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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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February 28, 2006

More on Outsourcing

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Posted by Derek

As it happens, I was looking through a recent New England Journal of Medicine yesterday after having posted that comment on outsourcing. (Yes, I do read it, even while whacking its editorial staff over the head about the VIGOR study).

There's a fine perspective in there on medical outsourcing, in this case the use of "nighthawk" firms that provide middle-of-the-night radiological opinions. After all, it's during the working day in Bangalore, and X-ray data is just a mass of binary digits like anything else that zips through the Internet, so why not?

The author lists some of the benefits to this (after all, radiologists need to sleep, too), and possible problems with these services, but concludes:

". . .it is easy to rail against this trend or to pray that it all happens after we retire. And observing the snail's pace of the quality, safety, and information-technology movements in health care one might predict that full-blown medical outsourcing is decades away. But judging by the speed with which high-tech call centers have migrated to Bangalore, the pace of change might actually be shockingly rapid.

People and institutions that are harmed by outsourcing will not take it sitting down, and I expect to see a flurry of initiatives to protect the status quo. Physicians and specialty societies will undoubtedly use the tools of legislation, licensure, certification, and reimbursement to thwart perceived threats to their livelihoods. Such efforts will nearly always be framed as protections of quality or patient safety, though some will be difficult to defend against charges of hypocrisy. . .

Though defensiveness and resistance are inevitable, I believe that a more productive strategy is for local caregivers, advocacy groups, and institutions to welcome - or at least accept - outsourcing that serves their patients' interests and to focus their attention on improving the quality and efficiency of the care they themselves deliver. . ."

Which, when you get down to it, is exactly what I was saying yesterday. I'll reiterate that I'm a free-trade advocate. I think that the free movement of goods and services is vital to economic prosperity. In turn, that economic prosperity is vital to keeping people alive and the world in what peace it has. Bastiat was right: when goods don't cross borders, soldiers will.

My opinions on the subject wouldn't be worth very much if they changed just because my industry is being affected. I think that American research firms can compete with anyone in the world, and if anyone would like to displace us as an engine of innovation, they are most welcome to try. We'll all be the better for it.

Comments (9) + TrackBacks (0) | Category: Business and Markets

February 27, 2006

But At My Back I Always Hear. . .

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Posted by Derek

I have an interesting article from Forbes to point out tonight: one of those lists of the best-selling drugs in the US, and a corresponding list of the fastest-growing ones.

A few things stand out. For one, five of the top ten drugs are showing declining sales. I suspect that this is close to the historical average, since some of these big sellers will always be things that are past their (gigantic) peak. Another striking feature is that the ten fastest-growing drugs include three antibodies and another protein. We small-molecule people tend to overlook these products because we're not the ones who do the research on them. But they're very big business indeed, and getting bigger every year. It would serve us organic chemists well, I think, to come up with ways that we can add something to the antibody field, because I think that we're going to want to be its friend.

And that brings up a conversation I was having with a colleague the other day. He was pointing out the huge amount of contract work that's being done in China and India these days. A lot of large and small companies are profitably outsourcing their chemical grunt work, and a lot of small firms outside the US are profitably taking it on. That got me to thinking again about a feeling that I just can't shake: that we medicinal chemists, individually and collectively, need to make sure that we are doing things that other people can't do for us.

Fifteen years ago, you could make a living banging out huge combichem libraries, but you can't do that any more. Ten years ago there were a lot of small outfits in the US that were doing custom synthesis, taking on all kinds of nickel-and-dime work, but if they've survived until now they've done it by branching out into things that the Indian and Chinese firms can't undercut them on. I think that the methyl-ethyl-butyl-futyl type of medicinal chemistry work is perhaps about to be loaded into the same hopper.

So, think about what you're doing for a living, fellow chemists. Is it something that someone easy to locate could do for a lot less money? It had better not be. Failing that, you'd better start to pick up some impressive new reasons to justify your paycheck.

Comments (22) + TrackBacks (0) | Category: Drug Industry History

February 26, 2006

Tied to the Mast

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Posted by Derek

Some readers will have already come across reports suggesting that some drugs for Parkinson's disease can lead to odd behavioral problems, including compulsive gambling. Given their effects on dopaminergic pathways, which seem to be involved in stimulus/reward behavior, it's a believable effect. (Actually, as I mentioned the other day, just about anything is a believable side effect with CNS drugs, especially at low rates of incidence).

Now (via Overlawyered) comes a case from Texas. A (once)-wealthy retiree named Max Wells is suing GlaxoSmithKline over their Requip drug (ropinirole), claiming that he wasn't warned that the drug could cause compulsive behavior. His particular compulsive behavior took place in Las Vegas, a city well equipped for it, and involved the loss of some 14 million dollars.

As the Austin newspaper story has it, Wells had started on another Parkinson's drug, Mirapex, in 2004 and lost several thousand dollars gambling, both online and in Vegas. (As it turns out, Boehringer Ingleheim is being sued over that drug, too, for similar reasons). He told his doctor about the problem, and was switched to Requip, which is when things apparently really started to roll.

Wells is also suing at least seven casinos, claiming that they knew that he was taking Parkinson's medication and should have been aware that he had a problem. I think these suits have even less of a chance, because casinos have been sued many times on similar "they should have stopped me" grounds. I recall a Philadelphia businessman in the early 1990s who took an Atlantic City casino to court because of his losses at his favorite game, which was high-stakes blackjack played with the aid of a bottle of bourbon. The casino, he contended, knew that he was impaired and should never have allowed him to continue. This argument didn't make much headway, as you'd probably guess.

