not move into managerial positions. There's room for a whole separate blog post on the people who (for one reason or another) never got the PhD degree but are the equal or superior of anyone who has, but for now I'm talking about the rest of the associate population.
As people get more experienced, they become more valuable, or at least they should. An experienced chemistry lab associate is one of the most readily employable people in the industry, under normal conditions. A company may or may not feel a need for another twenty-year middle manager type, but there's always a need for hands at the bench to make compounds, and good associates are the people who make the most. And with some time in the industry, they have a far better understanding of the real world of drug discovery than any PhD coming in fresh out of their post-doc.
Or at least they should. There are, though, some companies that treat their associates more like draft animals, putting them in the position I held in the summer of 1979 when I worked for in a greeting card factory before going to college. I was a "materials transport handler", which meant "See that big pile of stuff here? Haul it over there." It's the only time I've done manual labor for money for more than an afternoon, when I think about it. But I'm told that there are shops in this industry that tell their associates exactly what to do at every turn, up to the point (so I hear) of having them take spectral data and turn it over to their supervisors rather than interpret it themselves.
That's something you associate with the old-style German and Swiss labs, where there's a clear heirarchic division between the PhD holders in their offices and the "laboranten" out in front of the hood. Even there, I don't think this is quite as rigid as it used to be, so the thought of this here in the US is quite odd. But it does seem to go on, so I'm asking the readership: what's the status of the usual lab associate where you work?
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June 3, 2008
We recently encountered a problem that’s (unfortunately) a rather common one. An enzyme assay turned up an interesting hit compound, with some characteristics that we were hoping to see for leads against our target. A re-test showed that yes, the activity appeared to be real, which was interesting, since this hit was a welcome surprise from a class of compounds that we weren’t expecting much from.
It was a comparatively old compound in the files, and all we could find out was that it had been purchased rather than made in house. Looking around, it seemed that there were very few literature references to things of this type, and only one commercial source: the Sigma-Aldrich Library of Rare chemicals, known as SALOR. That, though, was a potential warning flag.
Those compounds come from an effort started by Aldrich’s Alfred Bader many years ago, who started trolling around various academic labs looking for unusual compounds that no one wanted to keep around any more. Over time the company has accumulated a horde of oddities that are often found nowhere else, but there are several catches. For one, these things are usually available only in small quantities, tens of milligrams for the most part. That’s plenty for the screening files, but you’re not going to make a bunch of analogs starting from what comes out of a SALOR vial. Another catch is that the compounds are sold, very explicitly, as is: the university sources tell Aldrich what’s on the label, so that’s what they sell you and caveat emptor all the way, dude.
So often as not, you get what we got, a nice-looking white powder which, on closer analysis, turned out to only have a vague relationship to the structure on its label. We knew that we were in trouble as soon as the first NMR came out: way too much stuff in one region, nowhere near enough in some others. Mass spec confirmed that this thing weighed more than twice as much as what it was supposed to. We’ve since pretty much nailed down what the stuff really is, and our interest in it has decreased as each of the veils has been removed from the real structure.
We’re correcting the data in our own screening files, of course. And yes, we’re going to tell the folks at Aldrich to change their label, too, assuming they have any of this stuff left. At least the next person will know what they’re getting. For once. But there are more of these things waiting out there – in every large compound collection, in every catalog, in every collection of data are mistakes. Watch for them.
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June 2, 2008
A longtime reader pointed me to this article from Business Week. Fuji Film of Japan, facing all kinds of problems like the other film makers of the world, has decided to put some of its money into a more exciting, profitable, high-margin business: pharmaceuticals! Back in February they made an offer for small-to-medium sized Toyama.
Readers who have been around the industry for a few years may shudder, remembering Kodak's disastrous experience with Sterling-Winthrop. (You couldn't have paid a gang of saboteurs to do a better - well, worse - job on Sterling and its employees; this PDF will give you some of the story). The details of the interview, which gets crazier as it goes on, do not inspire happy feelings. Well, unless schadenfreude counts as "happy", that is. Feast on this, for example, from Yuzo Toda, the company's VP for Life Sciences:
"The film in your camera is about 15 microns (one-thousandth of a millimeter) thick. Our color film has 17 different layers, each with a different function, and it contains nearly 100 different chemicals. Controlling the chemical reaction to develop these photos is extremely difficult. You have to start and stop the various chemicals at exactly the right time to make it all work. The trick is all in the conversion of chemicals. Drugs targeting a specific [organ or receptor in the body] work the same way. We have a chemical library of 200,000 compounds, which we think will help us with creating new compounds, and we have an expertise in nanotechnology. From our viewpoint, it's more a question of why not pharmaceuticals?"
Well, with a library of two hundred thousand compounds (cue Mike Myers as Dr. Evil, demanding his million dollars), I don't see what's going to hold them back. Considering the sorts of wonderfully druglike photosensitive absorbers and dye-coupling agents they're stocked up with, I'm sure the screening hit rates will be exciting, too. And yes, I am considering making "The trick is all in the conversion of chemicals" the new slogan of this blog, and I urge Fuji to make it the advertising tag line for their whole drug business.
But let's not pick on just one guy. Here's Toshio Takahashi, the company's CFO:
"Many drugs are made in higher dosages than we need. That's because they can't be fully absorbed by our bodies. It's a waste of resources, and it can have an adverse effect on organs such as the stomach and liver. We're researching compounds that will work in smaller doses because they will target a specific part of the body."
Now there's a thought. I wish Fuji luck with these innovative ideas, although I don't think I'm capable of delivering the quantities of luck that it appears they'll need. I assume that the people at Toyama don't talk this way, i.e., as if they'd just been beamed in from Neptune and then hit over the head, and for all I know they're burying their heads in their hands as they read this stuff, too. Who knows, maybe if Fuji can keep their hands off of them and not impart too many lessons from the film business, the deal could work.
But for now, check out the interview, and be glad it's not you. Sheesh.
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