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

Derek Lowe The 2002 Model

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

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

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December 28, 2011

Nowhere to Go But Up?

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Posted by Derek

I wanted to let people know that I've got a "Perspective" piece in ACS Medicinal Chemistry Letters, entitled "Nowhere to Go But Up?". The journal is starting to run these opinion/overview articles, and contacted me for one - I hope it's the sort of thing that they were looking for!

Comments (38) + TrackBacks (0) | Category: Drug Industry History | The Scientific Literature

The UCLA Lab Fatality: Criminal Charges Filed

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Posted by Derek

Most readers here will remember the fatal lab accident at UCLA in 2009 involving t-butyllithium, which took the life of graduate student Sheri Sangji. Well, there's a new sequel to that: the professor involved, Patrick Harran, has been charged along with UCLA with a felony: "willfully violating occupational health and safety standards". A warrant has been issued for his arrest; he plans to turn himself in when he returns from out of town this season. The University could face fines of up to $1.5 million per charge; Harran faces possible jail time.

This is the first time I've heard of such a case going to criminal prosecution, and I'm still not sure what I think about it. It's true that the lab was found to have several safety violations in an inspection before the accident - but, on the other hand, many working labs do, depending on what sort of standards are being applied. But it would also appear that Sangji herself was not properly prepared for handing t-butyllithium, which (as all organic chemists should know) bursts into flames spontaneously on exposure to air. She was wearing flammable clothing and no lab coat; no one should be allowed to start working with t-BuLi under those conditions. Being inexperienced, she should have been warned much more thoroughly than she appears to have been.

So something most definitely went wrong here, and the LA County DA's office has decided to treat it as a criminal matter. Well, negligence can rise to that level, under the law, so perhaps they have a point. Thoughts?

Update: here's a post that rounds up the responses to this across the blogging world.

Comments (97) + TrackBacks (0) | Category: Chemical News | Graduate School | Safety Warnings

December 23, 2011

Media Note

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Posted by Derek

I'm going to be on a short segment of Marketplace on public radio tonight, talking about cancer therapy. So if your holidays aren't complete without hearing me vent my opinions - and my wife, among others, tells me that hers aren't! - then tune in.

Comments (5) + TrackBacks (0) | Category: Blog Housekeeping

Holiday Break

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Posted by Derek

Posting will be irregular next week for the holidays. I may put up a recipe or two, the way I did last year, and I'll certainly jump in for any big stories that might pop up. Otherwise, I'll be lounging around, gathering my strength for the new year. And hoping that we don't get what we got last year - relentless snowstorms, pounding in one after the other, which started about one day after Christmas. The less time I spend slogging through 40 inches of the stuff to go out and rake it off the roof, the better. Makes it rather difficult for a guy to set up a telescope, too, even in the unlikely event of a clear sky.

So I'd like to take this opportunity to wish everyone who's celebrating it a Merry Christmas, and I'll certainly throw in a Happy Hanukah as well. The Iranians have already celebrated the winter solstice, but a belated best wishes go out to them, too. Anyone I've missed?

Comments (5) + TrackBacks (0) | Category: Blog Housekeeping

December 22, 2011

More From Hua - A Change of Business Plans?

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Posted by Derek

You may remember the mention of Hua Pharmaceuticals here back in August, and the follow-up with details from the company. They're trying to in-license drugs from other companies and get them approved as quickly as possible in China. The original C&E News article made them sound wildly ambitious, while the company's own information just made them sound very ambitious.

Now we have some more information: Roche has licensed their glucokinase activator program (for diabetes) to Hua (that's a development effort I wrote about here). And that's an interesting development, because the Hua folks told me that:

"Hua Medicine intends to in-license patented drugs from the US and EU, and get them on the market and commercialized in the 4 year timeframe in China. This is about the average time it takes imported drugs (drugs that are approved and marketed in the US or EU but are coming newly into the Chinese market) to get approved by the SFDA in China."

And that's fine, but Roche's glucokinase activators haven't been approved or marketed anywhere yet. In fact, I'm not at all sure of the lead compound ever even made it to Phase III, so there's a lot of expensive work to be done yet, and on a groundbreaking mechanism, too. The only thing I can say is that approval in the US for diabetes drugs has gotten a lot harder over the years - the market is pretty well-served, for one thing, and the safety requirements (particularly cardiovascular) have gotten much more stringent. Perhaps these concerns are not so pressing in China, leading to an easier development path?

Easier or not, these compounds have a lot of time and money left to be put into them, which is not the sort of program that Hua seemed to be targeting before. One wonders if there just weren't any safer bets available. At any rate, good luck to them, and to their financial backers. Some will be needed; it always is.

Comments (8) + TrackBacks (0) | Category: Business and Markets | Diabetes and Obesity | Drug Development

Merry Christmas, Fred

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Posted by Derek

I believe that this story has been mentioned in the comments here, but since I've heard from the actual person involved, I thought I'd pass on the canonical version. Someone I used to work with at Schering-Plough found himself (like many others in his position) out of a job in late October. He had a previously scheduled trip to Florida the next day, and as he boarded the plane, who should he see sitting in first class but Fred Hassan, the CEO of Schering-Plough who'd helped engineer the deal with Merck?

As the chemist involved put it, "After quickly scanning to make sure there wasn’t a body guard looking guy near him", he said "Hi, Fred!" Hassan looked up and asked "Do I know you?" "Well," said the chemist, "no, probably not, but I'm a medicinal chemist with Schering-Plough, and now Merck". Hassan smiled and said "Great, so how are you?" The response, in a loud voice, was "Well, I just got laid off!". He then walked on down to his seat in coach, and heard Hassan saying something about being sorry about that. And as he told me, he sat there in coach, smiling at the picture of Hassan thinking about this irate ex-employee on the plane with him for the next 2 and a half hours. . .