This Parkinsonian case is a bit different, but I don't think it's going to get very far. It might bring up interesting questions about free will and human behavior, but no court is going to want to wade into that philosophical swamp. If the facts are as stated, the case will surely be decided on more practical grounds: why Wells didn't go back to his doctor when he started compulsively gambling again on the new medication instead of spending the next several months ripping through millions of dollars, and how casinos are not required to evaluate the motives of their customers.

Comments (6) + TrackBacks (0) | Category: The Central Nervous System

February 24, 2006

What's French for "Trust Us"?

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Posted by Derek

Well, Sanofi-Aventis has held their meeting with analysts and taken questions, and there's still not much to say about the Acomplia (rimonabant) situation. They still say that they plan to launch the drug later this year, and that they plan to talk with the FDA in March. A Bloomberg story says that they hope to resolve the issues "within months", which they'd better do if they're planning on 2006.

As far as I can determine, they still haven't come out and said just what the FDA's concerns are. And that, to me, has to be a bad sign. If the problems were inarguably small, the company would surely be motivated to tell everyone about them. But it looks more like: "We think we can launch this year. But if we told about you all the FDA's concerns, you might not think so yourselves. So we're not going to tell you."

If more details come out, I'll revise my opinion. But failing that, can anyone think of a reason why this isn't the right way to interpret this?

Comments (12) + TrackBacks (0) | Category: Diabetes and Obesity

February 23, 2006

Blogroll Revamp

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Posted by Derek

Well, I'm going to try to post tomorrow morning about the Sanofi-Aventis investors meeting, when we should (in fact, had darn well better) hear some more about the rimonabant situation. And the debate over the New England Journal of Medicine and Merck is going on briskly in the comments to yesterday's post, so please take a look over there if you haven't yet.

So tonight I'll take a few minutes to rework the blogroll. Welcome newcomers Terra Sigillata, Science, Shrimp and Grits, the Mass Spectrometry Blog, Tobias Sing's Bioinformatics Blog, Snowdeal, Cosmic Variance, On Pharma, and Oncology Updates.

And note also the new locations of Uncertain Principles, Adventures in Ethics and Science, Aetiology, Gene Expression, Pharyngula, and Respectful Insolence at Scienceblogs.

No doubt there are other sites I should be linking to - suggestions are welcome!

Comments (7) + TrackBacks (0) | Category: Blog Housekeeping

February 22, 2006

NEJM vs. Its Contributors, Round Two

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Posted by Derek

The original "Expression of Concern" editorial over the VIGOR Vioxx trial in the New England Journal of Medicine was an odd enough document already. But today brought an "Expression of Concern Reaffirmed" in the journal, along with replies from the VIGOR authors.

It's going to take some doing to get these folks together, as you'll see. The NEJM's editors, in their "reaffirmation", add a few details to their December 8th expression. Their position is still that there were three heart attacks in the Vioxx treatment group that were not in the data submitted to the journal. And they're not buying the explanation that these took place after the end of the study, either:

"The authors state that these events did occur during the trial but did not qualify for inclusion in the article because they were reported after a "prespecified cutoff date" for the reporting of cardiovascular events. This date, which the sponsor selected shortly before the trial ended, was one month earlier than the cutoff date for the reporting of adverse gastrointestinal events. This untenable feature of trial design, which inevitably skewed the results, was not disclosed to the editors or the academic authors of the study."

Those academic authors (11 of them from seven different countries, led by Claire Bombardier of Toronto) have a reply to all this in the same issue. Regarding those three MI events, they say:

"The VIGOR study was a double-blind, randomized outcomes study of upper gastrointestinal clinical events. We, as members of the steering committee, approved the study termination date of February 10, 2000, and the cutoff date of March 9, 2000, for reporting of gastrointestinal events to be included in the final analysis. Comparison of cardiovascular events was not a prespecified analysis for the VIGOR study. . .the independent committee charged with overseeing any potential safety concerns recommended to Merck that a data analysis plan be developed for serious cardiovascular events. . .As a result, a cardiovascular data analysis plan was developed by Merck. Merck indicated that they chose the study termination date of February 10, 2000, as the cutoff date. . .to allow sufficient time to adjudicate these events. . . (The three events) were neither in the locked database used in the analysis for the VIGOR paper no known to us during the review process. However, changing the analysis post hoc and after unblinding would not have been appropriate."

The authors go on to say that including the three heart attacks does not, in their view, change the interpretation of the safety data. They also take issue with the journal's contention that the three events were deleted from the manuscript, saying that the table of cardiovascular events in the presubmission draft of the paper never included them in the first place.

The two Merck authors on the paper, in a separate letter, make the same point, and also mention that there was an additional stroke in the naproxen-treated group that didn't make the paper for the same reasons. They reiterate that including the three heart attacks wouldn't have changed anything:

". . .The article clearly disclosed that there was a significant different in the rates of myocardial infarction in the Vioxx and naproxen arms of the study and reported these rates as 0.4 and 0.1, respectively, with a relative risk reported as 0.2. The inclusion of the post-cutoff data myocardial infarctions changes the Vioxx rate to 0.5 but does not meaningfully change the relative risk or the conclusion that there was a significant difference between the two arms of the study. Indeed, with such a small number of events (which were not a primary end point of the study) - and with such wide confidence intervals around them - it is difficult to imagine that this small numerical change could affect the interpretation of the data."

