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: Twitter: Dereklowe

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June 26, 2007

Two Weeks Off

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Posted by Derek

Apologies to everyone for the gap in posting around here. As you probably gathered from the most recent one, things are hectic. We're preparing our house (Stately Lowe Manor, if you will) for listing on the local market - it's in good shape, but we've accumulated a lot of stuff over the last ten years, much of which won't make the move to Massachusetts. At the same time, we're visiting lists of houses up there. Things aren't dull.

So I'm going to go on hiatus for a couple of weeks while all this gets sorted out. I start at my new position then, and at that point blogging will resume. Until then, I have a question for everyone: what am I going to call the place? I'd like to be able to refer to the Wonder Drug Factory in the past tense, so I'll retire that name. Calling the new place the New Wonder Drug Factory seems cumbersome, and besides, it's only new for me.

Suggestions are welcome, and I'm very happy to be in a position to ask. I'll start things up here again in the second week of July, and see everyone then.

Comments (47) + TrackBacks (0) | Category: Blog Housekeeping

June 21, 2007

Real Life, Which Costs Real Money

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Posted by Derek

No time for a new post today, unfortunately. I'm on the road, up in the unexplored (by me) territory of suburban Boston, looking at schools and houses today and tomorrow. At the moment, I'm sitting in one of those free-wireless sandwich places, catching my breath and getting ready to look at real estate.

When I was a kid, if you'd told me that I'd be living in a place that cost what these do, I'd have expected the full James-Bond-villian setup: missile launching facility, access to underground submarine base, etc. Looking at the listings, I can only assume that the fashion for these amenities has passed. Probably just as well - I'm not sure I could get the wife and kids to wear the matching jumpsuit uniforms.

Comments (18) + TrackBacks (0) | Category: Blog Housekeeping

June 20, 2007

Bigger, Tougher, Longer? Or Not?

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Posted by Derek

Here's a question that was posed to me an an e-mail, which I thought I'd open up to everyone. Is the perception accurate that new clinical candidates (and new approved drugs) are getting more complex? And if so, are the processes used to make them getting longer and more complicated at the same rate?

I've seen the charts on the increasing molecular weight, etc., of candidates over the years, which is one surrogate for complexity. The relentless trend toward single enantiomers is probably a driver, too, so I'm certainly willing to credit the idea that the molecules are getting gradually woolier. What I'm wondering, though, is whether this is being reflected in the process work. Has anyone seen any statistics on "average number of chemical steps" or the like?

My guess is that it's been increasing, but more slowly. I think that modern synthetic methods are making up some of the difference, but I'd be interested in some actual, y'know, proof for this. Thoughts?

Comments (7) + TrackBacks (0) | Category: Drug Development | Drug Industry History

June 18, 2007

Right Down the Alli

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Posted by Derek

If you're wondering why Sanofi-Aventis would spend so much time and money on a tricky, problematic drug like rimonabant, just take a look at the reception of GSK's over-the-counter version of Xenical (orlistat), brand-named Alli.

What's ridiculous about all the coverage and hype is that the drug isn't (of course) new. And it frankly wasn't all that successful when Roche sold it by prescription. So it goes OTC and everyone goes crazy for it? No, not for long they won't. From what I can see, this is just pent-up demand for something, anything, that will help people lose weight without having to work too hard.

This is not the drug to do that. And that's putting things gently. It is, as it's been rightly termed, "the Antabuse of fat". It's there to keep you on a low-fat diet, and to make you pay if you stray. If you're taking orlistat but go out and eat a bucket of fried chicken, you're going to regret that excursion for years to come. Generally, people just gradually seem to stop taking the stuff regularly, which makes it less likely to do anything, which in turn provides the perfect reason to stop taking it completely.

So my forecast for Alli is strong sales - for a while. Then it takes a dive, never to scale those heights again, as the word gets out. And the demand continues to grow for a weight-loss drug that works. . .

Comments (49) + TrackBacks (0) | Category: Diabetes and Obesity

June 17, 2007

Access To Science

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Posted by Derek

Via Pharyngula, I came across this impassioned blog post on the problems that amateurs (and their children) have getting chemicals, lab equipment, and other science supplies these days. Regulatory attempts to cut down on access to potential explosives and company attempts to dodge potential lawsuits seem to be the main culprits.

