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

Derek Lowe The 2002 Model

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

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

Chemistry and Drug Data: Drugbank
Chempedia Lab
Synthetic Pages
Organic Chemistry Portal
Not Voodoo

Chemistry and Pharma Blogs:
Org Prep Daily
The Haystack
A New Merck, Reviewed
Liberal Arts Chemistry
Electron Pusher
All Things Metathesis
C&E News Blogs
Chemiotics II
Chemical Space
Noel O'Blog
In Vivo Blog
Terra Sigilatta
BBSRC/Douglas Kell
Realizations in Biostatistics
ChemSpider Blog
Organic Chem - Education & Industry
Pharma Strategy Blog
No Name No Slogan
Practical Fragments
The Curious Wavefunction
Natural Product Man
Fragment Literature
Chemistry World Blog
Synthetic Nature
Chemistry Blog
Synthesizing Ideas
Eye on FDA
Chemical Forums
Symyx Blog
Sceptical Chymist
Lamentations on Chemistry
Computational Organic Chemistry
Mining Drugs
Henry Rzepa

Science Blogs and News:
Bad Science
The Loom
Uncertain Principles
Fierce Biotech
Blogs for Industry
Omics! Omics!
Young Female Scientist
Notional Slurry
Nobel Intent
SciTech Daily
Science Blog
Gene Expression (I)
Gene Expression (II)
Adventures in Ethics and Science
Transterrestrial Musings
Slashdot Science
Cosmic Variance
Biology News Net

Medical Blogs
DB's Medical Rants
Science-Based Medicine
Respectful Insolence
Diabetes Mine

Economics and Business
Marginal Revolution
The Volokh Conspiracy
Knowledge Problem

Politics / Current Events
Virginia Postrel
Belmont Club
Mickey Kaus

Belles Lettres
Uncouth Reflections
Arts and Letters Daily

In the Pipeline

Monthly Archives

February 28, 2011

Down In Phase III. Again.

Email This Entry

Posted by Derek

Past performance (Phase II results) are no guarantee of future success (Phase III). That warning has been proven over and over in this business, and an awful lot of time, effort, and money have gone down the waste chute in the process. To give you an idea, though, of how hard it is to break out of that cycle, consider Renovo.

As the InVivoBlog details, Renovo was founded to try out ideas to reduce scar tissue formation. And their whole strategy was to go into humans as quickly as possible, to firm up the clinical relevance of their candidate therapies. That's a bit easier to do with something like scarring, if you can find patients willing to have small cuts made in their skin. That's just how one of the Phase II trials was run for the company's Juvista (recombinant TGF beta 3) - two cuts, one treated with the drug and one without. And the results looked quite good.

But not in Phase III. Earlier this month, the company announced that Juvista has completely, utterly missed its endpoints in the larger trial, and no one seems to know why. According to the InVivoBlog, investors were reduced on the conference call to asking if somehow the data collection had been messed up - surely some of the placebo group and the treatment group had been, uh, switched somehow? But no.

It's worth remembering, though, that not all the Phase II data were so convincing. In retrospect, the earlier trials that looked bad were predictive, while the impressive numbers appear to have been artifacts. But how do you figure that out in advance? And how do you run only the trials that will be predictive, and how do you know to trust them? I'm tempted to ask Francis Collins to get on this for all of us, but that would be unfair. I think.

Comments (17) + TrackBacks (0) | Category: Clinical Trials | Drug Development

February 25, 2011

Things I Won't Work With: Chlorine Azide

Email This Entry

Posted by Derek

Well, it's been a bit too serious around here this week. So I thought today I'd step back to a period when men were men and chlorine azide was a reactive, toxic, and unstable compound that was only good for finding out what sort of explosion it would set off next. What's that? You say that that's still about all it's good for? Staying power, that's what I call it. If you work with the halogen azides, you work with things whose essential character time does not alter.

"Until they blow up", you say. Ah, but that is their essential character. It's the things around them that alter. Make sure you don't put anything next to them that you're not comfortable seeing altered - you know, all sudden-like.

A reader forwarded this 1943 JACS article, the first comprehensive study of chlorine azide, and it's a joy to read. Part of the fun is, of course, watching these folks set off the fireworks. (The challenge with a substance like chlorine azide is finding something that it won't react with violently):

Owing to the extreme instablity of the compound accurate determinations of the bioing and melting points have not been made as yet. Numerous explosions, often without assignable cause, have occurred during the experiments. . ."

Another thing I always enjoy in these papers is the list of recommended protective gear. No leather suits this time and (interestingly) no earplugs. Nope, it's straight to the Iron Man look. These azidonauts endorse:

". . .masks and breast-plates of sheet iron worn by observers during times of danger. Each mask is provided with a rectangular pane (7 x 3 inches) of shatter-proof glass. Although scores of violent detonations have occurred, with resultant demolition of much apparatus, no personal injury has been suffered."

That last part is sort of a "no graduate students were maimed during the course of this research" statement, which really is good to know. But another nice thing about this paper is the way some parts of it are written, in a style which was a bit formal and archaic even for 1943. A sample:

"If small pieces of yellow phosphorus be added, with stirring, to a solution of chlorine azide in carbon tetrachloride at 0C, the solution gradually becomes turbid, and a succession of slight explosions takes place beneath the liquid. If stirring be omitted until the maximum turbidity is attained, the slightest agitation results in a detonation that demolishes the apparatus. . ."

Do not be omitting the stirring, then. I have to say, not being used to this sort of chemistry, that if I saw these events going on in my fume hood that a series of slight explosions might well take place beneath my iron breastplate. What else doth chlorine azide detonate with? Well, in case you had any doubt, the gaseous reagent "reacts violently" with sodium metal. They had four explosions at -78C, while the fifth run (persistence!) yielded a mixture of sodium chloride and sodium azide. (Actually, the other runs probably yielded that, too, albeit as a fine haze). I really have to salute the dedication involved in finding that out, though - after two or three violent explosions, you or I might be tempted to just say that we couldn't determine the products of the reaction. But they were made of sterner stuff back in 1943.

The date does make me wonder if there was war research money involved; I wouldn't be surprised. But chlorine azide has not been weaponized, nor will it be. It remains, with its chemical relatives, off in a part of chemical science that's safe from human exploitation. It's a spacious game preserve, that territory, and over the gate is the ornate motto Noli me tangere. Take heed.

Comments (61) + TrackBacks (0) | Category: Things I Won't Work With

February 24, 2011

Is Big Pharma Killing Startup Companies?

Email This Entry

Posted by Derek

That's the contention of venture capitalist Kevin Kinsella (of Avalon Ventures) as reported in this piece at Xconomy

“There have been numerous instances of what I refer to as bad behavior—combined with short-sighted, brass-knuckle negotiating tactics—by some pharma companies that really go to the heart of whether this partnership between Big Pharma and biotech can really continue,” Kinsella says. He maintains that the pharmaceutical industry is doing enormous damage to the life sciences venture capital ecosystem. “Their predatory business practices,” he says, “are pushing the sector almost to the point of extinction.”

He likens the process to commercial overfishing, and says that some CEOs may not even realize how much damage is being done. He lists several examples of bad behavior (see the article), but the common thread to them (to me) seems to be the attempt to keep every bit of the risk with the smaller company, until there's clearly money about to be made, at which time the money starts flowing to the larger outfit.

Trying to structure things this way, though, is how I've always understood the process to work. I'm not saying it's a good idea, just that it's not a new one. Maybe it's just been getting worse, but the big drug companies have always wanted to jam in those heads-I-win-tail-you-lose clauses. The way I heard it expressed 20 years ago was "So, you need a deal real bad? Well, here's a really bad deal!"

