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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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February 28, 2005

Tysabri's Fall

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Posted by Derek

Well, no one's in any doubt about the main thing moving the biotech and pharma stocks today. Biogen/Idec and Elan shares got dragged through the streets and thrown into the river when they announced that they were pulling their multiple sclerosis drug, the weirdly-named Tysabri. (Here's the letter from the companies to physicians, in PDF format.)

In short, a small number of patients who where getting Tysabri along with another Biogen product (Avonex, aka beta-interferon) came down with progressive multifocal leukoencephalopathy, fortunately also known as PML. It sounds bad, and it is. While multiple sclerosis is a disease characterized by autoimmune attack on the white myelin sheathes of nerve tissue, PML is characterized by rapid, severe demyelination - sort of a multiple sclerosis on fast-forward. It's associated with activation of JC polyomavirus, a relatively obscure agent that a majority of adults carry without showing any symptoms at all. Disruption of the immune system (along with some unknown activating event) can turn the virus loose.

All this comes as today's print edition of the Wall Street Journal had a writeup on Biogen/Idec as the best-returning stock of the last ten years. Last year's 80% gain on Tysabri optimism didn't hurt, and the rest of the article is full of glowing predictions of success which are now but fragile fossils. Even if the treatment makes it back to the market, I can't see how it can ever be what it was going to be.

Tysabri's a monoclonal antibody treatment, which is one reason I haven't talked about it much on this site. That's much more biological than chemical, and I've never worked in the antibody field. But the toxicity problems that have cropped up are going to be handled just like the ones that occur with small molecules. Withdrawing Tysabri voluntarily should help some. But all you have to do this evening is type the name into Google, and you'll see that the first batch of ambulance chasers is already on the case. "Free Case Evaluation for Side Effects Victims," they say. There will be more lawyers than victims, and not for the first time. It won't slow them down much.

Comments (4) + TrackBacks (0) | Category: Toxicology

February 27, 2005

Law Number One

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Posted by Derek

Three years ago (the Silurian era in blog time) I starting a series on "Lowe's Laws of the Lab." Time to bring them back, because I'd like to have them all in their own category over there on the right. Long-time readers will get a couple of repeats here, but I'm redoing the old posts a bit. (And I owe copies of the list to several people who've written in - could y'all drop me another another line?)

First, some background: when I was in graduate school, I sat down one evening and made out a list of what seemed to be inescapable laws of organic chemistry. I circulated the list among my friends, and some copies made their way around to research groups at other schools - for all I know, there are yellowing copies of those early versions still taped to someone's hood, somewhere. Looking back at the list, it's clear that I was not in a good mood when I wrote it out - but I did say that I was in graduate school, didn't I? No need for redundancy, then.

None of the laws are particularly original. Most chemists will look at them and go "Yep!" For example, Law #1 is:

You can never have too much starting material.

I sure proved that one over and over during my graduate days, as readers will have heard me complain about. My project got so long and unwieldy that it sucked in every available gram of material. I'd start off again, on larger and larger scales, only to find myself back up at the frontier, holding this little flask with 10 milligrams or so of clear syrup: all that remained of all that time and effort. I went up to crazy, ridiculous scales - initial reactions that used the biggest round-bottom flasks buckets I could find. To no avail. It all led back to yet another little flask with a little oily stuff in it.

Nothing I've seen since has persuaded me that this law isn't universal. Oh, it's true that the occasional project will crash right after a big bucket of starting material has been made. Into storage it goes, until someone thinks up a use for it (at which time there won't be enough of it.) But those cases are far outnumbered by the ones where each lab hoards their precious material, and every new batch gets a parade of supplicants asking for - well, not all that much, really - just enough to do a couple of things we've been trying to get around to for a while - I think all we'd need is, oh, not even more than half of what's in your flask. . .

Comments (0) + TrackBacks (0) | Category: Lowe's Laws of the Lab

February 24, 2005

Getting a Faster PhD?

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Posted by Derek

Being a harmless science blogger, I've stayed out of the whole Harvard/Summers/women-versus-men tar pit. (Proof that I don't spend all my time fishing for traffic, as if posts on patent law weren't enough evidence already.) If you want, you can find more discussion of that controversy than you could want on any of the current-affairs blogs. But, still, I was struck by a comment from Virginia Postrel. She's discussing what might be done to increase the female presence in the sciences, given that biological clocks for reproduction work very differently for women and men (i.e., fathering a child at 45 is a lot easier than getting pregnant at that age. Neither Virginia nor I make any claims about the wisdom of doing either one; we're just talking biological feasibility):

"If, however, you spend six years in grad school and another two as a postdoc, you'll be 30 when you get your first tenure-track post--and that's assuming you don't work between college and grad school. I don't have the numbers, but science training is notorious for stretching out the doctoral/postdoc process, in part because the researchers heading labs benefit from having all that cheap, talented help. Female scientists who want kids are in trouble, even assuming they have husbands who'll take on the bulk of family responsibilities."

Fortunately, that long a stint in academia is unusual by chemistry standards, but molecular biology is notorious in just the way she's talking about. I've seen biology postdoctoral positions break up marriages, because the other partner eventually just wanted to finally, finally move on with life. Her suggested remedies?

"So, if a university like Harvard wants to foster the careers of female scientists, this is my advice: Speed up the training process so people get their first professorial jobs as early as possible--ideally, by 25 or 26. Accelerate undergraduate and graduate education; summer breaks are great for students who want to travel or take professional internships, but maybe science students should spend them in school. Penalize senior researchers whose grad students take forever to finish their Ph.D.s. Spend more of those huge endowments on reducing (or eliminating) teaching assistant loads and other distractions from a grad student's own research and training."

