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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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October 31, 2005

Five Questions

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Posted by Derek

Here are a few more of those questions that come up during drug research. Readers with experience in the industry may have had to deal with these very ones, and will at least recognize them as the sort of head-scratchers that every project has to deal with. Most of them, as usual, have more than one right answer, depending on the circumstances. So. . .

1. You have good compounds as measured in an enzyme or receptor assay in vitro, but they do nothing what's supposed to be the relevant cell assay. Usually, the assumption is that they have trouble getting into the cells. But then you try them into another cell line that's not necessarily supposed to respond to this target, and they suddenly work just fine. Now what?

2. You have limited chemistry manpower on a project. You're all using a common intermediate, so you put some effort into making a big stock of it for everyone to use. But then a patent application publishes that comes uncomfortably close to what you're working on. The next application from those guys might pull the whole chemical series out from under you. How do you deploy your people to deal with this one?

3. Your team is cranking away, making compounds that are more and more potent in the primary assay against your protein target. The new ones are getting more and more selective against the potential side targets, too, so what's not to like? Well, the compounds are also getting bigger and greasier, and their blood levels are getting worse and worse when dosed in the animal models. When do you call a halt?

4. Several lines of evidence are beginning to make you think that your compounds are doing the right things for the wrong reasons. You're getting the effects you want in vivo, but your initial assays don't correlate with the animal data (or with each other) very well. Do you care, and if so, how much?

5. Your project is narrowing down to two potential candidates. The first one has fair to mediocre potency and selectivity in the assays, but wonderful blood levels. The second is as potent and selective as all get out, but has marginal blood levels and requires ugly dosing vehicles. Which one do you pick, and how do you decide between them?

Comments (10) + TrackBacks (0) | Category: Drug Development

October 30, 2005

Gooooaaaal!

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Posted by Derek

I do a fair amount of complaining (maybe I could just stop and put a period there. No?) about how people don't realize the difficulty of taking an idea for a new drug all the way to the market. But I shouldn't be the tiniest bit surprised, because depictions of research skip most of the work. How would anyone who doesn't do this stuff realize how time-consuming it is?

When I started doing real lab experiments, it struck me that I was spending an awful long time purifying messy reaction mixtures and trying to make sure that I'd made what I thought I'd made. Now, twenty-odd years later, it seems like I spend a awful lot of time doing those same things. There's no way around either one of them, but you'd never know it from virtually any depiction of scientists at work. Having a character spend three days running a chromatography over again (and again) because the peaks aren't well resolved doesn't advance the plot very well, does it? There's nothing page-turning about combining a long run of messy mixed fractions, evaporating out all the solvent - which always takes much longer than you thing it will - and sending them down yet another column, which will generate a few pure cuts and another heap of mixed fractions.

These delays are found in every operation of a research lab, and they scale in a fractal-type manner. Five-minute tasks have at least a minute's worth of delay in them (waiting for the thick syrupy starting material to dissolve so you can toss a magnetic stir bar in there without getting it stuck), and five-month tasks have at least a month's worth (figuring out why the large batch of material for the serious toxicology runs doesn't dissolve as well in the dosing vehicle as all the other batchs). And the five-year tasks? Try an extra year of enrollment for the pivotal clinical trials on for size.

So asking a drug researcher how they could have worked for X years without ever producing a drug is a bit like asking a soccer team: "You booted that ball around the field for ninety minutes and didn't even put the thing in the net?" Nothing plays defense like nature can.

Comments (4) + TrackBacks (0) | Category: Life in the Drug Labs

October 28, 2005

Pargluva Goes Down?

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Posted by Derek

I missed last night's announcement from Bristol-Meyers Squibb until this morning. It looks like the situation with Pargluva (muraglitazar) is even worse than people had thought.

The FDA had granted "conditional approval" for the drug, but that doesn't mean all that much. The conditions for approval weren't made public, by either the agency or the companies involved - all we knew was that they wanted to address cardiovascular risk factors. Now BMS says that the ongoing trials won't be able to answer the FDA's concerns, and that new trials would be needed, which they say might take up to five years. That could scuttle the drug entirely.

