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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

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

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

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August 31, 2011

The Finest Retraction Notice Ever?

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Posted by Derek

RetractionWatch has this gem from the Journal of Clinical Microbiology. My favorite part is midway through: "Moreover, we realized after our article had been published that major parts of the text had been plagiarized almost verbatim. . .".

Oh, yeah. There is that. But there's more at the link. The RetractionWatch people are trying to get more details, but I wish them luck. This looks like one of those things that no one is going to be very happy to talk about. . .

Comments (12) + TrackBacks (0) | Category: The Dark Side | The Scientific Literature

China's Pharma Ambitions: Hua Pharmaceuticals Responds

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Posted by Derek

I've had a detailed e-mail from John Choi, Chief Strategy and Business Office for Hua Medicine. That's the company that was featured in a bizarre-on-the-face-of-it quote from Chemical and Engineering News that I blogged on here the other day. That, you'll recall, was the one that seemed to suggest that Hua (with eight employees at the time of the article) was going to introduce "breakthrough drugs" within four years, which they'd manufacture and sell themselves. As many readers guessed, what this actually means is "other people's breakthrough drugs licensed in to China".

I'll let Choi tell his side of the story:

There was a lot of commentary generated from people that have not read the CEN article nor have any background to what we at Hua Medicine are doing, so I’d like to clarify and tell “our side of the story” as it were. I am a US trained MD-PhD (my PhD was at Harvard and MD at Cornell Medical), and was formerly a professional Venture Capitalists for the last 10 years in the US before joining Hua Medicine in China. So I am quite aware of the difficulties and timelines for drug development of biotech companies, having funded many of them. It typically takes 12-14 years (if successful) for a company starting pre-clinical work to get their products on the market, and the probability of succeeding in this according to Nature Reviews Drug Discovery is typically less than 10% from phase I to NDA approval. . .With that context, Hua is certainly not proposing that we can do all stages of pre-clinical work, getting through all phases of safety and efficacy clinical trials, and getting approval from the regulatory agencies, all in only 4 years from scratch with no previous work required! In fact, if you are familiar with China’s regulatory pathway, it typically takes LONGER to get regulatory approval in China than in the US or most other countries for that matter. In fact, unlike the US, for even internationally marketed products that have approvals in other countries, in China one must still go through at least a 30 patient Phase I/PK study and at least 100-patients-in-each-trial-arm Phase III clinical study for an imported drug to get approved (even though that drug may have been approved and marketed elsewhere such as the US for more than 10 years… It still doesn’t matter, if it is a compound never marketed before in China, the Chinese SFDA will require at least these minimum trials before approval).

What was taken out of context was 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. Typically it requires 10-16 months for Clinical Trial Approval (CTA) to be granted by SFDA which is the IND equivalent in the US (and allows a drug’s sponsor to begin trials in China), 2 years for completing the phase I and mandatory Phase III trials, and 12-16 months for an Imported Drug License (IDL) approval which is the equivalent of an NDA submission. Hence 4 years to get these imported drugs to market in China. As a matter of fact, Hua medicine is currently in the final stages of discussions for some of these marketed or later stage assets (for China licensing), and that was what was meant by the CEN article saying “the firm will launch breakthrough drugs in 4 years”. Hua is also backed by a premier set of US Venture capitalists with $50M in initial funding to pursue in-licensing of these marketed and late-stage assets (as you know, drug license rights do not come cheaply, after all), with more capital if needed to acquire more assets.

Well, that makes a lot more sense. I note that their founder (Li Chen) was the head of research at Roche's R&D center in China, so he presumably also knows what he's doing. Here's some of their investment backing, and here's their Board of Directors. I can still wonder a bit why any big outside companies would do these deals, since in many cases they've been making their own efforts in China (or have already signed up with other people trying to do this same sort of thing). But it would seem that the people at Hua have identified room to maneuver.

That said, the company may be getting more early publicity than it's ready for, if their web site is any indication. It would seem to have not been up for long, if the "Some news type here" line under the "News" heading is any indication. And that C&E News article may have been another example, since that part of it gave the impression that Hua was thinking about launching its own internal programs. (J. F. Tremblay, the author's article, was able to comment on that here.

Comments (17) + TrackBacks (0) | Category: Business and Markets

August 30, 2011

Why Isn't There an ArXiv For Chemistry?

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Posted by Derek

Nature has an article on the 20th anniversary of the ArXiv preprint server by its founder Paul Ginsparg. That's gradually worked its way through many parts of physics and mathematics to become a major route for releasing scientific results. (They're now getting about 7,000 submissions a month, with a million downloads a week). But many areas of science remain untouched:

Physicists were quick to adopt widespread sharing of electronic preprints, but other researchers remain reluctant to do so. Fields vary widely in their attitudes to data and ideas before formal review, and in choosing to share electronic preprints, each community will have to develop policies and protocols best suited to their users. A talk I gave in 1997 to a group of biologists helped catalyse the resource now known as PubMedCentral — run by the US National Institutes of Health. I served on the initial advisory board, which soon decided not to host any unrefereed materials, even carefully quarantined, in part for fear of losing essential publisher participation. There remain many legitimate reasons for individual researchers to prefer to delay dissemination, from uncertainty over correctness, to retaining extra time for follow-ups, to sociological differences in the way publication is regarded — in certain fields, the research somehow doesn't count until peer reviewed.

No community that has adopted arXiv usage has renounced it, however, so the growth has been inexorable. . .

But back in its early days, it looked like it would be even more inexorable than that:

The idea that print journals had outlived their usefulness was already in the air in the early 1990s. David Mermin memorably wrote in Physics Today in 1991: “The time is overdue to abolish journals and reorganize the way we do business.”1 By the mid 1990s, it seemed unthinkable that free and unfettered access to non-refereed papers on arXiv would continue to coexist indefinitely with quality-controlled but subscription-based publications. Fifteen years on, researchers continue to access both, successfully compartmentalizing their different roles in scholarly communication and reward structures.

The transition to article formats and features better suited to modern technology than to print on paper has also been surprisingly slow. Page markup formats, such as PDF, have only grudgingly given way to XML-based ones that support features such as manipulable graphics, dynamic views, linked annotations and semantic markup. . .

Well, in chemistry, that transition has been even slower. Our field is still very much dominated by the societies (ACS, RSC, etc.) and the commercial publishers like Elsevier, Nature, Wiley, etc. When's the last time - when's the first time - you heard of a significant organic chemistry paper appearing anywhere else? There's absolutely no equivalent of the ArXiv system, and although I know that the question has been asked before, I'll ask it again: why not? If someone had started such a thing back in the early 1990s, would it (could it) have taken off? Or are there other factors that would have kept it from doing so (the same ones as now?)

Comments (51) + TrackBacks (0) | Category: The Scientific Literature

August 29, 2011

Chinese Pharma: No Shortage of Ambition, Anyway

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Posted by Derek

When does China take the next step in drug research? They already have a huge contract research industry, and they have branches of many of the major pharma companies. But when does a Chinese startup, doing its own research with its own people in China, develop its own international-level drug pipeline? (We'll leave aside the problem that not even all the traditional drug companies seem to be able to do that these days). It still seems clear that we're eventually going to have a Chinese Merck, or a Chinese Novartis or what have you - a company to join North America, Western Europe, and Japan in the big leagues. The Chinese government, especially, would seem to find this idea very appealing.

Opinions differ, to put it mildly, about how far away this prospect is. But Chemical and Engineering News is out with an article on homegrown Chinese research that explores just this sort of question. But you run into passages like this:

In a meeting room in a building resembling a residential home in Shanghai’s Zhangjiang Hi-Tech Park, Li Chen and John Choi describe the business plan of their new company. Called Hua Medicine, the firm will launch breakthrough drugs within four years, they predict. Hua will manufacture the compounds and sell them with its own sales force. It will also license its internally developed drugs to multinational companies.

Yet right now, Hua is a modest operation that employs eight people. Hua doesn’t have an R&D lab yet, let alone a manufacturing facility. It operates in a loaned building formerly used by the administrators of the industrial park...

It can be easy to dismiss such ambitious business plans as simply talk aimed at gullible investors or government officials handing out subsidies. Except several start-ups are led by people who have long track records of success. Moreover, the money financing these start-ups comes not from relatives and friends, but from savvy investors knowledgeable about the drug industry.