I got my first real PhD-level job at 27, after a year's post-doc, but that's a year or so younger than average for organic chemistry. I spent my undergraduate summer breaks doing research internships (of greater and lesser value), but I should make clear to those outside the field that graduate students in the sciences already work all through the summer. When I was in grad school, we watched the law students across the street pack up and leave in the spring while we cranked away in the lab days, nights, weekends, and holidays. I treasure a memo in my files from the chemistry department head, pointing out that the university vacation calendar did not apply to grad students - and he wasn't just talking about summers, of course. Do not, the memo warned, attempt to take all these holidays, things with names like "spring break", even though you may hear people talking about them.

As for Virginia's other prescriptions, I think penalizing slowpoke professors is a great idea. I know that some schools talk about doing this, but I've never seen any of them follow through. I think that the inverse idea, rewarding those research groups with a high percentage of students finishing on time, would be worth looking into as well. There are plenty of groups that could use a better work ethic - not in terms of the number of hours put in, but in terms of making sure that everything the students do is devoted to the great and holy cause of getting the hell out of graduate school. That's something you should do on general principles, man or woman, whether you plan to start a family or not. Grad school is for getting through, not for lingering.

Reducing TA assignments would also help. I know that many professors, if they have enough grant money, try to get their students out of teaching assistant positions as early as the university will let them (I did one year of it, the minimum.) But if you work for someone without as much of the ready cash, you can be TA-ing until your last year, and in an increasingly bitter mood about it, too.

Speeding up graduate education can be done. You don't want to turn out a bunch of unprepared losers, but as far as I can see, the system we have now does that anyway, but often too slowly. It's true that real research projects take time - you're never going to get well-trained chemistry PhDs out the door in two and a half years. But you shouldn't be expecting five and six years out of people as the norm.

Comments (8) + TrackBacks (0) | Category: Academia (vs. Industry)

February 23, 2005

Exobiochemistry

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Posted by Derek

Back in the early days of my pre-Corante blog, I wrote a piece about some other kinds of chemistry that might be used in living systems. There's now a wonderful one-stop review for all sorts of speculations on this topic, which incorporates everything I've ever thought of and plenty more. Steven Benner at the University of Florida, who my fellow Corantean Carl Zimmer has interviewed, and two co-workers (here's his research group) published "Is There a Common Chemical Model for Life in the Universe?" in Current Opinion in Chemical Biology late last year. (here's the abstract; I can't find the full text available yet on the Web.)

I can't say enough good things about this article. This is the sort of topic I've enjoyed thinking about for years, but there were still plenty of things in this review that had never occurred to me. Benner goes over the likely requirements for life as we know it, life as we'd probably recognize it, and life upon which we can barely speculate. As a chemist, he's particularly strong on discussions of the types of bonds that could best form the complex molecules that chemical-metabolism-based life needs. Energetic considerations - how much chemical bond energy is available, how soluble the materials are, how reactive they are at the various temperatures involved - are never far from his mind.

He devotes sections to ideas about living systems without chemical solvents (gas clouds, solid states) and the more familiar solvent-based chemistry. There's plenty of water out there in the universe - which is why bad movies about aliens coming to drain our oceans are so laughable - and it's natural enough that we should concentrate on water-based life. But there's plenty of ammonia out there, too, along with methane, sulfuric acid, and other potential solvents like the supercritical dihydrogen found in the lower layers of gas giant planets.

So, is all this stuff out there? Is life something that is just going to happen to susceptible chemical systems, given enough time? If so, which ones are susceptible? Benner's thoughts are, I think, best summed up by his take on Titan:

"Thus, as an environment, Titan certainly meets all of the stringent criteria outlined above for life. Titan is not at thermodynamic equilibrium. It has abundant carbon-containing molecules and heteroatoms. Titan's temperature is low enough to permit a wide range of bonding, covalent and non-covalent. Titan undoubtedly offers other resources believed to be useful for catalysts necessary for life, including metals and surfaces.

This makes inescapable the conclusion that if life is an intrinsic property of chemical reactivity, life should exist on Titan. Indeed, for life not to exist on Titan, we would have to argue that life is not an intrinsic property of the reactivity of carbon-containing molecules under conditions where they are stable. Rather, we would need to believe that either life is scarce in these conditions, or that there is something special, and better, about the environment that Earth presents (including its water)."

As for me, I can't wait to find out. I want Titan rovers, Jupiter and Saturn dirigibles, Venusian atmosphere sample return, instrument-laden miniature submarines melting down through the ice on Europa and Enceladus: the lot. How much of this will I ever get a chance to see in my lifetime? Current betting is running to "none of it, damn it", but things can change. Depends on how easily and cheaply we can get payloads up to (and out of) Earth orbit.

Comments (6) + TrackBacks (0) | Category: General Scientific News | Life As We (Don't) Know It

February 22, 2005

An Antiviral Example

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Posted by Derek

I mentioned yesterday that sometimes you can find an antiviral target that doesn't depend on what the virus itself has to offer. As fate would have it, there are a few drugs coming along that use just such a mechanism against HIV.

They're based on their affinity toward a protein called CCR5, which sits straddling the outer membrane of some types of cells. It's one type of receptor protein, whose lot in life is to latch onto specific other molecules if and when they come by. Our lot in life in the drug industry is to make small molecules that bind to them - the various kinds of receptors are hugely important drug targets. (For those outside the field, briefly, part of a receptor stays on the outside of the cell membrane, and part of it loops to the inside. When a molecule binds to the outside loops, that binding event changes the shape of the whole protein and sets off a signaling cascade in the cell, which signals can be tied into just about every cell process you can think of.)