I'm not sure what to make of this. It's entirely possible that BMS and Merck don't have anything currently powered to address cardiovascular risk in the way the the FDA would like. People complained that the Cleveland Clinic article in JAMA was based on incomplete data, but if there were good cardiovascular numbers on this drug, they would have been in that data set. But five years seems like a long time, even if the FDA is really lowering the boom on them and requiring long-term data in a large number of people. Even then, even factoring in recruitment and data workup, that's a whopper of a trial.

Still, I think the companies are clearly looking at more time and money than they probably want to spend, on a drug that frankly was a bit disappointing in its clinical data. Pargluva lowers blood glucose, but so do the existing PPAR-gamma agents. They already do about as much as can be done through that mechanism. And the additional PPAR-alpha activity does seem to help HDL cholesterol and other blood lipid parameters, but the cardiovascular risk that seems to be there more than offsets those numbers.

Merck and BMS run the risk of spending a very large amount of money just in order to definitively prove that their drug should not be sold. Even if they were able to make their case, it's unlikely that they'd be able to make a strong case in the market: "Pargluva! Not As Bad As You Thought!" And the market would have changed by the time they staggered on to approval, anyway. They may just give this one a pass.

It'll be interesting to see how this plays in the press. It'll be easy to fit this into a template of "FDA messes up, independent review by Cleveland Clinic saves the day again." But that's not quite true, I think. The FDA advisory committee didn't distinguish itself, and the Cleveland team was quick to pick up on that, but the agency itself requested the additional data before the JAMA article came out. I don't know what might have gone on behind the scenes, but on the face of it, this was one of the cases that proves (as the fine print says) that the FDA doesn't have to abide by the decisions of its advisory committees.

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

October 27, 2005

Imclone Revisited

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Posted by Derek

One among the flood of earnings reports this week was Imclone. Their 3Q earnings press release was one of those good news/bad news documents familiar to readers of the financial pages. Revenues weren't too bad, with higher royalties coming in, although there was a decline in manufacturing revenue which was blamed on lower prices being paid by Bristol-Meyers Squibb for Imclone's sole product, Erbitux. As they hastened to add, though, "Purchases by Bristol-Myers Squibb are timed at their discretion to accommodate forecasts and safety stock needs, and are not necessarily indicative of historical in-market sales or future sales expectations." They'd better hope so.

If you go back to their second quarter 10-Q statement, though, you won't find much mention of these things in the "Outlook" section. They do point out that the price of Erbitux for the partners has gone down, but there's no mention of the possibility of BMS deciding not to buy much of it for a while.

At the same time, expenses were higher than expected. The biggest component of the increase was under the R&D heading. In Imclone's words: "the increase is principally attributable to expenses associated with clinical supplies sold to the Company's partners which are reimbursed as a component of collaborative agreement revenue." Unless they somehow have the clinical supplies of Erbitux completely separated out financially from the commercial ones, this would seem to mean that they're spending more money to deliver the drug to their partners, and getting less back for it.

Imclone has a special place in my heart. Since their return from the grave, I've written about them several times, and today's earnings report prompted me to revisit a few of those posts. Back on April 28 of last year, I wrote: ""Today's buyers can only hope for people who can't do math to come along and relieve them of their shares. More likely, the mathematically impaired are already in there buying right now, which will gradually limit the target audience for a profitable resale to either pretechnological tribesmen or the crews of recently arrived UFOs." Very intemperate of me. IMCL shares were heading toward $70 at the time.

After an incoming burst of testy e-mails, I followed up the next day with these conciliatory words: "Go on and hold that IMCL, guys, go ahead and mortgage the house to buy some more. Maybe you'll watch it go to $150; stupider things have happened. But I think that the odds are that you're going to wish you'd taken your profits in 2004."