I sympathize, and I just hope that the situation isn't as dire as it's made out to be. This isn't a new problem, though. Chemistry kits were already being drained of their more exciting components even in the early 1970s - my father went out and got me some supplemental chemicals back then, including a couple that I probably shouldn't have had. But from the sound of things, it's hard to even do that much under current conditions.

Even outside the hazardous parts of science, there's a general problem with a lot of equipment designed for kids being total junk. As an amateur astronomer, for example, it's not even safe to get me started on some of the telescopes that are sold as ideal for a young observer. And what's even more frustrating is that (compared to my childhood) good telescopes are more affordable and available than ever. There's no excuse for the unk. The situation isn't good in microscopes, either. As far as I can tell, you really have to go to the online surplus and auction sites and buy a used real microscope, if you can find a good one, because the ones marketed as starter instruments are trash.

I grew up with access to a fair telescope, a fine microscope, a good chemistry outfit, and more (model rockets, etc.) - which (now that I look back) was pretty good going on the part of my parents, considering where and when I had these things. I'm making sure that my kids have similar opportunities. There's no substitute for being able to use your hands if you're interested in science growing up. I hope that it's still possible.

Comments (16) + TrackBacks (0) | Category: Current Events

June 15, 2007

Rimonabant: Down to Earth

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Posted by Derek

Everyone will have heard the news about Wednesday's FDA Advisory Commitee vote on Accomplia / Zimulti (rimonabant). If you'd tried to convince folks a few years ago that this drug wouldn't make it to a vote until summer of 2007, and would be unanimously rejected when it did, you'd have been looked at with pity and concern. No, this drug was going to conquer the world, and now people are talking merger-of-desperation.

Hey, you don't even have to go back a few years. Here's an article from 2006:

"A new anti-obesity pill that market observers say could become the world's biggest-selling drug is close to getting approval from the European Commission. . .

Gbola Amusa, an analyst with research firm Sanford C Bernstein, said that Acomplia could achieve $4.1bn in annual sales by 2010, in part because it has been shown in clinical trials not only to trim fat but to increase levels of good cholesterol and control diabetes.

"In the blue sky scenario, this could become the world's best- selling drug as the indication is so broad," he said. "It has a path to revenues that we rarely ever see from a pharma product."

Oh, the blue sky scenario. I'm no stranger to it myself - I love the blue sky scenario. But how often does it ever descend to earth? It's not going to do it this time. Sanofi-Aventis was reduced to making the suggestion that every potential patient be first screened for depression, which doesn't sound like the sort of iron wrecking ball that usually gets welded to the world's best-selling drugs.

In the wake of this development disaster, here are a few points that may not get the attention they deserve: first, consider the money that S-A has spent on this drug. We're never going to be shown an accurate accounting; no one outside the upper reaches of the company will ever see that. But I seriously doubt if they've ever spent more on any program. There's an excellent chance that most of it will never be recovered, not by rimonabant - it'll have to be recovered by whatever drugs the company can come up with in the future. They'll be priced accordingly.

Second, think about the position of their competitors. All sorts of companies have pursued this wonder blockbuster opportunity. If you run CB-1 antagonists through the databases, all kinds of stuff comes hosing out. Merck and Pfizer are the companies that were most advanced - you don't get much more advanced than Phase III clinical trials - but plenty of others spent time and money on the chase. All of those prospects have taken grievous damage. Odds are that rimonbant's problems are mechanism-related, and proving otherwise will be an expensive job. This is something to consider when you next hear about all those easy, cheap me-too drugs.

And finally, it's worth thinking about what this says about our abilities to prosecute drug development in general. Just as in the case of Pfizer's torcetrapib, we have here a huge, expensive, widely anticipated drug that comes down out of the sky because of something we didn't know about. It's going to happen again, too. Never think it won't. This is a risky, white-knuckle business, and it's going to be that way for a long time to come.