Well. . .yeah. Let me join those who dismiss business plans that are as ambitious as that one. The way I understand the drug industry, if you're planning on launching a breakthrough drug within four years, you must have that drug in your hand right now, and it has to have had a lot of preclinical work done on it already (and in most therapeutic areas, it needs to have already hit the clinic). And note, these guys aren't talking about their one pet compound, they're talking about launching drugs, plural. Drugs that they discover, develop, manufacture and sell. And they have 8 people and no labs.

No, something is off here. I get the same feeling from this that I get from a lot of leapfrog-the-world plans, the feeling that something just isn't quite right and that the world doesn't allow itself to be hopped over on such a deliberate schedule. Thoughts?

Comments (47) + TrackBacks (0) | Category: Business and Markets | Drug Development | Drug Industry History

August 26, 2011

Kibdelomycin, A New Antibiotic. In A Way.

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Posted by Derek

We're going to need new antibiotics. Everyone knows this, and it's not like no one's been trying to do anything about it, either, but. . .we're still going to need more of them than we have. I'm not predicting that we're going to go all the way back to a world where young, healthy people with access to the best medical care die because they decided to play tennis without their socks on, but we're certainly in danger of a much nastier world than we have.

So I'm always interested to hear of new antibiotic discovery programs, and Merck is out with an interesting paper on theirs. They've been digging through the natural products, which have been the fount from which almost all antibiotics have sprung, and they have a new one called kibdelomycin to report. This one was dug out from an organism in a sample from the Central African Republic by a complicated but useful screening protocol, the S. aureus fitness test. This relies on 245 different engineered strains of the bacterium, each with an inducible RNAi pathway to downregulate some essential gene. When you pool these into mixed groups and grow them in the presence of test compounds (or natural product extracts) for 20 generations or so, a check of what strains have moved ahead (and fallen behind) can tell you what pathways you seem to be targeting. A key feature is that you can compare the profile you get with those of known antibiotics, so you don't end up rediscovering something (or discovering something that only duplicates what we already have anyway).
Kibdelomycin.png Now, that's no one's idea of a beautiful structure, although (to be fair) a lot of antibiotics have very weird structures themselves. But it's safe to say that there are some features there that could be trouble in a whole animal, such as that central keto-enol-pyrrolidone ring and the funky unsaturated system next to it. (The dichloropyrrole, though, is interestingly reminiscent of these AstraZeneca gyrase/topoisomerase antibiotic candidates, while both celestramycin and pyoluteorin have a different dichloropyrrole in them).

What kind of activity does kibdelomycin have? Well, this is where my enthusiasm cools off just a bit more. It showed up in screening with a profile similar to the coumarin antibiotics novobiocin and chlorobiocin, and sure enough, it's a topoisomerase II inhibitor. It appears to be active almost entirely on gram-positive organisms. And while there are certainly nasty gram-positive infections that have to be dealt with, I'm more encouraged when I see something that hits gram-negatives as well. They've got more complicated defenses, those guys, and they're harder to kill. It's not easy to get broad-spectrum activity when you're going after gyrase/Topo II, but the fluoroquinolones definitely manage it.

The Merck team makes much out of kibdelomycin being "the first truly novel bacterial type II topoisomerase inhibitor with potent antibacterial activity discovered from natural product sources in more than six decades". And they're right that this is an accomplishment. But the kicker in that sentence is "from natural product sources". Getting gram-positive Topo II inhibitors has actually been one of the areas where synthetic compounds have had the most success. Building off the quinolones themselves has been a reasonably fruitful strategy, and a look through the literature turns up a number of other structural classes with this sort of activity (including some pretty wild ones). Not all of these are going places, but there are certainly a number of possibilities out there.

In short, if kibdelomycin weren't an odd-looking natural product, I wonder how much attention another high-molecular-weight gram-positive-only topoisomerase inhibitor would be getting, especially with only in vitro data behind it. Every little bit helps, and having a new structural class to work from is a worthwhile discovery. But one could still want (and hope) for more.

Comments (15) + TrackBacks (0) | Category: Drug Assays | Infectious Diseases | Natural Products

Design a Molecule, Win an IPad (Which is More Than You Usually Get)

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Posted by Derek

For those of you who are (or have always wanting to try being) molecular modelers, Cresset Design is holding a contest you might enjoy. They're putting up a molecule and giving out temporary licenses to their modeling software, and inviting people to come up with the closest bioisosteric match. The winner gets a free IPad2.

Of course, you're not going to be able to win by suggesting a para-fluoro group or by making a tetrazole-for-carboxylate switch. In their words:

We will use the Field alignment score for your molecule to the reference molecule as the primary judgment in designing the winner. However, molecules with high 2D similarity or high calculated logP with receive a penalty and are unlikely to win. Also entries with reasonable chemistry and good synthetic feasibility will be favoured. Feedback showing the score for your molecule and describing which properties of the molecule are being penalised will be provided on request. The winner will be the molecule that, in the opinion of the judges, represents the best design chosen from the top scoring results.

Fair enough, I'd say. I look forward to a follow-up from them at the end of the contest; I'd like to see what sort of stuff comes in.

Comments (18) + TrackBacks (0) | Category: In Silico

August 25, 2011

Crazy Shape-Shifting Bullvalenes

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Posted by Derek

You don't hear much about bullvalene, outside of physical organic chemistry textbooks. bullvalene.png It's a funny-looking symmetric tricyclic compound, which just seems to be another weirdo hydrocarbon until you consider what it can do with all those alkenes. Everything is lined up just right to rearrange - and then the product you get is lined up just right to rearrange, which gives you a product that rearranges, and so on and so on. The molecule has no permanent structure at reasonable temperatures; this process never stops.
Bullvalene_rearrangements.png
We owe William von E. Doering and Wolfgang Roth for this one (the background story is here). I hadn't realized that the "bull" in the name was put in there by Doering's grad students - it was his nickname! (Believe me, there are a lot of research groups out there where that trick wouldn't provide anything printable). The molecule was synthesized by Gerhard Schröder of Karlsruhe, who continued to work in the bullvalene field (and on related cycloalkene oddities) for many years

There are 10!/3 distinct bullvalene structures, or 1,209,600 of the things. And while you can see the fluxional character in the NMR (one peak at high temperature in the carbon NMR, four sharp singlets at -60 C, and a mess at room temp), no one's really worked out what happens with substituted derivatives. They're going to wander around, too, but how much of that space do they explore? Schröder's group prepared a number of derivatives over the years and showed that they have dynamic structures, but figuring out just how dynamic is a complicated problem. Here's a picture of what happens with a tetrasubstituted compound, for example.
Bullvalene%20isomers.png
Now Jeffrey Bode (and coworker Maggie He) at the ETH in Zürich may have started to answer this question. They prepared a chiral trisubstituted bullvalone, no picnic in itself. That structure doesn't rearrange, but then they prepared an enolate and trapped it as an enol carbamate. That completes the three alkenes, and off things go. Of course, the alkenes are rather different from each other now, so not every pathway is going to be energetically similar, but there are still enough of them to make for quite a scatter.

When they analyzed the product(s) of that enolate trapping reaction, they found that there was still some chirality present. That must have been an exciting moment, but checking the HPLC carefully showed that there was a chiral impurity present that was left over from the starting material. Once that was cleaned out, it was clear that the situation was still pretty complex: they pulled out four fractions from the HPLC, all of which were mixtures of rearranging substituted bullvalenes. Two of the fractions had no optical activity at all, and showed (and kept) the same HPLC trace as each other over time. One of the other original HPLC cuts, though, had some residual optical activity, which disappeared over another 24 hours. During that time, too, its HPLC trace gradually evened out to be the same as the other two racemic cuts. The fourth cut of the original HPLC trace had even more optical activity in it, and normalized out even more slowly.

Their best explanation for all this is that the molecule starts off on its crazy course of interconverting rearrangements, but occasionally gets to a structure that, energetically speaking, is somewhat painted into a corner. Its pathways to get back out into the rapidly-rearranging manifold are higher-energy, so that part of the population retains chirality longer than the ones that took a different path. Eventually, though, everything does even out: the metastable structures back out of their respective dead ends and start flipping back around through the lower-energy rearrangement pathways.