I revisited the company and its never-boring stock on June 6: "Even with sizable market penetration, I still think that Imclone stock is no bargain at 70-odd dollars a share. Mind you, that's what it was on Friday. It'll be worth taking a look during Monday's trading to see what it's been inflated to since this news came out. My advice to IMCL shareholders continues to be: cash in and run laughing to the bank." Another round of peeved comments and mail messages followed.

The stock, I should mention here, peaked in early July of 2004, a bit shy of $90/share. Altitude sickness set in, though, and I said later that month, as the price fell steeply through the $60s: "In light of all this, I'd like to take a moment to address the Imclone-boosting stock cult, those few of them who might have read this far, anyway. Get out. Take the money and run. The alarm bell has sounded, and more than once. If you bought Imclone when it was in the dumper, you've had a great run. Celebrate and cash in! But if you bought it when I was ranting on the subject back in late June, you're in the red, and I fear that it's going to be even worse in the long run. Flee!"

I really hope that someone took that advice. It's been just about exactly a year since Imclone's stock was as high as $50. It wandered through $40 this spring. Today it finished up at just short of $34. And do you know something? I still wouldn't buy it. I'm not telling everyone to run away screaming, but there have to be better places to put your money. The price they're getting for Erbitux is not going to improve much. They're trying for new markets, such as head and neck cancer, but these are small ones, and you have to figure that there's off-label use going on already in these areas. And every year there's more competition from cheaper therapies which may well be as good or better. Would someone who owns IMCL please tell me why they do?

Comments (8) + TrackBacks (0) | Category: Business and Markets

October 26, 2005

The Latest in Pharmaceutical Technology

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Posted by Derek

I've been spending some time with a batch of compound recently, boiling it in ethyl alcohol all day long. I distill out the ethanol, then add more and boil it up again. And again. Why am I being so darn productive, you ask? Well, this is some material we received from a contract synthesis company, and while it's the right stuff, it came to us with nearly 10% chloroform in it. You find these things out by taking NMR spectra of the outsourced stuff as soon as you get it in, and preferably in more than one solvent. Trust but verify and all that, particularly from the low bidder.

Deuterated chloroform is a common solvent for NMR spectra, and it always shows a greater or lesser peak for the plain stuff. If we'd only run the spectrum in that, we might have just written it off as an ugly bottle of NMR solvent, but it's rather more difficult to explain its presence in a sample run in, say, DMSO. As it turns out, it's a contaminant left over from the last step of the synthesis, and it's the sort of thing you'd think that a day or two on the vacuum pump would take care of. After all, it's pretty volatile stuff, right?

Well, not in this case. This is one of those times when the solvent seems to have decided to work its way into the crystal lattice of a compound, because that chloroform's not going anywhere without a fight. This compound is not the most soluble stuff in the world, but hot ethanol gradually does the trick. Thus the repetitive distillation. Of course, now the compound is cut with ethyl alcohol instead of chloroform, but that's a much more benign thing to feed the rodents come assay time. Drunken mice we can allow for, but not ones that have been chloroformed from the inside out.

Comments (15) + TrackBacks (0) | Category: Life in the Drug Labs

October 25, 2005

Start Your Engines

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Posted by Derek

I'm going to take a break this evening from the med-chem side of my science. There's a paper in the preprint section of the ACS journal Nano Letters that's one of the neatest things I've seen in a while. Jim Tour's group at Rice has been working in this area for quite a while now, and they now report something they call a "nanocar."

It's a single large molecule, built from standard organic chemistry reactions. There are two straight axles, made out of acetylene compounds (which are rod-shaped), and another connecter between running between them. On both ends of each axle is a fullerene (a buckyball), and getting those attached was the apparently one of the trickiest parts of the whole synthesis, which took several years. The other tough part seems to have been hanging enough greasy chains off the various structural parts of the thing so that it could be dissolved in an organic solvent. Here's the synthetic scheme and a drawing of the molecule. (That link currently seems to work for non-subscribers - the full article is here.)