In the mid-1990s, studies on patients who appeared more naturally resistant to HIV showed that they had a mutated form of CCR5. It turned out that the receptor is one of the things that the virus uses to get into blood cells and infect them, but the mutated form didn't let HIV bind to it very well. That immediately led to the idea of blocking a normal patient's CCR5 with some small drug molecule - if the receptor were stopped up with that, maybe HIV wouldn't be able to bind to it, either.

This receptor-blocking idea is a favorite in drug research. It's usually a lot easier to gum up a receptor than it is to mimic the specific thing that turns it on. That's why everyone jumped on this idea so quickly. But "quick" is a relative term in the drug development world. I think that the relevant chemical series were found to bind to CCR5 somewhere around 1996 or 1997. The projects at the different companies took off from there - and here it is 2005, and we're starting to begin to talk about something getting close to being submitted for the FDA's consideration. The thing is, that's not a slow calendar at all. It's normal to fast, unfortunately for all of us.

Schering-Plough (whose preclinical research team included several former colleagues of mine), GSK, and Pfizer are in the lead in this area, with several other companies also taking a crack at it. Early clinical results were promising, and we should be hearing more soon. Here's hoping that they all work.

Comments (1) + TrackBacks (0) | Category: Infectious Diseases

February 21, 2005

Can Med-Chem Help With Bird Flu?

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Posted by Derek

If avian flu does gain a foothold in humans, what can drug companies do about it? (This should give you the latest headlines on the disease.) It's definitely something to worry about. There hasn't been a real rampager of a flu epidemic in a long time, and a pessimist would say that we're overdue.

The answer to my question is "Work on a vaccine!" Because if you rephrase it and ask "What can people like this Derek Lowe guy and his hotshot medicinal chemistry buddies do?", the answer is "Not much." It's not a widely appreciated fact among the public, but we have hardly any drugs that affect viral diseases. The disease with by far the largest number of therapeutic options is HIV infection, and if you find that an unnerving thought, you should.

The problem, as I've mentioned before, is that viruses don't give you much to work with. They have very small genomes, and thus code for a bare-bones set of proteins. Since those are generally what we'd attack, we're often at a loss to find a good drug target. Sometimes you can find a target in the human cells that the virus attacks, but that takes a lot of basic research into the infection process.

And even if we find a target, we're years away from a drug. Getting a chemical lead structure, optimizing it, making sure that it actually does some good (and doesn't do a corresponding amount of harm!) - it's a terribly slow process. And it's remained that way despite hundreds of millions of dollars waiting to be picked up off the ground by the first company that can shorten it. The incentives are there; the technology isn't.

That time scale probably won't be much use if we get into an epidemic one of these years. The virus will outrun us. The best thing we can be doing now is learning everything we can about the whole class of H5N1 influenza viruses and how to make broadly active vaccines against them and their combinations with human agents. Prevention, monitoring, and immunology are going to have to save us if we get into trouble. Because though it pains me to say it, people like me aren't going to be able to help.

Comments (7) + TrackBacks (0) | Category: Infectious Diseases

February 20, 2005

COX-2 Aftermath

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Posted by Derek

Overall, I found the conclusionsn of the FDA's COX-2 committee quite reasonable (and not too far from what I predicted during the day on Friday.) Perhaps their actions will calm things down a bit. After all, they had the chance to bay at the moon, yank everything off the market and call for heads on pikes. But they ended up saying (I'm paraphrasing just a bit): "Y'know, these drugs really do have side effects. But a lot of stuff does. And they do some people some good. Maybe if just the people who really need them take them, things will work themselves out."

This all should make Merck's path forward in their Vioxx lawsuits a little easier. They could still face a punitive-damages avalanche, of course, and a lot of lawyers will be working to get the snowpack loosened up. I assume that the first case will be tried in Mississippi, Texas, or some other jury award paradise - picking the right venue is part of the art.

I'm just glad that the "Toxic drugs! Film at eleven!" momentum has been lost. I think that the industry, the stock market, the public, and (most definitely) the press were really close to panic there for a bit. (Naturally enough, in the last case, since panic sells.) But outside of advertising revenue, it does no one any good. If you make the right decision in that frame of mind, it's generally by accident.

Comments (2) + TrackBacks (0) | Category: Cardiovascular Disease

February 18, 2005

Waiting for the FDA

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Posted by Derek

Well, we're finally coming to the end of the FDA's COX-2 marathon. My predictions will be overtaken by reality soon, but I know that a lot of people are following this, so I'll take a crack at it:

I don't think we're going to see any drugs pulled outright from the US market, but if there is one, it'll probably be Bextra. Assuming it stays on the market, I think that it and Celebrex will pick up additional warnings, along with guidance to prescribe it only to patients who can't tolerate the more traditional anti-inflammatories. The FDA has been trying to do that already, and I think we'll see it emphasized again.

And if those two drugs and Vioxx all suffer from the same risks, which I think is likely the case, then why shouldn't Vioxx come back on the market, as Merck's Peter Kim said the other day? He has a point. After all, the recall was voluntary, not FDA-mandated, and as far as I know, there's nothing keeping Merck from bringing the drug back.

As for Merck's follow-up COX-2 (Arcoxia) and Novartis's Prexige, neither of which is available in the US yet, I think that the FDA will want to see major cardiovascular data. Perhaps they'll let them through, eventually, with the same set of warnings and guidelines I expect to see attached to the current drugs. But if the companies want better terms, they're going to have to show some evidence why they should have them.