But here's the getting-worse-recently case:

Kinsella sees a confluence of forces that came together after the tech and biotech bubble burst in 2000, and has continued with the mortgage meltdown and ensuing capital crisis. As financial institutions scrambled to save themselves, they shed much of their payroll—including most of the Wall Street banking talent that had focused on the biotech sector. The investment banks that biotech built—Hambrecht & Quist, Robertson Stephens, Montgomery Securities—did not survive, and Kinsella says no “serious” banks remained to serve life sciences startups, or to underwrite biotech IPOs.

Another consequence of the Wall Street meltdown, Kinsella says, is that Big Pharma companies have been hiring the biotech bankers laid off during Wall Street’s financial purges. As he puts it, “The sell-side guys were going to Big Pharma [companies] and saying they can cut better partnerships or buyout deals since they have an ‘inside baseball’ understanding of venture-backed biotechs, and they know how to wring the most concessions from a biotech’s board.”

He may well have a point there, although my first thought after reading that was "GSK should have hired some of those guys before doing the Sirtris deal". But Kinsella goes on to argue that there's not much of an "IPO exit" any more, and hasn't been for several years, so smaller companies are more dependent than ever on doing deals with the larger ones. And his worry is that we're eventually going to end up with fewer small companies, and that disproportionately stocked with outfits trying to go it alone. The chances for mutually beneficial partnerships are, if he's right, going down rather quickly. . .

Comments (31) + TrackBacks (0) | Category: Business and Markets

February 23, 2011

Gonna Focus on Re-Engineering the Tools for the Process

Email This Entry

Posted by Derek

I have tried several times to get my hands around what NIH head Francis Collins is talking about here (note: open-access article), but I now admit defeat. Allow me to quote a bit, and we'll see if anyone else out there has more luck:

We have seen a deluge of new discoveries in the last few years on the molecular basis of disease. . .(But despite) increasing investments by the private sector, there has been a downturn in the number of approved new molecular entities over the last few years. Also, drug development research remains very expensive and the failure rate is extremely high.

Perhaps in part responding to these factors, and to the downturn in the economy, pharmaceutical companies have cut back their investments in research and development. We can't count on the biotech community to step in and fill that void either, because they are hurting from an absence of long-term venture capital support. So, we have this paradox: we have a great opportunity to develop truly new therapeutic approaches, but are undergoing a real constriction of the pipeline. One solution is to come up with a non-traditional way of fostering drug development — through increased NIH involvement.

Hmm. I may have missed the deluge that he's talking about, but we'll set that concern aside. What might this "non-traditional way" look like? Collins again:

I like to think of this in a broad sense of “what kind of paradigm can we initiate and expand between academic researchers and the private sector to move the therapeutic agenda forward?” . . .By having the NIH more engaged in the pipeline, we can also ask whether we can improve the success rates of drug development. . .We need to re-engineer the process, with a lot more focus on the front end.

Right! Another thick block of wobbling gelatin. Let's see, we're going to get the NIH engaged, and, um, give them the tools, and re-engineer things, and oh yeah, focus. Definitely going to focus. Any more details to add?

There are a lot of moving parts to this set of resources that ultimately need to be synthesized into a smooth process. One of my goals over the next year is to try to identify ways to put these together into a more seamless enterprise.

Good to hear. Please, those of you with access to (see above) Nature Reviews Drug Discovery, where this interview appeared, take a look and see if you can condense anything more out of it than I did. I mean, King Lear had a more concrete plan of action than this one: "I will do such things - what they are, yet I know not, but they shall be the terrors of the earth."

Update: an NRDD editor has let me know that the interview is open access. He also points out that the piece was done before the official announcement of the NCATS idea. My take is while that might account for a bit of the fuzziness, everything I've seen since then has been similarly soft-focus. . .

Comments (41) + TrackBacks (0) | Category: Academia (vs. Industry) | Drug Development

Want to Live Where Merck Used to Work?

Email This Entry

Posted by Derek

A reader from the UK passes along this link. If you're wondering what's going to happen to the former Merck site at Terlings Park, well, here would appear to be your answer. The company is now looking to turn the property into a residential development, having apparently (after several years) given up on the idea of ever shifting it as a research facility. Word has been (see the comments here) that the facilities were deterioring at this point, anyway, making such a sale even less likely.

Having worked at a research site that was later paved over and turned into a Home Depot, among other things, I've seen some definitively repurposed facilities before. But considering the state of pharma research in the UK as a whole, this is another bad sign. Terlings Park seems to have had a much better location than Sandwich for doing R&D, so good luck indeed to these efforts. . .

Comments (18) + TrackBacks (0) | Category: Business and Markets

February 22, 2011

Oncology Follow-Up Trials

Email This Entry

Posted by Derek

During the most recent Avastin controversy (with its conditional approval for metastatic breast cancer being pulled by the FDA), the role of follow-up studies in oncology became a big point of discussion.

Now there are reports that some companies aren't exactly following up in the way that they're supposed to. This isn't good. Conditional approvals are granted under the banner of "better to help people now than wait for more data", but eventually the numbers have to show up. After all, not all of these treatments are going to confirm when they're looked at more closely.

Not all of this can be put down to foot-dragging on the part of the companies. In some cases, it's proven hard to round up enough patients for further trials, and in others, the trial protocols themselves have become outdated. But there needs to be some way to review these things more regularly (as seems to be the case in the EU) to keep the process from getting tangled up.

You'll note from the article that opinions are all over the place on how lenient the FDA's approval process really is. You have people who say that the agency is dragging its feet on life-saving treatments, and people (looking at the same data set) who say that they're letting too much stuff through on the flimsiest grounds. We're not going to resolve that argument any time soon. But can we at least agree that we're going to require evidence at some point?

Comments (11) + TrackBacks (0) | Category: Cancer | Clinical Trials | Regulatory Affairs

Science and Revolution

Email This Entry

Posted by Derek

GIven everything that's happening across North Africa and the Middle East, I thought a quick geopolitical note might be in order. This is very far from being a world politics blog, but there is a connection to science.

Specifically, it's been notable for some time how under-performing these regions of the world are, scientifically. I last wrote about this topic here, with a link to this map. That's ten-year-old data, but the main changes would be shifts among the bigger players. From roughly the western border of India over to the Atlantic ocean, things haven't changed much - the only country in that swath that's made a serious R&D mark is Israel.

In some cases, that's perfectly understandable. No one expects a country at Afghanistan's level of development to have much of a research culture; they've got plenty of other priorities. But you hit some pretty gaudy GDP/per capita numbers when you cross the oil-rich regions, and that money has not been plowed into science and technology. That's in spite of the funding that Saudi Arabia, for one, has thrown into various King-This and Prince-That institutions. Maybe they're going for more applied training - I absolutely cannot recall seeing any notable research result out of the Saudi system. Examples welcomed in the comments, if there are any. And the other oil-rich states are even further out in the wilderness, scientifically. The UAE? Kuwait? You'd have to do some real digging to find much of anything, as far as I can tell. Science, research, and invention have just not been priorities for these places, and changing that isn't easy.

Then you hit countries like Egypt, which are in the broad and sad category of "countries that really should be doing better than they are". I'd put Iran on that list, too. Scientifically, nations in this category have some infrastructure, but it's usually not enough to produce anything noteworthy. Their expatriate scientists and engineers, though, have flourished. There's clearly a lot of talent going to waste inside these places. Algeria and Morocco, too? They don't look so bad, though, when opposed to the next category, the Syrias and Libyas of the world. There's some GDP in these places (although nowhere near as much as there could be), but scientifically, they're absolutely off the map.

