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

Derek Lowe The 2002 Model

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

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

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June 30, 2005

Where's the Combo?

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Posted by Derek

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

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

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

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

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

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

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

June 29, 2005

Vaccines and Human Folly

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Posted by Derek

Things seem to have taken a bit of a turn for the worse around here. Let me take a day to set the record straight on a few things.

I believe that vaccinations have been a tremendous boon to human health. Here in the developed world, we've forgotten what the infectious diseases are like that we vaccinate against: try the table at this site to remind yourself. We can argue about rare side effects, but we need to avoid remedies worse than what we're trying to cure.

The classic example is Japan in the 1970s. They had two deaths from the pertussis vaccine, a tragedy by any definition, which led to a 1975 halt in Japan's vaccination program. And that contributed to an even larger tragedy from 1977 to 1979: a pertussis epidemic that killed 41 people. Pertussis, in case you didn't know, is whooping cough, a funny name for something that kills children and doesn't have to.

Japanese scientists took the lead in developing even safer pertussis vaccines, which was sound research in a good cause, and I'm happy to talk about that, too. What I am not happy about are pages upon pages of increasingly vituperative insinuations that vaccines are poisoning millions of people, giving them cancer and fatal diseases, and that pharmaceutical companies and the medical establishment are standing around snickering while it all happens. Readers of the comment sections of the recent posts here will recognize what I'm talking about.

These accusations are, of course, untrue, and their entertainment value is beginning to erode. I am not interested in debating them, any more than I am interested in debating the details of Scientology or the supposed activities of noctural alien proctologists. Now, it is anyone's right to stuff their own head with whatever debris they choose, and it's even their right to urge others to do the same. But you don't get unlimited room to do it here. I strongly urge anyone who feels irresistible impulses to post thirteen-page comments in this vein to get their own blog and generate their own traffic.

I'm talking about etiquette, not censorship. I will continue, naturally, to let anyone post comments that disagree with my own opinions. But gigantic screeds are another thing entirely. If you have some of those to get off your chest, feel free to post a brief overview and a link. Send people to your own site, and enjoy the visitors.

Comments (27) + TrackBacks (0) | Category: Patents and IP

June 28, 2005

Cancer Delusions

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Posted by Derek

Time for another public-health issue that someone has done an excellent job covering. That would be Colby Cosh, taking on a fuzzy-minded editorial on cancer rates. This is a fine example of going to the data to see if someone really knows what they're talking about, and I could only wish that all journalists were as handy with a graph as Colby is. Quoth Cosh:

"The effort to play on the emotions--and there is no more emotional topic in Western life than cancer--is so poorly disguised; the contemptuous attitude toward reason is so transparent. I believe this has become more widely known, and pieces like Mr. Anderson's are now commonly regarded by newspaper readers as mere static. And no one thinks there is any harm in having it about, right up until the moment we completely lose the ability to communicate candidly with one another, or to persuade by any means but sheer amplitude."

His further thoughts on non-Hodgkins lymphoma, which actually does seem to be rising, are well worth checking out, too. All this is accented by a well-publicized recent survey of beliefs about cancer, whose full text is available here. The one that particularly gets me is "There is currently a cure for cancer but the medical industry won't tell the public about it because they make too much money treating cancer patients." Actually, you could probably have substituted just about any disease in that question and found the same distressingly high agreement.

The percentage of people agreeing with that place a lower bound on the number of survey respondents who know nothing about economics. (We'll leave knowledge of biology out of it for now.) How much money would people pay for a cure for cancer, compared to current therapies? More, possibly? Would there be any incentive to offer one, then, especially considering that new cancer patients come along all the time? And just when did we pharma companies all get together to share our secret cancer cure, anyway? Why wouldn't a company decide to break ranks and blow its competitors completely out of the market? And who was it that decided that they didn't want a Nobel Prize and the everlasting gratitude of millions of suffering people? Oy.

Comments (9) + TrackBacks (0) | Category: Cancer

June 27, 2005

Thimerosal, Again

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Posted by Derek

Robert F. Kennedy, Jr. has helped to put this issue right back on the front pages again. I spoke a lot about thimerosal in vaccines, and its putative link to autism, back in late 2002, which is when the controversy last flared to this degree. (I've put those old posts over into the Autism category on the right for reference.)

I've read Kennedy's Rolling Stone / Salon article, and it's quite a piece of work. Kennedy is no stranger to exaggeration and to outright misrepresentation, and he's in typical form here. (Try checking out the corrections that have already run, and be sure to check back for updates. A keyboard macro that says "Salon and Rolling Stone regret the errors" would come in handy, no doubt.)

I'd like to refer everyone to the Blissful Knowledge blog and to Orac for thorough coverage of this issue. These folks have done all the heavy lifting, and there's a lot of stuff to lift here. I'm in debt to them.

The short take-home? There is still no persuasive evidence linking thimerosal to autism, no matter what Robert Kennedy tells you. But this story will take years to die - ah, what am I talking about? It never will. The New York Times ran an excellent article last weekend by Gardiner Harris, making just that point. There are people who will live the rest of their lives convinced that thimerosal has caused thousands of cases of autism, no matter what amount of evidence piles up to the contrary.

I remember reading posts on this on Blissful Knowledge back in late 2002, when I was writing mine. My children, 4 and 2 years old at the time, have been fine since then. But the author of that site discovered a year later that his own son was autistic, a diagnosis that causes me physical pain each time I just hear about it. As a parent, I cannot imagine what it must be like to deal with the reality, and I have deep sympathy and respect for those who have to. I hope that my profession can eventually do something to help. I do not think, based on the evidence we have, that my profession is to blame.

Comments (21) + TrackBacks (0) | Category: Autism

June 26, 2005

How Not to Do It: Vacuum Pumps

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Posted by Derek

I wandered into the lab one Saturday morning while I was in graduate school - (OK, scratch that, I wandered into the lab most Saturday mornings while I was in graduate school, which was one of the things I hated about it.) And as I walked past the vacuum pump, I noticed something a little odd.

For those who don't work in a synthetic chemistry lab, the vacuum pump is where you put flasks of stuff after you've evaporated most of the solvent off of them. The pump pulls the last volatiles residues out of your syrup, crystals, or powder, leaving you with a dry weight that you can use to check your reaction yield, get pure spectra of the material, and so on.

The pump was making a different sound than usual. There was more of a rattle in it this morning, and less of a hum, if that makes any sense. I looked the thing over, trying to see what was going on, and finally I checked the row of stopcocks. Pay dirt! One of them was wide open, and the reason the pump was making that unusual sound was that it was trying to pump the air out of the entire chemistry building.