As they get more of a handle on these molecules, they hope to start to control some of the rearrangement population, messing with the various rate constants so that the isomers sort themselves out (possibly) into discrete populations. There could be some very unusual applications for such shape-shifting molecules, although I have to say that training them away from their bucket-of-marbles-on-the-floor tendencies will not be easy. Still, this is the kind of physical organic chemistry I've always been happy to read about (and glad that I'm not having to do myself!)

Comments (12) + TrackBacks (0) | Category: Chemical News

August 24, 2011

Disappearing Information, Courtesy of Aldrich Chemical

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Posted by Derek

I've been in the lab all afternoon setting up reactions, and that prompts me to write about something that I've been noticing. Is it just me, or does Aldrich seem to be abandoning the practice of putting any useful information on their labels?

This has been creeping up for a while, but I worry that instead of an anomaly it's the way of the future. I just got in several bottles of reagents from Aldrich, and basically all they have on their labels are the names of the compounds. No molecular weight, no density, no melting or boiling point: nothing but a line of type surrounded by an Aldrich label. And while I can go look these things up, and while my electronic notebook often is able to provide the information, it would still be a lot more convenient to have it on the label as well. You know, like it used to be.

I assume that this is a cost savings. As a rule, I assume that the most likely answer to any question that starts out "I wonder how come they. . ." is "money". But it's a shame.

Comments (53) + TrackBacks (0) | Category: Life in the Drug Labs

What Are Impact Factors Doing to Chinese Science?

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Posted by Derek

Here's a useful (and rather brave) editorial from Chinese chemist Nai-Xing Wang in Nature. He's pointing out that the government's funding agencies are taking a crude and harmful approach to who gets research support: publish, and publish according to their schemes, or flippin' well perish:

The biggest problem remains the obsession with journal impact factors. Generally speaking, articles in journals with high impact factors are judged to appeal most to readers, but not every paper published in a high-impact-factor journal is high quality, and papers published in lower-ranked journals are never worthless. Yet some administrators in China take a very crude approach: high-impact-factor publications mean excellent work.

Research proposals are judged according to the impact factor of a scientist's previous publications. (And referees are usually selected on these criteria too.) Worse, the salaries of my chemistry colleagues go up or down depending on a complex mathematical formula based on the impact factor of the journals in which we publish our work — which we must supply in a detailed list.

Now, this sort of thing has been going on around the scientific world for a while, and it's going to be hard to put a complete stop to it. But the Chinese system that's described is about the most blatant that I've come across. The effects are pernicious:

If a high impact factor is the only goal of chemistry research, then chemistry is no longer science. It is changed to a field of fame and game. There are other effects too. Administrators in almost every university and research institute like to evaluate researchers by their papers at the end of each year. As a result, chemists often choose easy research topics that can be written up inside a year. . .

You get what you subsidize; I don't think that law is ever broken. And if the Chinese government wants people to crank out lots of papers in what they feel are high-end journals, well, that's what people will do. But if they want something useful to come out of all that effort, well, things might need to be adjusted a bit. But "useful" is a slippery word. For the people who are gainfully employed in keeping the current system running, it's just about as useful as it can be the way it is.

Comments (26) + TrackBacks (0) | Category: The Scientific Literature

August 23, 2011

SRT1720: Good (And Confusing) News for Obese Mice

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Posted by Derek

Readers of this blog will be fairly familiar with the long, interesting story of sirtuin activators. Today we will speak of SRT1720, of which we have spoken before. This molecule was described in 2007 as an activator of Sirt1 with beneficial effects in rodent models of diabetes. But both of those statements were called into question by a series of papers which found difficulties with both the in vitro and the in vivo results (summarized here). The GSK/Sirtris team fired back, but that paper also served as a white flag on the in vitro assay questions: there were indeed artifacts due to the fluorescent peptides used. (Another paper has since confirmed these problems and proposed an off-target mechanism).

But that GSK response didn't address the in vivo assay questions at all - we still had a situation where one group said that these compounds (SRT1720 in particular) were beneficial, and another said that it showed no benefit and was toxic at higher doses. Adding to the controversy, another paper appeared late last year that went back to nematodes, and found the SRT1720 did not extend their lives, either. The state of this field can be fairly described, then, as "extremely confused".

Now we have a new paper whose title gets right down to it: "SRT1720 improves survival and healthspan of obese mice". First time I've seen "healthspan" as a word, I might add, and another interesting sidelight is that this appears in Nature Scientific Reports, the publishing group's open-access experiment. But now to the data:

What this (large) team did was place one-year-old male mice on a high-fat diet in the presence of two different doses of SRT1720 in the chow, corresponding to 30 mg/kilo and 100mg/kilo. The effects on lifespan were notable: standard-diet animals had a median lifespan of 125 weeks, and that was shortened to 94 weeks on the high fat diet. But on that diet plus the lower dose of SRT1720, the median lifespan was 103 weeks, and on the higher dose it was 115 weeks. It's interesting, though, that this took place while the animals ate the same number of calories and gained the same amount of (extra) weight as the control group.

Blood work and histopathology revealed many more differences. The high-fat animals (with no SRT1720) showed the expected problems that you see in such studies - fat accumulation in the liver, increased numbers of beta-cells in the pancreas, higher insulin levels, and so on. But the SRT1720-dosed animals showed a good deal of reversal of all these effects. DIgging down to the molecular level, inflammatory markers, indicators of apoptosis and DNA fragmentation were increased in the high-fat animals, and these were also mitigated by SRT1720.

There are many other effects mentioned in the paper, but I'm not going to go into all the details - hey, it's open-access, so if you're really into this stuff you can find it all. Suffice it to say that a long list of deleterious effects of a high-fat diet on rodents seem to be partially to fully reversed on treatment with SRT1720, particularly at the higher dose, without significant evidence of toxicity. But how do we reconcile that with the report that the compound showed no benefit, and toxic effects to boot? I'll let the authors tackle that one:

Our results continue to support the beneficial pharmacological effect of SRT1720 in models of metabolic disease despite a recent report by Pacholec and colleagues to the contrary14 where the authors report 100 mg/kg SRT1720 is not tolerable and increases mortality in mice and that the compound does not elicit beneficial effects in the Lep ob/ob mouse model of diabetes. This conclusion is inconsistent with not only our findings but also several additional studies where SRT1720 has been reported to exert positive effects in multiple models of metabolic disease including Lep ob/ob mice, diet-induced obese mice, MSG-induced hypothalamic obese mice15 and Zucker fa/fa rats. Pacholec and colleagues did report that fasting insulin levels are reduced by SRT1720 administration, which is in agreement with our findings (Fig. 2) and with data reported previously in diet-induced obese mice. The putative toxicity of SRT1720 administered at a 100 mg/kg oral dose to 8 mice over 18 days is inconsistent with a study where the compound exhibited no toxicity at a 5-fold higher dose for 15 weeks12 nor is it consistent with our long-term feeding study involving over 100 mice consuming an equivalent daily dose. In fact, our mice showed increased survival and improvement in multiple physiological parameters in response to SRT1720 treatment and did not display overt signs of toxicity even after more than 80 weeks of treatment.

So yes, there's pretty much a flat contradiction here, and I have no idea of how to resolve it. This paper doesn't reference the failure of SRT1720 to show effects in nematodes, but that's another piece of the puzzle that can't be ignored, either. One possibility is that the doses of the compound need to be rather heroic. Believe me, by the usual pharmacological standards, extended dosing at 100 mpk is pretty heavy-duty (and, I might add, basically unattainable in humans under normal conditions, especially humans on a high-fat diet).

So for now, I have to throw up my hands. This latest paper seems very thorough, and represents a really significant effort on the part of a long list of highly competent people. But there can be no doubt that the SRT1720 story (and the story of sirtuin activators in general) is still very complex and hard to evaluate, because the various problems and complications that have been found can't be dismissed, either. There's something here, all right, and it could well be very important. But what are we looking at?