So we might end up, after all the mud is washed off the walls, with more COX-2 drugs on the market than we have now. Odd, eh? They'll be fighting inside what's supposed to be (and probably will be, in fact) a smaller market, though. The real financial damage has already been done, because this class of drugs will never be what it was a few months ago. Makes you wonder if a big launch of Arcoxia, et al., is even going to be worth the effort.

Which brings up one more point: in the above, I mentioned prescribing COX-2 drugs "only to patients who can't tolerate the more traditional anti-inflammatories", and I'll bet that many people read that and added ". . .just like they should have all along." And it's true that we probably wouldn't have even seen the cardiovascular side effects in that smaller patient population (nor would we have been bombarded with COX-2 ads, for that matter.)

But that's what companies do - try to broaden their market as much as possible. I think that Merck and Pfizer overdid it in the pain market, true. But keep in mind that some of the bad news about these drugs came from trials of them against other possible targets (colon cancer, for example.) The only way we're going to find out if they work in these indications is to run those trials, and finding bad news instead of good is the risk that we in the industry take. I think it's better to try and lose than to never try. Some may disagree. . .

Comments (4) + TrackBacks (0) | Category: Business and Markets | Cardiovascular Disease | Toxicology

February 17, 2005

Law and Disorder

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Posted by Derek

I don't just spend all day in my office unraveling patents (or knitting my own); I do go out into the lab to make the wonder drugs from time to time. Today I spent the afternoon trying to separate two very closely related compounds - and not too darn successfully, either, as I found out just before I left work.

And once I get them apart, I'm still faced with trying to figure out which one is which. There are spectroscopic methods we can use, but it'll take a day or two. (Before I start complaining about that kind of thing, I should recall that I live in the days of powerful NMR machines with all kinds of tricky pulse sequence experiments. Forty years ago, figuring out which of these compounds was which might have taken a couple of months.)

But that said, these delays are something that a research chemist has to get used to. That's one of the things that I didn't realize as an undergraduate chem major: that professional organic chemists spend so much of their time purifying the things that they make just to get them to the point where they can start figuring out what they are. Understandably, these are just the steps that any dramatic treatment of the science has to leave out.

I can just see the detectives in a crime show asking the forensic chemist for the ID of the strange substance found in the murder victim's blood. "Hard to say," says the lab-coated one. "Our HPLC was acting up - we needed a new guard column 'cause Sam over there keeps plugging them up. Then we messed around for two days trying to get the peak cleaned up, and now the stuff doesn't ionize worth a hoot on the LC/MS, so I've asked the NMR guys if they can. . ." Holding their ears, the detectives walk away and a commercial for cat food comes on.

Comments (2) + TrackBacks (0) | Category: Life in the Drug Labs

February 16, 2005

Dysfunctional Disclosure

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Posted by Derek

I spent the last part of the day wrestling with a competitor's patent application, trying to decode the darn thing, so I won't be sitting here looking at this monitor for very long tonight. There's a "best mode" requirement in patent law, where you're supposed to disclose the best way you know of to realize your invention, but there's no requirement that you have to make it easy to find. Plenty of drug companies bury their gems in truckloads of patent gravel.

I have to say, after looking through a lot of recent applications, that I think that the amount of disclosure needed to show utility should be increased. You see patents claiming structures of (this kind, insert vague generic structure that claims things out to Neptune), as inhibitors of (reverse whateverase, ya-ya kinase, etc.) for the treatment of what ails you. Fine by me. But shouldn't you have to put in some real numbers from your "reverse whateverase" assay (or, uh, whatever?)

Some people do, and good for them. And many other companies get around disclosing too much by assigning little plus-mark symbols for levels of activity, and then giving a table of compounds with one, two, or three plus marks next to each compound. That's just very slightly better than nothing, but it's an open book compared to the bozos who spend the last twenty pages of their applications describing, in horrible detail, every step of every assay they can think of - and then mention, offhandedly, that the compounds of this invention were tested in these assays and were found to be, you know, active and stuff. Should the patent offices of the world really let people get away with that one?

Comments (1) + TrackBacks (0) | Category: Patents and IP

Glaxo v. Pfizer: Sales Force Stand-Down?

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Posted by Derek

Glaxo SmithKline's chairman, Jean-Pierre Garnier, made headlines a few days ago with his comments on the size of the marketing budgets in the industry. His main focus is on the sales force, which is about the most expensive form of marketing we have. From the Reuters story linked to above:

"We do believe there is an arms race out there in terms of sales forces and that if you were to redesign the system from scratch you would end up with smaller sales forces," Garnier told reporters in a post-results conference call. "If more common sense comes back to the picture, I think it will be a good thing for the industry. Certainly, we are eagerly observing what others are doing."

The number of representatives promoting rival medicines has now reached the level where physicians are becoming overwhelmed and it would make much more sense to divert some of the marketing spend to more productive areas, he said.

"We do not need those large sales forces to do the job. We need them because the competition is planning to increase their noise level," Garnier said.

He's got a point, I'm sorry to say, although not for all the reasons he gives. We spend a lot of money on marketing in this business, as any number of people will be overjoyed to tell you. And like any other business, we expect a return on it. Why else does a company spend money? For some time, we've been able to earn as high a return on our cash by promoting existing drugs as we can spending it on R&D - in some cases, higher. That's partly because of all the money to be made from the drugs, and partly because of the spotty returns on research in the last ten years or so. Naturally enough, we've seen plenty of promotion.

But I have to think that the sales force has crossed over a threshold at some companies. Doctors have been getting swarmed by sales reps, many of whom don't even get close to seeing an M.D. any more. Further expenditures on more salespeople bring a smaller and smaller return, to the point where it stops making economic sense. Things have gotten to the point where you're better off giving the money to us dice-rollers over in the labs.