Comments (15) + TrackBacks (0) | Category: Business and Markets

December 21, 2011

Chemistry, The Movie!

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Posted by Derek

For some comic relief, here's a list that was going around on Twitter: Chemistry, The Movie. What titles would you suggest? To give you the idea, some of the ones that have already come up include "Boron Free", "The Wizard of Osmium", and "The Bench Connection". More at the link (and on Twitter, #ChemistryTheMovie), if you can stand it. But if you can't take, for example, "Weekend at Swernie's", you'd be advised to click somewhere else (!)

Comments (51) + TrackBacks (0) | Category: Chemical News

AstraZeneca's Problems

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Posted by Derek

Not exactly a load of happy holiday news from AstraZeneca here - they're already facing one of the nastiest patent cliffs in the industry (second only, and arguably, to Eli Lilly), and now they've had still more development compounds crash out on them.

There's olaparib (AZN-), which is an inhibitor of the DNA repair pathway enzyme PARP, Poly-ADP ribose polymerase. There are a number of PARP inhibitors making their way through the clinic, but olaparib's performance can't be giving comfort to anyone else in the field. It looked promising a couple of years ago in an ovarian cancer trial, but that, folks, was only progression-free survival. As time went on, it became clear that there wasn't going to be any benefit in overall survival, and that's what the world cares about, as it should. The compound's still in trials against other forms of cancer, and who knows, it might have better effects there. Oncology is a crap shoot if ever there was one. But ovarian cancer was the big first hope for AZ, and that's been written off.

The other compound that's hit the skids recently was TC-5214, mecamylamine, a nicotinic antagonist, which would have been a new mechanism for depression. But not if it doesn't work, and the compound missed its primary endpoint in the clinic, as I wrote about here last month. That one came in from Targacept, as olaparib came in from KuDOS, and these results have people wondering in the press about what this says about AstraZeneca's whole inlicensing strategy.

The problem is, these are two fields (cancer and depression) that have very high failure rates no matter who's doing the inlicensing. And while it's true that AZ seems to have had a lot of bad luck, some of that might just be the normal course of events if you're targeting these conditions. Having it happen while your other patents are expiring is bad, of course, but being in a position to have to depend on these therapeutic areas is a tough place to be to start with. (Not that there are a lot of safe places to work, true, but these are especially tricky). And it leads to things like this:

“AstraZeneca seems to have had more than its fair share of misfortune when it comes to the development pipeline,” analysts at Barclays Capital in London wrote in a note to investors today. “Additional development failures increase the probability that management will reassess the likely return on investment from additional R&D investment and cut costs further.”

Well, that'll really make R&D more productive. . .

Comments (15) + TrackBacks (0) | Category: Business and Markets | Cancer | The Central Nervous System

December 20, 2011

Best Paper You Read This Year?

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Posted by Derek

Since the year is winding down, I had a question for the readership: what's the best scientific paper you read this year? Let's restrict the field to chemistry and biology; I'm not ready for particle physics. And I don't necessarily mean "best written", although you're free to nominate some if you can find any that stood out. What I had in mind was more "Most interesting" or "Most unexpectedly useful", or "Most surprising". I've got a couple in mind myself - I'll turn the suggestions into another post or two.

Comments (58) + TrackBacks (0) | Category: The Scientific Literature

December 19, 2011

Trifluoromethylation, The Easy Way?

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Posted by Derek

In case people haven't seen it, this trifluoromethylation method from the MacMillan lab looks quite interesting. Now, not everyone loves the idea of sticking CF3 groups all over their molecules, and if you're a medicinal chemist you'll want to exercise restraint, but it's still an inarguably useful group. And the chemistry is interesting, too, using visible-light photoredox chemistry, an area that's been getting a lot of attention recently and seems pretty promising.

There's quite a list of reactions that have been done via this route, usually involving ruthenium or iridium catalysts and either fluorescent light or blue LEDs. (A trivia note: that ruthenium compound linked to looks more like good saffron powder, both in solid form and solution, than anything I've ever seen. It's all that Iranian food I get at home, I guess). Labs to watch include MacMillan's at Princeton, Corey Stephenson's at BU, and Tehshik Yoon's at Wisconsin, among others. Photochemistry has been a neglected field in many ways - perhaps taking it out of the ultraviolet and finding useful new reactions will slowly bring it back into the usual toolkit.

Comments (8) + TrackBacks (0) | Category: Chemical News

Deals of the Year in Biopharma (Bonus: Names That Can't Happen)

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Posted by Derek

Over at InVivoBlog, they're running down their picks for "Deal of the Year" in various categories, so if that's one of your interests, you should have a look. I hadn't realized that when Abbott split off their pharma business that the blog had run a poll suggesting a new name for the drug company. The winner? Costello.

Too bad it won't happen. Reality also interfered with Bayer a few years back when they were introducing Levitra, their Viagra competitor (and very close chemical cousin). Alas, the name "Bayagra" was not seriously considered - that would have been fun to watch. . .

Comments (11) + TrackBacks (0) | Category: Business and Markets

December 15, 2011

More on Chinese Pharma Espionage

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Posted by Derek

Well, a lot of comments have come in about the last post on Chinese industrial espionage - some temperate, some not. I wanted to fill out another post responding to some of these, so, in no particular order:

1. "Everyone does this all the time". Indeed. Espionage is a constant fact of international relations; the "gentlemen do not read each other's mail" comment was wildly out of sync with reality even in its own time. I don't mean to suggest that I'm shocked by the fact of Chinese intelligence-gathering, although its scope and thoroughness is impressive. But I think that everyone should be aware that it goes on - and that pointing out that it's going on is also a move in the same game. We're not hearing so much about this from the US government now for no reason; someone thinks that there's an advantage in making these accusations public in such detail.