Looking at everything together, I'm still coming down on the side of Merck and their academic collaborators in this part of the fight. The post-launch cardiovascular data on Vioxx and its advertising and promotion are worth debating separately, but as for the VIGOR study, I think the NEJM is overreaching. Still, from Merck's viewpoint, I think the damage has already been done. . .

Update: Y'know, it occurs to me that there are a few people who aren't as upset about all this editorial wrangling: the editors of JAMA and the other top-ranked medical journals. They'll be getting some manuscripts that otherwise would have gone to NEJM.

Comments (25) + TrackBacks (2) | Category: Cardiovascular Disease | The Scientific Literature | Toxicology

February 21, 2006

Gold and Lasers

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Posted by Derek

There's been a lot of work in the last four or five years using nanoparticles of gold in biological systems. When they're are brought down to this size their electronic properties get quite unusual - in gold's case, the particles become huge absorbers and scatterers of certain wavelengths of light. They're thousands of times better then the kinds of dyes that organic chemists like me can crank out, which gives you potentially huge signal-to-noise in microscopy applications and assays.

Another exotic property these things have is that they convert the energy they absorb very efficiently into heat, and it didn't take long for people to have the idea of using this effect for cancer therapy. Heating cells, after all, kills them. Of course, you'd want to have some way to get the metal particles to stick only on to cancerous cells, and this has been realized by linking antibodies to the surfaces of both hollow and solid gold nanospheres.

The latest advance in this area has come from changing shapes. Rods are predicted to absorb more efficiently and at much different wavelengths than other shapes, and a joint Georgia Tech/UCSF team (who had worked earlier on the solid gold nanospheres) has verified these effects. They were able to grow rods of various sizes and aspect ratios and to conjugate them to anti-EGFR antibodies. EGFR, of course, is a well-known cancer target (via inhibition of angiogenesis), which is hit by several small molecules as well as antibodies like Imclone's Erbitux.

Each of these types of particle has its advantages. The gold nanosphere/antibody conjugates actually absorb at slightly different wavelengths when they interact with EGFR-expressing cancerous cells compared to noncancerous ones, which could make for a useful diagnostic assay. This can really only be done ex vivo, though, in thin preparations, because the wavelengths of light needed are also absorbed by the tissue itself.

The rods don't manage to show the differences between cells, although (as with the spheres) you can see the differences (scroll down on that page) qualitatively in how many particles are bound to the cell surfaces. But they do have a property that's potentially even more useful: their absorbing wavelengths are shifted to the near-infrared, which penetrates tissue much better (up to four inches)! You need green 520nm light for the spheres (with a convenient argon laser wavelength nearby at 514nm), but the rods need red 800nm light from a titanium/sapphire laser. When cell cultures are hit with that wavelength, the heating of the gold nanorods kills them off - and the EGFR-expressing cancerous cells can be killed by laser light of only half the strength needed for normal cells.

That's probably just barely enough of a gap to be therapeutically useful, for several reasons, not least because for tumors inside the body, I think that you'd be dosing the outer skin layers with too much wattage in order to hit the deeper tissues. No doubt work is already underway on widening the window between the two effects. I can certainly imagine some possible next steps as well: simultaneous treatment with conjugates of different antibodies, for example. Since many cancerous cell lines overexpress more than one type of cell surface protein, you might be able to hit them in several ways at the same time.

As much as I love small molecules (and the organic chemistry used to make them) I have to admit: they may not be able to hold their position against ideas like this. We can try to target things like EGFR that are overexpressed in many cancers, but we don't have much of a guarantee of success, because overexpression doesn't make a pathway crucial enough by itself. But overexpression alone is all you need with this technique, and the cellular pathways downstream don't matter a bit. It's a liberating thought. . .

Comments (13) + TrackBacks (0) | Category: Cancer

February 20, 2006

Rimonabant Bangs Into. . .Something

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Posted by Derek

Sanofi-Aventis basically has their future riding on their obesity therapy Acomplia (rimonabant), which was (until a day or two ago) expected to be approved before the middle of this year. But the FDA gave them one of those "Approvable, But. . ." letters which sow fear and confusion whenever they arrive.

The fear is self-explanatory, and the confusion comes because the letters don't have to be made public. No one knows what the FDA's concerns are, because Sanofi-Aventis doesn't have to say - yet. But in the case of a drug that was expected to be this big, and one that S-A's management was telling everyone just the other day was in fine, fine shape, they're going to have to come out with something soon or risk a complete loss of confidence and credibility.

There are quite a few possibilities, as this post at Pharmagossip lays out. I have to say, rimonabant has always made me a bit nervous, and that's not just hindsight talking. Back in 2004 I wrote about some possible bad side effects of the drug, and last year I worried in general about the problems of taking such a drug (huge buildup, huge market, totally new mechanism of action) to market.

You see, the problem is, I did the first half of my career in CNS drug discovery. Drugs that act on central nervous system receptors can do all kinds of odd stuff, and we most definitely do not know enough about brain chemistry to predict what those interesting surprises might be. The endocannabinoid receptor that rimonabant targets is very much an evolving story - it's even less worked out than the other brain targets. The thought of a CNS drug whose target is relatively less well understood than the others should be enough to make anyone gaze thoughtfully out the window for a bit.

The field has other brisk and tangy qualities. For example, the patient population tends to have an alarmingly heterogeneous response to CNS drugs, as a look at the antipsychotic and antidepressant markets will show you. Drugs that work fine for one person do nothing for another, and we don't yet know why. I can see no reason why rimonabant should be any different.