Garnier's comments clearly refer to Pfizer's situation, because that's the marketing machine that everyone else in the industry fears. But with all due respect, I don't think that it's all a case of "We're only doing it because Pfizer does it", though. If Pfizer's getting a lower return on its sales force than it could make by spending the money somewhere else, then that's their problem (and Glaxo's gain). Each company has to make that decision on its own, based on the markets it competes in and the products it has to sell.

And conversely, if Pfizer's getting a higher rate of return by running a monster sales force, then the rest of the industry just has to deal with it somehow - ideally, by making better products or by competing in Pfizer's under-served markets. Both of which are good for the customers, I might add, and we'll end here with the standard round of applause for Adam Smith and his Invisible Hand.

Comments (14) + TrackBacks (0) | Category: Business and Markets

February 14, 2005

Bigger and Greasier

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Posted by Derek

When I was talking about chemical space the other day, I alluded to the attempts to cut it down to "druglike space" by use of rules of thumb. The most famous of these is Chris Lipinski's "Rule of Five", a summary of which can be found here. Lipinski and his Pfizer co-workers looked over a data set of drug candidates and noticed that there were some reasonably clear cutoffs for oral absorption and general cell permability. They suggested that you need:

1. Fewer than five hydrogen bond donors (which can be estimated by counting the total number of OH and NH groups in the molecule.)
2. A molecular weight of less than 500.
3. A logP of less than 5
4. And fewer than 10 hydrogen-bond acceptors (estimated by the total of N and O atoms in the molecule.)

The "rule of five" name came from the cutoffs all being multiples of five, in case you're wondering why there are only four rules.

(A quick explanation for non-chemistry types: "logP" is a measure of how greasy your compound is, and I mean that quite literally. Although it's often estimated computationally these days, experimentally it's determined by shaking a standard amount of a compound in a flask containing water and the oily 8-carbon alcohol, octanol. Those form two layers, as you'd imagine. The log of the ratio of how much of your compound goes into the octanol layer versus the water layer is your logP. A thousand-fold preference for octanol (a logP of 3) is considered to be just fine for a drug, so you can imagine how greasy a compound with a logP of 6 is.)

There's a recent paper by John Proudfoot at Boehringer Ingleheim (Bioorganic and Medicinal Chemistry Letter 15, 1087, for those of you playing along at home) which looks at a more comprehensive list of compounds than the original Lipinski batch. He finds that the cutoffs might be more like 470 for molecular weight and 3 for hydrogen-bond donors, but otherwise his analysis tracks Lipinski's pretty closely. (He notes that only a handful of drugs ever violate both those cutoffs simultaneously.)

His paper also includes a year-by-year analysis from 1937 to 1997. The only clear trend is that molecular weights have been increasing, from under 300 to the point where we're banging up right against that 500 line. Personally, the largest molecule I've ever submitted for testing weighed quite a bit more than that, but I had my reasons. It came in at exactly 747, and I couldn't resist.

Lipinski's done a lot of publishing and speaking on this topic in the eight years since he first published his rules, and they've seen a tremendous amount of use. Perhaps they've seen some abuse, too, because (as he himself would no doubt tell you), they're not written in stone. They're based on the 90th-percentile cutoffs for each property, so there are outliers. The "Rule of Five" is a tool meant to pare huge lists of compounds down to manageable size, not to blindly decide the fate of individual drug candidates.

I've seen people make Rule-of-Five objections to a compound after its in vivo behavior has already been demonstrated, to which the proper response is "Who cares?" You wouldn't want to stuff your drug discovery project with compounds that violate several of the rules, but if you have good activity after an oral dose, then what more are you looking for? Other things being equal, we try to make compounds that don't step over too many of these boundaries, but being dogmatic about them, especially single rule violations, is foolish.

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February 13, 2005

Pfizer's Prospects

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Posted by Derek

I have company, naturally, in my views on Pfizer's prospects. Here's a story from the AP which does a good job wrapping all the doubts up into one package. But you can't please everyone: I notice people over on the Pfizer discussion board on Yahoo, moaning about "Why does the AP hate Pfizer?" (Why else, in their worldview, would anyone say such things?) The usual stock-board answers are trotted out - it's the "shorts," don't you know, and the evil money managers who want your shares cheap. Makes you wonder when we're going to root all those people out, so stocks will have no choice but to rise forever, doesn't it? Oh, speed the day when there are no cheap stocks!

So much for the amateurs - how about the professionals? I should try to do a chart of the sorts of quotes we're seeing now versus the ones from the days when Pfizer's stock was higher and they were an Unstoppable Behemoth. (I've been saying the same nasty stuff all along, but I don't get paid.)

Now, it's true that I work for one of Pfizer's competitors, and you should take that into account. (I don't own any Pfizer shares or have any options positions, though, nor am I short, although that wouldn't have been a bad idea.) No, I've managed to say nice things about some other companies that are also out to eat my lunch - it's just that Pfizer's style and strategy are just the opposite of what I think a drug company's should be. They have good people there, and they have some interesting things in their pipeline, and neither of those are going to be enough.

We should face up to it: it's possible for a Big Pharma to get too big, at least if they're going to go around promising double-digit growth to all comers. I'm not sure just when you cross that line, but I feel pretty safe in saying that Pfizer is on the other side of it.