2. "More to the point, the US does this too, and thus has no room to talk". This is merely a tu quoque argument, and as such doesn't address any underlying issues. Of course the US engages in espionage, and I hope that we're good at it. But for the most part, we're doing it for a different purpose than some of the Chinese activity that's been revealed. I tend to think that more of ours is national-security related, and less pure economics - more "How can we figure out what these guys are up to?" and less "How can we jump-start our aerospace industry?"

Now, one big reason for that is that the US is not as far behind anyone else in the world as China feels itself to be behind in some key industries. They have more to gain. I'm sure that China does plenty of national-security spying, but for a country whose economy is as export-driven as China's, economic reasons and national security reasons are even more tangled together than usual. And yes, other countries have done just this sort of thing in the past. See the story of how the British got rubber-tree seeds to plant in Malaysia. Or earlier, how they learned the details of tea production and got that going in India, and that's not even mentioning their strategy of smoothing out the trade imbalance with opium sales. We shouldn't allow ourselves, though, to think that this stuff is just for the history books.

3. "OK then, what's more, the US did just this kind of economic/industrial snooping back when it was an up-and-coming nation".. This is another tu quoque, but the facts are as stated. In the 19th century, the US was generally a backwater compared to the European powers, and we did indeed have a reputation as the Kings of Shoddy Unauthorized Knockoffs (even of our own inventions). Charles Dickens was enraged when he visited to find how many pirated versions of his works were for sale, and this tradition took a long time to die out. (See, for example, the saga of how Donald Wollheim unilaterally decided in the 1960s that Tolkein's publishers had not properly secured the US copyright for The Lord of the Rings).

But while we were at our peak as intellectual property buccaneers, we were not simultaneously considered both a world power and a huge financial market. China is not to the rest of the world as the US of the 1850s was. Our big exports were agricultural products; we did not have huge factories on which many of the world's largest corporations were depending. China, in catch-up mode though it may be, is not a technological backwater. It has nuclear weapons and a manned space program - mind you, both of those were developed partly through just the sort of short-cutting we're talking about.

4. OK, that means that every Chinese post-doc is a spy. Or a potential spy, right? Here's where I flip over to the other side. Now, there surely has been intelligence gathering by such routes. But it appears that a lot of work is being done from back home, by large groups associated with the People's Liberation Army and various Chinese intelligence agencies. And when you consider what a lot of postdocs end up working on, you can see that most of it isn't going to confer much of an advantage on anyone - what are they going to do, steal K. C. Nicolau's strategy for an 89-step synthesis? I think it would be a lot more useful for US institutions to spend their time hardening their security against wholesale data-scooping than giving their foreign postdocs the fish-eye. Most of them are just trying to make better lives for themselves.

So where does this leave us? I think that China's position is unique. They're an enormous country of huge economic and political importance. And their economy is a mixture that might be called "authoritarian capitalist", no matter what they call it themselves. So for a country like the US, they're simultaneously a vital trading partner, and a potential political adversary and rival. (And the US is the same thing to China, naturally). It's a tricky balance, and there are a lot of conflicts of interest.

We're seeing one in the drug industry. No major company can afford to ignore the Chinese market. The financial advantages of pharma outsourcing have been hard to ignore, too (leaving aside the question of its effectiveness, which varies). But no company can afford to ignore the possibility that Chinese industry (or the Chinese government itself) might rip them off. These things exist simultaneously, and it's very much worth the effort keeping both of them in mind.

Comments (57) + TrackBacks (0) | Category: Business and Markets | Current Events | The Dark Side

Chinese Pharma Espionage?

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Posted by Derek

That's a pretty blunt headline, but this is a pretty blunt article in Businessweek. It will do nothing to allay the concerns people have about all the pharma collaborations being done in China. The article claims that hundreds of US corporations have had data stolen in what appears to be a deliberate program:

China has made industrial espionage an integral part of its economic policy, stealing company secrets to help it leapfrog over U.S. and other foreign competitors to further its goal of becoming the world's largest economy, U.S. intelligence officials have concluded in a report released last month. . .Intelligence documents obtained by Bloomberg News show that China-based hackers have hunted technology and information across dozens of economic sectors and in some of the most obscure corners of the economy, beginning in 2001 and accelerating over the last three years.

Here's a report (PDF) from McAfee on cyber-intrusions. It doesn't mention China by name, but the author confirmed to the Bloomberg people that that's who he's talking about (not that it took any great powers of deduction). And this is not just about defense and electronics:

In the biotechnology sector, their victims include Boston Scientific, the medical device maker, as well as Abbott Laboratories and Wyeth, the drug maker that is now part of Pfizer Inc.

The hackers also rifled networks of the Parkland Computer Center in Rockville, Maryland, according to documents provided to Bloomberg News by a person involved in government tracking of the cyberspies, who declined to be identified because the matter isn't public. Parkland is the computing center for the Food and Drug Administration, which has access to drug trial information, chemical formulas and other data for almost every important drug sold in the U.S.

Now that's worth thinking about. By the time a drug gets to the FDA, everyone knows what its structure is, and can figure out how to make it. But there's a lot of clinical information in the system that doesn't necessarily get disclosed in detail, and that certainly has value. It should go without saying, though, that the files from inside a drug company could be quite valuable indeed.

And this does put the recent pharma emphasis on the Chinese market in an interesting light, doesn't it? As I say, I hate to be so direct about it, but you can't get much more direct than hacking into someone's files and ransacking them, either. Right?