This FDA action may have borne out some of these fears, or it may be that Sanofi is just involved in an argument about a too-aggressive labeling proposal. Here's betting that they fill in some details real soon now. The longer they wait, the worse it'll be for them. By. . .Wednesday, I'd say?

Comments (5) + TrackBacks (0) | Category: Diabetes and Obesity

February 19, 2006

Because I Never Lie, and I'm Always Right

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Posted by Derek

Something recently made me think back to an undergraduate physics lab that I once had to do. This was elementary optics, so we had the standard collection of lenses on a beaten-up optical bench as we did our Newtonian thing. There would be little reason for me to remember it if it hadn't been for the comment of one of my lab partners.

We were setting up another phase of the experiment, and the instructions said for us to put the lenses in a set configuration and see if we got such-and-such effect. "That can't be right", this guy said, moving them to a different spot that he thought would work better. They didn't, and we ended up doing it the way the lab manual had laid out. But I've returned to that scene several times over the last twenty-five years, trying to figure out what bothered me about his response.

After all, a good researcher shouldn't just take someone else's word for everything, right? And if you have a hypothesis, and can test it, you should go ahead and do it, right? On the face of it, my old partner's attitude towards our lab that day shouldn't have gotten on my nerves, but it did. There was something wrong about it, but I kept trying to work out what it was - in a way that didn't put me on the just-follow-the-lab-book side of the argument, where I didn't want to be.

It finally dawned on me. My problem with the guy wasn't that he didn't trust the lab manual. It was that he trusted himself way too much. It would have been one thing to try what was in the book, then say "I wonder what happens if you move this lens out here?" That would actually be a good sign. But the statement "That can't be right"isn't one, especially not from an undergrad doing an optical demonstration whose results have been known for three hundred years.

Now, of course, I have a lot more room to maneuver as a scientist. Most of the experiments I run are things that no one has ever done before, not on these particular molecules in this particular way. I'm pretty sure I know what's going to happen, but I get surprised a lot. And when it comes to the effect of my compounds on cells and animals, I get surprised all the time.

But it's surprisingly easy to forget how little I know. After sixteen-plus years doing this, I have to watch my tendency to talk to younger colleagues as if I know what's going to happen with their ideas. I don't. I have my experience to draw on, of course, which makes me say things like "Are you sure you want to put a napthyl in that molecule?" or "Cyclohexyl groups are a metabolism magnet - that's going to get torn up". I'd say that a good solid majority of the time, those two statements are correct. But once in a while they're not, and most of the time I don't have as much evidence to back up my prejudices as I do with those two examples.

So now I know why I've never forgotten the guy who said "That can't be right". I've been trying, all this time, to keep from turning into him. The struggle continues.

Comments (5) + TrackBacks (0) | Category: Who Discovers and Why

February 16, 2006

What's It Worth to You?

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Posted by Derek

So now we come (again) to the topic of cancer drug pricing. The New York Times ran an article on this the other day which has gotten a lot of attention. In it, Alex Berenson points out that prescriptions for the antibody therapies like Avastin and Erbitux cost a huge amount of money.

This isn't news, unfortunately. See this 2004 article by Matthew Herper in Forbes, for example, or see my posts from around that time here and here. What the NYT article makes much of, though, is what it says is a new rationale for the costs:

"Until now, drug makers have typically defended high prices by noting the cost of developing new medicines. But executives at Genentech and its majority owner, Roche, are now using a separate argument — citing the inherent value of life-sustaining therapies.

If society wants the benefits, they say, it must be ready to spend more for treatments like Avastin and another of the company's cancer drugs, Herceptin, which sells for $40,000 a year. . ."

You won't catch me disagreeing about the value of pharmaceuticals. But this argument can only be taken so far, because (as those links from two years ago make clear) drugs like Avastin really only add a few months of life. That's nothing to make light of, but I fear that it's also not much of a basis for Genentech and Roche to talk about how society should be willing to pay for such outcomes. Can you fix a price for two extra months of life? We're going to have to.

The NYT article has an excellent example of someone who's done the calculation for himself:

"Ellis Minrath, who has pancreatic cancer, said he had chosen not to take Tarceva, a drug from Genentech that is approved for lung cancer and has shown promise in pancreatic cancer. He did so after learning that it would cost him about $1,000 a month in co-payments, even though he is covered by Medicare.

"If anybody came out and said, 'By God, this is the stuff. You want to get well, find a way to buy it,' that would be one thing," said Mr. Minrath, who is 87. "But that isn't the case. The forecast of how much it's going to do is not that wonderful. . .

I agree with Mr. Minrath's decision, and I strongly endorse his right to make it. As an 87-year-old with pancreatic cancer, he seems to have studied his situation objectively and realized the odds he faces. He is very, very likely to die within the next few months, and (although we've never met) I'll be sorry to see him go, because he sounds extremely sensible. Personally - and I hope I never have to work this decision out for real - I would lean toward a similar "leave more for my heirs" position. Other patients in different situations may well come to different conclusions, and that's up to them (and in the real world, up to their insurance companies) as well.

What we need, of course, is some cancer drugs that don't make us put prices on months. I'd rather be working out the value of whole years or decades. Therapies which can do that will be the place to make the "society should suck it up" argument, but making it for Avastin and the like seems rather premature. What will we do when we find something that's good?