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February 10, 2005

The Bones of the World

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Posted by Derek

These two posts (here and here) over at Uncertain Principles are well worth reading if you like discussions of the divide between people who understand science and people who don't. Chad Orzel, being a physicist, instantly translates "doesn't understand science" to "doesn't understand math", which is fair enough, especially for physics. His analogy to the language of critical theory, as found in English literature classes and the like, has threatened to turn the comments threads for both posts into debates about that instead, but Chad's doing a good job of trying to keep things on topic.

What he's wondering about, from his academic perspective, is how to teach people about science if they're not scientists. Can it be really done without math? He's right that a fear of mathematics isn't seen as nearly as much of a handicap as it really is, and he's also right that physics (especially) can't truly be taught without it. But I have to say that I think that a lot of biology (and a good swath of chemistry) can.

Or can they? Perhaps I'm not thinking this through. It's true that subjects like organic chemistry and molecular biology are notably non-mathematical. You can go through entire advanced courses in either field without seeing a single equation on a blackboard. But note that I said "advanced". I can go for months in my work without overtly using mathematics, but my understanding of what I'm doing is built on an understanding of math and its uses. It's just become such a part of my thinking that I don't notice it any more.

Here are some examples from the past couple of weeks: a colleague of mine spoke about a reaction that goes through a reactive intermediate, an electrically charged species which is in equilibrium with a far less reactive one (which doesn't do much at all.) That equilibrium is hugely shifted toward the inert one, but pretty much all the product is found to have gone through the path that involves the minor species. That might seem odd, but it's not surprising at all to someone who knows organic chemistry well. A less reactive species is, other things being equal, usually more energetically stable than a more reactive one, and the more stable one is (fittingly) present in greater amount. But since the two can interconvert, when the more reactive one goes on to the product, it drains off the less reactive one like opening a tap. There's a good way to sketch this out on a napkin, where the energy of the system is the Y coordinate of a graph - anyone who's taken physical chemistry will have done just that, and plenty of times.

Here's another: a fellow down the hall was telling us about a reaction that gave a wide range of products. Every time he ran one of these, he'd get a mix, and bery minor changes in the structure of the starting material would give you very different ratios of the final compounds. That's not too uncommon, but it only happens in a particular situation, when the energetic pathways a reaction can take are all pretty close to each other. The picture that came to my mind instantly was of the energy surface of the reaction system. Now, that's not a real object, but in my mental picture it was a kind of lumpy, rubbery sheet with gentle hills and curving valleys running between them. Rolling a ball across this landscape could send it down any of several paths, many of them taking it to a completely different resting place. Small adjustments from underneath the sheet (changing the height and position of the starting point, or the curvature of the hills) would alter the landscape completely. Those are your changes in the starting material structure, altering the energy profile of all the chemical species. A handful of balls, dropped one after the other, would pile up in completely different patterns at the end after such changes - and there are your product ratios.

Well, as you can see, I can explain these things in words, but it takes a few paragraphs. But there's a level of mathematical facility that makes it much easier to work with. For example, without a grounding in basic mathematics, I don't think that that picture of an energy surface would even occur to a person. I believe that a good grasp of the graphical representation of data is essential even for seemingly nonmathematical sciences like mine. If you have that, you've also earned a familiarity with things like exponential growth and decay, asymptotes, superposition of curves, comparison of the areas under curves and other foundations of basic mathematical understanding. These are constant themes in the natural world, and unless they're your old friends, you're going to have a hard time doing science.

That said, I can also see the point of one of his commentators that for many people, it would be a step up to be told that mathematics really is the underpinning of the natural world, even if some of the details have to be glossed over. Even if some of them don't hit you completely without the math, a quick exposure to, say, atomic theory, Newtonian mechanics, the laws of thermodynamics, simple molecular biology and the evidence for evolution would do a lot of folks good, particularly those who would style themselves well-educated.

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February 9, 2005

How'd We End Up Here, Anyway?

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Posted by Derek

Regular reader Qetzal pointed out this analysis of the drug industry's problems, and it's well worth reading. Enoch Huang is a director of molecular informatics for Pfizer, and it's a sign that we're well into the 21st century that his job title doesn't sound odd to me. He was speaking as part of a panel at Harvard Business School, and quoth Huang:

"The number one enemy facing our industry isn't so much Canadian importation or possible regulation on price. It's our own drug candidate attrition. Within Pfizer, and I think it's representative of the industry, the odds of a clinical candidate - that's when you're done making the molecule and you're sending it off to see whether it works and is safe and can make approval - is 1 in 25. That's something like 96 percent failure rate. It's staggering number, [when] coupled with the cost of R&D versus the productivity measured in new chemical entities, which is essentially flat. It's an unsustainable business model for Pfizer and the industry. . ."

Well, I spent yesterday's post beating up on Pfizer, so I'll just note that "unsustainable" is a word that comes often to mind when I think about the company. But Huang is right about the problem and its implications for the industry. Note, though, that his figures are even worse than the historical ones that I cited here back in September, and that he attributes most failures to toxicity, rather than lack of efficacy - I think that over the years these categories have switched places. But all that aside, it's hard to see how we can go on like this, and the failure of our new technologies to reduce these odds is especially galling. (Here's a poll of researchers on these very subjects.)

This takes us back to a point raised in a comment to yesterday's post. There are analysts saying that not only does the drug industry spend too much on marketing, but it spends too much on R&D. Well, as a researcher, my answer to how much a drug company should be spending on research is "as much as they can possibly stand," but that's not as facetious as it sounds. Because of the wasting-asset feature of patent protection, we absolutely have to discover new things all the time, and then try to get them out on the market and sold to someone. Cutting R&D, unless you have a really, really good idea of where you're now wasting the money, would be an act of desperation.