Side note: this work was the subject of a writeup by Nicholas Wade in the New York Times the other day. It reveals that there's another arm of this study - normal mice, on normal chow, also treated with SRT1720. Those results, out next year, will be very interesting indeed, although I can only think that they're just going to keep the fires burning. I'd also like to note (as one comment on this blog did) the tone of most of the online comments on the Times story. They can, I think, be summed up as "Great, the big evil drug companies have found something so people can just stay big and fat and not die early, and they're going to sell it to us for a zillion dollars while their corporate masters stay thin and healthy and laugh at us all". Read through a few of them and see if I haven't captured their general spirit - and think for a bit about what that tells us, both about the public perception of drug research and (perhaps) about the sort of people who leave comments over at the Times.

Comments (39) + TrackBacks (0) | Category: Aging and Lifespan | Diabetes and Obesity

August 22, 2011

DRACOs: New Antivirals Against Pretty Much Everything?

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Posted by Derek

I've been meaning to write about this paper from the RIder group at MIT's Lincoln Labs, which shows some very interesting approaches to killing off a wide variety of viruses. They've dubbed these new agents DRACOs, for Double-stranded RNA Activated Caspase Oligimerizers, which is certainly one of those acronyms with a lot packed into it.

So now to unpacking it. The first key point is the double-stranded RNA (dsRNA) part. For a long time, that was thought to be a form that isn't wasn't found in human cells (as opposed to single-stranded stuff). We now know that short dsRNAs (up to twenty-odd base pairs) are part of human biology, but viruses produce much longer strands of it during their replication process - or, more accurately, they hijack human cellular machinery to produce it. (Viruses, as a rule, don't do anything for themselves that they don't absolutely have to).

Naturally enough, cells have evolved ways to recognized long dsRNAs as a sign of infection - there's a whole list of proteins that recognize these things and bind to them. Some of them inhibit its downstream processing directly, by just hanging on and gumming up the works, while others set off responses further downstream. One of those is apoptosis, programmed cell death, a brutal but effective fall-on-your-sword pathway that gets initiated by all sorts of unfixable cellular problems. (When a cell's internal controls give a "Fatal Error" message, it's taken literally). And naturally enough, viruses have evolved ways to try to evade these defenses, both by targeting the dsRNA detection proteins and by inhibition of apoptosis pathways. (As a side note, it's always been interesting to untangle these counter-counter-countermeasure situations whenever a new cellular pathway relating to infection is worked out. You find, invariably, that hundreds of millions of years of evolutionary pressure have built up crazily elaborate frameworks around all of them).

This approach tries to speed up the dsRNA-means-apoptosis connection. A DRACO turns out to be a good-sized protein with two functions: one end recognizes and binds to dsRNA, and the second contains a signal to induce apotosis. If multiple copies of the DRACO protein stick to the same viral dsRNA strand, that should be enough to initiate cell death and interrupt the viral replication process. The team tried out a whole range of possibilities for both those functional domains, with the best (so far) using either Protein Kinase R (PKR) or RNAaseL domains to recognize viral RNA and an Apaf caspase recruitment domain for apoptosis signaling. Another key modification was the addition of a PTD (protein transduction domain) tag, which allows large proteins like these entry into cells through active transport. (Cells only take in whole proteins through gatekeeping transport mechanisms; otherwise they just sort of bounce off - this effect was confirmed with DRACOs that lacked the PTD tags).

So, basically, this is the sort of protein that you might expect evolution to stumble onto eventually, but now the connecting line has been drawn by hand instead. It's worth noting at this point, though, that this general idea has occurred to others before: here's a paper from Boston University trying the same sort of strategy. That one was published online in 2009, but didn't make it to print until May of this year, which makes you wonder if that's a typical delay for that journal (FASEB J.) or not. It's also worth noting that, for whatever reason, this new MIT paper does not cite the one from BU.

How did they work? Pretty well. The PTD tags did what they were supposed to, taking the proteins into cells rapidly. Once inside, the DRACOs themselves hung around for several days before being degraded, which is another big hurdle. And they did indeed protect against infection by an impressively wide range of viruses in cell culture: rhinovirus, encephalomyelitis, adenoviruses, arenaviruses, bunyaviruses, flaviviruses, reovirus, and flu. A lot of nasty pathogens fall into those bins.

But that's in cell culture, which is a long way from a living organism. To their credit, the team went on to try out their idea in live mice, and they show some encouraging results. Administering their best DRACO candidates to mice and then exposing them to influenza virus took the survival rate (at ten days) from under 10% in the control groups up to 60-70% survival for the PKR version and up to 100% survival for the RNAaseL version.

It's an impressive graph, but there are some things to note about it. For one, the DRACO proteins were administered by injection - these are probably never going to be feasible as oral medications, since they're large proteins which will just get digested. But again to their credit, the MIT group also tested dosing via intranasal injection (yep, squirting the protein solution up the noses of mice, truly the glamorous end of science). That also showed a strong protective effect after influenza virus exposure, which is a good sign.

Now comes the next concern. You might have already wondered about my mention of the injection route, since we already give millions of people a year injections to combat viral infection: flu shots. Those, though, are vaccines meant to last the whole season (and beyond). DRACO proteins get cleared out in mice on a time scale of days; they wouldn't be expected to have any long-range immune effects. (Of course, their broad antiviral effects, versus the sometimes way-too-specific nature of a vaccine, is a strong point in their favor). But this brings up another issue that's going to have to be addressed: when you look at the graphs of the mice experiments, you note that the DRACOs were given either on Day 0 or Day -1 compared to the exposure to virus.

That's actually a big deal in this field. The problem with antiviral therapies has always been that you don't usually know that you've been infected until, well, after you've been infected. Sometimes that lag time is rather long, and it's always long enough for the virus to get a good running start. Symptoms, after all, don't occur until things are well under way. In the real world, the two opportunities for antiviral therapies are (1) something that you can take long before you're even exposed, and that lasts for a long time (like a vaccine) or (2) something that you can take after you've already realized that you're sick (like an antiviral drug). So far, the DRACO proteins fall in between these two, and the next challenge for these agents is to see if they can stretch into one or the other. The authors, no fools, realize this:

Based on these encouraging initial animal trials, future work should be done to test and optimize antiviral efficacy, pharmacokinetics, and absence of toxicity in vitro and in vivo. Future experiments can further characterize and optimize dsRNA binding, apoptosis induction, cellular transduction, and other DRACO properties. More extensive trials are also needed to determine how long after infection DRACOs can be used successfully, or if DRACOs are useful against chronic viral infections without producing unacceptable levels of cell death in vivo.

It's going to be very interesting to see how this field develops. It's a promising start, for sure, but there are still a lot of ways for things not to work out. Just getting this far along in the "promising start" phase is a real accomplishment, though, and more than many people have ever been able to manage.

Comments (15) + TrackBacks (0) | Category: Infectious Diseases

August 19, 2011

Day Off - Some Links and Some Ancient Greek

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Posted by Derek

I'm adding a day to the weekend, so science is going to have to march on without me for a while. I do have a few miscellaneous links to things that have been piling up, though: here's the Chronicle of Higher Education on growing links between drug company research and academia, and (for something completely different) here's a rather crazed editorial at Marketwatch calling for the immediate abolishment of the FDA. ("Everyone would start marketing crazy drugs to cure cancer, impotence, etc. And my response is – so what?").

And here's a short review in Organic Process R&D on a reaction that I've never done, but which looks interesting: direct amine substitution of C-H bonds. You do that with various semi-exotic rhodium catalysts, and I'm not aware of any other useful ways to do it at all. Anyone out there had any experience with this?

To cap things off, if anyone's looking for something to do in their spare time, well, do what I've been doing on the train rides home: help transcribe some ancient Greek papyri. No, I'm not kidding. These are unstudied examples of the Oxyrhynchus papyri, a trove of discarded writings from an Egyptian city of Roman and post-Roman times, excavated in the 1890s and still being worked through. (The book City of the Sharp-Nosed Fishis a good overview of what's been found so far).

They'll put scanned ones up on the screen for you, and you can transcribe the Greek letters for their database. I'd recommend hitting the "Next" button at first until you get one that's in nice, dark, all-capital lettering; those are pretty easy to work with. Some of the dashed-off script ones, though, are a real challenge, and you'll be surprised at how much handwriting varies. Here's a useful comparison of that sort of thing, and this is another excellent resource on reading papyri. If (like me) you don't have a whole lot of ancient Greek at your disposal, you can always try to translate text strings you find using this tool at Tufts' Perseus site. Mind you, these guys mashed all their words together with no spaces, so it can be a bit tricky - one help is that kappa-alpha-iota ("and") shows up a lot. Enjoy! I find it, weirdly, to be a lot of fun.