That isn't good for them. And in an academic lab, it's not like you could just reach into a cabinet and pull out another vacuum pump when you burned one out. They aren't cheap, and we spent time fixing the ones we had rather than attempt to ever buy new ones. So I twisted the glass stopcock closed, muttering foul gerunds, and left an unpleasant note taped to it. Something about how if you were the last user of this pump, you left the procreating stopcock open, and you shouldn't reproducing do that, etc. And I went about the rest of my merry morning's work.

The next morning, I wandered into the lab yet again. (I was there most Sunday mornings, too, damn it all.) And as I walked past the pump, I could swear that something was odd yet again. Surely not. I went back, looked it over, but couldn't see anything out of whack. Then, hardly believing it, I moved my taped note back to find the same stopcock, left wide open again. The slackjaw that did it it had to hold the note up to get to the stopcock, which really defied belief. There was the poor vacuum pump, trying to evacuate the air out of the state of North Carolina again.

I went stomping through our labs, looking for the culprit. But I was the only person there. No one in my group had done anything like that, so I wondered if someone else had been in there. . .then I remembered a Moroccan biochemist from another group who came over sometimes to hang out with the guy around the corner from me. Maybe. . .I went over to the next hall, and there was the pride of Marrakesh himself, humming tunelessly as he wandered about his lab.

So in I went, demanding to know if he'd been in our lab that morning, used our vacuum pump, and so on. He gave me a big grin: "No, I have not used this pump. But I have gone past it this morning, and I have thought, Hmmm, she is sucking ze air, no?" My testy reply was that if I found out that he'd been leaving the pump open then he would be sucking ze air, yes. For whatever reason, our apparatus went unmolested after that.

Comments (7) + TrackBacks (0) | Category: How Not to Do It

June 23, 2005

News Flash: I May Not Be a Fool

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Posted by Derek

I now have my experimental results, at long last. And, well, I have to say that I seem to have something.

This batch was set up with fifteen different chemical structures, and I was looking for the same effect in each run. For each structure, there was an experiment that should have shown the effect I'm after, producing a new product, then a control (without a key ingredient) which should have shown little or nothing, and another control (with the key ingredient present, but with another compound added that should have blocked it from doing anything.)

I thought at first that I had fallen completely on my face, because as I looked over the first five or ten structures, I saw the same discouraging pattern. Next to nothing in the blank control runs, which was fine. But the numbers from the corresponding key-ingredient experiments were identically low, which was the inescapable sign of nothing going on. I'd also seen some where the experimental run showed something, but the corresponding blank showed the same exact levels - again showing that my experimental conditions weren't changing anything, but that I just had a high background rate of reaction.

I was using strong language by the time I got to number twelve, which showed a pretty high value in the experimental run. I looked over to the blank run, expecting to see the same levels, another high-background dud - but it really was a blank this time. Almost nothing there. The experimental run was at least fifty times higher. I held my breath as I looked at the second "inactivating control" run, and there it was -it went right back to the blank value, as it should if my hypothesis was correct. I had set up all the experiments in duplicate, and this morning I got the repeat data, which matched the first set very tightly. It appears to be real.

And to go along with this, these experiments also included the best candidate from my first attempts, the one that got me excited about running these follow-ups in the first place. It had made a lot of product again, although just three or four times the high background rate in the blank reaction, as it had been before. But had the inactivating control experiment knocked it back down to those values anyway? It had.

And both that one and the new winner are structurally quite similar, and they're the only two of that exact class that I've run. It's becoming increasingly clear to me that I finally have something that works, after three years of on-and-off attempts. I hardly know what to do with myself.

Well, that's not quite true. I have another variation ready to go, with ten or fifteen new structures of a different type, and I have time to incorporate what I've learned from this run before they go off. It's time to see just how far this stuff can be pushed.

Comments (8) + TrackBacks (0) | Category: Birth of an Idea

June 22, 2005

Fan Mail

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Posted by Derek

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

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

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

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

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

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

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

June 21, 2005

Morphine in the Brain: Go For It, or Not?

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Posted by Derek

So, I do a post where I wonder if the reductionist target-driven approach to drug discovery is running out of gas, then I do one on the possibility of some interesting new drug targets in the brain. Am I deliberately talking out of both sides of my mouth, or do I just not remember what I've written the day before?

Actually, I can hold both of those views simultaneously. Order now and I'll send you my exciting at-home kit which will allow you to do the same! Here's how it's done: the morphine-synthesizing enzymes in brain cells that I spoke about yesterday are, indeed, possible drug targets. But I'm defining "target" pretty loosely here, as "theoretical possibility for therapeutic intervention." The step beyond that is "validated target", and we're a long way from that.

The problem is, no one has the faintest idea what brain cells are up to when they make morphine. I should start out by saying that we don't know which brain cells, of the insane number of different types, actually make it in vivo, what parts of the brain they're located in, or what factors cause them to increase or decrease its production. And once it's made, we don't know what it does or why. Presumably it's binding to the known opioid receptors, whose biology was complicated enough already, thanks. (See this recent paper, pointed out in a comment to the last post.) But there are already families of endogenous peptides that do that, so you have to wonder why morphine is in there, too. Under physiological conditions, perhaps there are other signaling roles for it (intracellular ones, maybe?) of which we are entirely ignorant.

But it's fair to assume that it's in there for a reason, and it's also fair to assume that disrupting its production would have an effect, even if we don't know that that might be. That makes endogenous morphine production a potential target, and an interesting one. But if we wait until these questions are well worked out, we could be in for a long wait. That's been the problem with many molecular-level targets, and Monday's post spoke about some of the difficulties with them.

How do you get more information? One way to approach the problem would be to disrupt one of the key enzymes used in endogenous morphine synthesis, once we know what they are, and see what happens. You could do that with RNA interference in cell cultures, but it can be hard to see what the effects are unless you touch on something vital. That's especially true with CNS targets, because cells in a dish are an extremely poor surrogate for the complex properties of the intact brain. A better route would be to go into whole animals: you could knock out the enzyme in mice and see how they develop, but the big question with knockout animals is how they compensate during development for that induced loss of function. Sometimes the changes you bring on end up being too subtle to catch, and you get what looks just like a normal mouse.