But it's for sure that we're wasting a lot, and I hope we eventually find out where we're doing it. Huang mentions that the reductionist approach to drug discovery itself may have gone too far. That's the standard industry way, and has been for years now: coming up with well-defined molecular targets, screening them in isolated in vitro systems, and working your way up from there. It's intellectually appealing, and has led to some huge successes, but we may have ridden that horse about as far as it can carry us.

The hope for genomics (and the other -omics) has been that they would throw new logs on the reductionist fire. If we just understood things better, the hope has been, then we could pick off relevant drug targets with the systems we already have. The industry has already spend vast amounts on this project, but we may now have to face spending even more to switch to a different sort of system entirely.

What would that look like? This gets back to the discussions of animal models I've posted on recently, and the line of thought is pretty messy. If we're going to get away from reductionism, then the closer to the real living system we are, the better. We'd need better animal models (no easy task), and we'd need to get compounds into them as quickly as we could. And from there, we'd need to get into humans as quickly as possible, too, on the same principle. But to do that, we're going to need to know more about toxicology, because otherwise we're going to to either spend a huge amount running our current tox models in animals, or run unacceptable risks in early clinical trials.

To that point, a recent article in Nature Reviews: Drug Discovery, one of their series on animal models, said that we shouldn't be afraid of using sheer brute force to test our way through these things. It may come to that, but that's going to take some sheer brute cash.

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February 8, 2005

Maybe They Should Fire Them All?

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Posted by Derek

So I see that Pfizer's stock is up today, partly on news that an oncology compound of theirs worked very well in a clinical trial against stomach cancer.. Well, it's not their compound, actually; they bought it from a little outfit called Sugen. Well, actually, they just went ahead and bought Sugen, and the compound came with it. It's a pattern. Hardly any of Pfizer's big compounds are from Pfizer, and when they go out shopping for one, they often just buy the company it came from. They must be on the mailing list for some kind of coupon offer that the rest of us don't get.

Where was I? Pfizer's stock price, yes. Good clinical news is certainly a legit reason for a drug stock to go up, and congratulations to everyone involved. But the other reason for Pfizer's stock action, a bigger one in terms of earnings per share, was the report that they might be about to cut 10,000 jobs from their sales force. The market liked the sound of these layoffs, as it often does, because those savings show up pretty quickly in a company's earnings reports.

That figure should give you an idea of what a leviathan Pfizer really is. There are plenty of well-known companies whose sales force couldn't be cut like that without first hiring a few thousand people. Perhaps I'm a bit thick-headed, though. Is it a good time to be bidding up the stock of a company that's thinking about heaving 30% of their sales force overboard? The reason you do such a thing is, well, slow sales. Firing people isn't going to make the sales pick up - just the reverse, actually.

At the very least, I wouldn't touch Pfizer until after the FDA hearings on COX-2 inhibitors next week. I can't imagine that their Celebrex sales are doing very well so far this year, but that meeting could really put on the brakes. Add that to slower sales for Neurontin and Viagra, and the medium-term patent expiration of Lipitor, and I can only ask again what I've been asking for a few years now: just how is Pfizer going to make this work?

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February 7, 2005

One Problem Solved, Anyway

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Posted by Derek

Before I start off tonight, I wanted to welcome another advertiser on the site, the folks at GenomeWeb over there in the corner. Glad to have 'em!

Thanks to the people who commented on yesterday's question. My Corantean overlord(s) suggested a useful solution as well, since (as Jack Vinson guessed), I'm set up to only display the most recent posts on the front page. Pasting in the old material, saving it as a draft, and then changing its date sends it directly to the category without having it appear up front.

So, the first thing I've added from the archives is my series on chemical warfare, which was written in September of 2002. It's in that "Chem/Bio Warfare" category over on the right, naturally enough. (This was written in the run-up to the Iraq war, and the last post in the series was soon overtaken by events. I note, though, that I speculated that Iraq might have far less in its stockpiles than people had estimated - I just didn't realize quite how much less.) But most of the series is still worth a read, if you're interested in that sort of thing. You'll learn about the morning that a German chemist first synthesized a human nerve gas, not realizing quite what he'd made until it was time to dive for the door. And you'll hear about my own cold-sweat encounter with phosgene gas, which I hope not to repeat any time soon.

This'll be it for tonight. I'll be heading into the lab tomorrow morning to see if I have a useful one-pot way to make a five-membered heterocycle, or if I have an orange mess in the bottom of my flask. The most likely outcome is that it won't work, and if it works, the most likely result is two different isomers (with the wrong one predominating.) But I don't know any of that for sure, and that's why we run the darn experiments, y'know. Hope springs eternal - that's one thing we prove in research every morning.

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February 6, 2005

A Technical Question

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Posted by Derek

A quick question to those of you who are Movable Type gurus - and you're probably more of an MT guru than me, even if you just rolled off the back of a turnip truck.

Is there an easy way to publish directly to a category archive? I have some older posts (from the pre-MT days) that I'd like to bring back into circulation, but they don't need to show up here on the main page. I'd just like to have 'em appear under the relevent categories (with a quick note to that effect out here.)

Among the things I want to bring back are my series on chemical weapons, which I've had requests for. There's also a series of posts that will go into "Birth of an Idea". They chronicle the long gestation of an idea that I've had to increase the drug discovery success rate, and they're a good overview of the mood swings that a really powerful idea will bring on. I haven't worked in that area much in the last few months, but I'm looking for a good way to bring it back to the front burner in my lab. Once I do, the mood swings will no doubt recur. . .