Comments (54) + TrackBacks (0) | Category: Business and Markets | The Dark Side

December 14, 2011

Burzynski Revisited

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Posted by Derek

Here, courtesy of Science-Based Medicine, is a comprehensive look at the Burzynski cancer clinic's methods. If you have any interest at all in cancer quackery or semi-quackery, or especially if you know of anyone desperate enough to approach the Burzynski people themselves, here's everything you need to know from a med-chem point of view.

Comments (10) + TrackBacks (0) | Category: Cancer | Snake Oil

An NMR Poster

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Posted by Derek

Here's a very nice poster-style presentation of proton NMR and spectral interpretation, courtesy of Jon Chui. I wish I'd had something like it when I was learning the topic, and it's a very useful way to picture it even for those of us who've been taking spectra for years. Recommended.

Comments (4) + TrackBacks (0) | Category: Analytical Chemistry | Chemical News

Now That's A Catalyst

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Posted by Derek

Sorry about the lack of posting today; it's been a busy one. But I do have something that follows up on one of my less useful chemical bulletins, the one the other day about using uranium catalysts. Ben Warner sends along this paper from his time at Los Alamos, and yes, that means what you think it means. You may have done the Meerwein-Pondorf-Verley reaction, but if you have, I'll bet that you wimped out with some laid-back aluminum compound.

But you could have used plutonium, and how does that make you feel? Uranium (III), as it turns out, just doesn't cut it. Accept nothing but plutonium, folks; you can't beat it. And I now return you to your regular research, which I hope has nothing to do with this post at all!

Comments (8) + TrackBacks (0) | Category: Chemical News

December 13, 2011

Nothing Says "Chemistry" Like Nonsense!

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Posted by Derek

The University of Ottawa has it all: colored solutions in their test tubes, thoughtful young scientists to look at them intently, and the absolutely required nonsensical chemical structures on the board in the background. What more do you want from a research department, eh? Throw in some purple spotlights and I'm sold. (Link via Chemjobber and Barney Grubbs on Twitter).

Update: embarrassing spelling fixed. Canadian readers are welcome to email me their complaints about the time they visited Woshington, DC.

Comments (45) + TrackBacks (0) | Category: Chemical News

The Sirtuin Saga

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Posted by Derek

Science has a long article detailing the problems that have developed over the last few years in the whole siturin story. That's a process that I've been following here as well (scrolling through this category archive will give you the tale), but this is a different, more personality-driven take. The mess is big enough to warrant a long look, that 's for sure:

". . .The result is mass confusion over who's right and who's wrong, and a high-stakes effort to protect reputations, research money, and one of the premier theories in the biology of aging. It's also a story of science gone sour: Several principals have dug in their heels, declined to communicate, and bitterly derided one another. . ."

As the article shows, one of the problems is that many of the players in this drama came out of the same lab (Leonard Guarente's at MIT), so there are issues even beyond the usual ones. Mentioned near the end of the article is the part of the story that I've spent more time on here, the founding of Sirtris and its acquisition by GlaxoSmithKline. It's safe to say that the jury is still out on that one - from all that anyone can tell from outside, it could still work out as a big diabetes/metabolism/oncology success story, or it could turn out to have been a costly (and arguably preventable) mistake. There are a lot of very strongly held opinions on both sides.

Overall, since I've been following this field from the beginning, I find the whole thing a good example of how tough it is to make real progress in fundamental biology. Here you have something that is (or at the very least has appeared to be) very interesting and important, studied by some very hard-working and intelligent people all over the world for years now, with expenditure of huge amounts of time, effort, and money. And just look at it. The questions of what sirtuins do, how they do it, and whether they can be the basis of therapies for human disease - and which diseases - are all still the subject of heated argument. Layers upon layers of difficulty and complexity get peeled back, but the onion looks to be as big as it ever was.

I'm going to relate this to my post the other day about the engineer's approach to biology. This sort of tangle, which differs only in degree and not in kind from many others in the field, illustrates better than anything else how far away we are from formalism. Find some people who are eager to apply modern engineering techniques to medical research, and ask them to take a crack at the sirtuins. Or the nuclear receptors. Or autoimmune disease, or schizophrenia therapies. Turn 'em loose on one of those problems, come back in a year, and see what color their remaining hair is.

Comments (9) + TrackBacks (0) | Category: Aging and Lifespan | Drug Development | Drug Industry History

December 12, 2011

Don't Dose That Patient Until You Pay Up

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Posted by Derek

Now here is an awful, awful idea, and it's made it all the way to the Supreme Court. Oral arguments were heard last week in Mayo Collaborative Services v. Prometheus Laboratories, and this one really has the potential to screw things up.

Why am I so downbeat? Wait until you hear the basis of this case. Prometheus has a patent whose first claim is as follows:

(1) A method of optimizing therapeutic efficacy for treatment of an immune-mediated gastrointestinal disorder, comprising:

(a) administering a drug providing 6-thioguanine to a subject having said immune-mediated gastrointestinal disorder; and

(b) determining the level of 6-thioguanine in said subject having said immune-mediated gastrointestinal disorder, wherein the level of 6-thioguanine less than about 230 pmol per 8x10^8 red blood cells indicates a need to increase the amount of said drug subsequently administered to said subject and wherein the level of 6-thioguanine greater than about 400 pmol per 8x10^8 red blood cells indicates a need to decrease the amount of said drug subsequently administered to said subject.

There, that sounds like a nice little chunk of medico-legal boilerplate. But look closely: what they're claiming is the process of using a blood test to decide whether or not to administer a drug. Prometheus Labs did not discovery any immune-mediated gastrointestinal diseases. They most certainly did not discover thioguanine, nor did they discover that giving thioguanine is beneficial to people who are deficient in it. No, they make a test kit, and they are claiming the process of checking a patient's blood levels (their test kit's function) in order to make a medical decision. The Mayo Clinic planned to offer a competing test kit, and Prometheus sued, and here we are.