Comments (29) + TrackBacks (1) | Category: Cancer | Drug Prices

February 15, 2006

Pfizer Takes a Deep Breath

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Posted by Derek

I haven't mentioned Pfizer's inhaled insulin project in a while, but a few weeks ago they got the stuff approved, at (very) long last. The development of Exubera, which is certainly a cheerful brand name, has been anything but uplifting, though Here's a piece I did three years ago, when the story already seemed to have been going on for a long time.

Insulin, of course, is the very definition of a well-established drug, but that's only if you inject it. Slowing things down have been problems which are unique to inhaled powders: the effect on lung function over time, the changes in dosage under suboptimal conditions (allergy, flu, etc.), and the reproducibility of the dose. These are particularly worrisome for insulin, which is a tough situation: it's vital to its users, and it has a lower margin for error (both under- and over-dosing) than most other drugs. As I put it in that 2003 post, if you take twice as much aspirin as you should, it'll be rough on your stomach. If you take twice as much insulin, you're going to end up on the floor (and there had better be someone around with a candy bar).

You can see this troubled history in the drug's labeling, which Frederick Cohen at Crownstone has been going over. To pick one interesting detail, patients will be required to have a baseline pulmonary function test before starting the drug, with monitoring thereafter. And this brings up the current worry: how much will Exubera (and its baggage) cost, and who's going to pay for it? The product won't be launched until mid-year, and no one knows quite what its price will be. Pfizer's just saying that it will be "competitive", an answer which is synonymous with "Go away", but you can find estimates of up to four times the cost of injectable insulin (my guess is 2.5x). Call it a convenience premium. Will it fly?

Well, here's a piece in Business Week that's enough to make you wonder. It's written by a pair of consultants from the Bruckner Group, an outfit that's very big on outcome-based medicine, and from that perspective they think Exubera's in trouble even before it launches:

". . . Based on our analyses and interviews with major managed-care decision-makers, we expect that payers will either dramatically limit Exubera's availability to patients, impose very high co-payments, or reject coverage of it outright. . .For Exubera to achieve widespread preferential formulary status, payers will need to see a credible and compelling value proposition rather than an argument centered on patient convenience. The crux of the issue is whether an inhaled therapy will improve compliance and lead to significant improvements in patient health."

As they point out, the data on other inhaled therapies isn't too reassuring. Studies have indicated that asthma inhalers, for example, are often misused, both quantitatively and qualitatively. The Flumist inhaled flu vaccine has also been a disappointment compared to its injectable competition.

Pfizer may be counting on its (justly) famous marketing powers to put Exubera over. If the landscape, though, really is changing to more rigorous cost/benefit calculations, that might not do the trick. I realize that the BW authors have an interest in promoting this viewpoint, but I hope that they're on to something. I'd rather see more of the competition between drug companies taking place over medical evidence and financial benefit, rather than the size of the sales forces. Salesmanship alone can't put over a lousy drug. But it can take away from the issues that really should be decisive.

Tomorrow we'll take a look at how this applies to oncology, where things are getting really interesting. . .

Comments (18) + TrackBacks (0) | Category: Diabetes and Obesity | Drug Prices

February 14, 2006

First Slide, Please

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Posted by Derek

I spent a good party of my day today in various meetings, but (fortunately) I didn't have to present anything at any of them. There have been some close calls over the years.

Back at a former company, I sat down in one of our group meetings, idly wondering who was going to be presenting today. What a pleasant surprise to find out that it was me! "I asked Derek a couple of weeks ago to put something together on this approach to our binding data that he's been working on. . ." said my boss, as I looked at him in dawning terror. Yes. . .yes. . .he did do that, didn't he. . .it's all coming back to me now. . . I had nothing prepared, nothing at all. Actually, I had very little to talk about in the first place, because the approach he was referring to hadn't yielded anything interesting. I'd dropped it just a couple of days after he'd asked to talk about it. Now, if I'd remembered that I was supposed to present, I could have at least left some doubts in people's minds about whether I was on to something. But as I staggered through a grim chalk talk, the true state of affairs became horribly clear.

Not all of these situations have ended in disaster. I recall a meeting where a number of us were presenting on our current projects. I had just been put in charge of a new one, which fact had somehow not registered on me as I wandered in to the conference room ready to hear from everyone else. After the first couple of speakers, a tiny bell went off in my head. I turned to a friend of mine sitting next to me and took a look at the agenda: yep, there I was. Coming up after two more speakers. Well, now.

I excused myself and sauntered over to the door. As soon as it closed, I bolted for my office and threw together a fast handful of slides (fortunately, I had the makings already, otherwise I'd have been doomed for sure). I returned in plenty of time, and gave what was a much more coherent presentation than it had any business being. Procrastination is one thing, but putting the presentation together twenty minutes after the meeting had started - that still stands as my record, and I've no desire to break it.

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February 13, 2006

Heart-Warming Stories of Success

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Posted by Derek

One of the things about the Rishton article that set off some of my colleagues at work is the section where he discusses small-company successes. They've got a point, because the list is a bit off. Among the companies that he mentions as being very productive are Neurogen. I have a problem with that choice, partly because I've known people who've worked and interviewed there. I'll give them credit for surviving as long as they have, but the reason that's worth congratulating is that the company has, to my knowledge, never made a dime.

They've been at it for ten or fifteen years now, and have never brought a compound to market. Now, I can't be too hard on them, because they're working in the CNS field, which is a well-known Boulevard of Broken Dreams in drug development. But still, their success rate (measured where it really counts) is zero. The sort of success they've had is in getting other companies to invest money in them, which many have done over the years. That's nothing to sneeze at, but it may not be something that we should all emulate, either.