Comments (29) + TrackBacks (0) | Category: Clinical Trials | Diabetes and Obesity | The Central Nervous System | Toxicology

June 11, 2007

Rimonabant, Out In the Light

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Posted by Derek

The FDA briefing documents for Wednesday's discussion of Accomplia / Zimulti (rimonabant) have been posted, and they're an interesting read indeed. As everyone in the industry knows, this drug was once looked on as the next potential record-breaker, and writing the first part of this sentence in that verb form tells you a lot about what's happened since. It's the first antagonist targeting the cannabinoid CB-1 receptor, and at one point it looked like it was going to make people lose their excess weight, shed their addictions, and for all I know refinance their mortgages.

But then the delays hit in the US - long, long ones, delays which made fools of everyone who tried to predict when they would be over. And the drug meanwhile made it to market in Europe, where it has very quietly done not very much.

Now we may be seeing some of the reasons for the FDA'a "approvable" letter over a year ago. It's not efficacy - the FDA's briefing summary states that:

"Rimonabant 20 mg daily vs. placebo was associated with statistically and clinically
significant weight loss. Rimonabant 5 mg daily vs. placebo was associated with
statistically significant but clinically insignificant weight loss. . .rimonabant 20 mg daily vs. placebo was associated with a statistically significant 8% increase in HDL-C and a statistically significant 12% decrease in TG levels. There were no significant improvements in levels of total or LDL-C in the rimonabant 20 mg daily vs. placebo group. . .rimonabant 20 mg compared with placebo was associated with a statistically significant 0.7% reduction in HbA1c in overweight and obese subjects with type 2 diabetes taking either metformin or a sulfonylurea."

Not bad - just the sort of thing you'd want to go after the whole obesity/diabetes/cardiovascular area, you'd think. But the problem is in the side effects, and one in particular:

"The incidence of suicidality – specifically suicidal ideation – was higher for 20 mg
rimonabant compared to placebo. Similarly, the incidence of psychiatric adverse events,
neurological adverse events and seizures were consistently higher for 20 mg rimonabant compared to placebo. . ."

They're also concerned about other neurological side effects, and seizures as well. The seizure data don't look nearly as worrisome, except in the obese diabetic patients, for whom everything seems to be amplified. And all of this happens at the 20-mg dose, not at the 5 (which doesn't do much for weight, either, as noted above). And for those who are wondering, yes, on my first pass through the data, I find these statistics much more convincing than I did the ones on the Avandia (rosiglitazone) association with cardiac events.

I had my worries about rimonabant a long time ago, but not for any specific reason. It's just that I used to work on central nervous system drugs, and you have to be ready for anything. Any new CNS mechanism, I figured, might well set off some things that no one was expecting, given how little we understand about that area.

But isn't it good to finally hear what the arguing is about? Sanofi-Aventis has been relentlessly tight-lipped about everything to do with the drug. I can see why, after looking at the FDA documents, but this isn't a problem that's going to go away by not talking about it. The advisory committee meeting is Wednesday. Expect fireworks.

Comments (10) + TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Diabetes and Obesity | The Central Nervous System | Toxicology

June 7, 2007

The Chamber of DNA Secrets

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Posted by Derek

There are plenty of headlines today about the large Wellcome Trust-funded genomic study of common diseases. Unfortunately, most of those headlines are misleading. The ones that say "Genes Identified For Common Diseases" are the most common wrong ones, but any that include secrets, keys, new dawns, locks being opened, or mysteries being solved are also full of it. (You'll need to go to people who know what they're talking about for less sensational coverage - try the RSC, for one).

Not that this isn't a fine study, and a very interesting piece of work - far from it. This is just the kind of rigor and effort (14,000 patients, 3,000 controls) that's needed to trace out these sorts of connections. Contrary to popular belief, most genomic effects on disease are subtle and shifty, and tangled up throughly with both environment and with dozens (hundreds? thousands?) of other genetic markers. These folks are doing the right thing in the right way.

But the press, at least some of it, isn't. The genes identified in this study are not enough to tell you if you're going to get a particular disease or not, not by themselves. And they're not going to lead to therapies any time soon, either, because in many cases we have no idea how or why they're connected to the diseases in question. Nor do we have drug candidates that target the proteins that the genes code for, and it wouldn't surprise me a bit if most of them turn out to be un-druggable from the start with our current technology. I speak from sad experience on that issue, like many other folks in the drug industry.