So now we get to asking why this should be so. Some of it can be put down to development, as mentioned above, but even the countries in this region that are better developed still aren't making much of a mark. I realize that I may be coming across as culturally insensitive here, because I'm assuming that R&D is the sort of thing that any society with enough money and talent would choose to do. But I'm willing to defend that assumption. I think that these activities really are a key part of a modern economy, and provide a productive outlet for a lot of brainpower. Instead, we have countries that are too poor to even think about these things (Afghanistan), too occupied in keeping the boot pressed down (Syria), several that have decided to sit back and enjoy their money (the oil sheikdoms), and a few that would like to do this sort of thing but aren't getting so much out of their efforts, like Iran.

And that brings us to the volatile topic of religion. Most of the region we're talking about is Islamic, of course. And while it led the world for a good while in mathematics, astronomy, and other sciences, it's also been clear for a long time that it later adopted a different attitude towards homegrown advancements in science and engineering. And this could well have something to do with the religious character of society. The pursuit of secular knowledge can, in some religious environments, seem like at best a distraction from more important matters, and at worst an active source of evil and discord. The present-day countries have all sorts of varying amounts and styles of religious observance, but this is always going to be a factor to consider.

And now we have revolutions ongoing in a lot of these places, and you have to assume that there are more to come - if not right now, then eventually. My own interest in Iran leads me to think, for example, that the lid is going to come off there at some point - and the longer the wait is, the worse the boilover will be. The question that everyone has, though, is what will replace the former regimes, once the lids have blown off? I would like, naturally, to see an Egyptian Republic (for example) that has a chance to get its act together. But that's not going to be easy, to put it very mildly. There are a lot of problems to solve, and a shortage of people who've had to opportunity to try solving them under the former regime of the Big Boss Leader. I fear that the most likely result is the advent of a new boss - who may be wearing a uniform, or robes, or even a nice suit, but who has the same ideas in mind as the last guy. I very much hope I'm wrong about that. Doors are opening; let's hope that many of them don't just slam shut again.

Comments (40) + TrackBacks (0) | Category: Current Events

February 21, 2011

Cutting The Cuts to Save Money on the Money-Saving

Email This Entry

Posted by Derek

Here's something that not everyone may have considered: there have, of course, been plenty of mergers and takeovers in the drug business over the last few years. These are driven by the need to fill pipelines and cut costs, and one of the biggest cost-cutting moves has been the outsourcing trend. (There are so many links to past discussions around here on these topics that I'm not even going to bother putting them up!)

But think the process through: if drug firms in the US and Europe consolidate, what does that do to the outsourcing suppliers? Well, it hits them, too. That's an article from India's Economic Times (via FiercePharma), and its quotes will sound eerily familiar:

"When global drugmakers cut cost, the pre-clinical and early phase drug development outsourced to Indian firms are among the easy targets," said a Mumbai-based pharma analyst with a global brokerage firm. . .

Yep, it's come to the point that we're cost-cutting the cost-cutting measures. In a way, it's sort of comforting to know that everyone's in the same boat. But what a boat it is.

Comments (29) + TrackBacks (0) | Category: Business and Markets

February 18, 2011

Smell The Vibrations? Fruit Flies Might Be Able To. . .

Email This Entry

Posted by Derek

A few years ago, I wrote here about Luca Turin and his theory that our sense of smell is at least partly responsive to vibrational spectra. (Turin himself was the subject of this book, author of this one (which is quite interesting and entertaining for organic chemists), and co-author of Perfumes: The A-Z Guide, perhaps the first attempt to comprehensively review and categorize perfumes).

Turin's theory is not meant to overturn the usual theories of smell (which depend on shape and polarity as the molecules bind into olfactory receptors), but to extend them. He believes that there are anomalies in scent that can't be explained by the current model, and has been proposing experiments to test them. Now he and his collaborators have a new paper in PNAS with some very interesting data.

They're checking to see if Drosophila (fruit flies) can tell the difference between deuterated and non-deuterated compounds. The idea here is that the size and shape of the two forms are identical; there should be no way to smell the difference. But it appears that the flies can: they discriminate, in varying ways, between deuterated forms of acetophenone, octanol, and benzaldehyde. Deuterated acetophenone, for example, turns out to be aversive to fruit flies (whereas the normal form is attractive), and the aversive quality goes up as you move from d-3 to d-5 and d-8 forms of the isotopically labeled compound.

The flies could also be trained, by a conditioned avoidance protocol, to discriminate between all of the isotopic pairs. Most interestingly, if trained to avoid a particular normal or deutero form of one compound, they responded similarly when presented with a novel pair, which seems to indicate that they pick up a "deuterated" scent effect that overlays several chemical classes.

There's more to the paper; definitely read it if you're interested in this sort of thing. Reactions to it have been all over the place, from people who sound convinced to people who aren't buying any of it. If Turin is right, though, it may indeed be true that we're smelling the differences between C-H stretching vibrations, possibly through an electron tunneling mechanism, which is a rather weird thought. But then, it's a weird world.

Comments (35) + TrackBacks (0) | Category: Biological News | Chemical News

February 17, 2011

Health Care Reform and the Drug Industry: How Goes It?

Email This Entry

Posted by Derek

We haven't had enough controversy and arguing around here this week, have we? Let's talk politics for the morning, then. Here's a piece from a former VP for public affairs at Pfizer, arguing that PhRMA got thoroughly snookered during the health care reform bill. He's looking over the current budget proposal:

For biotech and pharmaceutical companies, the president’s budget repudiates one of the most important benefits of their “deal” with the White House: the ability to market biotech drugs without generic competition for twelve years. The president would reduce that period to seven years, precisely the position of the generics industry and a position that the pharmaceutical industry had fought aggressively before it decided to make a deal with the president.

I worried about this sort of thing at the time, in the last post in which I had the nerve to bring up this issue. (In fact, if you go back and read some of the dissenting comments to that post, the twelve-year exclusivity provision was listed as one of the main reasons the bill was a good idea for the industry). Even I didn't think my last paragraph would start coming true quite this quickly, though. (I'll note in passing that my worries about the "doc fix" were justified, too). And yes, it's true that the President's budget proposal is a political football, put onto this earth to be kicked around by all parties, and that nothing in it will necessarily turn into reality. But still - isn't that a rather short time to be about-facing on this provision? Less than a year?

There's an alternate explanation: that the twelve-year provision was never really in there at all. We just thought it was! No, that wasn't marketing exclusivity at all, but data exclusivity. Or not - was it a mix of the two? What sort of mix? All sorts of people are writing to the FDA these days, telling them what they think the law actually means. Not that the agency is legally bound to listen to a word of it.

Even without any backtracking on exclusivity, the article maintains that health care reform was a loser for the drug industry. The author goes on on to detail the various other costs of the bill as it was passed, and then gets to the biggest structural problem:

While the healthy part of the pharmaceutical market will be pounded, the government-run segment of the market, Medicaid, will be expanded by 16 million patients. Medicaid has the worst pricing structure and the worst track record in paying for innovations of any sector in the United States market. Like government health-care systems around the world, Medicaid must be dragged to pay for medical advances. Unlike employers and seniors in Part D, Medicaid patients cannot vote with their feet if their health plan does not provide the new medicines they want. The incentives in Medicaid all run against paying for pharmaceutical innovations.

So, Obamacare significantly expands the worst sectors of the pharmaceutical market while degrading the best.

Well, fine, you may say, this are quotes from an opinion piece at National Review, and what else would you expect but that they're opposed to the bill over there? But these issues would be worth thinking about even if they were squawked out by flocks of crows. I really do worry that the drug industry made a serious mistake by agreeing to the health care reform bill - not only agreeing to it, mind you, but committing large amounts of money to beating the drum for it and seeing that it got passed. And that means that PhRMA made a serious mistake by putting Billy Tauzin in charge of that effort. Perhaps a backslapping deal-maker wasn't what was needed?