Another company on his list is Sepracor, and you'd have to consider them a special case, wouldn't you? After all, I don't think that we can all make a living by ripping off(or more charitably, piggybacking on) other people's patents - can we? That's what got them to where they are today. Their current success story, Lunesta (eszopiclone) is the S enantiomer (the left-handed form) of an older Aventis drug, zopiclone (note the generic name: S-zopiclone, get it?) I understand and agree with Rishton's point about working on druglike molecules, but somehow I don't think this is quite what he had in mind. . .

Comments (13) + TrackBacks (0) | Category: Drug Development

February 12, 2006

Kinase Inhibitors: Doomed From the Start?

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Posted by Derek

Gilbert Rishton, ex-Amgen and now with an Alzheimer's institute in academia, sent along this paper the other day (PDF) which is worth a look for anyone in our business. Titled "Failure and Success in Modern Drug Discovery", it's a very opinionated look at the subject.

I sent it around in my department at the Wonder Drug Factory, and reactions were strong and all over the map. Several people found it right on target (and rather refreshing) while others were more reserved or outright hostile. One of the more controversial sections contends that drug discovery efforts are seriously overweighted in kinase inhibitors because the compounds are likely to be intrinsically toxic via general signal transduction inhibition in non-target organs. I'm pretty sure that I buy the first part, but I'm not sure about the second.

I think that the big problem in kinase inhibition is that we don't understand the details of the biochemical pathways anywhere near well enough in most cases. So we look at the state of the art and say "Well, it's clear that XYZ kinase is a key player in this pathway, so let's go inhibit it". But if we do, likely as not we find that there are so many compensating mechanisms that inhibiting XYZ hardly does anything. But that's if we have a selective compound, mind you. Most of the time we're hitting enough other kinases that it's impossible to say just what's causing any particular in vivo effect.

Anyway, take a look at the article and feel free to post comments that you might have. There's something in it to offend almost everyone. I'll be returning to some of its themes in later posts. . .

Comments (16) + TrackBacks (0) | Category: Drug Development

February 9, 2006

Ban Intelligent Design?

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Posted by Derek

Over at Pharyngula, I find that there's a bill in the Wisconsin state legislature which would ban the teaching of Intelligent Design in science courses. Since I've commented on this issue several times, I thought it would be instructive for me to say what I think about this proposal.

It's an awful idea. Just awful. As tempting as it might be at first, this is truly the wrong way to deal with ID in the classroom. Its advocates already enjoy themselves no end complaining about the rigid, dogmatic Darwinists trying to suppress Intelligent Design's brave, pathbreaking dissent - y'know, like Galileo, right? This will just hand them a wonderful party favor.

And besides, this isn't the way to settle these issues. One of the main things that drives scientists crazy about ID is that it sets itself up as some sort of equivalent alternative scientific explanation (while offering nothing close to what a legitimate challenge to evolution would have to bring). If we're going to have a fight about what's science and what isn't, then we should settle it by debating the evidence and the logic, not by getting someone to change the rules for us.

I can hear the protests now: "But isn't that what happened in Dover? You people got the court to throw ID right out of the schools!" Ah, but it was thrown out after loads of testimony from both sides, after cross-examination of everyone's expert witnesses, in an opinion by a judge who sat down to weigh the evidence. That's what torpedoed the ID side in Dover: careful, rigorous examination of everything they had to say. And it'll work every time.

So I hope that this Wisconsin idea dies before ever being brought to a vote. Don't do us scientists any favors, guys - we can handle this on our own. I have a great deal of contempt for the Intelligent Design movement, and I want to see it given the drubbing it deserves in open debate, over and over again, until it goes away.

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February 8, 2006

Garnier Strikes Back

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Posted by Derek

I haven't said anything about the recent film "The Constant Gardener". Truth be told, I had no desire to call any more attention to it. True to John le Carre's source novel, the story involves a brutal, corrupt international pharmaceutical conspiracy, which destroys the lives of poor Africans and kills critics who get in its way. As someone who's worked in the industry, I found that pretty hard to take. The dress code at the drug companies doesn't mandate white robes, but they sure aren't any blacker than the ones for any other business.

I see, though, that Jean-Pierre Garnier of GSK finally was moved to say a few words about the film. (And no, he didn't call it the feel-good popcorn flick of the year). He wasn't as harsh as I would have been:

"None of the scenario elements and plots in this movie have any relation to reality. . .It is a nice piece of fiction, let's enjoy it. It's entertainment, but it's not what we are all about."

I can't imagine that he found it very entertaining. It's hard to enjoy yourself when you've just paid money to see the way you earn your living depicted as evil and destructive. Positive reviews of the film have mostly either ignored its politics (and concentrated on the Acting) or praised it for its "mature" "socially conscious" approach to teaching us all our lessons. Spare me.

I believe that it was Ben Stein who once said that only in Hollywood could you have a setup of a murdered drug dealer in a dangerous neighborhood, with the villian turning out to be a wealthy businessman from the suburbs. Portraying an industry, which is actually saving and trying to save millions of people from suffering, as an assortment of amoral killers is the same formula. It's isn't new, and it isn't shocking. It isn't brave, and it isn't true.

(Note: if you're a subscriber the The Atlantic Monthly, this column by Clive Crook on the depiction of capitalism in the movies is worth a look).