You'd probably be better off with a small-molecule enzyme inhibitor which could be dosed in a normal adult animal. If it's selective and nontoxic enough, you'd have a chance to see what the loss of endogenous morphine does under real-world conditions - assuming that it's something that can be noticed at all in an animal model, and assuming that you're sharp-eyed enough to catch it. Does it affect motor control, memory, emotional state, sensory input, or what? If you give it to a rat and he goes off and flops down, is that because he's dizzy, because his legs don't feel right, because he feels sick to his stomach, because he's suddenly sleepy, or because he's overcome with waves of rodent ennui? You can untangle some of those, but it isn't easy. You'd know, though, that it certainly does something, even if you're not quite sure what it is.

So, your choices are: go with the molecular approach, but be prepared to wait years for answers. (Be prepared to wait decades if the answer ends up requiring a molecular-level understanding of something like long-term memory or emotional state.) Or, go with the whole-animal approach once you've got some idea of the target, but be prepared to see no changes, or changes that you're unable to interpret or extrapolate to humans.

What I'd do, were I in charge of such an effort, is give the molecular approach some time at the beginning to see if they could narrow things down a bit. Is morphine made only in the brain, or also in the peripheral nervous system or also in other tissues entirely? What regions of the brain look most important? What enzyme should we be targeting to best affect the whole system? These could take a while, but not as long as working out the whole story would. Once we had some idea about the enzyme, I'd turn around and screen against it, looking for some chemical matter to try animal studies with. Getting something suitable might be a matter of months, or it might be a matter of years. How much time and money were you thinking about spending? This would be a major effort, clearly, and one unlikely to take place inside one research organization, no matter how dedicated and well-funded.

But here's the problem: this target, compared to some of the things that came spilling out during the genomics craze, is actually pretty well-grounded. Think about it - we have receptors that we know will bind morphine, and a lot is known about their biology (even if we don't understand what morphine is doing in there with them in vivo.) We're pretty sure that this will be a CNS target, rather than, say, cancer or diabetes (although I'd never say never until I saw more data.) We even know what kind of enzymes to search for in the morphine biosynthesis pathway, based on what we know from plants.

No, although I've just spent all this time talking about how hard it would be, this project would have a real head start compared to many of the things out there. And if you find that a bit unnerving, then you can see why the strict molecular from-the-bottom-up approach is running into problems.

Comments (3) + TrackBacks (0) | Category: Drug Development | The Central Nervous System

Data, At Last

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Posted by Derek

A rare mid-day update: finally, after weeks of delays, I'm getting the analytical data run on my most recent set of experiments. These are based on what looked like successful results back in April (see these posts for the details), and if I have any idea of what's going on, they should work.

And that's the scary part. Late this afternoon or tomorrow morning, I'll either know that I'm on the track of something interesting, or I'll have slid most of the way back down the hill. Again. It's been like this every time I've come up to a crucial experiment in this work. As I've said, scientific progress depends, to an unappreciated extent, on the willingness to look like a fool. It's tough work, waiting to find out if you are one or not. . .

Comments (0) + TrackBacks (0) | Category: Birth of an Idea

June 20, 2005

More Brain Surprises

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Posted by Derek

All sorts of odd things have turned out to be neurotransmitters, that's for sure. I wrote about this over a year ago, in a post about hydrogen sulfide, of all things, and its role in the brain.

Well, there's another odd one that's been uncovered. And like hydrogen sulfide (or carbon monoxide, also a neurotransmitter, if you can believe it), it's a molecule that we already know about. Heck, we already know that it does all sorts of things to the brain. We just didn't know that the brain could make its own. Are you ready?

It's morphine. Who would have thought? The brain certainly has plenty of opioid receptors, but it was thought that some classes of short peptides (enkephalins and endorphins) were the endogenous ligands that bound to them. Morphine and the other alkaloids of its family were supposed to be the interlopers from the plant kingdom that could mimic our peptides, but it appears that story is going to need revisions.

A group at Halle (Germany) has done the detective work here. There were reports over the years of small amounts of morphine in mammalian cells, but no one was sure what to make it them. With modern analytical techniques, everything is contaminated: you can find little bits of almost anything you're looking for. Morphine had shown in up things like lettuce, milk, and rat chow before, in trace amounts, so who could say?

The connection seems solid now. The Halle group took human neuroblastoma cells in culture and gave them isotopically labeled dopamine as a starter. That's the (distant) precursor for morphine in poppies, and the cells used it to spit out small amounts of isotopically labled morphine. The same went for a number of other known morphine intermediates (but not quite all of them.) It appears that human cells use a very similar set of reactions to make morphine, but differ from the plant route at one key step.

The authors note, dryly, that "The function of endogenous morphine is still a matter of discussion." I'll bet it is. Why on earth do we make morphine when we have the enkephalins and endorphins? But it's at least a 19-step synthesis for the cells, and you can be sure that they're not going through that for nothing. The paper points out that identifying the various enzymes involved in the synthesis could provide some interesting targets for CNS drug discovery, and I'll bet that they're right about that, too.

Comments (5) + TrackBacks (0) | Category: The Central Nervous System

June 19, 2005

What Makes A Target, Anyway?

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Posted by Derek

I had a question a while back about how often researchers are fooling themselves when they think they've found a new signaling pathway or a new disease target. That one's pretty easy to answer, to a rough approximation: the less work you do, the better the chance that you're fooling yourself.

But it can take years before you know if you were right, so there's really not enough data to give a more quantitative answer. Take a notorious example, beta-amyloid in Alzheimer's disease. That's been noted as a sign of the disease every since Alois Alzheimer described it nearly one hundred years ago. Huge mountains of data have piled up since then about the disease and what might be causing it, but we're still not one hundred per cent sure if amyloid plaques in your brain give you Alzheimer's or if Alzheimer's gives you amyloid plaques in your brain. Most of the money is on the former, but it's not quite a sealed case yet.

The same uncertainty hovers around everywhere. Let's say you study a particular form of cancer, and you find that there's a particular kinase that's always found in greater than normal amounts in the tumor cells as compared to normal ones. Is that a new target for therapy? The answer is a firm, resounding, "maybe!"

Perhaps it's the real deal, but there are other enzymes that will step right in to do your kinase's job if you inhibit it - in that case, you'd better be prepared to take those on, too, or get ready to pack it in. Perhaps it's part of the real problem, but it's just a sideshow. If it's not the key or limiting step in any given pathway, inhibiting it won't do anyone much good. Or maybe it's there to phosphorylate the realculprit, in which case you should put some resources on tracking that thing down, too - it could be a better handle on the disease. But on the other hand, maybe your kinse is only acting downstream of that real culprit, phosphorylating something else entirely, which is an extreme example of the sideshow possibility mentioned above. Or it may be that this kinase is upregulated because it's part of a mechanism that's trying (unsuccessfully) to get the cancer cell to shut down. You probably wouldn't want to inhibit that!