Okay, that gets politics out of my system for a bit. The whole health care reform bill is going to end up in the Supreme Court anyway, on commerce-clause grounds, so arguing about specific language may turn out to be a waste of time. But while I'm in the mood, though, I'll close with (what else?) a quote from Barry Goldwater. A government that's big enough to give you everything you want, he used to say, is big enough to take it all away. . .

Comments (63) + TrackBacks (0) | Category: Current Events | Regulatory Affairs

February 16, 2011

The Key Player in the Sanofi-Genzyme Deal Speaks Out

Email This Entry

Posted by Derek

In light of the two companies reaching an agreement on price yesterday afternoon, a behind-the-scenes participant in the deal asked people to remember what set the whole process in motion.

"If it weren't for me, this never would have gotten off the ground", claimed Vesivirus 2117. "Moving into that facility in Allston was the step that made it all possible", the virus claimed. "Does anyone think that Genzyme wouldn't just be humming along as before if it weren't for me? The stock price, the confidence of the shareholders - all that went down through my efforts, and I just want to make sure that credit is given where it's due".

The virus, which is not known to infect humans, pointed out that you don't have to directly invade the human body to affect human affairs. "Subtlety, that's the thing," the organism stated. "You come in through the front door - nose, mouth, whatever - with all your guns blazing, and sure, you get the press, the headlines. But right from the start, they're trying to bring you down. Now, infecting cell cultures, there's no immune system to worry about, and if they've never seen you before, well, no one knows you're there. Until you're really, really there, if you know what I mean."

The virus went on to say that its tenacity was just as crucial as its element of surprise. "They're been cleaning the place out for a year now", it said with satisfaction. "And are they sure that they've gotten rid of me? Is the FDA sure? I think not." Vesivirus 2117 said that it welcomed the chance to work with whoever Sanofi-Aventis assigned to its area. "Viruses, you know, we're international. Bonjour!"

Comments (21) + TrackBacks (0) | Category: Business and Markets

February 15, 2011

Noted, Through Massive Self-Restraint, With Almost No Comment Whatsoever

Email This Entry

Posted by Derek

Update: call off the dogs! I've heard from a colleague of Dr. Pepys, who strongly believes that this was a tongue-in-cheek remark. He assures me that Pepys has been around the clinical development block a number of times in the field of amyloidosis, which is a hard enough area to give anyone a good idea of what discovering a useful therapy is really like.

This would not be unheard of - both for a newspaper story to quote a flippant remark out of context, and for the tone of such a remark to be completely lost once it appeared on paper. After looking the situation over, I think that's just what's happened here. It's a sad thing, though, that a remark like this is close enough to some real opinions that it could be taken as read. . .

From the Financial Times:

GlaxoSmithKline aims to sign up 10 academic “superstars” this year for long-term partnerships to help develop medicines more effectively and cheaply. . .

The move comes as the UK pharma group cuts back on costly but unproductive early-stage in-house research and attempts to shift from investment in fixed assets towards more flexible partnerships with external developers.

GSK has recently finalised its first such contract with Professor Mark Pepys, head of medicine at the Royal Free and University College Medical School in London, designed to develop a treatment for a rare form of amyloidosis. (Glaxo senior VP Patrick) Vallance said he planned to sign 10 such deals this year. . .

“It’s a wonderful idea,” said Prof Pepys. “We all agree that big pharma is useless at discovering new drugs and has to get its ideas from somewhere else."

Were I working for GSK, I would be very, very excited. Finally, a clear statement of what the company thinks of its own employees. The Sirtris deal (and others) have hinted at the contempt under the surface, but it's good to get it out into the open. Isn't it?

Comments (118) + TrackBacks (0) | Category: Press Coverage

February 14, 2011

New Cures! Faster! Faster!

Email This Entry

Posted by Derek

I wrote here the other day about the NIH's new translational medicine plans. The New York Times article that brought this to wide attention didn't go over well with director Francis Collins, who ended up trying to disabuse people of the idea that the NIH was going to set up its own drug company.

But there's been an overwhelming negative response from the academic research community, largely driven (it seems) by worries about funding. Given the state of the budget, flat funding would be seen as a victory by NIH, so this isn't the best environment to be talking about putting together a great new institute. The money for it will, after all, have to come out of someone else's pile. Collins spends most of that statement linked above denying this, but it's hard to see how there won't be problems.

I think, though, that there's an even more fundamental problem here. In the latest BioCentury, there's an interesting sidelight on all this:

In comments submitted to NIH, Joseph Zaia, associate director of the Center for Biomedical Mass Spectrometry at the Boston University School of Medicine, argued against setting timetables for research results. “I do not believe that running medical science on a short sighted business time schedule will produce more cures faster. It will, however, deplete NIH resources very rapidly and possibly tear down an infrastructure of knowledge that took decades to create.”

Zaia complained that the NCATS “process seems to be driven by the FasterCures movement sponsored by Michael Milken,” which he said has “been masterful in manipulating the political system for their purposes, and forcing NIH into this reorganization.”

FasterCures’ Margaret Anderson, executive director of the non-profit group that advocates for accelerating medical innovation, submitted a letter strongly endorsing NCATS, which she said “will provide a significant stimulus to moving ideas out of the lab and into the clinic.”

And that's the problem. Over the last few years, an idea has taken hold that there are all kinds of great ideas for all kinds of diseases that no one is doing anything with. Now, I'm not going to claim that everyone is trying every single thing that could possibly be tried, but I really don't see how there's this treasure chest of great discoveries that aren't being followed up on. Drug companies of all sizes are always watching for such opportunities - I've been a part of many such efforts to jump on these as they show up.

My guess is that many of these advocates have a different definition of what a "great discovery" is than I do. There are all kinds of things that come out in the literature, often with breathless press releases from the university PR office, that make it sound like the latest JBC paper has the cure for cancer in it. But the huge majority of these things don't pan out, generally because they're just part of a much, much larger (and more complicated) story. And that's why things tend to fail on the way to (and through) the clinic.

Am I exaggerating? Well, many advocates in this area have taken to using the phrase "valley of death" to describe the gap between basic research and success in the clinic. Here's Amy Rick of the Parkinson's Action Network:

Rick said patient groups are concerned that the valley of
death is growing, and they want government to help bridge it. The prospect that there are “good discoveries that are basically collecting dust” is “terrifying to patients,” she said.

“What we are finding from a patient perspective is that discoveries that are being made in very exciting basic research are not being acted upon,” Rick told BioCentury This Week. “They are not moving through the pipeline. So the patient community is pushing very hard — if private money isn’t filling that space, the government should be moving some of its funding into that space.”

I have a great deal of sympathy for the patient population - they're our customers in this business, after all, and any one of us could join their ranks at any time. (Drug company researchers come down with all the maladies that everyone else does). But the patient population is not the group of people discovering and developing drugs. What looks like agonizingly slow progress from outside is often just the best that can be done. It can be hard to imagine how crazy, complex, and frustrating medical research can be unless you've tried doing it. Nothing else quite compares.

I worry that some of these people have an unrealistic view of how things work (or should work). This all reminds me of Andrew Grove, ex-Intel, and his complaints that the drug research business wasn't moving as fast as the semiconductor industry. It sure isn't. That's because it's a lot harder.