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February 7, 2006

Return of Neowater

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Posted by Derek

An interesting development in the comment threads to the "Nanotech Wonder Water" post was the appearance of Miguel Cizin, of DoCoop, makers of Neowater itself. He's doing a good job looking out after his company's name, and I'm glad to have him here.

I've had a chance to look through their patent application, and I've devoted some thought to the claims made for Neowater. I agree that water takes on different properties next to a solid interface, and I'm willing to stipulate that (othewise insoluble) nanoscale particles might be a way to deliver such interfacial properties throughout bulk water. Starting from that, I have some questions and proposals which I hope that Miguel Cizin and DoCoop will have a chance to take a look at. Warning to my non-chemical readers - I'm about to put on my lab coat good and proper:

1. How much of Neowater's characteristics can be explained under the usual framework of colligative properties? That is, by how much is the boiling point of Neowater elevated, and by how much is its freezing point depressed?

2. Similarly, what's its vapor pressure at STP? Does it show a negative deviation from Raoult's Law (as you'd expect from the descriptions in the patent of Neowater's structure), and is this deviation much greater than expected given the low levels of particulate matter contained? The literature on the DoCoop web site, I should note, mentions that Neowater evaporates more slowly than regular water.

3. In the same vein, what's the surface tension of Neowater as compared to the water it's produced from? I could imagine it going either way - if large clusters of water are occupied around the nanoparticles, the surface layer of water may not form in as ordered a fashion, leading to lower surface tension. On the other hand, if Neowater is better thought of as a collection of larger polar "balls" of hydrated particles, perhaps the value could end up higher.

4. What's the conductivity of Neowater as compared to its untreated form? How does it change in the presence of small amounts of electrolytes as compared to regular water?

5. Have the rates of standard nucleophilic displacement reactions and/or cycloadditions been measured in Neowater? The presence or absence of a polar transition state and the resultant effect on reaction rate would make an interesting test of its properties. (Neowater is stated to be a "more hydrophobic" form of the liquid). Which reminds me: have Neowater's dipole moment and dielectric constant been determined?

6. Has deuterated Neowater been prepared? If so, how do its properties differ from protic Neowater as compared to the differences between water and deuterium oxide? If deuterated Neowater is available, it would make for some extremely interesting NMR experiments, since the DoCoop literature makes much of Neowater's properties with respect to biomolecules. I agree that water in cells is hardly comparable to bulk water - after all, as Arthur Kornberg is fond of stating, "cells are gels". One would thus expect to see conformational changes in the NMR spectra of proteins as they're run in d-Neowater. (Readers are invited to submit candidate biolmolecules for such a test, if I get a chance to run it).

There, that's enough physical chemistry for one evening. I look forward to seeing what we can find out, and to extensions of these ideas by the audience.

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February 6, 2006

J&J Shakes Things Up

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Posted by Derek

Well, as one of my readers noted in a comment on Friday, Johnson and Johnson seems to be doing a bit of restructuring in their drug discovery departments. I haven't seen a press release on this from the company yet, and I don't know if they're required to put one out, but it's newsworthy to people like me. Word starting going around at other companies during that working day, and more details have come out since then.

It appears that they're going to shrink their big Raritan, NJ site, at least as far as research is concerned, and consolidate things more in Spring House, PA. If my sources are correct, though, there are several hundred positions that are going to disappear in the process. I should emphasize that I don't have all the details, but that's what it's sounding like.

This is a bit unnerving, because J&J wasn't on anyone's list of companies that were having trouble. It's true that they don't have any of the huge multibillion-dollar drugs that everyone hears about, but they've always seemed like a pretty solid organization. Their presence in the medical-devices market gives them a useful non-pharma revenue stream, although the recent Guidant wrangling shows that that's not exactly a quiet, restful business, either.

Anyone with more information is welcome to add it in the comments section to this post. I hope that the folks affected will be able to land on their feet.

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February 5, 2006

Stream of Consciousness

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Posted by Derek

You know, people make sulfonamides all the time. . .we love sulfonamides in med-chem, right? So why can't I make a simple little sulfonamide off this heterocyclic system, eh? OK, right, there aren't any examples of these things in the literature - not last time I checked, anyway - so maybe there's a reason, but having no examples in the literature is the whole reason I'm trying to make 'em in the first place.

Right. . .send this one down for LC/MS anyway, maybe there's some of the right stuff in there and at least I'll know what it looks like. Yikes, that doesn't dissolve worth a hoot in straight methanol; if I send down a cloudy vial like that they're going to beat me with sticks. Maybe some acetonitrile. . .if this were really a sulfonamide, wouldn't it dissolve better in methanol, anyway? Ah, who am I kidding, these compounds do whatever they want to. If I ever write a book on heterocyclic chemistry, and God forbid, I'll divide them into two kinds of ring systems: friendly and hostile.

Yeah, that'll sell. I'd do better with that idea I had in grad school: "Quantum Mechanics: A Hand-Waving Approach". There's a real market for that one, and by now a hand-waving approach is exactly what I'd be capable of. Man, I remember that course - sitting there doing integrals for particle-in-a-box problems until midnight, and when I tried to go to sleep my brain was still integrating by parts. Couldn't turn it off. What a relief when I woke up and it had finally stopped - never had that happen again, and I've stayed away from quantum so as not to take any chances. What a mess that was - I'd forgotten so much calculus that I had to re-learn, and it had been what? Four years? It's only been twenty since then; I'm sure I'd be a real whiz.