Unraveling all this is not a job for the impatient, or for the light of wallet either, for that matter. So many of these pathways have turned out to be more complicated than anyone had ever imagined, that it's gotten to the point that people are questioning the whole reductionist-molecular-biology approach to drug targets. Eight or ten years ago, I would have considered that a radical or even crazy position. These days, I kind of want to sign up. . .

Comments (6) + TrackBacks (0) | Category: Drug Assays

June 16, 2005

Pfizer Opens Their Wallet - Again

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Posted by Derek

Well, as a comment to Tuesday's post mentioned, no sooner do I talk about the antifungal market than Pfizer turns around and buys a company with a promising antifungal drug. Vicuron has concentrated on antiinfectives in general, which has been a rough place to be over the last ten years or so. Good ideas are hard to find, and if you come up with an amazing new antibiotic, you can expect to see its use restricted as much as possible. And rightly so, in hopes of delaying the onset of resistance. That's good medical practice, but it does tend to put a kink in the sales figures.

Pfizer's deal makes a lot of sense. Their last big new antibiotic ran into trouble a few years ago over side effects: Trovan (alatrofloxacin), another fluoroquinolone. They acquired Zyvox (linezolid), the first oxazolidinone antibiotic, when they purchased Pharmacia/Upjohn, and they still sell an awful lot of Zithromax (azithromycin). But I don't believe that there was much coming along in their antiinfectives portfolio, and they have immediate problems to be fixed. Last summer, Pfizer lost patent protection for Diflucan (fluconazole, which I mentioned the other day), and the patent for azithromycin expires later this year.

The Pfizer deal-makers have been on hiatus recently, but they'll probably keep busy for a while now, because the company is facing even more patent expirations over the next few years. As the clock keeps ticking, Pfizer will probably be forced to go out and buy things before their mighty marketing machine starts sucking air. They're already talking about cutting costs and head count, and I've heard from inside the company that some people there are uneasy about the future. And perhaps they should be - no one's ever tried to have a drug company as big as Pfizer before, and it's not for sure that it's such a great idea. Not everything scales up. Research productivity, for example, may actually have a negative correlation with size.

I've wondered, loudly, for years how they're going to manage. Nothing's made me change my mind. An antibiotic and an antifungal will help, but Pfizer's going to need a lot, lot more.

Comments (3) + TrackBacks (0) | Category: Business and Markets | Infectious Diseases

June 15, 2005

How Safe Is This Stuff?

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Posted by Derek

Prompted by a comment to the benzene distillation post, I've been searching for some accident rate or life expectancy data for organic chemists. It's not easy to find. I'm pretty sure that the American Chemical Society collects this sort of thing (and since they have a group rate for term life insurance, it would seem that someone has looked into the matter), but the numbers don't seem to be public. Anyone know of a source?

My belief is that organic chemistry isn't a particularly hazardous profession. The risks go down as you get out of graduate school, where there's much less supervision, in facilities that are often not the most up to date, with many more dangerous people running around. We've weeded out most of the really deadly folks here in industry, and I'm sure that there's a steep power-law distribution that has them accounting for way more than their share of trouble.

Almost every serious accident I've ever been around has been someone's fault - that is, as opposed to JOOTT (Just One Of Those Things.) Nope, the bad ones have all been due to someone screwing up, generally in a way that made independent observers groan and shake their heads afterwards. Distilling things that shouldn't be distilled, making things on a scale that they shouldn't be made (with the available equipment), grievously mishandling fiery and corrosive reagents, setting up closed systems and cranking the heat up on them - that's the sort of thing I mean.

And as far as I can tell, the best way to improve your safety record is to get rid of the people that seem capable of doing this stuff. The worst ones aren't particularly trainable, anyway; you're much better off without them. "Against stupidty, the Gods themselves contend in vain", and no safety program is going to stand a chance, either.

Comments (13) + TrackBacks (0) | Category: Life in the Drug Labs

June 14, 2005

Fungal Problems

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Posted by Derek

You want a tough therapeutic area to work in? Try antifungals. There are plenty of problems that conspire to make it a real headache.

For one, fungal infections have a way of binning themselves into two categories, marked "pretty trivial" and "pretty life-threatening." Athlete's foot is a good example of the first one, and coccidioidomycosis is a good example of the second. Actually, that disease shows another form of the trivial/deadly dichotomy. Many people with coccidioidomycosis never realize that they had it, or that they had anything at all. It shows up as a mild cough or cold, and then disappears. But in some people, most especially HIV sufferers or other immune-comprimised patients, it's extremely bad news indeed.

So there are large markets where people aren't willing to pay much to be treated, and a number of much smaller, very desperate markets scattered all over the place. That's a tough situation, and the best thing would be to find a real blunderbuss antifungal that would pitch in for all of them.

And there actually is one, but it's a pretty nasty drug. For the worst systemic fungal infections, though, amphotericin B is basically all there is. It's given intravenously, and you have to keep a close watch on the side effects, which run to things like high fever, vomiting, and kidney damage. A less vicious, orally available drug that works as effectively would be a real advance.

It's not like people haven't tried. Fluconazole and Itraconazole are worthy attempts, but they suffer from their own side effect problems. Check out the general information here, and note, for example, the number of drug interactions. The "conazoles" are notorious for interacting with some key drug-metabolizing enzymes, particularly CYP 3A4, and thus sending the blood levels of other medicines all over the place.

And to top it all off, there aren't that many good drug targets in this area, or at least, not any more. There are companies that have bailed out of the whole field for lack of anything reasonable to do. There's some hope that the sequencing of fungal genomes might lead to some new targets, but that hasn't worked out too well with other organisms, and I include humans in that list. We can always hope.

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

The Research Exemption Lives!

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Posted by Derek

The Supreme Court has ruled on the Merck/Integra case that I wrote about here last month, and reversed the most recent lower court ruling. And I'm glad to see it. This all turns on a 1984 change in the patent law, called 271(e)(1) for short, which says, broadly, that it's not an act of patent infringement to make or use a patented invention during its patent term "solely for uses reasonably related to the development and submission of information under a Federal law which regulates the manufacture, use, or sale of drugs. . ."