Comments (15) + TrackBacks (0) | Category: Blog Housekeeping

August 18, 2011

Is Anyone Doing the Pfizer Screening Deal?

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Posted by Derek

A couple of years ago, I wrote here about an initiative from Pfizer. They were proposing letting other (smaller) companies screen their compound collection, with rights to be worked out if something interesting turned up.

The thing is, I haven't heard about anyone taking them up on it. Does anyone know if this ever got off the ground, or did it get lost in the trackless Pfizer territories somewhere? It sounded like a reasonable idea in some ways, and I'm curious if it ever went anywhere. . .

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

The NIH Wonders About the Future of Biomedical Workers

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Posted by Derek

A reader passes along this request for comment by the NIH. The "Advisory Committee to the NIH Director Working Group on the Future Biomedical Research Workforce" is asking for thoughts on issues such as the length of time it takes to get a PhD, the balance between non-US and US workers, length of post-doctoral training, the prospects for employment after such is completed, general issues relating to whether people choose biomedical research as a career at all, and so on.

These are, of course, issues that have come up here repeatedly (as well they should), so if you want to have a shot at influencing some NIH thinking on them, they're asking for anyone's thoughts by October 7. (Use this form).

Comments (9) + TrackBacks (0) | Category: Business and Markets | General Scientific News | Graduate School

August 17, 2011

New Ways to Fluorinate

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Posted by Derek

There have been some neat ways to make fluorinated molecules reported recently, which I wanted to mention. We med-chemists just love our fluorines - as long as we don't have to use, like, fluorine itself to make them - because they armor-plate parts of our molecules against being metabolized and can change the binding profiles of the parent structures like nothing else can.

Over at New Reactions, there's a nice writeup on a new way to generate difluorocarbene, which (as it should) immediately adds to alkenes to give you difluorocyclopropanes. (It'll add to alkynes to give you the somewhat more exotic difluorocyclopropenes, too). This is from G. K. Surya Prakash and George Olah, and from the looks of it, it's simplicity itself: take your alkene and some TMS-CF3 in THF, and either run it hot with sodium iodide or in the cold with the anhydrous TBAF substitute TBAT. So there's what looks like a perfectly useful med-chem structural motif, suddenly made widely available.

The second paper is from the Baran and Blackmond labs at Scripps, and is a completely new way to introduce trifluoromethyl groups onto heterocyclic rings. This one generates trifluoromethyl radicals under very mild conditions, using the hitherto-obscure (but stable and relatively cheap) Langlois reagent as a source. You don't need any special group on the substrate to make this work - it charges right in and attacks the more active C-H bonds of the parent heterocycle. A wide variety of useful ring systems are shown to work, and it looks like you can change the regiochemistry by varying the solvent. I'm sure that people will think of other uses for the CF3 radical, now that it's much easier to get ahold of, but this one just by itself is going to be adopted very quickly.

These, I have to say, are just the kinds of new reactions that working chemists like to see: they make useful compounds that have been hard to access, they use commercial reagents, the conditions are not hideous and require no special equipment, and the authors have taken the time to demonstrate them on a very wide range of structures. The more things like this that get discovered, the better off we are.

Comments (29) + TrackBacks (0) | Category: Chemical News

August 16, 2011

Screening Quickly Through the Mutants

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Posted by Derek

Here's another paper at the intersection of biology and chemistry: a way to check the activity of a huge number of mutated esterase enzymes, all at the same time.

Protein engineering is a hot field, as well it should be, since enzymes do things in ways that we lowly organic chemists can only envy. Instead of crudely bashing and beating on the molecules out in solution, an enzyme grabs each of them, one at a time, and breaks just the bond it wants to, in the direction it wants to do it, and then does it again and again. If you're looking for molecular-scale nanotechnology, there it is, and it's been right in front of us the whole time.

Problem is, enzymes get that way through billions of years of evolution and selection, and those selection pressures don't necessarily have anything to do with the industrial reactions we're thinking of these days. And since we don't have a billion years to wait, we have to speed things up. Thus the work at places like Codexis on engineered mutant enzymes, and thus a number of very interesting takes on directed evolution. (Well, interesting to me, at any rate - I have a pronounced weakness for this sort of thing).

This latest paper, from the University of Greifswald in Germany, builds on the work of Manfred Reetz at the Max-Planck Institute, who's been very influential in the field. Specifically, it follows up on the idea in this paper from his group and this one from the Quax group at Groningen in the Netherlands. That technique involved selecting for specificity in esterase enzymes by giving organisms a choice of two substrates: if they hydrolyze the right chiral starting material, the cleaved ester furnishes them with a nutrient. If they hydrolyze the wrong one, though, they produce a poison. Rather direct, but with bacteria there's no other way to get their attention - survival's really all they care much about.

And that technique worked, but it was a bit laborious. The largest number of different variations tested was about 2500, which seems like a lot until you do the math on protein mutations. It gets out of control very, very quickly when you have twenty variations per amino acid residue. Naturally, some of the residues shouldn't ever be touched, while others will have only minimal effects, and others are the hot spots you should be concentrating on. But which ones are which? And since you absolutely can't assume that they're all acting independently of each other, you have your work cut out for you. (Navigation through this thicket is what Codexis is selling, actually).

This latest paper adds flow cytometry, cell sorting, to the mix. Using dye systems and one of these machines to distinguish viable bacteria from dead or dying ones lets you take a culture and pull out only the survivors. When the authors expressed different esterases (with known preferences for the two substrates) in E. coli, they got the expected results - the ones with an enzyme that could cleave the nutrient-giving substrate grew, while the ones that unveiled the poison (2,3-dibromopropanol) halted in their tracks.

They then took another esterase with very modest selectivity and created a library of mutant variations - about ten million mutant variations - and expressed the whole shebang in a single liquid colony of E. coli. This was then exposed to the mixture of substrates, and anything that grew was pulled out by the cell sorter and plated out on agar (also containing the selection mixture of substrates). They got 28 clones to grow in the end, and characterized three of these more fully as purified enzymes. Of those, two of them were, in fact, much more selective than the starting enzyme (giving E values, enantiomeric ratios, of 80 to 100 as opposed to 3). Another, interestingly, was not selective at all.

And when you look at the sequences and the mutations that were picked out, you can see how tricky a business this is. One of the two selective enzymes had its valine-121 residues mutated to isoleucine (V128I) its phenylalanine-198 residue mutated to cysteine (F198C). The other was broadly similar, with one added mutation: that valine-121 was changed in this case to serine (V121S), the F198 was mutated to glycine (F198G), and also valine-225 was changed to alanine (V225A). Now, some of those aren't very big mutations (V to I, V to A), but what's even more interesting is the sequence of the unselective clone that they characterized: that one had V121I, F198G, V225A. So it had a mix of the exact mutations found in the two selective enzymes, but was itself a dud.

I'm glad to see that this worked, although you have to wonder how efficiently it moves in on a target when you get two decent hits out of ten million starting mutations. (The relative ease of screening goes a long way towards making up for that). But what I'd like to see is a mix of this technique with the one that I wrote about a few weeks ago, where a bacterium was evolved to use a chlorinated DNA base. That one used a particularly slick directed-evolution device, which would be quite interesting to apply to this food-versus-poison idea. You'd have to do some fine-tuning, especially at first, since the liberated poisonous substrate would be killing off the just and the unjust alike (which is the same problem that this current paper faced). But it seems like there should be a way to run things so that you're not just screening a big library of random mutations in the enzyme, but actually pushing the enzyme to evolve in the direction you want. Thoughts?

Comments (12) + TrackBacks (0) | Category: Chemical Biology

Is Carl Icahn Going Away?

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Posted by Derek

The latest regulatory filings show that Carl Icahn appears to have sold his Biogen position out completely as of the end of June, although he had still held over 8 million shares a week or so earlier. And he also appears to own no Amgen at present, and has sold out of Regeneron.

We last discussed Icahn's biopharma investments here, but it looks as if he's exiting the sector. And while I can't say that I'll miss him, it's perhaps food for thought if he's finding no positions worth taking over here, either. . .