Those fullerenes are wheels. They can turn independently, because the bond between them and the next acetylene is freely rotatable, and that seems to be just what they're doing. By finally making one of these that could be taken up into a solvent, Tour's group managed to get some of these things onto a gold metal surface, which is a perfect background to use for Scanning Tunneling Microscope (STM) imaging. And here they are. (The fullerenes show up very well in STM imaging, and they're pretty much all you can see.) Buckyballs are already known to stick very well to gold, so Tour's people had to heat up the metal to get things moving. Once they got up to about 170 C, though, the molecules - the nanocars - began to roll around.

Now, molecules sitting on metal surfaces move around all the time, but they mostly just slide and hop by thermal wiggling. There are several lines of evidence to show that these are really rolling, though. For one thing, a three-wheeled symmetrical variety was made, and it just spins in place. (That link also has a nifty rendered version of both types of molecule, but those are rather idealized portraits. For one thing, they don't show all the long side chains decorating the frame, which would make the whole car look rather Rastafarian.) The cars also appear to only move along their long axis, with slight pivots as one set of wheels breaks free before the other side does. (The nano-differential has yet to be invented). Finally, the team used the STM tip to drag a nanocar along, and showed that it couldn't be towed sideways - the wheels dug in rather than rolling.

It's easy to dismiss this work as a stunt, which is what I once did with one of Tour's other ideas. But this is the beginning of the real thing. A larger, more functionalized version of the nanocar might carry other molecules along and dump them at will, which is what this group seems to be working on now. These are small steps toward controlled nanoscale delivery, which is a small step toward a nanotech assembler.

We're a long way from that. But for now, there are any number of interesting experiments waiting to be run. You have to wonder how these things will behave on other surfaces, for one thing. If they drive better on some than others, you could imagine directing them around on small roads which have been fabricated by chip-building techniques. There are other molecular forms that could be used as wheels, and other potential ways to move them around rather than just heating them up. Just looking at these structures gave me an idea of my own: how about making the axle part of the molecule by incorporating a structure that would absorb at particular infrared wavelengths? That would show up as motion in the chemical bonds, and might provide a means to make a motor to drive these things. Eventually we're going to have grad students standing around an STM rig, betting on which of their designs will make it across an atomic landscape first. . .

Comments (5) + TrackBacks (0) | Category: General Scientific News

October 24, 2005

Hype or Hope?

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Posted by Derek

Last week's news about Herceptin made quite a splash, and there are several reasons for that. The main one is the correct one: this is good news for breast cancer patients, and a real advance in the treatment of the disease. The other reasons for all the excitement may not be quite as justifiable, though. In short, while this is significant, it's a long way from a cure.

Herceptin (trastuzumab) is an antibody targeted to a growth factor receptor called HER2 (more background from a previous post here, and from Genentech here. Those are the short version and the long version, more or less). If the cancer doesn't express HER2, it will not respond to Herceptin. The more dependent the tumor is on HER2 for its growth, the better the antibody will work, which is a common theme among cancer therapies. (An extreme version is found with Iressa, where if the tumor doesn't have the rare mutation that makes it dependent on the drug's targets, it doesn't work at all).

So, how many breast cancers express HER2? There are several ways to assay that, and the numbers disagree a bit, but a bit under 20% seems like a reasonable answer. Put more harshly, for about 80% of breast cancer patients, herceptin is of little or no use. This has been proven quite thoroughly, but it's going to be hard to explain to patients who are newly diagnosed and want to know where that cure is that they've read about.

I haven't seen any headlines that have tried to explain that these results are good news for only a certain group of breast cancer sufferers. Many of the press reports get around to mentioning this eventually, although rarely in the first paragraphs - you wonder how many people are still reading when they get to the fine print. The fine print, in this case, would include the numbers that show a twelve per cent increase in disease-free survival after three years. That's big news in oncology, but isn't generally the kind of number that you makes you throw around the word "cure". I hope that some of the people in these news stories have been quoted out of context.

It's true that by the time you add up the taxanes, the estrogen receptor ligands like Tamoxifen, the aromatase inhibitors, and the general advances in surgery and early detection, that breast cancer is a less fearsome disease than it was five (or ten, or twenty) years ago. But advances in this area get overhyped because - and I hate to bring this up - the disease itself is overhyped. Don't get me wrong - it's bad. But it's far from the worst.