Now, think about a world in which such processes are patentable (here's a column at Ars Technica that's done that already). Prometheus seems to be claiming that the awareness of needing to test for thiopurine levels in order to decide whether to dose a patient is enough to infringe their patent. Doesn't matter if the physician doses anyone or not - just the idea of testing their blood is enough. IP rights have been infringed. Money must change hands. Ka-ching. Imagine every new bit of medical practice broken down into the smallest patentable, monetizable steps. A physician reads about a new finding that might affect clinical practice - but not so fast! Better check to see what the patent rights are. Wouldn't want to get sued for applying the scientific literature without the proper licensing fees. As the AMA's amicus brief has it:

"If claims to exclusive rights over the body’s natural responses to illness and medical treatment are permitted to stand, the result will be a vast thicket of exclusive rights over the use of critical scientific data that must remain widely available if physicians are to provide sound medical care"

If you follow intellectual property issues, you'll have noted the similarity of this case to software and business-method patents, which have been a gigantic tar pit of litigation for some years now. But the tide of tar is not finished rising. The IP lawyers are, as you'd expect, watching this case with great interest, some with thoughts of perpetual employment, and some in a sort of fascinated horror. This problem has been developing for a long time, since the main legal decisions on what constitutes patentable matter actually appear to contradict each other, and perhaps this will be the case that begins the ugly process of sorting all that out. (Or perhaps the Supreme Court will recoil from that task and decide this case on some narrower basis, kicking the issue a few years into the future).

Here's a more technical legal summary of the oral arguments at the Patently-O site. It appears that Justice Breyer will be a key player in the eventual opinion; he spent by far the most amount of time asking questions during the orals. And here (also from Patently-O) is a new law review paper from Case Western on the whole tangled subject of medical diagnostic patents. This post at Patent Baristas has links to the various briefs filed on both sides of the case.

Comments (17) + TrackBacks (0) | Category: Patents and IP

December 9, 2011

Pharma Overview

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Posted by Derek

Here's a report from Science Careers on "A Pharma Industry in Crisis". Readers here will find much of what's said to be familiar - partly because they interviewed people like me and Chemjobber for the piece (!) But it's worth a look as a where-we-are-now perspective.

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

Drugs, Airplanes, and Radios

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Posted by Derek

Wavefunction has a good post in response to this article, which speculates "If we designed airplanes the way we design drugs. . ." I think the original article is worth reading, but some - perhaps many - of its points are arguable. For example:

Every drug that fails in a clinical trial or after it reaches the market due to some adverse effect was “bad” from the day it was first drawn by the chemist. State-of-the-art in silico structure–property prediction tools are not yet able to predict every possible toxicity for new molecular structures, but they are able to predict many of them with good enough accuracy to eliminate many poor molecules prior to synthesis. This process can be done on large chemical libraries in very little time. Why would anyone design, synthesize, and test molecules that are clearly problematic, when so many others are available that can also hit the target? It would be like aerospace companies making and testing every possible rocket motor design rather than running the simulations that would have told them ahead of time that disaster or failure to meet performance specifications was inevitable for most of them.

This particular argument mixes up several important points which should remain separate. Would these simulations have predicted those adverse-effect failures the author mentions? Can they do so now, ex post facto? That would be a very useful piece of information, but in its absence I can't help but wonder if the tools he's talking about would have cheerfully passed Vioxx, or torcetrapib, or the other big failures of recent years. Another question to ask is how many currently successful drugs these tox simulations would have killed off - any numbers there?

The whole essay recalls Lazebnik's famous paper "Can A Biologist Fix A Radio?" (PDF). This is an excellent place to start if you want to explore what I've called the Andy Grove Fallacy. Lazebnik's not having any of the reasons I give for it being a fallacy - for example:

A related argument is that engineering approaches are not applicable to cells because these little wonders are fundamentally different from objects studied by engineers. What is so special about cells is not usually specified, but it is implied that real biologists feel the difference. I consider this argument as a sign of what I call the urea syndrome because of the shock that the scientific community had two hundred years ago after learning that urea can be synthesized by a chemist from inorganic materials. It was assumed that organic chemicals could only be produced by a vital force present in living organisms. Perhaps, when we describe signal transduction pathways properly, we would realize that their similarity to the radio is not superficial. . .

That paper goes on to call for biology to come up with some sort of formal language and notation to describe biochemical systems, something that would facilitate learning and discovery in the same way as circuit diagrams and the like. And that's a really interesting proposal on several levels: would that help? Is it even possible? If so, where to even start? Engineers, like the two authors of the papers I've quoted from, tend to answer "Yes", "Certainly", and "Start anywhere, because it's got to be more useful than what you people have to work with now". But I'm still not convinced.

I've talked about my reasons for this before, but let me add another one: algorithmic complexity. Fields more closely based on physics can take advantage of what's been called "the unreasonable effectiveness" of mathematics. And mathematics, and the principles of physics that can be stated in that form, give an amazingly compact and efficient description of the physical world. Maxwell's equations are a perfect example: there's classical electromagnetism for you, wrapped up into a beautiful little sculpture.

But biological systems are harder to reduce - much harder. There are so many nonlinear effects, so many crazy little things that can add up to so much more than you'd ever think. Here's an example - I've been writing about this problem for years now. It's very hard to imagine compressing these things into a formalism, at least not one that would be useful enough to save anyone time or effort.

That doesn't mean it isn't worth trying. Just the fact that I have trouble picturing something doesn't mean it can't exist, that's for sure. And I'd definitely like to be wrong about this one. But where to begin?

Comments (36) + TrackBacks (0) | Category: Drug Development | Drug Industry History

Uranium, Eh?