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

August 15, 2011

mINDY Mice - No Obesity, No Diabetes?

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Posted by Derek

Caloric restriction increases healthy lifespan. That's true in a range of organisms, and probably in humans. But it's never going to be popular - and what's more, it's not going to be feasible, either, given how clearly people like to eat. So the search has been on for just how it exerts its effects, with a number of interesting clues turning up.

And now there's another one. There's a longevity gene in fruit flies known as INDY (short for, I fear, "I'm Not Dead Yet", and if you don't get that reference, you should probably turn in your geek license. This would be a good time to note, as required by law, that the fruit fly people are a longstanding and apparently endless fountain of weird nomenclature). Reducing INDY expression definitely lengthens lifespan in flies and in the nematode C. elegan.

A recent paper in Cell Metabolism, from a large-multicontinent team involving the Shulman group at Yale and many others, explores the effects of the mammalian homolog, mINDY, in mice. The knockout mice are smaller, although they take in the same number of calories. They are much leaner, though, with remarkable less fat. Their metabolism seems to be ramped up, as you might figure from that situation, and they're especially good at fat oxidation in the liver. Very interestingly, they maintain this phenotype as they age, while normal mice tend to put on more fat. They have lower basal glucose and insulin levels, and are better at clearing glucose, apparently through better uptake in skeletal muscle. They also seem resistant to the bad effects of a high-fat-chow diet, show a much reduced tendency to putting on weight and developing insulin resistance. All in all, this is what you'd call a desirable metabolic phenotype, and it fits in very well with what has been worked out in the fruit flies.

So what does this gene code for? Turns out that it's a citrate transporter, which might not be the most obvious thing at first, but it makes sense. Citrate is converted to acetylCoA, which is the building block for fatty acid synthesis. Cutting down its availability basically starves the liver tissue, which depends on fatty acids for a good part of its energy needs, and causes it to efficiently burn off whatever fatty acids it can acquire. And this effect might just be one of the things that produce the benefits of caloric restriction - in other words, you might not have to deprive your whole body of calories, just the key parts of it. To show that I'm not overinterpreting here, I'll let the authors say it:

These data suggest that mIndy may be a key mediator of the beneficial effects of dietary energy restriction. Since prolonged caloric restriction is very difficult to achieve in humans, our observations raise the tantalizing possibility that modulating the levels or function of mIndy could lead to some of the health-promoting effects of calorie restriction, without requiring severe caloric restriction.

And as they go on to suggest, this makes for a very interesting target for obesity, diabetes, and fatty liver disease. What about extending lifespan? Well, I've dug through the paper several time, and can find no mention of mice older than 8 months, and no numbers on their longevity. I assume that this will be the subject of another paper as the rodents get older - it's too big an issue to ignore, and this paper seems determined not to say a word about it.

Comments (26) + TrackBacks (0) | Category: Aging and Lifespan | Diabetes and Obesity

August 12, 2011

A Startlingly Good Leukemia Trial

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Posted by Derek

You've probably seen the headlines about a new experimental treatment for leukemia. For once, the excitement seems justified - this is a remarkable and very promising result, and it's worth taking a close look at it.

As reported in the New England Journal of Medicine, a patient in this study had been diagnosed with chronic lymphoid leukemia (CLL) since 1996. In this condition, B cells proliferate uncontrollably, piling up in the bone marrow and the lymph nodes. This patient had run through several courses of chemotherapy over the years. He would go for periods with no signs of disease, but it would always come back (in harder-to-treat form, naturally). By the time of this study, he was in bad shape and running out of options. Those, frankly, are the patients who are appropriate to enroll in a trial like this one - you want to treat cancer with what we know can treat it before going to something that might well not work at all (or might even make things worse).

And this particular idea had not shown as much promise in the past as everyone had hoped, despite being immunologically reasonable. The idea is to take T-cells from the patient and modify them to express a new antigen receptor, then infuse them back in and let them go to work on the tumor cells. But previous attempts to do this (against lymphoma, ovarian cancer, and neuroblastoma) hadn't had much effect, since the modified T cells had apparently not proliferated once back in the patient. Without the cells taking off on their own, it really doesn't seem feasible to infuse enough of them from outside to show a significant effect.

In this case, the chimeric antigen receptor (CAR) was designed to go after CD19, a surface protein found on all B-cells. That's as solid a target as you could find for treating CLL, but without something new, trying to have engineered T cells clear them out would very likely fall short in this case as well. But this time, the T-cells were outfitted (via a lentivirus vector) not only with the anti-CD19 CAR, but with signaling domains from CD3-zeta and CD137. These are known to be involved with (respectively) coupling surface antigen recognition to intracellular processes and with T-cell proliferation in general. Animal studies had suggested that this combination could deliver a more robust response from the T-cells after being sent back.

And a robust response is what happened. Before treatment, the patient was given a drug regiment to deplete his lymphocytes (in order to give the new T cells a clear field to work in), and at that point his bone marrow was found to be widely infiltrated by cancerous B cells. He then went through three consecutive days of infusions with his own T cells, 5% of which had been modified. Nothing untoward happened during this stage. And in fact, it doesn't appear as if much at all happened for a couple of weeks, which must have had everyone wondering.

But on day 14, the patient started experiencing chills and fever, followed by nausea and enough severe flu-like symptoms to send him into the hospital. Blood work showed no evidence of infection, but large increases in uric acid, lactate dehydrogenase, and other factors, with signs of kidney damage as well. But this was actually good news. Because at this same time, more than20% of his circulating lymphocytes turned out to be the engineered T cells, which had indeed proliferated and were vigorously going after the B cells of the leukemia. (At this point, it wouldn't surprise me if the folks running the study were beginning to wonder what they'd turned loose). The patient's kidneys were, in fact, having a hard time keeping up with the amount of cellular debris that they were being asked to sweep out of the blood stream; he lost over a kilo of cancerous cells.

On day 23, there was no evidence of CLL in the patient's bone marrow. The swollen lymph glands had resolved, and a CT scan confirmed that the masses seen before treatment had disappeared. None of the cancerous B-cell types that were present before the therapy (two clones, both with mutations in p53) could be detected. Ten months later, they still can't. As far as can be told, this case of refractory leukemia has been completely cured.

Two of the three patients treated in this fashion showed this effect - the third still shows signs of leukemia in the bone marrow, but appears to be asymptomatic. Most interestingly, it appears that the T-cell effect is persistent, and may continue as a "surveillance" mechanism in the treated patients.

Now, this is all excellent news, because this sort of therapy can be adapted to a wide variety of tumors. The main requirement is that there is some sort of surface antigen that's specific to the tumor type, but that still leaves you with a wide field to work in. It's important to note, though, that in one way this experiment did something quite strange: it worked much better than anyone expected. The dose of engineered T cells was much smaller than used in previous trials, and was deliberately chosen to be on the low side because no one was quite sure what to expect. Given the response, that was certainly a good move. I've no idea what would have happened if the therapy had been more aggressive, but it couldn't have been good.

I hope, though, that everyone involved is enjoying this as much as possible, because this is a rare event indeed. Having things go suddenly, crazily right in a clinical trial is a once-in-a-career thing, if ever. The field of immunological cancer therapy has been given a huge boost, and now all the other groups working in the area have a huge motivation to spur them on. This is potentially some of the best oncology news in years, so let's hope that it continues to work out.

Comments (43) + TrackBacks (0) | Category: Cancer

August 11, 2011

In Which We Learn Lots About Wine Swirling

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Posted by Derek

Well, we could use some comedy around here these days, and here's someone from the Napa Valley wine business to help us out. Let's work up to this one slowly: do you drink wine? If you do, do you swirl it around in the glass at any point? Do you think it matters, for the taste, which direction you swirl it?

Didn't see that one coming, did you? But never fear, answers are at hand. (Thanks to LeighJKBoerner on Twitter, via Chemjobber.

. . .When you swirl your wine to the left (counter clockwise) the scent you pick up is from the barrels over the grapes, what we call the spice shelf. When you swirl the wines to the right (clockwise) you pick up more flavors from the fruit. . .The question comes up, why is that? Now, as a master herbalist and aroma-therapist, and as someone who has lectured extensively on natural health, anatomy and physiology I know a thing or two about plants, and how people perceive them. So, based upon what I know about how living cells function, these are my insights.