The rate of breast cancer, like many other cancers, appears to be declining (PDF), measured both by incidence and by death rate. It's well behind that of lung cancer in the female population, which moved into first place nearly 20 years ago (see the graph on page 5 of this PDF), but it gets easily ten times the press, and surely generates ten times as much worry. Lungs, though, are not visible manifestations of femininity, and come with no cultural or political meaning attached. I'm sure that there's a ribbon color for lung cancer, although I don't know what it is, and I don't know when their Awareness Month might be. This is especially odd when you consider that most of the high incidence of lung cancer is from a completely avoidable cause. . .

(I see that Medpundit has a very similar take on this: "Don't sell the house" is her advice.)

Comments (14) + TrackBacks (1) | Category: Cancer

October 23, 2005

The Tar Pit Beckons

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Posted by Derek

Over at Pfizer, reality is finally flapping down on its big, black wings. It's been circling for a while. Looking at the stock chart, you can make a case that somewhere around 2000 was when they stopped beating the S&P index, and the middle of last year is when they stopped staying even with it. I've had a lot of things to say about Pfizer on this blog (and its predecessor) over the last few years, and most of them have been unkind. (Here are a couple of posts that will give you the idea).

The short version: (1) Pfizer's ever-increasing size means that most everything scales up except what they need the most: research productivity. (2) Billion-dollar drugs must roll off their conveyer belt, one after the other, and that's something that no one has ever figured out how to do. (3) Lipitor, mighty monster that it is, is the main thing keeping the music playing. But it will go away, and there is nothing to replace it. Perhaps nothing ever could. (4) While a massive sales force is quite a thing to have, they do need things to sell, don't they?

I've thought more than once, as I write things like this, that I must have killed off any chances I had to work over there. But I don't see Pfizer doing a lot of hiring for the next few years - do you? It's a sad situation, but perhaps it'll serve as an example for the rest of industry. Somehow, I don't think that all these acquisitions were made with the goal of being a poster boy. . .

Comments (12) + TrackBacks (0) | Category: Business and Markets

October 20, 2005

This Had Better Be Good

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Posted by Derek

I wrote a brief wrap-up on the FDA's concerns about the new Bristol-Meyers Squibb / Merck diabetes drug Pargluva (muraglitazar). It's officially "approvable", but the FDA wants more cardiovascular safety data before it can be sold. But just this morning the JAMA web site has rushed out an article from a team at the Cleveland Clinic on the drug's clinical trial data. (Accompanying editorial here). It's very disturbing, in more ways than one.

At the time, I said that "By my reading, the cardiovascular event profile of the drug subjects looks slightly but noticeably worse than that of the placebo group. There are plenty of possible extenuating factors, and the number of patients involved is small, but I think that this is going to be a problem for the companies during the FDA hearing. Here's the list of questions the FDA has proposed for discussion (PDF again), and you can see that edema and cardiovascular safety loom large. . ." That's fine, as far as it goes, but I didn't dig far enough into the data, and I wonder if the advisory panel did, either.

What the authors of this new paper have noticed is the number of patients taking a low dose of muraglitazar - lower than the companies ended up seeking approval for. They didn't show enough beneficial effects for that dose to be worthwhile, but since muraglitazar's cardiovascular problems appear to be strongly correlated with dose, these patients also had no cardiovascular events at all. The problem is that these patients were included in the risk calculations, and that makes the drug look safer than it would be under real-world conditions.

The Cleveland group's recalculations now put the risk of cardiovascular events with clinically relevant doses of muraglitazar at 20% higher than the placebo group, and at 67% higher than the combined placebo-standard of care group. (That includes patients treated with pioglitazone, a PPAR-gamma compound that's been approved for some years now). Put that way, this sounds like a huge increase, but it's important to remember that both of these figures, though real, are pretty small. The placebo group had about 34 events per 1000 patient years, and the drug treatment group, in the new analysis, had around 40 events. So, back-of-the-envelope, for every thousand patients on muraglitazar, you might expect an extra 6 cardiovascular incidents per year. The similarities to the Vioxx data are not hard to spot, and in fact the authors of this paper have been very much involved in that controversy as well.