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February 3, 2005

Elbow Room

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Posted by Derek

I mentioned going through the scientific literature yesterday - it's only when you start on a deep search that you realize what huge swaths of chemical space are covered by patent claims. Of course, just about every word in that sentence needs some clarification.

"Chemical space", the universe of possible structures, is of course gigantic. Even if you confine yourself to the basic elements of organic chemistry - carbon, hydrogen, nitrogen, oxygen and sulfur - you still end up with insane numbers, with ten-to-the-sixtieth-power being one of the orders of magnitude being tossed around. Clearly, in a number that size you could lose all the chemical compounds prepared so far in human history and never see them again.

Plenty of those compounds are found (only) in the patent literature. But chemical patents typically claim much, much more territory than they ever exemplify. I spoke about this last spring.) As I mentioned then, those huge claims don't mean all that much when it comes to spraying down the area against competitor patents. If you want to know more, heaps more, about patentability in these situations, try this section of the US Patent Office's Manual of Patent Examining Procedure. It's an illustration in prose of what the phrase "grind to a halt" is supposed to convey, but I regret to admit that I've read the whole thing.

Back to the outer reaches of chemical space: I'd be in violation of my medicinal chemistry club pledge if I didn't point out that big swaths of it are a priorialmost certainly useless for drug discovery. Molecules can be too big, too polar, too greasy, or too rock-like to ever be of any medicinal use. That much everyone agrees on, but when you start to apply numerical cutoffs to those ideas, the arguing starts. More on this next week.

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February 2, 2005

Up There, and Down Here

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Posted by Derek

Instead of blogging tonight, I went outside with the telescope and froze my extremities. My wife loaned me a fashionable wool scarf, which saved my ears while I observed the winter sights. Every time I see Saturn (or Jupiter, which wasn't up yet), I wonder how much of those yellow and brown colors are the same things that stick to the top of my chromatography columns in the lab. I had a look at the yellow-orange dot of Titan, and thought about the methane rain that might have been pattering down on the Huygens probe at that very moment.

Not far away from Saturn's current position (in the constellation Gemini) is the "Eskimo Face" nebula. By the time I got around to that one, he didn't look much warmer than I felt, so I packed it in.

In earthbound exploration, tomorrow I'll be making a class of compounds that has never been made before, at least according to Chemical Abstracts. That's just what we need to plant the patent flag and claim the territory, and I was glad to see things show up that were fairly close, but not quite there. That way I can be fairly sure that the chemistry will work.

It's always worrisome when you get hundreds of hits from a literature search, because you know that you're going to have a hard time finding (and claiming) something new. But it's also troubling when you get zero hits across a broad class of related structures, because at this late date, there might well be a reason for that which you, too can rediscover. Of course, you can get literature hits that are all for uses like hair dyes, photoresist agents, corrosion inhibitors, and arthropodicides. Then while you figure you can probably make the compounds, you have to worry a bit about their status as something that you could ask someone to eventually put in their mouth. . .

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February 1, 2005

Merck Takes Another One

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Posted by Derek

A lot of people at Merck must be wondering just exactly what they're being paid back for. If you'd sat down a couple of years ago and tried to come up with a doomsday timeline for Merck, you couldn't have done much better than what's actually happened. The latest is Friday's ruling (PDF) that Merck's patent for a weekly dosing formulation of their osteoporosis drug Fosamax is invalid. That's their second-biggest selling drug - the biggest, Zocor, is coming off patent next year, don't you know.

Teva, a generic powerhouse, already has an application in to sell Fosamax (alendronate) in 2008, when the original chemical matter patent expires. But the biggest-selling form of the drug is the weekly dose, and Merck had (so they thought) wrapped up patent protection on that one until 2018. They'd won a round in the District Court in 2003, which found that Teva's application infringed on the Merck formulation patent. But Teva appealed, and the Court of Appeals for the Federal Circuit, to Merck's dismay, reversed the District Court ruling.

That doesn't leave Merck too much room, as I understand it. The Supreme Court doesn't take many patent cases - the last one, I think, was the Festo appeal, and that dealt with more fundamental questions of patent law. This, unfortunately for Merck, just looks like another patent fight, and as such I'd be surprised if the Supreme Court agrees to hear it.

One of the grounds for reversal is an obviousness argument against Merck's patent, based on a 1996 article in a trade publication on the desirability of a weekly dose of alendronate. The other reversal argument comes down to the interpretation of a single word in the original patent claims. Merck claimed a method for treating osteoporosis by administering "about 70 mg" of the compound once weekly, and a method for preventing it by administering "about 35 mg" of the compound weekly. Based on other language in the patent, the District Court believed that this "about" language was an attempt to take into account the different salt forms and formulations of alendronic acid, in order to deliver the exact 35 or 70 mg of sodium alendronate. Teva's application was for 35 and 70 mg dosages, and they were held to infringe.

The CAFC, noting that Merck had acted "as its own lexicographer", pointed out that this would mean that "about 35 mg" now was being held to mean the same thing as "exactly 35 mg.", Noting the weirdness of this, they sharply yanked the definition back to the more commonly accepted one. Teva is now in the clear, and Merck (who probably hoped to throw the largest shadow they could with that adjective) finds themselves in trouble.

There's a testy dissent to the ruling (also in that PDF file above), which the majority opinion describes as ". . .pursuing a philosophical argument as to the deference which should be given to the trial court. Claim construction being a legal matter it is reviewed de novo and this is still the law notwithstanding the desire of some members of this court to consider creating an exception to that rule." Perhaps Howard Bashman has some background on this intra-judicial elbow-throwing. The Patent Law Blog has some comments, too, along with a more technical discussion of the case than I've given here.

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