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Posted by Derek

For those of you keeping count of how many elements you've used in your chemical careers, you now have another possibility. This paper suggests that uranyl anions are good for epoxide polymerization, so who knows, they may be good for something else as well. I don't anticipate adding this one to my life list, but there's at least a chance of it now. . .

Comments (29) + TrackBacks (0) | Category: Life in the Drug Labs

December 8, 2011

The Loss of the Middle (Drugs and the People Who Find Them)

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Posted by Derek

This report on a speech by Roche's CEO, Severin Schwan, will surprise no one. He's forecasting that the pharma world is heading for a bimodal distribution. On one end, you'll have the companies that have managed to find things new enough and efficacious enough to convince regulatory agencies and payers that they're worth the price. And on the other, you'll have the generics. The in-between stuff, the me-too drugs and line extensions and things that don't work as well as anyone had hoped - that's going to get squeezed, and if that's all you have in your product portfolio, you're going to get squeezed, too. It's not that those things have no value, but they don't have enough to keep R&D efforts going at their current attrition rates and expenditures.

The analogy to the people doing this work is pretty close, too. Look at Pfizer's plans (which as far as I know are still in effect) to have a smaller number of "drug designers" and a bunch of lower-cost people cranking out the compounds in the lab. That's the same bimodal landscape, right there. You have a smaller, highly compensated group at one end of the scale, and a larger, less costly group at the other. What disappears are the folks in the middle.

The problem is, you can assign marketed drugs to the expensive-or-generic categories pretty rationally, based on efficacy and pricing. But assigning the people, well, that's a different matter. How exactly do you identify your star "drug designers"? Even after you narrow down to only the smarter and harder-working people, there are still more of them around than you need under that Pfizer system. So where do they go? Well, we've all been seeing the answer that question. Out on the street, and out into the job market, there to take their chances.

And at the other end, there are probably a lot of people in the make-this-list-of-analogs labs who are capable of much more than that, but haven't had the chance to prove themselves. The whole situation seems like a real misuse of human capital, and we really have to find conditions that don't lead to such wastes. But what conditions are those, and how do we get to them?

Comments (33) + TrackBacks (0) | Category: Business and Markets | Drug Industry History

December 7, 2011

Plan B and the FDA: Unprecedented

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Posted by Derek

I haven't been blogging about the Plan B contraceptive issue, and I'm certainly staying out of the politics of the whole thing. But today's news that the FDA was planning to make it available over-the-counter, but was overruled by Health and Human Services. . .well, that brings up a question.

Can anyone else recall a case like this, where the FDA was not, in fact, the final word on drug regulation? Having HHS overrule appears to be completely legal under the provisions of the Food, Drug, and Cosmetic Act, but when's the last time it happened? And if this is the first time, how much of a precedent does it set for extra-FDA lobbying and politicking?

Comments (35) + TrackBacks (0) | Category: Regulatory Affairs

Merck in China

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Posted by Derek

So Merck now says that they're going to spend 1.5 billion dollars to build a new research center in China, eventually employing 600 people. Considering the number of people they've laid off here in the US, this news is not going to make a lot of people here very happy. Mind you, I believe that they've let a lot more than 600 positions go in R&D over here, so it's not like a zero-sum game - given the state of the drug industry, it's a lot worse than a zero-sum game. And it's worth remembering that this is actually a very small part of Merck's research budget.

And that's why they're doing it. China is, famously, a big market, and for the drug industry it's getting bigger all the time. And while costs are going up there, you can still get more people (and a larger facility) there for the same amount of money than you can get here, and many of those people are going to be hard-working and capable. Most importantly (I think), you're also purchasing clout and goodwill with the Chinese government, by showing that you're serious about their country, and seriously friendly when it comes to spending money there. You'll also get to know a lot of very useful government agencies, and a lot of very useful government people. I'm not overjoyed that it works like this, but it does work like this. Given the tangle of business and government interests there (where does one start and the other stop?), it's really the only way to get anything accomplished.

Now, in the long run, I don't think that this is good for China, doing business this way. But Merck (and the other companies going similar deals, both inside and outside the drug industry) are betting that it'll keep on going like this for some time, and that this sort of money will turn out to be well spent.

Comments (54) + TrackBacks (0) | Category: Business and Markets

December 6, 2011

Novartis: No More Neuroscience

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Posted by Derek

Neuroscience is a long-established graveyard for drug discovery - there are a lot of serious disorders there, but it's very hard to do anything about them. So the "unmet medical need" is being exacerbated by both of those factors at once.

And if you need some empirical proof of those assertions, look no farther than the press releases. GlaxoSmithKline and AstraZeneca have already bailed out of the field, and now it looks like Novartis is joining them. That doesn't leave too many big players, and there are two effects to that which come immediately to mind: that progress may slow down, because there's not as much money and effort going on, but that this leaves the door open for smaller organizations who can take advantage of any new discoveries and/or get lucky.

I spent the first eight or nine years of my med-chem career doing CNS, and am not overwhelmed by the desire to do it again - at least, not under standard drug-discovery conditions. But the rewards are still out there - on a high, high shelf - for those who want to try.

Comments (22) + TrackBacks (0) | Category: Business and Markets | The Central Nervous System

Riding to the Rescue of Rhodanines

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Posted by Derek

There's a new paper coming to the defense of rhodanines, a class of compound that has been described as "polluting the scientific literature". Industrial drug discovery people tend to look down on them, but they show up a lot, for sure.

This new paper starts off sounding like a call to arms for rhodanine fans, but when you actually read it, I don't think that there's much grounds for disagreement. (That's a phenomenon that's worth writing about sometime by itself - the disconnects between title/abstract and actual body text that occur in the scientific literature). As I see it, the people with a low opinion of rhodanines are saying "Look out! These things hit in a lot of assays, and they're very hard to develop into drugs!". And this paper, when you read the whole thing, is saying something like "Don't throw away all the rhodanines yet! They hit a lot of things, but once in a while one of them can be developed into a drug!" The argument is between people who say that elephants are big and people who say that they have trunks.