But I'm not going to push that comparison. This is a different case than Vioxx, a drug that (for many patients) really does seem to do more than existing compounds can. The problem here is that muraglitazar (and all the PPAR alpha-gamma compounds that have gone into development) was supposed to be better for cardiovascular outcomes than the plain PPAR-gamma compounds that are already out there. Needless to say, it was also supposed to be better than a damned placebo, which it isn't. The entire dual-PPAR-agonist idea is in trouble. The whole point of adding PPAR-alpha activity was to improve blood lipid profiles, and pretty much the whole point of doing that is to improve cardiovascular health. The first part is working, but the second part, the important part, just doesn't seem to be happening. Looking at the data, I find it hard to imagine why anyone would take muraglitazar over the exisiting therapies, when there's no evidence for what is supposed to be its main advantage.

As if that weren't bad enough, there's also a background worry about cancer rates with PPAR compounds. The muraglitazar data aren't totally reassuring on this front, either. Other compounds in this class died because of carcinogenicity in long-term rodent studies, and muraglitazar is the first compound to actually make it past such studies. But the data submitted to the FDA show that rats given the compound at high doses do indeed show bladder cancer - it just seems to be less of a problem than it was for the earlier compounds from Merck, Kyorin, Novo, Dr. Reddy's, et al. For a marginal compound, though, this is a real issue.

I don't necessarily think that the people at BMS (and Merck, a latecomer to this compound) were sitting around wondering about just how to snow the FDA. But it would certainly cheer me up if I could rule that out, wouldn't it, now? At the very least, the companies weren't being as critical of themselves as scientists have to be, and they've committed a mistake that would flunk a PhD candidate or get a paper tossed back from a well-refereed journal. Something has gone seriously wrong here. We're supposed to be better than this.

What on Earth were they thinking, submitting data in a way that makes it look like they were trying to pull a fast one with the cardiovascular risk factors? Now, of all times? Who knows, maybe people at BMS had just convinced themselves that things were fine, somehow - the capacity for human self-deception is limitless. But didn't anyone at Merck turn pale and have to sit down when they saw these numbers? I didn't realize how bad the situation was back in September, but even then I wondered about this, saying: "I can't predict which way this one is going to go, and neither can anyone else. But post-COX-2 is a bad time to be coming to the FDA with possible low-level cardiac risks in your clinical data. . ." Now that the risks look even worse, I'm baffled. You people want the sky to come down on your heads?

Comments (6) + TrackBacks (0) | Category: Clinical Trials | Diabetes and Obesity | The Dark Side

October 19, 2005

Complaints From a Fossil

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Posted by Derek

You know, I sure hope that there's a special issue of J. Med. Chem. coming up, all about computational chemistry and molecular modeling. No, I haven't lost my mind - yet. I was looking at the advance publications page on their web site this morning, which had 72 accepted papers on it slated for publication.

Fine, just fine. The problem is, at least twenty of them have little or no reality-based chemistry in them. I define that, understandably enough, as real compounds which were made and tested and put into a vial somewhere. True, the majority of the papers on the list are more traditional med-chem, and many of those have computational methods as a component. But to have over a quarter of the papers with only modeling, docking, simulations and scoring? There is, last I heard, a Journal of Computational Chemistry. And a Journal of Molecular Modeling. And a Journal of Molecular Graphics and Modeling. For that matter, the American Chemical Society itself, publisher of J. Med. Chem., publishes the Journal of Chemical Information and Modeling.

I know, I know, these aren't as prestigious, but where are all the medicinal chemistry papers going these days? (I mean the ones with experimental details, of course. The ones without any are going, as always, to Bioorganic and Medicinal Chemistry Letters.) There's some real irony in this situation, because one of those papers actually does a good job blowing up the reasons for some of the others to exist. More on this anon.

Update: Here's a dissenting view. . .