Of course, it was while I was sitting there at my desk in that ancient lab, staring at those integrals that I looked up and saw a kilo jar of benzidine on the shelf right next to where I was sitting. Benzidine. . benzidine. . .that rang a bell, and then I realized, oh yeah, bladder cancer, benzidine's the one that gives you bladder cancer, and here I am camped next to a pony keg of the damn stuff. If I tried to order that through our system now a bunch of sirens would probably go off.

They should have gone off, anyway, when I ordered that new reagent from Big Jim's Discount Chemicals, or whoever it was, some outfit I've never heard of. Month and a half later, and it hasn't shown up. The inventory system keeps sending me e-mails, "Please Enter This Overdue Order". I should set up an auto-reply: "Please Put It In Your Ear". But if I did that, odds are that I'd end up sending it to everyone in the department somehow. . .hard to see the upside of that. And that reagent was going to be the thing to make these sulfonamides. . .aargh, sulfonamides. . . .

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February 2, 2006

Nanotech Wonder Water?

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Posted by Derek

Genetic Engineering News is sort of an odd publication. Primarily a vehicle for big, glossy color ads, it publishes some articles of its own: guest editorials, roundups of news from conferences and trade shows, that sort of thing. And it also publishes plenty of things that are (that have to be) slightly rewritten press releases - the sort of articles that start off:

"InterCap Corp. and SynaDynaGen say that their research collaboration on biosecurity proteomics through RNA interference and four-dimensional mass spectrometry, now with the great taste of fish, is yielding results that will make customers roll over on their backs and pant. Speaking at the Weaseltech Investor's Conference, company spokescreatures vowed to. . ."

One of these in the December issue, though, is weird enough that you can hear the editorial staff wrestling with their better selves. Phrases like "The company claims. . ." and "Company spokesmen maintain. . ." keep running through the whole article. It's titled "Water-Based Nanotech for the Life Sciences", and profiles a small Israeli company called (oddly) DoCoop. What DoCoop is selling is water.

But not just any water. . .Neowater! (Trademarked, natch). This is "a stable system of highly hydrated, inert nanoparticles", which supposedly have thousands of ordered hydration shells around them. This, the company says, modifies the bulk properties of the water. And what does that buy you?

Well, according to the company (there, I'm doing it, too), it will do pretty much everything except change the cat's litter box for you. It makes reactions run faster, at lower concentrations. It improves all biochemical assays and molecular biology techniques - PCR, RNA interference, ELISAs, you name it. Brief mentions are made of delivering molecules directly into cells with the stuff. It has applications in diagnostic kits, in drug delivery, in protein purification, and Cthulu only knows what else.

Some of these claims would seem to directly clash with each other. In the space of a few paragraphs, we hear that Neowater behaves "like a strong detergent", but somehow accelerates the growth of bacteria in culture. But at the same time it also prevents the formation of biofilms. And it increases the potency of antibiotics against bacteria, too. How it manages to do these things simultaneously is left, apparently, as an exercise for the reader.

The company claims that it has plenty of customers, and that it's working with several pharmaceutical companies to develop some of these applications. A search through the literature turned up one European molecular biology paper that mentioned using their PCR enhancing kit, so they've sold some Neowater for sure. But I'd like to turn this one over to the readers: have any of you seen this stuff? Know anyone who uses it?

And is everyone else's crank radar pinging as loudly as mine is? The thing is, unless a superior variety has up and evolved on us, cranks don't usually go out and form their own molecular biology reagent companies and place press releases in Genetic Engineering News. I'm profoundly sceptical of the claims this company makes, but I have the feeling that they're sincere in making them. Very odd, very odd indeed.

Comments (31) + TrackBacks (0) | Category: Biological News

February 1, 2006

The Good New Days

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Posted by Derek

I've been working on a longer post on antisense drugs (which, in case you're wondering, are different - most of the time - from nonsense drugs), but it's not quite ready yet. Home life and the Wonder Drug Factory are keeping me hopping these days.

The other day I was talking about old-fashioned reactions that we still use all the time, and I can testify to that from recent experience. I've been messing around with Grignard reagents all week, for one thing. But one of the comments to that post mentioned that I shouldn't give people the impression that those reactions are all that we use, and that's a good point.

For example, I've said before that if I had to pick one type of reaction that's run every day now that wasn't well-known when I was in graduate school, it would be a palladium-catalyzed coupling. The most commonly run is the Suzuki reaction, and we've been doing those all week, too. I would absolutely hate to do without this family of carbon-carbon bond forming methods - in fact, it's hard to imagine how we ever did.

But even though it's been around since 1979, not many people ran these reactions in the mid-1980s when I was in grad school. Palladium chemistry was seen as this exotic stuff that did weird things, and did them mostly in the hoods of organometallic chemists. As that decade wore on, though, the Suzuki and other such couplings became better known, and they just completely conquered the world in the 1990s. Now there are whole sections of the chemical catalogs devoted to them. You probably could buy about a half-dozen arylboronic acids back in 1985, but an entire industry has sprung up around such things now. And since new improvements and extensions keep coming all the time, the catalogs will surely look even stranger in another fifteen years.

My only real complaint about the Suzuki reaction is that there are so many ways to run it - solvents, catalysts, additives, temperature. You can generally get it to give you some product, no matter what conditions you choose. But in many cases, optimizing it to a reproducible high yield is like black magic. My pet theory is that any given palladium coupling reaction can be made to run in over 90% yield, if you're just willing to devote enough of your life to finding out how. Most of the time, I take what they give me and move on.

Comments (11) + TrackBacks (0) | Category: Life in the Drug Labs