The Biocentury article is right in line with my thinking here:

FASEB’s Talman argues that patient groups and the public are overly optimistic about the breakthroughs that could be made by shifting resources to translational science. He believes basic scientists are partly to blame because “there is too much of a tendency for basic or clinical scientists to sell our work.” In the process, he said, “we can come across as saying that the newest discovery can lead to a cure.”

Senior NIH officials have contributed to the belief that cures are around the corner by dangling the prospect of quick payoffs in front of congressional appropriators. For example, in 1999, Gerald Fischbach, then director of the National Institute of Neurological Diseases and Stroke, told a Senate committee that with sufficient funding it was reasonable to expect a cure for Parkinson’s disease within five years. The NINDS budget has increased from $902 million in FY99 to $1.6 billion in FY10, but PD hasn’t been cured.

Starting in 2004, National Cancer Institute Director Andrew von Eschenbach claimed in numerous public speeches that it would be possible to “end suffering and death from cancer by 2015,” a claim that current NCI Director Harold Varmus has repudiated.

When he led the human genome sequencing effort, NIH Director Collins himself made comments that the press, public and politicians interpreted as promising that it would directly and quickly lead to new medicines for common diseases.

“There is a real danger of over-promising,” Keith Yamamoto, executive vice dean of the University of California San Francisco School of Medicine, told BioCentury. “Scientists too often take an intellectual short cut. They think they will not be able to explain the nuances of why basic discovery takes so long, so they just say if you give me the money we are about to cure the disease.”

He added: “That’s thin ice — it is our responsibility to explain why things are as difficult as they are.”

It sure is. I know that patients and the general public get tired of hearing about how it's hard, how discoveries take time, all that sort of thing, while the diseases just keep marching on and on. But it's all true. I honestly don't think that most people realize, despite that huge amounts of knowledge we've managed to accumulate, just how little we know about what we're doing.

Comments (39) + TrackBacks (0) | Category: Academia (vs. Industry) | Cancer | Drug Development | The Central Nervous System

February 11, 2011

Merck, J&J, and Remicade: Waiting Nervously

Email This Entry

Posted by Derek

Is Merck going to hold on to Remicade (and its follow-up) or not? That topic came up around here (and not just here) right after the merger with Schering-Plough was announced - it was the whole reason for the elaborately structured legal charade that Schering-Plough was buying Merck, after all. The issue is in arbitration, and a ruling could come any day now. Or in the spring, or who knows - but Wall Street is starting to bite its nails.

It'll be easy to spot when the decision comes down. Merck stock will suddenly move a good 5 per cent - but in which direction? I'll go ahead and get my prediction down, in case we get word soon: I think Merck will lose out. The best that they can hope for, I think, is a fairly small share of the profits, and they may well not even get that. Whoever advised Merck's executives that this issue could be finessed - and the executives who believed that theory - will, in that case, not come out looking very good at all.

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

Drug Problems: A Diagnosis

Email This Entry

Posted by Derek

There's no shortage of "What's Wrong With the Drug Industry" article these days. I wanted to call attention to another one that's just appeared in JPET. I don't agree with all of it, but it does make some important points.

If I had to give a one-line summary of its thesis, it would be "Drug discovery forgot pharmacology and lost its way". The author, Michael Williams of Northwestern (and of 35 years at Merck, Novartis, Abbott, and Cephalon) is a pharmacologist himself, and feels that the genomics era (and indeed, the whole target-driven molecular biology era) has a lot to answer for. He also thinks that people have become seduced by technology:

Rather than creating synergies by using multiple complementary
technologies to find answers to discrete questions in a focused and coherent manner, technology-driven drug discovery has become a discipline that justifies its existence by searching for questions. An example of this is the proteomics approach to target validation, where the intrinsic complexity of the protein component of a cell or tissue necessitates a reductionistic approach where experimental samples must be separated into bins to facilitate analysis with timelines for data generation that can stretch into months or years.

To those with a technology bent, new iterations on a technology, regardless of its utility, inevitably become “must haves,” with acquisition and implementation becoming ends unto themselves. . .

One place I disagree with him is in his assertion that "Implicit in the HTS/combinatorial chemistry paradigm was/is that each target was equally facile as a starting point for a drug discovery project". That hasn't been my experience at all - there's always been a lot of arguing about which targets should be taken to screening and of what kind (how many GPCRs versus enzymes versus what-have you). Williams makes his point in the context of the genomics frenzy, when it was thought that all kinds of targets would be emerging. But at least where I worked, the hope was that genomics would provide a lot of good, tractable target that we hadn't known about, rather than just a long list of orphan receptors and whatzitases. (Mind you, that list is exactly what we ended u with).

Williams then discusses the problem of whether some targets are, in the end, truly intractable. The "just one more whack at it, and we'll get there" approach sometimes works, but it does try the patience:

Drugs active at opioid receptors remain the gold standard of analgesic care and include morphine, codeine, and oxycodone. With the discovery of the mu, delta, and kappa receptor subtypes in the 1970s, it was anticipated that development of selective agonists for these receptors would result in drugs that had a reduced liability for the respiratory depression, tolerance, constipation, and addiction associated with classical opioids. Some 40 years later, despite considerable efforts in medicinal chemistry and molecular biology to refine/define the structural characteristics of receptor-selective NCEs, the ”holy grail” of side effect-free opioids appears as elusive as ever, with a multitude of compounds showing compelling preclinical data but failing to demonstrate these properties in the clinic. . .

Another of his examples in this line are the muscarinic ligands, which I know from personal experience, as a search of my name through the literature and patent databases will show. And although GPCRs are among the most valuable target classes of all, we still have to face up to some disturbing facts about them:

Thus, for both of these G protein-coupled receptor families, a major question is whether their function is so critical, nuanced, and complex as to preclude advances based on the molecular approaches currently being used that may lack the necessary heuristic relationship to the complexity/redundancies of the systems present in a more physiological or disease-related milieu. Based on progress over the past 40 years, it may well be concluded that the opioid and muscarinic receptor families represent intractable targets in the search for improved small-molecule therapeutics. But maybe the next NCE….???

At the end of the article is a table of possible approaches to get out of the preclinical swamp. Interestingly, it's noted that it was "generated at the request of one of the reviewers", who probably asked what the author proposed to do about all this. I won't reproduce it all here, but it boils down to being more rigorous about data and statistics, using the hardest, most real-world models, and giving people the time to pursue these approaches even if they're going against the crowd while doing so. I don't see any his recommendations that I disagree with, but (and this isn't his fault), I don't see any of them that I haven't seen before, either. There needs no ghost, my lord, come from the grave, to tell us this.

Comments (23) + TrackBacks (0) | Category: Drug Development | Drug Industry History

February 10, 2011

The Top 200 Drugs

Email This Entry

Posted by Derek

If you haven't seen the "Top 200 Drugs" posters, available as PDFs from this group at the University of Arizona, then give them a look. It's good to have this information in graphical form, with chemical structures attached.

One thing that stands out as you browse through the table is the number of compounds that make you say "Hold it - that's a drug?" I think that's one of the most valuable things about the poster, actually. It's worth seeing how simple some useful compounds are (valproic acid, anyone?), or what functional groups have made it through. The next edition of the poster will surely feature Gilenya (fingolimod), whose structure baffles and offends almost every chemist at first glance.

It's a dose of humility, seeing these things. And while it's true that we get regular doses of humiliation in the research business, our pride is pretty resilient, too.

Comments (45) + TrackBacks (0) | Category: Business and Markets | Drug Industry History

February 9, 2011

Thallium Poisoning? In This Day and Age?

Email This Entry

Posted by Derek

Thallium poisoning? Now someone in the lab has really lost it. But that seems to be what happened in New Jersey, with a chemist from Bristol-Myers Squibb accused of doing in her husband.