Justice Scalia wrote the unanimous opinion, a PDF of which which is available from this list of recent decisions. It covers the issues thoroughly and concisely, and if you're really into this stuff you'll want to read the original. But here's a summary, if you're not up for 17 pages of opinion (which isn't as bad as it sounds, considering the Supreme Court's traditional paper margins):

The Court found it apparent that 271(3) was designed to exempt all uses of patented inventions that were reasonably related to the development and submission of any data under the Federal Food, Drug and Cosmetic Act (the FDCA, which established the FDA.) Said Scalia, "There is simply no room in the statute for excluding certain information from the exemption. . ."

Integra argued that "the only preclinical data the FDA is interested in is that which pertains to the safety of the drug in humans," and that broader studies on mechanism of action, PK, etc. weren't meant to be exempt under 271(e). But Scalia noted that the FDA requires summaries of all these studies when an Investigational New Drug application is filed, and that these are necessary to assess the whole risk/benefit question of whether a human clinical trial should be allowed.

Integra's counterargument to that is that Merck's experiments are disqualified from the exemption, because they weren't conducted under the FDA's Good Laboratory Practices (GLP) protocols, and thus weren't intended for regulatory use. But the Court cited the law as showing that GLP studies are only required for safety assessments, and that earlier work (on mechanism, efficacy, PK, etc.) doesn't have to be run under GLP. (And they want to see non-GLP safety studies, too, if you have them, along with an explanation for why they weren't run under the protocols.)

The Court of Appeals for the Federal Circuit, when they ruled for Integra, found that the Merck/Scripps experiments "did not supply information for the FDA, but instead identified the best drug candidate to subject to further clinical testing. . .The FDA has not interest in the hunt for drugs that may or may not later undergo clinical testing for FDA approval. . .Thus, the Scripps work sponsored by Merck was not solely for uses reasonably related to clinical testing for the FDA."

The Court rejected this line of argument, which, as Scalia writes:

". . .disregards the reality that, even at late stages in the development of a new drug, scientific testing is a process of trial and error. In the vast majority of cases, neither the drugmaker nor its scientists have any way or knowing whether an initially promising candidate will prove successful over a battery of experiments. That is the reason they conduct the experiments. . . We decline to read the "reasonable relation" requirement so narrowly as to render 271(e)(1)'s stated protection of activities leading to FDA approval for all drugs illusory.

. . .the use of a patented compound in experiments that are not themselves included in a "submission of information" to the FDA does not, standing alone, render the use infringing."

Scalia and the court are completely right here, as far as I'm concerned. Drug companies constantly make each other's patented compounds for comparisons against their own, and if 271(e)(1) was interpreted as the CAFC had it, we'd be constantly second-guessing ourselves about whether we'd infringed or not. It would slow down the development of new drugs, without a doubt, and in some cases it would bring preclinical programs to an immediate halt while licensing issues were thrashed out. Which they might never be - why should a company give a competitor a license to try to beat its patented compound? Better to go tell them to grit their teeth and wait for the patent to expire.

But that's not going to happen. We're back to the "research exemption" as we've understood it, and that's a good thing.

Comments (5) + TrackBacks (0) | Category: Patents and IP

June 12, 2005

How Not to Do It: Distilling Benzene

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Posted by Derek

Summer students are showing up at academic and industrial labs around the country right about now. A certain percent of them will blow something up within the next three months, and that percent will be several standard deviations above the ka-boom rate of the other lab members. I'm not trying to say mean things about summer students. I merely speak the truth.

I had a summer undergraduate working with me for a while in grad school, and he taught me several lessons, of varying utility. One day he needed some dry benzene for a reaction, so I helped him set up a still in my hood. One-liter round-bottom flask, some benzene, a little sodium. My intern, who I'll refer to as Toxic John, put a heating mantle on the thing and turned it on.

A little while later, I walked past my hood and noticed that the stuff was boiling merrily. A bit too merrily, actually - it was really hopping around in there. I turned down the Variac (basically a big dimmer-switch type AC transformer that's used to step down the voltage to equipment like heaters) and went on my way. But I came back a little while later, and it was still rolling away in there.

If anything, it was worse. I turned down the Variac again, wondering just what was going on, and why my guess about the inital setting had been so wrong. A few minutes later, things hadn't improved much. The benzene was really leaping around, splattering and erupting. I looked a little more closely at the Variac this time, and noticed something that had escaped me: the heating mantle wasn't plugged into the damn thing at all.

Nope, it was plugged right into the wall socket, as some of my experienced readers will have guessed. As soon as I noticed that, I dropped the lab jack that was holding the heating mantle, which gave me a good look at the glowing red coils showing through the woven glass lining. I could feel it on my face like a sun lamp. Cursing, I pulled the thing out of my hood and heaved it into the hallway, right into a shopping cart that we kept out there for visits to the stockroom.

I went looking for Toxic John as the mantle popped and clicked. It was cooling down, but I wasn't. "John!", I shouted (I was pretty crabby back in grad school), "you plugged the mantle into the wall! No wonder it looked like a volcano in there!"

"What's the matter," he asked me. "Benzene doesn't burn, does it?" "Doesn't. . .burn. . ." I said slowly, as a nearby post-doc put a warning hand on my shoulder. "Well," said John, making his case, "it's inert to bromination!" That line of reasoning didn't impress me much, and as I recall, I told him that if he had any more insights like that we were going to find out if he was inert to bromination himself. Then I went off looking for the professor who'd just taught him sophomore organic chemistry, to let him know that his work, once again, had been in vain.

Comments (10) + TrackBacks (0) | Category: How Not to Do It

June 9, 2005

Dr. Rath Does What He Can

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Posted by Derek

There's a doctor named Matthias Rath who for some years has been taking out big ads in the New York Times and the International Herald Tribune. Rath is a big proponent of megavitamin therapy for just about everything, and by some cosmic coincidence he also has a line of vitamins for sale. No doubt he has a web site and a half, but damned if I'll link to it.

His ads are thunderous, paranoid denunciations of the pharmaceutical industry, the likes of which I haven't seen since the Church of Scientology took off after Eli Lilly and Prozac in the early 1990s. If you want some Instant Rath, take those and add some Lyndon Larouche-level conspiracy theories (for a while there, Rath was all but blaming drug companies for 9/11), and mix well. Season to taste, but if you've really got a taste for this stuff stuff, there's no hope for you.

His latest manifestos have been targeted to South Africa, and they're just what that country doesn't need. Rath rants about antiretroviral drugs being sinister poisons, while apparently everyone could be cured of HIV if they'd just guzzle his multivitamins without pause. The South African activist groups demanding free retroviral drugs are, according to him, tools of the "international drug cartel" that exists in the fevered reaches of his head.