Comments (13) + TrackBacks (1) | Category: The Scientific Literature

Procrastination Assistance

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Posted by Derek

Looking for another way to avoid doing some work for a bit? The latest Tangled Bank roundup of science-blogging is up. This weekend, I update the blogroll. There are too many good ones that I'm missing.

Comments (1) + TrackBacks (0) | Category: Blog Housekeeping

October 18, 2005

Waiting for Pargluva

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Posted by Derek

Well, that title above doesn't sound like something you'll see on a Broadway marquee, does it? As predicted here, although it didn't exactly take psychic powers, the FDA has asked for more cardiovascular data for the new PPAR alpha-gamma drug Pargluva.

Merck and Bristol-Meyers Squibb are quoted as saying that they're "eager to talk" to the agency to find out what's required, and I'll bet they are. Analysts have pushed the likely launch date of the drug back to late next year.

I'm starting to wonder if the PPAR drugs are ever going to able to live up to the expectation that many people had for them. The whole point of an alpha-gamma combination was to reduce blood sugar and improve cardiovascular health at the same time, which makes the emergence of cardiovascular risk with Pargluva particularly annoying.

That whole nuclear receptor field is still a wonderful area for basic research, but turning things into useful drugs has been harder than anticipated. For a while there, it looked as if we'd be able to take all sorts of combination of the three subtypes and turn out drugs for all sorts of indications - diabetes, high blood lipids, various cancers, wound healing, what have you. And perhaps we still can, after another ten or twenty years of hard labor.

(Some of my personal history with these compounds will be illustrated within the next month or so in Bioorganic and Medicinal Chemistry Letters, for those who are interested.)

Comments (2) + TrackBacks (0) | Category: Diabetes and Obesity

October 17, 2005

James Cramer, Biocryst, and You

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Posted by Derek

I sent a copy of my post on Biocryst (BCRX) to Jim Cramer at his CNBC e-mail address, even though I'd said some unkind things about his pick, and he was kind enough to respond. His take was exactly that of a man who used to trade stocks for a living. He pointed out to me that the stock opened between 13 and 14 after he recommended it, then climbed to 17. If I'd bought a thousand shares, he went on to say, I'd have "the down payment on a decent car", and if I'd bought 5000 shares I'd be looking at tuition money.

As he put it, he's not asking for any praise from me, but feels that I "should at least accept the fact that the trade was money good." Well, I can't deny it: I do accept that anyone who ran out and loaded up on BCRX after he boosted it made money on the trade, and that's what that a stock transaction should do for you. But as I said to him in my reply, 5000 shares at $13 is a bit more "mad money" (to use the title of his CNBC segment) than I happen to have sitting around, so that may not be a very realistic example.

I should add that anyone who opens up a $70,000 position in a small NASDAQ stock because someone on TV said it was a good idea had better have a lot of money to lose. Most people who can afford to drop that kind of money probably aren't acting on tips they hear on investment shows, though, or at least I hope they aren't. This kind of thing can actually turn a profit on a majority of your individual trades, but the whacking losses that show up every so often will more than make up for those. Rabbits that try to make a career out of dodging 18-wheel trucks have exciting careers, and may feel for a while as if they're ahead of the game, but tend to end badly. You may be able to tell that I'm not what they call a "momentum investor".

And there's another factor that Cramer (and other well-known stock pickers) don't always want to address. As stock-blogger The Stalwart put it the other day, "Jim Cramer likes to say "There's always a bull-market somewhere" and in the short-term he's right; it's wherever he says it is". Exactly. Cramer's counterargument to me is, basically, that he was right because he told a million viewers to go buy the stock and see? It went up!

To his credit, though, I see that he fielded another question on his radio program today about Biocryst, and advised people to take their profits: "the trade's done". He doesn't seem to have sent it down by doing so, though, which is only natural. People are much slower to pull the trigger on sell orders than they are to buy, and there are plenty of hopeful sorts who still seem to be crowding into the stock.