A note to the Newark Star-Ledger and some other newspapers: even though a hot isotope of it is occasionally used in medicine, the thallium in this case was not radioactive. It doesn't have to be; it's a good old-fashioned chemical poison. The element enters cells readily, being taken up as if it were potassium, but once it's there it starts disrupting all kinds of processes by latching on to sulfur atoms. It was good enough for Agatha Christie to use it for one of her plots, which (interestingly) seems to have publicized it enough that several other thallium plots were discovered or foiled because of her novel.

As even Wikipedia points out, thallium was "once an effective murder weapon", but the emphasis is one "once". That time is long past. Forensically, it's not the first thing that you think of, certainly, but it got picked up at autopsy in this New Jersey case. And it's not like there's any other way a person could get a high level of the element in their tissues, nor, with modern analytical techniques, can it be mistaken for anything else. Honestly, anyone who believes that they have a good chance of getting away with a thallium murder is just not thinking the whole business through.

There are no details about how the crime was done, but we can assume that some kind of soluble thallium salt was put into the victim's food. Thallium chloride is the cheapest source (as usual - Primo Levi was right when he said "chlorides are rabble"), but I'm not sure how cost-conscious the accused was. She very likely got the compound from work - and even there, it wouldn't surprise me if she had to order it up on some pretext, which will certainly make the investigation easier. Thallium's not a very common metal in organic chemistry - I've seen some uses for it, but nothing compelling enough to make me want to try it.

It's odorless and tasteless stuff, by all accounts. But it's a stupid poison. I'm not going to speculate on better methods - I haven't put that much thought into the topic, really - but there have to be some, possibly with obscure and nasty natural product toxins. Not that it's so easy to get ahold of those, but the Engineer's Triangle still applies, to murder as to everything else: Good, Fast, Cheap: Pick Any Two.

So in the end, we have what looks like a vindictive (but not very competent) poisoner, a dead victim, and all kinds of trouble and fallout for the innocent bystanders in all the families concerned. A sordid business.

Comments (63) + TrackBacks (0) | Category: The Dark Side | Toxicology

Fanapt: Not Paying Out

Email This Entry

Posted by Derek

Poker players in the audience may remember the old story of the guy who lost three cars over the years by drawing to try to fill inside straights - the first two when he came up empty, and the last time when he made his hand. You can have the same experience in drug development, too, for higher stakes.

Remember Fanapt (iloperidone)? That's the antipsychotic compound that bounced around from company to company during the 1990s, and nearly sank Vanda Pharmaceuticals a few years ago when the FDA gave them a "Not Approvable" letter. I predicted at the time that we'd never hear from them again, but to my surprise (and to Vanda's, I'd guess), the FDA reversed itself and let the compound through in 2009.

Novartis signed up to market the drug, and it was launched early last year. Some analysts predicted about $100 million in sales, growing to two or three times that number - not a blockbuster, but very welcome indeed for Vanda (and for earlier developer Titan, who still retained some rights). And now, reports Adam Feuerstein, we have the full-year numbers: $31 million, most of which appears to have been initial inventory stocking. Not good.

I've already tried to teach my kids not to draw to the inside straight. The more advanced player needs to try to work out if the pot offers a payout consistent with the risks, and to figure out what the chances of that payout might be, even if the hand comes through. . .

Comments (10) + TrackBacks (0) | Category: Business and Markets | The Central Nervous System

February 8, 2011

Too Much Outsourcing: Has the Line Been Crossed?

Email This Entry

Posted by Derek

We've talked a lot about outsourcing on this blog, since it's been one of the biggest features of life in this industry over the last few years.

It's not hard to see why. Costs. We spend too much money finding drugs (which don't always make it back even when they succeed). Anything that cuts costs more than it cuts productivity is going to be tried.

But any idea can be taken too far. Here's Boeing's current CEO, talking about the cost overruns on the 787 Dreamliner project, and how they were made worse by overzealous outsourcing:

. . .the 787's global outsourcing strategy — specifically intended to slash Boeing's costs — backfired completely.

"We spent a lot more money in trying to recover than we ever would have spent if we'd tried to keep the key technologies closer to home," Albaugh told his large audience of students and faculty.

Boeing was forced to compensate, support or buy out the partners it brought in to share the cost of the new jet's development, and now bears the brunt of additional costs due to the delays.

Read the whole article; it's extremely interesting, and especially so for those of us in the drug industry. There was a Boeing employee who specifically criticized this process some years ago, and the whole return-on-net-assets view of the business world, and the company seems (belatedly) to be giving him his due. His line about how the biggest return would come from having someone else build the plane and then slapping a tiny Boeing decal on the nose is funny, but in a painful way.

So here's the question: have companies in our industry reached this point? And if so, which ones? Reports like this one make me think that some organizations have crossed that invisible line, and will regret it. I think that "zero outsourcing" is probably a bad idea. But "way too much outsourcing" could be worse. . .

Comments (48) + TrackBacks (0) | Category: Business and Markets | Drug Industry History

Whistleblowers: Paid Too Much?

Email This Entry

Posted by Derek

A former prosecutor says that the huge payouts in some recent whistleblowing cases in the drug industry have gotten out of hand. The law, says Michael Loucks, was never intended to reach up into these sorts of figures, and he's suggesting a cap of $2 million as a reasonable incentive.

I'm not sure if I agree with that or not. It's true that a New England Journal of Medicine report last year found that most pharma informants in such cases say that they were not motivated by the money involved:

Although the relators in this sample all ended up using the qui tam mechanism, only six specifically intended to do so. The others fell into the qui tam process after seeking lawyers for other reasons (e.g., unfair employment practices) or after being encouraged to file suit by family or friends. Every relator we interviewed stated that the financial bounty offered under the federal statute had not motivated their participation in the qui tam lawsuit. Reported motivations coalesced around four non–mutually exclusive themes: integrity, altruism or public safety, justice, and self-preservation.

And that seems believable. But what I'm thinking about is the motivation for the people who are promulgating the behavior that the whistles get blown on. These are not people for whom personal integrity is as strong a motivating factor (although self-preservation would certainly still rank high). Many of them, I'd venture to guess, are in fact people who would fear that others might be motivated mostly by a large payout. And if that's true, the publicity around the large whistleblower awards might help restrain them.

Why don't such people just take the money and run, themselves? Several reasons, I'd say, not least of which is the fact that they're generally quite implicated in the very behavior that the Department of Justice would like to prosecute. But another motivation for that sort of personality is the loss of status and position that such a decision would mean. I'm convinced that having power is a strong motivator for most people, and for some it's the primary one. Money is great, and the other benefits are great, too - but for many people, it's being the boss that is the sweetest part of the job (along with the prospect of working one's way up to being an even bigger boss, of course). Blowing the whistle means saying goodbye to that, irrevocably.

As an aside, people for whom personal power is the prime motivation do not tend to turn out well if they get their wish, to put it mildly. This is a good time to quote Lord Acton. I also recall Gore Vidal's essay "Robert Graves and the Twelve Caesars", pointing out what a depressing spectacle they tended to make once the experience of empire got through with them:

Yet what, finally, was the effect of absolute power on twelve representative men? Suetonius makes it quite plain: disastrous. Caligula was certifiably mad. Nero, who started well, became progressively irrational. Even the stern Tiberius's character became weakened. In fact, Tacitus, in covering the same period as Suetonius, observes: 'Even after his enormous experience of public affairs, Tiberius was ruined and transformed by the violent influence of absolute power.' Caligula gave the game away when he told a critic, 'Bear in mind that I can treat anyone exactly as I please.' And that cruelty which is innate in human beings, now give the opportunity to treat others as toys, flowered monstrously in the Caesars.