That's not to say that we won't figure out how these things are involved in disease, or how to attack them therapeutically. But we didn't just open a locked chest full of the secret keys to health here - we found fragments of a map that'll tell us where to look for the clues to the pieces of an even bigger puzzle. It's the state of things, though, that this really is an advance, and it wouldn't hurt the public to know.

Comments (6) + TrackBacks (0) | Category: General Scientific News

June 6, 2007

Massachusetts Moving

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Posted by Derek

And while I'm on the subject of that last post, I wanted to make a quick appeal to the readership. My new position will be taking me to the research-happy Greater Boston area, which I'm looking forward to. At the same time, though, there are the usual moving issues - balancing commuting, real estate, and schools for the kids.

I'd be very glad to hear from readers with personal experience with the towns, schools (and roads!) of that part of Massachusetts. My wife and I have some ideas of where we'd like to start looking, but I'd like to get as much reality into the hopper as possible. The e-mail address is up there on the left - thanks!

(Oh, and if anyone's looking for a nice house in the New Haven area, give me another week or two and I'll have something to show you. . .!)

Comments (38) + TrackBacks (0) | Category: Closing Time

A Post I've Been Looking Forward to For Months

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Posted by Derek

I'm very glad to announce that I've accepted an offer of a new research position. Thus ends a stretch of unemployment that began officially at the end of January, with warning having been served the previous November. That explains the somewhat irregular recent schedule of this blog - I've been wrestling with several offer and relocation issues simultaneously, which is not such a bad problem for someone in my situation.

I'll be starting in the early part of July, and I'm very much looking forward to getting back into the business. My jobless period hasn't been as hard to take as I'd feared, but I can see how it would tend to wear on a person - for example, my severance pay runs out right about now, and facing that milestone without prospect of employment would have been no fun at all. Looking back, March was probably the low point, since by then I'd been searching for a while with no great success. The serious job prospects came into view in April and May.

This position will require a move, though - that's one thing I was hoping to avoid, but the nearby pharmaceutical industry had (and still has) no spare place for someone like me. I was ready to take on some 50 mile commutes to stay, but you can't commute to a job that isn't there. A great many of my colleagues (including almost all the chemistry PhDs) have had to do the same eventually, from one or two states over to across the country.

I believe that I'm one of the last of the Wonder Drug Factory chemists to find employment. I'm glad that I waited, since the position I'm headed to looks like a very good one, with opportunities to do officially what I sometimes had to do on the side. The home office of the WDF may have ended up doing me a favor by evaporating my former job, not that they had any such intention.

It's a bit unsettling for me to realize, though, how much my search was helped out by things that had no official connection to my old position - this blog, for one thing. I had calls directly from some of its readers, and in other cases it was a valuable piece of evidence that I'd been keeping up with a wide range of issues in the field. And as for my experience, when it came time for interviews, I found in more than one case that work that I'd taken on outside my formal responsibilities did me a lot of good. Of course, I've got an appropriately long CV full of what I'm supposed to have been doing all this time. But I can't help thinking that, in this market, years of doing only what I'm supposed to have been doing would have been necessary, but not sufficient. Food for thought.

BTW, I'm looking for some reader input if you're in the Boston area - see the next post - thanks!

Comments (31) + TrackBacks (0) | Category: Closing Time

June 4, 2007

Phase Zero?

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Posted by Derek

We have a new phrase to toss around in in the industry: "Phase Zero". That's what they're calling a recent trial of an anticancer drug from Abbott (ABT-888), which was tested in humans before any safety dosing (Phase I) had been done.

So, how exactly can you do that? By giving extremely small amounts of the drug, that's how, and looking to see if you can detect a change in some marker for eventual efficacy. In this case, the marker was inhibition of the activity of PARP, poly(ADP-ribose) polymerase, which is involved in the cellular response to DNA damage. Inhibiting it should make cells much more likely to die once such damage had been detected, which one of many such signals that cancer cells tend to ignore under normal conditions. Abbott's drug seemed to do the trick, so work on it will continue.

The good part of this is that the drug got into humans more quickly than usual, and that its mechanism of action has now been verified (to a first degree of approximation, anyway - it hits the target). This should make a company a bit more confident about moving on to larger trials, and could potentially weed out losers early in the game.