It's hard to know how to answer such otherworldly accusations. Try, for example, the idea of drug companies funding groups who are screaming for their patents to be abrogated and their profits confiscated. I'm having a hard time making the connection. All in all, I'd rather be stuck in an elevator for three days with a dozen Intelligent Design advocates than spend five minutes with Matthias Rath.

South Africa's attitudes and policies toward HIV are enough of a mess already, as those who remember former president Mbeki's handling of the epidemic know. According to an article in Nature Medicine, the South African Traditional Healer's Association has sided with Rath, and a recent press conference from health minister Manto Tshabalala-Msimang featured one of her many endorsements of garlic, lemon peel, and beets instead of antiretrovirals. Meanwhile Rath is lobbying South Africa's parliament directly, amid accusations that he's planning to set up a factory to sell his own vitamin pills.

And meanwhile, at least 20% of South Africa's adult population is infected with HIV. What could be a great nation is threatened with an ugly slide back into the third world, while wastes of good carbon like Matthias Rath spend their time fighting the only known treatments. It makes you wish you could just avert your eyes.

Comments (8) + TrackBacks (0) | Category: Infectious Diseases | Snake Oil

June 8, 2005

A Day in the Life of Peter Rost

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Posted by Derek

I last wrote about Pfizer executive Peter Rost back in September, after he'd unburdened himself on the subject of Canadian drug reimportation. As readers will recall, his position on this issue is roughly that Canadian drug reimportation is a wonderful idea that needs to be implemented with all possible speed, which puts him rather at odds with the views of most pharmaceutical executives.

So, you're wondering, how's Rost doing these days? Today's New York Times catches up with him:

"No man is an island. But Peter Rost is getting close.

Dr. Rost, a vice president for marketing at Pfizer with a history of corporate whistle-blowing, has for the last year publicly criticized the pharmaceutical industry over the price of drugs. Along the way, Dr. Rost has become increasingly isolated at Pfizer, the world's largest drug company.

First, his employees stopped reporting to him. Then his supervisors stopped returning his calls and now he does not know whom to report to. His secretary left, he said, and he was moved to an office near Pfizer's security department at a company building in Peapack, N.J."

The article goes on to say that Rost tried to log in to his Pfizer e-mail the morning after he recently appeared on "60 Minutes", and found his access denied. If you read to the end, though, you find that by that afternoon, he was connected again, and that Pfizer claims that this is a glitch that has affected other employees.

And if you don't read carefully, you'll miss the line about how this was the first time Rost has tried to access his Pfizer e-mail in two weeks. Now, that makes the case for his isolation better than anything else in the article. Who on earth could go without their office e-mail for two weeks? As it turns out, Rost also got word out to the Newark Star-Ledger about his problem, and mentioned to them that he doesn't get in to the office much. The Associated Press seems to have received an update from him, too.

I don't doubt that Rost is being treated by Pfizer as if he were giving off neutrons. Anyone who makes statements like he has, in any industry, is going to get the same, if they're not pitched out onto the street first. Rost has escaped that fate, apparently, because Pfizer's marketing of the growth hormone genotropin is under investigation, and Rost was in charge of that at Pharmacia when Pfizer took over. He's likely to be protected under whistle-blower law, and firing him would be a public relations problem for Pfizer under any circumstances. So, they can mostly hope that he leaves, and try to make that an attractive option, but that's about it.

There are worse fates. If you haven't lived in the area, "Peapack, NJ" sounds like it must be surrounded by oil refineries or something. It's actually surrounded by beautifully landscaped estates. That's the horsey, expensive part of New Jersey, not the asphalty 24-hour-check-cashing part. But Rost seems to be able to afford it, since at the very end of the article we find that his annual compensation is over $600,000. Many Times readers probably found themselves wishing that their own companies disliked them as much.

Now, Rost is telling the truth as he sees it, and any information he has about misconduct has to be put in a different category than his ideas about reimportation. Given the career consequences (paycheck aside, along with his recent raise,) I have to respect him for speaking his mind, while still largely disagreeing with his opinions. But he shouldn't have expected anything much different than what he's getting from Pfizer, and calling the news organizations about it with updates seems a bit much.

Comments (8) + TrackBacks (0) | Category: Press Coverage

June 7, 2005

Experimental Update

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Posted by Derek

Since I mentioned a while back that I was setting up a crucial run of experiments, I thought I should let the (three or four) people who are following this story know what's going on.

What's going on is that I'm slowly chewing a hole through my desk. The instrument that I need to get these samples analyzed went down just as I was finishing up the experimental run. And that's not "down" as in "let's replace the fitting with a new one from the drawer here," that's "down" as in crucial-hardware-back-ordered-from-another-continent. As in two service techs up to their elbows in the thing for three days - that kind of down. As of today, the machine still isn't its old self.

My original run of experiments is probably untrustworthy at this point - I'm saving it to try out backup analysis techniques. I set up another run of fresh ones, which are now in the freezer, waiting to be analyzed when there's something to analyze them with. I console myself with the thought that they must have some pretty good stuff in them, because the universe is sure doing a good job of keeping me from ever finding out.

Comments (7) + TrackBacks (0) | Category: Birth of an Idea

When the Alternative is Nothing

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Posted by Derek

Placebo-controlled trials are usually considered the standard (and most stringent) measure of a drug's efficacy. It's a surprisingly high hurdle to clear. All sorts of things that people swear by, and all sorts of new things that you'd be sure would work fail when they're up against a similarly sized and colored dose of sugar.

But you can't always run a placebo group, because it isn't always ethical to do so. For a life-threatening condition, the comparison group has to be the current best standard of care (which, after all, is what you're trying to beat.) For lesser diseases, a trial against a known therapy can also be appropriate, although it's usually done after a placebo-controlled one has already been run.

But there's one situation where you can run a placebo control for a deadly condition: when the best standard of care is nothing at all.

Several forms of cancer fall into that category. Pancreatic, renal, and hepatic cancers, for example, exhaust their best available treatments very quickly. Some of the patients in that situation then offer themselves as subjects for clinical research, for which we in the drug industry are extremely grateful. With any luck, we'll be able to find something that works well enough to unblind as quickly as possible.

And when that happens, the disease is no longer in the "placebable" category. There's now an active agent, a possible treatment, and thus a new standard of care. Several cancers have moved off the list in recent years, and here's hoping that the process continues.