Let's pause a moment, because I want to make sure that everyone's braced for those insights. Make sure that you're ready to keep up with a master aromatherapist and natural health lecturer, because it's going to get pretty, um, technical at this point:

Like all living things wine cells have a magnetic polarity, just like humans and the Earth. The positive pole is more highly charged, just like the North Pole of the Earth, which is why there are Northern Lights in the Arctic Circle, but not Southern Lights in the Antarctic. (Link added for clarity, and because I just couldn't resist - DBL) This polarity tends to keep wine cells generally upright, spinning on their axis when they are being swirled. This magnetic action within a liquid is commonly demonstrated in laboratories. Because plant molecules are mostly liquid, when they form they are also subject to the electromagnetic forces that are a component of the rotation of the Earth. As a result, the pores on the surface of the molecules develop based on that rotation, like the shingles on a roof.

He probably lost you at "wine cells" - see, I told you it was going to be hard to keep up. Note that a follow-up to this adjusts that language, saying that "The proper term would be molecule or even atom", which is surely pretty much roughly the same thing as a cell, right? When you're talking about wine? That second article is worth reading all by itself, by the way, for the kind of check-out-my-credentials display that would do well for a bird of paradise during mating season. But let's get back to the science:

". . .when you swirl the wine clockwise the pressure of the surrounding fluid forces the fruit flavors out through the pores. It also pushes any flavors concentrated on the surface down onto the skin of the molecule. . .

. . .Everything has a polarity right down to the atomic level, and when put into suspension in a liquid it rotates in relation to that pole. Because we are on a planet that has both a polar system and a consistent rotation, everything forms with a pole and a circular patterning. Wind it one way and it tightens and wind it the other and it unwinds.

Honestly this is just basic physics related to molecular science and plant chemistry, something which herbalists and herbal researchers deal with all the time. A pretty sober group of people. . .

So there you have it! Those herbal researchers, they must be right up there on the edge of knowledge if they deal with this kind of stuff all the time. All of this, and it's all half-understood second-hand gibberish, of course, reminds me of the biodynamic wine movement, which from what I can tell is stuffed just as full as it can be with, well, let's just call it half-understood second-hand gibberish.

Check out "Preparation 501", a key part of the process: "Ground quartz is buried in cow horns in the soil over summer. The horn is then dug up, its contents (called horn silica or '501') are then stirred in water and sprayed over the vines at daybreak." You don't need much, though - it's reputed to be very powerful stuff. But honestly, I think I'd rather deal with the mystical-life-force cow horn buriers than with people who try to tell me that it's all just simple physics, all the while yammering about magnetic fields and the skins of molecules. Or atoms. Whatever.

Comments (78) + TrackBacks (0) | Category: Snake Oil

Lundbeck Cutting R&D

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Posted by Derek

Danish CNS specialists Lundbeck reported good financial numbers for the quarter, but they also announced how they're hoping to keep them up: by cutting R&D jobs across the company. This is affecting their US site in Paramus, NJ, as well as the main operation in Denmark.

I've heard that it's affecting both particular disease areas as well as cross-project groups like PK and the like. The company says that it's going to outsource more of this work, and use some of the money to hire. . .more sales staff. The state of the current industry, right there.

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

Scientific Retractions: A Growth Industry?

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Posted by Derek

The Wall Street Journal has an interesting article based on data from Thomson Reuters on the frequency of retracted papers. It seems to be increasing dramatically:

Since 2001, while the number of papers published in research journals has risen 44%, the number retracted has leapt more than 15-fold, data compiled for The Wall Street Journal by Thomson Reuters reveal.

Just 22 retraction notices appeared in 2001, but 139 in 2006 and 339 last year. Through seven months of this year, there have been 210, according to Thomson Reuters Web of Science, an index of 11,600 peer-reviewed journals world-wide.

They mention Retraction Watch, as well they should. But ten years ago, would there have been enough new material to keep that blog running? Pharmalot has some more from its founder about what might be going on. There are, of course, more journals than ever these days, and many of them are junk. But it's not the bottom-tier journals that are driving this trend, I'd think, since honestly, when does anyone ever retract a paper in one of them? Consistent with that view, this bar chart of PubMed retractions by journal is heavily weighted towards the big dogs. A lousy or nonreproducible paper in one of the top journals is more likely to be of enough interest to attract attention, but one in J. Whatever will just sit there.

No, when you look at this chart, it appears that retractions-per-papers-published have been climbing, so the answer must be some combination of more mistakes, more fraud, or better policing. Retractions due to fraud seem to be where most of the growth is, according to this study, so that takes us down to the latter two explanations.

Software has definitely made the lazier sorts of fraud easier to detect, automatically flagging copy-and-paste hack jobs. But those aren't the kinds of things that show up in the better journals, are they? We may be seeing a mix of greater incentive to commit fraud and a rise in skepticism among readers. There have been enough cases, enough highly-publicized retractions and scandals, that more people may be willing to wonder if some exciting new result is true at all.

That's not a bad thing. The rise in fraud is a bad thing, but a corresponding rise in scrutiny is the only thing that's going to cure it. There are always a few pathological types out there that kind of know that they're going to get caught and kind of don't care. Those we shall always have with us, and not much is going to discourage them. But as for the rest of the fraudsters, the thought that they have a better chance of being found out and punished should give them something to think about.

Comments (15) + TrackBacks (0) | Category: The Dark Side | The Scientific Literature

August 10, 2011

The Economics of the Drug Industry: Big Can't Be Big Enough?

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Posted by Derek

I wanted to extract and annotate a comment of Bernard Munos' from the most recent post discussing his thoughts on the industry. Like many of the ones in that thread, there's a lot inside it to think about:

(Arthur) De Vany has shown that the movie industry has developed clever tools (e.g., adaptive contracts) to deal with (portfolio uncertainty). That may come to pharma too, and in fact he is working on creating such tools. In the meantime, one can build on the work of Frank Scherer at Harvard, and Dietmar Harhoff. (Andrew Lo at MIT is also working on this). Using simulations, they have shown that traditional portfolio management (as practiced in pharma) does achieve a degree of risk mitigation, but far too little to be effective. In other words, because of the extremely skewed probability distributions in our industry, the residual variance, after you've done portfolio management, is large enough to put you out of business if you hit a dry spell. That's why big pharma is looking down patent cliffs that portfolio management was meant to avoid. Scherer's work also shows that the broader the pipeline, the better the risk mitigation. So we know directionally where to go, but we need more work to estimate the breadth of the pipeline that is needed to get risk under control. Pfizer's example, however, gives us a clue. With nearly $9 billion in R&D spend, and a massive pipeline, they were unable to avoid patent cliffs. If they could not do it, chances are that no single pharma company can create internally a pipeline that is broad enough to tame risk. . .

That's a disturbing thought, but it's likely to be correct. Pfizer has not, I think it's safe to say, achieved any sort of self-sustaining "take-off" into a world where it discovers enough new drugs to keep its own operations running steadily. And this, I think, was the implicit promise in all that merger and acquisition growth it undertook. Just a bit bigger, just a bit broader, and those wonderful synergies and economies of scale would kick in and make everything work out. No, we're not quite big enough yet to be sure that we're going to have a steady portfolio of big, profitable drugs, but this next big acquisition? Sure to do the trick. We're so close.

And this doesn't even take into account the problems with returns on research not scaling with size (due to the penalties of bureaucracy and merger uncertainty, among other factors). Those have just made the problems with the strategy apparent more quickly - but even if Pfizer's growth had gone according to plan, and they'd turned into that great big (but still nimble and innovative!) company of their dreams, it might well still not have been enough. So here's the worrisome thesis: What size drug portfolio is big enough to avoid too high a chance of ruin? Bigger than any of us have.

Here's de Vany's book on the economics of Hollywood, for those who are interested. That analogy has been made many times, and there's a lot to it. Still, there are some key divergences: for one thing, movies are more of a discretionary item than pharmaceuticals are (you'd think). People have a much different attitude towards their physical well-being than they have towards their entertainment options. Then again, movies don't have to pass the FDA; the customers get to find out whether or not they're efficacious after they've paid their money.