But there are bad parts, too. For one thing, the patients in a phase zero trial have no hope of benefit from the drug: the dose is just too small. The small doses could give results that (for better or worse) aren't relevant to the later real-world ones, too. Another problem is that reliable biomarkers are thin on the ground despite great sums of money being spent to find and validate them. If you're going to let the future of your drug ride on one of these trials, you'd better be confident that you know what it's telling you. (And if you're not going to let the future of the drug ride on a phase zero trial, why are you running one, eh?)

What would be worth knowing is how many drugs fail because of lack of effect on their intended target, as opposed to those which hit the target but still have no effect. You'd also want to know: of that first group, what portion are going to be amenable to robust biomarker studies. Those two fractions would tell you how much of an impact this whole idea will have. Right now, I think the error bars are way too large to make a prediction. . .

Comments (10) + TrackBacks (0) | Category: Cancer | Clinical Trials

June 3, 2007

Pecunia Non Olet?

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Posted by Derek

Today's New York Times had a long front-page story from Janet Roberts and the paper's Scourge of the Drug Industry, Gardiner Harris. Titled "After Sanctions, Doctors Get Drug Company Pay", it details (through the example of one particular Minnesota psychiatrist) a practice of physicians who have had medical board problems continuing to get money for participating in clinical studies.

Dr. Faruk Abuzzahab has definitely had his run-ins with the medical authorities. And over the years he's also definitely had payments from various companies. It's not a story to make you feel warm and fuzzy, that's for sure. There are some things about it that puzzle me, though. For one thing, it appears that Abuzzahab is no bargain as a clinical investigator:

"Separately, the F.D.A. in 1979 and 1984 concluded that Dr. Abuzzahab had violated the protocols of every study he led that they audited, and reported inaccurate data to drug makers. He routinely oversaw four to eight drug trials simultaneously, often moved patients from one study to another, sometimes gave experimental medicines to patients at their first consultation, and once hospitalized a patient for the sole purpose of enrolling him in a study, the F.D.A. found. . .

A simple Google search reveals Dr. Abuzzahab’s 1998 medical board disciplinary file, which was reported at the time by a local newspaper and a TV station. In 1998, The Boston Globe featured Dr. Abuzzahab in a front-page article questioning the safety of psychiatric drug experiments. And in 1999, the NBC program “Dateline” did a segment about a woman who committed suicide while in a drug experiment he supervised.

In June 2006, the medical board criticized Dr. Abuzzahab, this time for writing narcotics prescriptions for patients he knew were using false names, a violation of federal narcotics laws.

Despite all this, drug makers continued to hire him. Dr. Abuzzahab’s résumé lists 11 publications or research presentations since 2000, when the medical board lifted its restrictions on his license."

Well, I haven't seen the guy's résumé, but a PubMed search shows only one paper since that year, and only one other since 1983. His publication record thins out drastically after the early 1980s; this is not someone who cares about blazing across the sky of the scientific literature.

What exactly does he care about, though? Money? According to the graphic that accompanies the story, Abuzzahab received $55,000 from several drug companies over an eleven-year period. That's better than a kick in the ankle, but it doesn't seem like enough cash to turn a busy psychiatrist's head, either. I've not had the opportunity to find out if I can be bought or not, fortunately, but I can tell you this: it would take more than five grand a year to do it.

And just what is it that GSK, Wyeth, J&J and the other companies who've paid him are hoping to get? The first thought is that they're hoping to influence his prescribing habits, because it doesn't sound as if the clinical data he's generating are worth all that much. Is that amount of money enough to do it? Presentations by a well-known and well-respected figure could also be expected to influence the scrip-writing of others, but Dr. Abuzzahab doesn't seem, in recent years, to have been that kind of person.

No, this sort of thing doesn't look good at all. The Times story gives a reader the impression that companies are disproportionately funding physicians with disciplinary problems, although there's no evidence to back that up. But the funding should be disproportionate in the other direction, which doesn't seem to be the case. Not good, not good at all.

Comments (5) + TrackBacks (0) | Category: Clinical Trials | The Dark Side | Why Everyone Loves Us