The authors prepared a good-sized assortment of rhodanines and similar heterocycles (thiohydantoins, hydantoins, thiazolidinediones) and assayed them across several enzymes. Only the ones with double-bonded sulfur (rhodanines and thiohydantoins) showed a lot of cross-enzyme potency - that group has rather unusual electronic properties, which could be a lot of the story. Here's the conclusion, which is what makes me think that we're all talking about the same thing:

We therefore think that rhodanines and related scaffolds should not be regarded as problematic or promiscuous binders per se. However, it is important to note that the intermolecular interaction profile of these scaffolds makes them prone to bind to a large number of targets with weak or moderate affinity. It may be that the observed moderate affinities of rhodanines and related compounds, e.g. in screening campaigns, has been overinterpreted in the past, and that these compounds have too easily been put forward as lead compounds for further development. We suggest that particularly strong requirements, i.e. affinity in the lower nanomolar range and proven selectivity for the target, are applied in the further assessment of rhodanines and related compounds. A generalized "condemnation" of these chemotypes, however, appears inadequate and would deprive medicinal chemists from attractive building blocks that possess a remarkably high density of intermolecular interaction points.

That's it, right there: the tendency to bind off-target, as noted by these authors, is one of the main reasons that these compounds are regarded with suspicion in the drug industry. We know that we can't test for everything, so when you have one of these structures, you're always fearful of what else it can do once it gets into an animal (or a human). Those downstream factors - stability, pharmacokinetics, toxicity - aren't even addressed in this paper, which is all about screening hits. And that's another source of the bad reputation, for industry people: too many times, people who aren't so worried about those qualities have screening commercial compound collections, come up with rhodanines, and published them as potential drug leads, when (as this paper illustrates), you have to be careful even using them as tool compounds. Given a choice, we'd just rather work on something else. . .

Comments (7) + TrackBacks (0) | Category: Drug Assays | Drug Development | The Scientific Literature

December 5, 2011

Naming Your Company After Yourself

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Posted by Derek

This morning's post got me to thinking - are there any examples of modern biopharma companies that have taken the name of their founder and come out well? Back in Ye Olde Days, that was the default setting, of course, as it was for most companies. If you founded an industrial concern, you either named the thing after yourself, or called it something dead-on obvious like The American Rubber Gasket Company. There's no telling what people would have thought in 1882 if you'd decided to call your company some. . .made-up word instead.

But I'm trying to think of a successful last-name-of-founder drug company in recent years, and I'm drawing a blank. Am I missing something, or should we put this on the list of potential warning signs?

Comments (60) + TrackBacks (0) | Category: Drug Industry History

More on Alex Denner

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Posted by Derek

For those of you keeping an eye on such things in the biotech investment world, here's a more in-depth profile of former Carl Icahn biotech man Alex Denner. You'll pick up on some of his background, as well as perhaps-less-useful information such as that he eats at Nobu three times a week. People in the industry are mostly wondering what else he feels like having for lunch. . .

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

Rexahn Rides Again

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Posted by Derek

You may remember Rexahn Pharmaceuticals being mentioned here in 2010. They're the company whose lead antidepressant drug Serdaxin showed no significance versus placebo in Phase IIa trials, and whose CEO (Dr. Ahn himself) then calmed the investment community by saying that the trial was never designed to show any statistical significance, anyway, and was therefore a success. You know, because it showed that patients could benefit from the drug, even though it didn't show that patients could benefit from the drug. You may think I'm exaggerating, but go back and read Ahn's statement and see if you still think that.

And when you do, you'll discover that Serdaxin is nothing else than clavulinic acid, the beta-lactamase inhibitor, and not the first thing you'd think of as a CNS agent. But Rexahn has pushed on to Phase IIb with it, and this time they seem to actually have been going all the way, looking for a statistically meaningful effect and everything. That hasn't gone so well, although the press release does what it can:

The randomized, double-blind, placebo-controlled study compared two doses of Serdaxin, 0.5 mg and 5 mg, to placebo over an 8-week treatment period. Results from the study did not demonstrate Serdaxin’s efficacy compared to placebo measured by the Montgomery-Asberg Depression Rating Scale (MADRS). All groups showed an approximate -14 point improvement in the protocol defined primary endpoint of MADRS. All groups had a substantial number of patients who demonstrated a meaningful clinical improvement from baseline. The study showed Serdaxin to be safe and well tolerated.

What really attracts me to this follow-up is another quote from Dr. Ahn: "These results contradict findings from previous studies of Serdaxin in depression, which is disappointing", he stated. Those previous studies, of course, are the ones that didn't reach significance, either, so I'd say that the latest results are right in line. But then, I have a different outlook on life. Serdaxin doesn't look like it'll do much for me, though.

Comments (12) + TrackBacks (0) | Category: Clinical Trials | The Central Nervous System

December 2, 2011

Blog Traffic: A Thank-You

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Posted by Derek

Just wanted to note that November saw nearly 441,000 page views here, for one of the best months ever on the site. Thanks to everyone who stops by! I never thought a blog about drug discovery, smelly chemicals, and other such compelling topics could ever get that sort of exposure. . .

Comments (43) + TrackBacks (0) | Category: Blog Housekeeping

Not Just FDA-Bashing?

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Posted by Derek

There have been a lot of complaints about the FDA over the years, from all sorts of people. Many of these complaints are, well, incompatible: there are those who feel that the agency is letting too many bad compounds through, and not keeping a close enough eye on drug companies and their marketing departments. Then there's another vocal contingent that think that the agency is stifling innovation with overbearing regulations. Those can't both be right.