And there's always this:

The Party seeks power entirely for its own sake. We are not interested in the good of others; we are interested solely in power. Not wealth or luxury or long life or happiness: only power, pure power. . .Power is not a means, it is an end.

It is, fortunately, a long way from Mr. O'Brien there (or Tiberius) to a typical hard-charging, rule-bending executive. But it's a difference of degree - not of kind.

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

February 7, 2011

Not Letting Pfizer's UK Site Go to Waste?

Email This Entry

Posted by Derek

Let's hope that this works out - there's an attempt going on to bring in as many small-company investors as possible to keep parts of Pfizer's former Sandwich site open (and employing scientists):

George Freeman, the Tory MP and biotech expert, is calling on the Government to open Pfizer's site in Sandwich to venture capitalists and biotech angels in a bid to save as many of the 2,400 jobs, due to be axed when the plant closes, as it can.

Mr Freeman is in contact with top UK entrepreneurs, including Hermann Hauser, who founded Acorn computers, and serial biotech businessman Andy Richards, about how best to help the Pfizer scientists recycle their knowledge and skills into spin-outs or other similar ventures.

The problem with such efforts is that getting them off the ground after a site closure has been announced can be difficult. Even at their best, they won't be able to keep as many people discovering drugs as the old site did - but it's still much, much, better than nothing. Any UK readers with knowledge of what's going on, feel free to add details in the comments. . .

Comments (25) + TrackBacks (0) | Category: Business and Markets

Fragments Versus DOS: A Showdown

Email This Entry

Posted by Derek

Nature has side-by-side editorial pieces about fragment-based drug discovery versus diversity-oriented synthesis (DOS). I've written about both topics here before (DOS here and here, fragments here and here), and it should be fairly clear that I favor the former. But both ideas deserve a hearing.

Background, for those who aren't having to think about this stuff: the fragment-based approach is to screen a reasonable set (hundreds to low thousands) of small (MW 150 to 300) molecules. You won't find any nanomolar hits that way, but you will find things that (for that molecular weight) are binding extremely efficiently. If you can get a structure (X-ray, most of the time), you can then use that piece as a starting point and build out, trying to keep the binding efficiency high as you go. Diversity-oriented synthesis, on the other hand, tries to make larger molecules that are in structural spaces not found in nature (or in other screening collections, either). It's a deliberate attempt to make wild-blue-yonder compounds in untried areas, and is often used to screen against similarly untried targets that haven't shown much in conventional screening.

The two articles make their cases, but spend some time talking past each other. Abbott's Phil Hajduk takes the following shots at DOS: that it's tended to produce compounds whose molecular weights are too high (and whose other properties are also undesirable), and that it needs (in order to cover any meaningful amount of chemical space at those molecular weights) to produce millions of compounds, all of which must then be screened. Meanwhile, Warren Galloway and David Spring of Cambridge make the following charges about fragment work: that it only works when you have a specific molecular target in mind (and that only then when you have high-quality structural information), that it tends to perform poorly against the less tractable targets (such as protein-protein interactions), and that fragments (and the molecules derived from them) tend not to be three-dimensional enough.

Here's my take: I like phenotypic screening, where you run compound collections across cells/tissues/small animal models and see what works. And fragment are indeed next to useless for that purpose. But I agree with Hajduk that most of the DOS compound libraries I've seen are far too large and ugly to furnish anything more than a new probe compound from such screens. There are many academic labs for whom that's a perfectly good end point, and they publish a paper saying, in short, We Found the First Compound That Makes X Cells Do Y. Which is interesting, and can even be important, but there's often no path whatsoever from that compound to an actual drug. I'd prefer that DOS collections not get quite so carried away, and explore new structural motifs more in the range of druglike space. But that's not easy - new structures are a lot easier to come by if you're willing to make compounds with molecular weights of 500 to 1000, since (a) not so many people have made such beasts before, and (b) there are a lot more possible structures up there.

Now, if I have a defined target, and can get structures, I'd much prefer to do things the fragment way. But this is where the two editorial talk past each other - they both beat the drum for what they do well, but they do different things well. It's the parts where they overlap that I find most interesting. One of those is, as just mentioned, the problem that DOS compounds tend to be too large and undevelopable (with one solution being to go back and make them more tractable to start with). The other overlap is whether fragment collections can hit well against tough targets like protein-protein interactions. I don't know the answer to that one myself - I'd be glad to hear of examples both pro and con.

So we'll call this a struggle still in progress. With any luck, both techniques will keep each other's partisans on their toes and force them to keep improving.

Comments (33) + TrackBacks (0) | Category: Drug Assays | Drug Development

February 4, 2011

Merck's Strategy vs. Pfizer's

Email This Entry

Posted by Derek

Here's an interesting contrast after all the Pfizer discussion here over the last few days. Merck's CEO, Ken Frazier, has actually pulled the firm's earnings-per-share guidance, saying that the recent trouble with vorapaxar and regulatory concerns in general make it impossible to say for certain what EPS growth will be. He also says that he'd rather have a freer hand to pay for both sales and research, in the interest of long-term growth.

Not everyone's buying it:

Analysts on Merck’s conference call were skeptical about the reasoning behind the guidance change. Catherine Arnold of Credit Suisse, who called the change “befuddling” in her note to investors, told Frazier that investors expected Merck to “share the pain” of shareholders and noted that vorapaxar, launching in 2012, should have been a “drag on earnings, not a positive.” Frazier replied that Merck’s cost-cutting efforts were ahead of schedule, but that he was faced with a decision to either withdraw guidance or commit to cutting projects that could make money in the future. He also argued that because Merck’s sales reps already visit cardiologists to sell heart drugs, selling vorapaxar, too, would not cost much more.

Well, if he's sincere in this, I have to salute the guy. I don't think that the Schering-Plough merger was a good thing, and Merck has certainly laid off people and disrupted a lot of things because of it. But if they're not going to pull a Pfizer - which I will define for now as "Keep cutting to make the numbers, and when you can't do that any more, then go out and buy someone else who has things to sell and then cut them" - then good for Merck. This topic came up explicitly during the earnings conference call:

Jami Rubin - Goldman Sachs Group Inc.: More of a strategic question. Just given the setback that you've faced with vorapaxar, I'm just wondering if you can provide us with your view of the research model going forward? I mean, might it make sense for some of these the very large, very expensive, very risky outcomes trial such as vorapaxar, how do you buffer these trials? I mean, might it have made sense to isolate some of these subgroups before pursuing a large trial, and I know that it's obviously what's happening with anacetrapib. Maybe if you could talk just in terms of how you see the R&D spend going forward. Also, it's interesting that yesterday or the day before Pfizer announced a significant cut to its R&D. And I'm just wondering if you can talk about your R&D spend going forward, and if you see opportunities to really rethink that budget and to improve the R&D output. . .

Kenneth Frazier You asked some very typical questions in that set of questions. Let me start with vorapaxar. So I assume that what you're essentially asking is in hindsight, could we have done two separate trials. One in the ACF population, one with essentially the prevention population. I can't comment on the trial design. It was so long ago, but what I can say is that as we, as a committee with Peter and Adam and Peter Kellogg and myself, what we do regularly in the company is try to assess all the programs that we're relying on. We try to look at them from a science and technical and medical standpoint. We also try to look at them from a commercial standpoint. So we try to engage each program one by one, in addition to having the kinds of tough metrics we have in place around ROI and value creation in the pipeline. What I would also say is that we recognize that our strategy comes with it a certain amount of complexity, lengthiness and unpredictability because we are seeking innovative medically important therapies. And with vorapaxar, we know the risk of trying new mechanisms and approaches. I still continue to have optimism because the DSMB continued in 2P, we will see what the data shows. If the data shows a benefit to that population, this could still be a very important drug going forward.