I've little doubt that BCRX will continue to go up for a while. The public fears of avian flu will lift it. Am I going to buy any? Absolutely not. I know too much about the science to be comfortable joining that kind of herd. Am I going to short it? Not yet, although I've heard from a reader who was already short before I wrote about the possibility. I hope he's got some reserves handy.

If I join him, I'll post the trade. My temperament generally doesn't allow me to try to make money by counting on ignorance on the long side, but for some reason I've no problem letting ignorance help me out on the way back down. The problem is, I tend to underestimate the craziness and greed of my fellow investors. . .

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

October 16, 2005

Matthias Rath, Pioneer

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Posted by Derek

It's been a little while since we checked in on Dr. Matthias Rath, vitamin entrepreneur and scourge of my chosen field of work. But there have been some wonderful developments that I'd like to share with everyone. A note from a reader brought him to mind:

"Your education may not be serving you in a changing world. From some of what I have read you remind me of the physics professor who is still teaching the Bohr atom, sure that the quantum madness will go away. I highly recommend, before uttering another "sure" word on medical cures, you find and interview 10 patients whose HIV has been arrested by alternative treatment and 10 cancer patients who were diagnosed terminally ill and whose condition was reversed under Dr Rath's methodologies. I have followed them, in awe, watching as they were liberated from the naivete of the modern medicine you hold high. . ."

As I pointed out in a reply, it would do Doctor Rath a world of good for him to humiliate the medical establishment in a clinical trial showdown. You'd think that that we should be able to get the World Health Organization or some other worthy organization to referee, and if Rath's treatments are that good, he'd have nothing to fear. Think of it - the drug companies would have to eat dirt and Dr. Rath would be an instant hero for his amazing medical advances. No more nasty comments from snide onlookers like me, no more threats of arrest. . .why doesn't he come and settle our hash already?

I think we already know the answer to that question, don't we? But in case you've any doubt, take a look at the latest news from South Africa, where Dr. Rath has been parading patients who he claims have been fighting off HIV infection by taking his vitamins. As it turns out, they seem to have been supplementing the supplements:

Two HIV-positive women presented to the media in June by the Dr Rath Health Foundation as examples of how its vitamins can reverse Aids have admitted that they were on antiretroviral (ARVs) drugs all along. A third woman, a high profile Rath Foundation agent who has been promoting the vitamins in Gugulethu, died a few months after rejecting ARVs. . ."

Well, that's one way to do it. Dr. Rath, once again, is on the cutting edge of clinical practice. Think of the power of this technique! You could probably show that chocolate ice cream is an effective cholesterol-lowering agent, as long as you dosed people with a statin on the sly. Imagine how much proprietary-recipe chocolate ice cream you could move that way. . .and at twenty dollars a bowl, most likely. Oh, I'm in the wrong business, I tell you. If I could just cut every bit of human conscience out of my psyche, to the point that I could deceive terminally ill people into forsaking their only chance of survival and spending the last of their money on my worthless crap instead - I could be down there with Dr. Rath, wallowing around in the hundred-dollar bills like a pig in a trough. Doesn't he look happy, though. . .

Comments (14) + TrackBacks (1) | Category: Snake Oil

October 13, 2005

Buy! It's More Expensive Than Usual!

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Posted by Derek

Note: This post has a follow-up with Jim Cramer's reaction to it here.

The small-pharma flavor of the month seems to be Biocryst Pharmaceuticals, but it's not one of their current development projects that has everyone jumping up and down. It's a drug that failed its Phase III trials two years ago. Despite the best efforts of various stock newsletters and of multimedia stock tout Jim Cramer, though, I'm managing to resist the company's stock.

The words "avian influenza" are the missing piece to this puzzle. The drug, peramivir, is a neuraminidase inhibitor developed as a flu treatment, which is the same mechanism as the marketed drugs Relenza and Tamiflu. With the current worries about a possible pandemic, antivirals of all sorts are getting a second look.

In this case, you have to go back a few years for the first look. Peramivir was in Phase II trials during the late 1990s, and in 1999 the results were announced: not too bad. Their endpoint was reduction of viral titer, the b