I'm at neither end of this spectrum. I think that we need an FDA, and that its purview should be roughly what it is now. That is, I think that the agency should require proof of safety and efficacy for marketed drugs, and that this proof should include rigorous clinical trials. I think that it should, in fact, make sure that drug companies don't go too far in their efforts to market their compounds, with "too far" to be determined (as it is now) by continuous wrangling. But I don't mean to suggest that the agency is doing all of its jobs optimally, or that it couldn't think of new ways to fulfill its mission.

Here's an example, a column in Bio-IT World that (at first glance) comes across as just more FDA-hammering. But there are some interesting ideas, once you get past the boilerplate. Such as:

While wholesale FDA reform is needed, doing it right would entail a monumental effort that could take years. But there are modest steps we can take in the meantime. How about carving out one or more FDA-free Enterprise Zones where doctors, scientists, and volunteer patients can make their own decisions unfettered by the heavy hand of regulators? Imagine an experimental terminal-illness wing of the Cleveland Clinic where informed consent was the only law. How hard would it be to draft enabling legislation?

Defenders of the FDA’s prerogatives would fight such proposals tooth and nail. But what kind of nanny state arguments can be made against conducting such a policy experiment when anyone who objects doesn’t have to be treated? Breakthroughs that emerge would still have to pass through the FDA gantlet before they would be generally available. The difference is that researchers could continue making improvements while treating volunteers during this long process.

Now, it's fair to ask how heavy the hand of regulation is in the case of terminal illnesses. We already have an awful lot of unusual therapies being tried in such situations. But could we accomplish more under these proposed conditions? Should we? I invite debate in the comments.

Comments (23) + TrackBacks (0) | Category: Regulatory Affairs

Acronym-Fest: GSK and Its DPUs

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Posted by Derek

Back last year we were talking here about GlaxoSmithKline's R&D makeover. The company had reorganized into "DPU"s (Discovery Performance Units), each of them operating under much more of a "succeed or you're out" atmosphere. Now Bloomberg has a look at how that's going:

Glaxo is conducting one of the industry’s boldest experiments, changing the way it looks for new medicines to emulate biotech companies and spur innovation. The U.K.’s largest drugmaker has broken up research into competitive teams and put scientists back at the center of the process. But freedom carries a price: researchers who don’t adapt must go.

Talent was “buried in the ocean” under the old system, says Moncef Slaoui, Glaxo’s head of research and development and one of the architects of the overhaul. Scientists now “live or die with their project.”

This month, London-based Glaxo completed the first appraisal of its new model. The company is now deciding which teams deserve more funding and which ones don’t. The conclusions will probably be made public in February when Glaxo reports full-year earnings. . .

That will be worth a close look when it happens, for sure. The article goes on to a standard feature of such pieces - what, indeed, would a re-org be like without some bad words for the old system?

(Dave) Allen says he remembers discussions dating as far back as the early 2000s with former Glaxo R&D head Tachi Yamada and Slaoui, who succeeded him in 2006, on the importance of scientists in the drug-discovery process.

The old Glaxo “was arrogant,” says Robin Carr, who heads a DPU looking at ways to treat lung damage. “It had the biggest machine and the biggest hammer and it (thought it) could just grind out success.”

That's funny - I remember the "old" Glaxo advertising itself as being full of nimble, empowered Centers of Excellence for Drug Discovery (as they were called), which supposedly had a free hand to do whatever it took to bring drugs to market. There were several re-re-orgs along the way, and it appears that the current DPUs are supposed to be the smaller units that were inside a lot of the CEDDs.

It's basically too early to tell if this new model is helping - I note that the article mentions that some investors were impressed when the company's CEO, Andrew Witty, talked during at a recent conference call about the number of compounds that GSK has in development. Given the timelines involved, that can't have much to do with the new structure. But eventually its effects should be felt, one way or another, and it looks like February will be the next look under the hood. . .

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

December 1, 2011

Worst Biotech CEO of 2011?

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Posted by Derek

I would be neglecting my duties if I didn't mention Adam Feuerstein's "Worst Biotech CEO of 2011" voting, which is going on here. If you have a strong opinion on this matter - and opinions on such things tend to be strong - then hop over and make yours known.

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

Nevirapine: Not Chiral. Paper: Not Right. Editorial Staff: Not Doing Their Job

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Posted by Derek

Readers may remember a now-retracted paper that I first blogged about here, the one that claimed to have isolated the reverse transcriptase inhibitor nevirapine as a natural product. Moreover, it claimed that the isolated material was chiral, which would have been very interesting indeed if it were true. (And, as that last post says, would have been worth making a big point of, if the authors really had understood what they were claiming).

Now a group from Manchester has weighed in on that topic. And what they find is what anyone who'd examined the field should have expected: that the nevirapine molecule, although capable of existing in two chiral forms, equilibrates between them on a time scale of seconds at room temperature. Isolating the atropisomers by standard means is not possible.

So everything about that original Tetrahedron paper was wrong; it never should have made it through the review process. And that's why I highlight such things - not to heap scorn on the original authors, which doesn't do that much good, but to heap it on the people who let such papers into print. Reviewers and editors are supposed to notice when a paper has made very unusual claims, and they're supposed to ask the authors to back them up. But the folks at Tetrahedron were asleep at the switch when this one came through. It's important for them (and other editorial staffs) not to let that happen, and it's important for a journal's readers to realize that it can.

Addendum - as an aside, I note that one of this blog's entries (the second link above) is cited in the references of this latest paper. I'm glad to be a cite-able source!

Comments (8) + TrackBacks (0) | Category: Natural Products | The Scientific Literature