Comments (2) + TrackBacks (0) | Category: Cancer

June 6, 2005

A Drug's Target, Finally

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Posted by Derek

Well, a large group from Schering-Plough and Merck have published the definitive paper on the real target of S-P's cholesterol absorption inhibitor, ezetimibe (Zetia), which drug I've spoken about here and here. It's published in the preprint section of the Proceedings of the National Academy of Sciences, which is a pretty nice journal to be in, and (for a number of reasons) not one that drug company research finds its way into all that often.

The drug and its equally active metabolite hit a protein in the intestinal wall called NPC1L1. This was the suspect in the previous publication on this topic, but now they've nailed it down. The authors were able to express the protein in cells and get a radioligand binding assay going for it using the isolated membranes, which turned out to be a pain. Depending on how you prepare the membrane and what detergents you use in the assay, the binding could change by a factor of 5 in what were supposed to be samples of the same thing. Only membranes from the cells that had expressed the protein showed any binding, and this result was extended to whole animals by generating a strain of mice with NPC1L1 knocked out, and intestinal membranes from their cells, in turn, no longer bind ezetimibe at all.

The paper hammers things flat in every direction: a series of ezetimibe analogs that bound with a thousand-fold range of potency on the intestinal membranes showed the same spread when tested in the NPC1L1 expressed-protein binding assay. Interestingly, intestinal membranes from different species showed a wide range of binding behavior, with mouse being the weakest and rhesus monkey by far the strongest, and that exactly parallels the drug's behavior when dosed in these animals. Humans are in the middle, by the way. (I should mention that the best chance to get a correlation this nice is with a drug like ezetimibe, which hardly gets out of the gut at all. Different species can vary so much once a compound gets out into circulation that a direct link to a binding assay is often obscured.)

So, this is the drug's target, beyond doubt. The doubt kicks in very quickly, though, when you ask what NPC1L1 does and why ezetimibe's binding to it blocks cholesterol uptake. The paper advances two hypotheses - that cholesterol binds directly to NPC1L1 - that it's the cholesterol transporter itself. Alternatively, it could be regulating the real transporter, and since Schering-Plough had already investigated a lot of the obvious candidates, that might well be a further unknown protein.

Note how long this all took. Nothing good comes quickly in drug discovery. The first compounds in the ezetimibe series were discovered in 1990/91, and efforts to identify the molecular target went on for many years. How long, you have to wonder, would it have taken to find this important pathway without first finding the compound which illuminated it?

Comments (1) + TrackBacks (0) | Category: Cardiovascular Disease

June 5, 2005

Biotech At Last, Eh?

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Posted by Derek

There's a recent piece in Business Week Online that says nice things about the biotech and pharma industries, and I should be happy about that. But there are so many misconceptions in it that I'm going to fisk the darn thing instead.

After a lead-in which discusses a patient who responded to the Sugen/Pfizer kinase inhibitor for kidney cancer, the BW pieces says that cases like this:

". . .have convinced many doctors that medical care is reaching a tipping point. Not that most patients will be healed right away -- the vast majority of sick people continue to dose themselves with tiny bits of chemicals, otherwise known as pills, that represent medicine's Old Guard.

But the times are changing. The past 30 years of biological discoveries, insights into the human genome, and exotic chemical manipulation have unleashed a wave of biological drugs, many of them reengineered human proteins. These molecules have the power to change the prognoses for a huge range of diseases all but untreatable just five years ago. "

Well, first off, Malcolm Gladwell should ask for royalties for use of the phrase "tipping point." But as he doubtless knows, and the authors of the Business Week article should, the drug industry doesn't quite work that way. This isn't a marketing campaign. Advances come on independently, each at its own pace and with its own problems. If several come at roughly the same time, coincidence is as much a factor as anything else. And it's worth remembering that this particular inflection point has been proclaimed about every ten months since the mid-1980s.

Second, the Sugen/Pfizer compound is nothing more than one of those "tiny bits of chemicals" (known as pills, it seems) straight from the Old Guard. It is nothing even close to a reengineered protein. No exotic chemical manipulations are required to make it; a talented undergraduate could whip up a batch (although I wouldn't recommend that to any talented undergrads who might be reading this.) That's just how we folks in the Old Guard like our compounds to be - not terribly expensive to make.

Later on, we get into the academia (good!) versus the pharmaceutical industry (bad!) debate:

""What's interesting is that it is really the academic researchers that pushed biotech forward, not corporate research and development," says Allan B. Haberman, principal of pharmaceutical consulting firm Haberman Associates in Wayland, Mass.

Academic researchers, unlike traditional drug companies, were willing to champion biotech approaches to drugs even when they were long shots. ImClone Systems' (IMCL) Erbitux, a colon-cancer treatment approved last year, would not exist today if not for the efforts of its discoverer, Dr. John Mendelsohn. The scientist-clinician spent 20 years working to find a company willing to commercialize his discovery that some tumors could be stopped by blocking a certain growth enzyme.

Even Gleevec, the most effective cancer drug of the past decade, was almost abandoned by Novartis (NVS). An outside cancer specialist, Dr. Brian J. Druker of Oregon Health & Science University, coaxed the company into pursuing its development."

Let's take those one at a time. It's true that many of the basic discoveries that have led to the current biotechnology industry came from academic research. That's just as it should be. But none of it would have been turned into human therapies without that "corporate research and development." Allan Haberman's statement makes it sound like the industry just sat around while the universities cranked out all the gold, which is untrue. [Note: see Haberman's own take on this in the comment section.]

The examples that follow help prove the point. The thing is, for every Erbitux and Gleevec story, there's a Cell Pathways counterexample - scrappy outsiders who pushed long-shot drugs with all their might, and all the venture-capital and equity funding they could get, only to find that they didn't work. Only the success stories are remembered, it seems. If the Cell Pathways drug had worked, it would be in this story, too. But it didn't, and it wasn't because it wasn't "biotechy" enough, either.

And it's not like Erbitux is that great a drug, either, frankly, as I've pointed out here numerous times. Imclone has been just fantastic at generating headlines, some of them inadvertent, so Erbitux is one of the things that people think of first. But it's hardly the stuff of a revolution. And Gleevec (another one of those small chemicals, by the way) is only "the most effective cancer drug of the last decade" if you have the rare cancers known as GIST or subtypes of CML. But if you don't, it's basically useless, not that that's stopping thousands of desperate people from trying it out. The reason Novartis didn't want to push the compound was that they thought that its potential market was just too small. They didn't realize that they were developing the world's first billion-dollar orphan drug.