On the Pfizer question, obviously, I can't comment on anyone else's view of their particular pipeline or the investment requirements that they face at this time. But I will tell you that we are mindful of the need to drive productivity, greater productivity in our R&D program. Peter Kim and his colleagues understands that we are focused on it. We are trying to take cost out. We're trying to increase the probability of success as we go forward. But as a company, I think we are saying that we are committed to innovation as a strategy, and we believe that over the long term it will pay off. And if you'll indulge me one minute, last week I attended the funeral of John Horan, who was the CEO of Merck a number of years ago before Roy Vagelos. One of the things he was proud us of was that he kept the focus on research during a fallow period for Merck Research in the 70s, and that's exactly what led to a state of innovation that has made the modern-day Merck. So I am not blind to what investors want us to do. They want us to invest in prudent ways and ways that actually drive ROI and productivity. But we, as a company, believe that the only sustainable strategy in the health care environment that we're in is real innovation that makes the difference to patients and payers. . .

As I said above, I can disagree with some of the ways that Merck is trying to run its R&D business, not that they're asking for advice from me. But it at least appears as if their heart - and their head - might be in the right place. Or they at least want to make it appear as if they're in the right place. And that they're willing to tick off some Wall St. analysts in order to be seen to be doing that. Which should count for something - you'd think.

Comments (37) + TrackBacks (0) | Category: Business and Markets | Drug Industry History

February 3, 2011

Pfizer's CEO Speaks

Email This Entry

Posted by Derek

If you'd like to hear Pfizer's CEO, Ian Read, try to explain what's going on a the company, Matthew Herper has his recent Q-and-A with the press here. As you might imagine, he's got a story to tell you about how cutting the company's R&D again is going to make it even more innovative.

But I particularly was struck by this part:

One of the main goals of the changes is to try and prevent any repeat of Pfizer’s disastrous investment in Exubera, the inhaled insulin, which the company spent years developing before it hit the market and bombed. Without accountability, Read says, projects were handed off from one team to the next without demands that they actually be ready.

Now, I'm someone looking in from outside, but accountability doesn't seem to me to be the biggest problem that the Exubera project had. I took at crack at the subject myself, and I still think the biggest problems were groupthink, self-deception, and a feeling that the penalties for speaking up against the trend were too great. Ian Read's press conference, on the other hand, has a tone of "Now we're really going to come down on anyone who screws up like this, and you know what? That isn't going to help with any of those factors. It might even make them worse.

But hey, at least it's not costing Pfizer as much to aim people out onto the sidewalk as it used to. The standard severance package was cut just a few months ago. . .

Comments (28) + TrackBacks (0) | Category: Business and Markets

February 1, 2011

Pfizer Part Two: Cuts at Groton

Email This Entry

Posted by Derek

Not only is Pfizer wielding the ax in England, but they're cutting 1,100 jobs back at HQ in Groton, while moving some therapeutic areas around. My neighborhood (Cambridge) is going to get more Pfizer-y as a result, but it's for sure that several others are getting less so.

The company's getting out of allergy, urology, respiratory diseases and other areas completely. Who out there can imagine that this is the end of the process?

Comments (101) + TrackBacks (0) | Category: Business and Markets

Bad News: Pfizer Closes Site in Sandwich

Email This Entry

Posted by Derek

Just today, Pfizer's announced that they're closing the longtime research site in Sandwich, Kent. 2,400 people work there, and although the company says that perhaps several hundred may find positions elsewhere, this is a major blow to drug discovery operations in the UK. No, we're not off to a good start in 2011 at all. . .

Comments (71) + TrackBacks (0) | Category: Business and Markets

The NIH's New Drug Discovery Center: Heading Into the Swamp?

Email This Entry

Posted by Derek

I've been meaning to comment on the NIH's new venture into drug discovery, the National Center for Advancing Translational Sciences. Curious Wavefunction already has some thoughts here, and I share his concerns. We're both worried about the gene-o-centric views of Francis Collins, for example:

Creating the center is a signature effort of Dr. Collins, who once directed the agency’s Human Genome Project. Dr. Collins has been predicting for years that gene sequencing will lead to a vast array of new treatments, but years of effort and tens of billions of dollars in financing by drug makers in gene-related research has largely been a bust.

As a result, industry has become far less willing to follow the latest genetic advances with expensive clinical trials. Rather than wait longer, Dr. Collins has decided that the government can start the work itself.

“I am a little frustrated to see how many of the discoveries that do look as though they have therapeutic implications are waiting for the pharmaceutical industry to follow through with them,” he said.

Odd how the loss of tens of billions of dollars - and vast heaps of opportunity cost along the way - will make people reluctant to keep going. And where does this new center want to focus in particular? The black box that is the central nervous system:

Both the need for and the risks of this strategy are clear in mental health. There have been only two major drug discoveries in the field in the past century; lithium for the treatment of bipolar disorder in 1949 and Thorazine for the treatment of psychosis in 1950.

Both discoveries were utter strokes of luck, and almost every major psychiatric drug introduced since has resulted from small changes to Thorazine. Scientists still do not know why any of these drugs actually work, and hundreds of genes have been shown to play roles in mental illness — far too many for focused efforts. So many drug makers have dropped out of the field.

So if there are far too many genes for focused efforts (a sentiment with which I agree), what, exactly, is this new work going to focus on? Wavefunction, for his part, suggests not spending so much time on the genetic side of things and working, for example, on one specific problem, such as Why Does Lithium Work for Depression? Figuring that out in detail would have to tell us a lot about the brain along the way, and boy, is there a lot to learn.

Meanwhile, Pharmalot links to a statement from the industry trade group (PhRMA) which is remarkably vapid. It boils down to "research heap good", while beating the drum a bit for the industry's own efforts. And as an industrial researcher myself, it would be easy for me to continue heaping scorn on the whole NIH-does-drug-discovery idea.

But I actually wish them well. There really are a tremendous number of important things that we don't know about this business, and the more people working on them, the better. You'd think. What worries me, though, is that I can't help but believe that a good amount of the work that's going to be done at this new center will be misapplied. I'm really not so sure that the gene-to-disease-target paradigm just needs more time and money thrown at it, for example. And although there will be some ex-industry people around, the details of drug discovery are still likely to come as a shock to the more academically oriented people.

Put simply, the sorts of discoveries and project that make stellar academic careers, that get into Science and Nature and all the rest of them, are still nowhere near what you need to make an actual drug. It's an odd combination of inventiveness and sheer grunt work, and not everyone's ready for it. One likely result is that some people will just avoid the stuff as much as possible and spend their time and money doing something else that pleases them more.

What do I think that they should be doing, then? One possibility is the Pick One Big Problem option that Wavefunction suggests. What I'd recommend would also go against the genetic tracery stuff: I'd put money into developing new phenotypic assays in cells, tissues, and whole animals. Instead of chasing into finer and finer biochemical details in search of individual targets, I'd try to make the most realistic testbeds of disease states possible, and let the screening rip on that. Targets can be chased down once something works.

But it doesn't sound like that's what's going to happen. So, reluctantly, I'll make a prediction: if years of effort and billions of dollars thrown after genetic target-based drug discovery hasn't worked out, when done by people strongly motivated to make money off their work, then an NIH center focused on the same stuff will, in all likelihood, add very little more. It's not like they won't stay busy. That sort of work can soak up all the time and money that you can throw at it. And it will.

Comments (36) + TrackBacks (0) | Category: Academia (vs. Industry) | Drug Assays | Drug Development | Drug Industry History