Then comes this whopper:

"Traditional pharmaceutical companies shied away from biotech for years, unwilling to bet on unproven technologies. It didn't help that biotech's earliest accomplishments met with setback after setback in the 1980s and '90s.

Today, Big Pharma is paying for its risk-averse stance: Major players have few promising products in their development pipelines, and most are stuck with a business model heavily dependent on blockbuster drugs. Boston Consulting Group estimates that, as a result, biotech firms produced 67% of the drugs in clinical trials last year but shouldered only about 3% of the $40 billion that the drug industry spent on R&D."

Shied away from biotech for years? We pumped uncountable billions into it, much of which we never saw again. And as for that business model, the one heavily dependent on blockbusters? That's what we logic choppers call post hoc, ergo propter hoc. Once a company finds a huge winner, it becomes dependent on that revenue by default. And I have trouble imagining anyone saying "You know, this drug could sell two billion dollars a year. We'd better drop it. I don't think we can handle that kind of money."

Later, the article takes a look at some specific therapeutic areas, such as cancer. The next excerpt contains a couple of nearly unnoticeable palmed cards - see if you can spot them:

"Unlike heart disease, where patients choose between seven nearly identical cholesterol-lowering statins, targeted cancer therapies come in many forms. There are drugs that block tumor-growth factors, starve the tumor by inhibiting blood-vessel growth, combine radioactive isotopes with tumor-seeking proteins, and use vaccines to train the body's immune system to attack cancer cells.

There is even a next wave of multitargeted drugs that could start winning FDA approval as early as next year. Sutent, the drug keeping Julia Barchitta alive, is a member of this emerging class, known as multi-kinase inhibitors. They block blood-circulating proteins that are responsible for both tumor growth and blood vessel creation. Other closely watched candidates in this class include sorafenib, developed by Bayer (BAY) and Onyx Pharmaceuticals (ONXX) for kidney cancer, and lapatinib, a breast cancer drug from GlaxoSmithKline (GSK). These multitargeted therapies seem particularly effective against the hardest to treat cancers, giving hope to some of the sickest patients."

The idea that "cancer" is a single disease category just like "heart disease" is ridiculous. And note that "heart disease" is being defined as equivalent to "high cholesterol" - thus the mention of the statins. But Pfizer has gone to great lengths to prove that Lipitor is actually different from the other statins (and other companies have gone to great lengths only to end up proving the same thing, to their sorrow.)

Cancer is a constellation of hundreds of diseases, all characterized by uncontrolled cell growth. The complexities of the pathways involved give us plenty of potential mechanisms to target, and there we have the second switcheroo in this section. Those wonderful drugs that were being held up as examples earlier in the article - Erbitux, Gleevec - are targeted to only one or two of those mechanisms. And although that was their big selling point at the time, that's probably why they don't work very well. Those "multitargeted" drugs are not a refinement on this idea, they're the opposite idea.

The popular press is having quite a time catching up with this. You still see articles extolling the bold new era of tightly targeted cancer drugs, but they're being overtaken by the articles extolling the bold new era of messy blunderbuss cancer drugs. It's true that these compounds aren't in the same side-effect league as, say, the old cytotoxic agents like cisplatin, but they're a long way from the lasering-in-on-the-single-important-factor storyline from a few years ago.

The rest of the article focuses on stem cell therapies, and that will have to wait for another long post all its own. The cancer section closes out with a quote from Judah Folkman, who is an honest man:

". . .cancer specialists are hopeful that, as more targeted therapies come on line, they can be combined into cocktails that will keep cancer patients alive for years. Renowned cancer researcher Dr. M. Judah Folkman of Children's Hospital in Boston says the most important thing is that the drugs give patients hope: "We have something to offer [patients] now, and if it keeps them alive a little longer, something else might come along."

That sort of deflates the buzzing balloon that the rest of the article represents, doesn't it? Try turning that quote into a headline, won't you? But it's the truth. . .

Comments (9) + TrackBacks (0) | Category: Cancer | Drug Industry History | Press Coverage

June 2, 2005

How Much Success?

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Posted by Derek

One of the commenters brings an often-asked question: what percentage of drugs have been helped along by molecular modeling, and by how much? You could ask the same thing while substituting "combinatorial chemistry" in there, too. And I wish I knew the answer. Actually, failing that, I just wish that somebody knew the answer. The problem is, this is the kind of information that doesn't always get out, and some of what does is wrong.

I think that most estimates based on the literature would be too high. There's a press-release factor at work here, which leads some companies to claim projects or compounds as great successes for their technology, even if it didn't have that much to do with them. Or even if they were things that almost surely would have been discovered anyway - isn't the point of these techniques to find insights that you would have missed?

I've personally seen projects that were retroactively baptised as examples of some hot research technique, just to make everyone look good (or to justify the expense.) And if you were in a completely different part of the company, you might have believed the official story yourself. So the problem isn't just that companies don't share this kind of information, it's that they even kid themselves about it even when no one from the outside is watching. Under these conditions, an accurate estimate is just not possible. And yes, that makes it rather difficult to assess whether the time and effort has really been worthwhile, doesn't it?

Comments (4) + TrackBacks (0) | Category: Drug Development

June 1, 2005

As Thin As a Soap Bubble

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Posted by Derek

Words of wisdom from Jane Galt over at Asymmetrical Information:

"The appalling povery of Sri Lanka or Mozambique is not some bizarre aberration that can be tracked to a cause we can cure. We are the aberration; Sri Lanka and Mozambique are the normal state of human history."

Very sad, and very true. I've often had the same thought with respect to my work as a scientist. This is the only time in all of human history that I could have done some of the things that I've done. The human race has had capable and expanding technology for only a short time compared to the millennia spent hacking our living from the ground and running for our lives. The average snapshot of a person my age, taken any time over the last couple of hundred thousand years, has been of someone nervously gnawing on a bone while the wind howls around their shelter of rocks and branches. Well, that would be the scene only if I'm not already over the average male lifespan over that period, which I may well be.

No, my situation (and yours, too, if you're reading this at all) is a crazy outlier out on the right-hand edge of the curve: a nice climate-controlled roof over my head, a recent meal and no worries about the next one, no fear of wild animals or bands of club-wielding scavengers, no smallpox or polio to carry me off. And instead of grunting out a subsistence living, I get to sit in a well-appointed room and get paid for thinking up new ideas and trying them out with rare and expensive equipment.

Francis Bacon had it right: our trade is "the effecting of all things possible." We should never forget to enjoy it as much as possible, and do everything we can to keep it alive.

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