On the other hand, copyright lasts a lot longer than a patent does (although it's a lot easier along the way to pirate a movie than it is to pirate a drug). And classic movies, as emotional and aesthetic experiences, don't get superseded in quite the same way that classic pharmaceuticals do. Line extension is much easier in the movie business, where people actually look forward to some of the sequels. Then there's all the ancillary merchandise that a blockbuster summer movie can spin off - no one's making Lipitor collectibles (and if I'm wrong about that, I'd prefer not to know).

Comments (47) + TrackBacks (0) | Category: Business and Markets | Drug Industry History | Who Discovers and Why

August 9, 2011

Drug Research Areas You Wish You'd Never Heard Of

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Posted by Derek

A conversation the other day got me to thinking: over the course of my career, I've worked in the following therapeutic areas (more or less in chronological order): CNS (dementia, then Alzheimer's), diabetes, osteoporosis, obesity, oncology, anti-bacterials, multiple sclerosis, and antivirals. That covers a fair amount of ground, but there are still areas I've never really touched on - not much that would qualify as cardiovascular and not much inflammation, for example. So I'm sure that there are readers out there who have seen more drug discovery territory than I have - anyone who thinks that they have the local record, feel free to leave details in the comments.

A second question is whether there are therapeutic areas that you'd always wanted to try but never have. (Anti-infectives would have been in that category for me until the last few years). The opposite of that is well worth asking, too: are there disease areas that you regret ever having touched on? For my part, I learned a lot doing my Alzheimer's work, but in retrospect, much of it was a ferocious waste of effort, considering the results, so I'd probably put that one at the top. Other candidates?

Comments (54) + TrackBacks (0) | Category: Life in the Drug Labs

What An Offer

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Posted by Derek

The glamorous side of blogging is that you get chances like this, delivered right to your e-mail queue:

". . .I am working with a couple of small-cap biotech companies who have good fundamental technologies, but are not on the radar screen of a lot of investors. We are looking for some influential bloggers to put some spotlight on these companies, so more people can be exposed to the value proposition and opportunities available. In the past we have worked with some bloggers who have written both paid as well as unpaid articles on these companies. I would like to explore your interest and to discuss this further. . .

I explained to this person just what my level of interest was, in terms that I don't think were misinterpretable, and pointed out that if their operation was not, in fact, a pump-and-dump penny stock scheme, then they should take more care not to make it sound exactly like one. But I thought I would at least get some use of of this sleazy offer by getting a few things on the record.

I write paid columns for Contract Pharma and Chemistry World, and I occasionally do paid pieces for other (respectable!) outlets. But in none of those do I tout stocks, companies, or products. As for the material on this blog, it's produced for free, which (by no coincidence) is what I charge for reading it. The only money that changes hands around here is if someone buys something through an Amazon link, and I try to keep those down to things that people could actually find useful and relevant - no links to plasma TV sales, for example, although if you want to buy one through Amazon, please do feel free.

And of course, I stay away from anything that might involve (or be thought to involve) material information concerning my place of work. But there are no commercial considerations involved in my choice of topics or my expressed opinions on them. If I have a stock position in a company - a rare event, these days, since my kids and my mortgage have seen to it that I don't have a vast fund of free-floating investment capital - then I say so. (A careful look though the archives would show that depending on me for investment advice is not necessarily a winning plan, although it would at least be full of excitement).

So there you have it. No pay-for-play around here. But if you across someone going on about what a great thing this tiny biotech you've never heard of is, well, exercise the usual amount of caution.

Comments (10) + TrackBacks (0) | Category: Blog Housekeeping | The Dark Side

August 8, 2011

More On Cancer Drug Shortages

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Posted by Derek

I wrote here back in June about the growing problem of shortages of oncology drugs. The blog post I linked to then (at Marginal Revolution) blamed regulatory factors and price controls as two major contributors to the shortages, but pointed out that you can't point your finger at just one factor. A pile of them, taken together, can gum up the system enough to cause trouble.

Now Ezekiel Emanuel in the New York Times has weighed in with a good editorial on the situation, and it blames. . .price controls and regulatory factors. For those who thought I was engaging in dangerous FDA-bashing in my last post, here's another factor to consider:

Historically, this “buy and bill” system was quite lucrative; drug companies charged Medicare and insurance companies inflated, essentially made-up “average wholesale prices.” The Medicare Prescription Drug, Improvement and Modernization Act of 2003, signed by President George W. Bush, put an end to this arrangement. It required Medicare to pay the physicians who prescribed the drugs based on a drug’s actual average selling price, plus 6 percent for handling. And indirectly — because of the time it takes drug companies to compile actual sales data and the government to revise the average selling price — it restricted the price from increasing by more than 6 percent every six months.

The act had an unintended consequence. In the first two or three years after a cancer drug goes generic, its price can drop by as much as 90 percent as manufacturers compete for market share. But if a shortage develops, the drug’s price should be able to increase again to attract more manufacturers. Because the 2003 act effectively limits drug price increases, it prevents this from happening. The low profit margins mean that manufacturers face a hard choice: lose money producing a lifesaving drug or switch limited production capacity to a more lucrative drug. . .You don’t have to be a cynical capitalist to see that the long-term solution is to make the production of generic cancer drugs more profitable.

What many people don't realize is that the US has some of the cheaper generic medicines in the world, on average. But a solution that involves allowing drug companies (even the generic ones) to make more money is going to be politically difficult to implement. . .

Comments (14) + TrackBacks (0) | Category: Cancer | Drug Prices

Read the Comments

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Posted by Derek

Just wanted to point out to anyone who's not reading the comments here that the ones to this post are of extremely high quality. If you want to hear the thoughts of a lot of intelligent, experienced people on what's wrong with the drug industry and what might be done to fix it, have a look.

Comments (9) + TrackBacks (0) | Category: Drug Industry History

Gilenya's Price

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Posted by Derek

A couple of weeks ago, we had this discussion about the cost-effectiveness of drugs for multiple sclerosis. It was pointed out that Novartis's new Gilenya (fingolimod) is priced even higher than the drugs in the study that found that MS drugs are among the priciest in the world for their medical benefit.

Now the United Kingdom's NICE has said that Gilenya has not (so far) shown enough efficacy to justify its price. There's going to be a lot of emotionally engaged comment on both sides of this issue, but people should have been able to see this coming. And by "people", yes, I also mean Novartis.

Comments (10) + TrackBacks (0) | Category: General Scientific News | The Central Nervous System

August 5, 2011

Bernard Munos Rides Again

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Posted by Derek

I've been meaning to link to Matthew Herper's piece on Bernard Munos and his ideas on what's wrong with the drug business. Readers will recall several long discussions here about Munos and his published thoughts (Parts one, two, three and four). A take-home message:

So how can companies avoid tossing away billions on medicines that won’t work? By picking better targets. Munos says the companies that have done best made very big bets in untrammeled areas of pharmacology. . .Munos also showed that mergers—endemic in the industry—don’t fix productivity and may actually hurt it. . . What correlated most with the number of new drugs approved was the total number of companies in the industry. More companies, more successful drugs.

I should note that the last time I saw Munos, he was emphasizing that these big bets need to be in areas where you can get a solid answer in the clinic in the shortest amount of time possible - otherwise, you're really setting yourself up with too much risk. Alzheimer's, for example, is a disease that he was advising that drug developers basically stay away from: tricky unanswered medical questions, tough drug development problems, followed up by big huge long expensive clinical trials. If you're going to jump into a wild, untamed medical area (as he says you should), then pick one where you don't have to spend years in the clinic. (And yes, this would seem to mean a focus on an awful lot of orphan diseases, the way I look at it).

But, as the article goes on to say, the next thought after all this is: why do your researchers need to be in the same building? Or the same site? Or in the same company? Why not spin out the various areas and programs as much as possible, so that as many new ideas get tried out as can be tried? One way to interpret that is "Outsource everything!" which is where a lot of people jump off the bus. But he's not thinking in terms of "Keep lots of central control and make other people do all your grunt work". His take is more radical:

(Munos) points to the Pentagon’s Defense Advanced Research Projects Agency, the innovation engine of the military, which developed GPS, night vision and biosensors with a staff of only 140 people—and vast imagination. What if drug companies acted that way? What areas of medicine might be revolutionized?

DARPA is a very interesting case, which a lot of people have sought to emulate. From what I know of them, their success has indeed been through funding - lightly funding - an awful lot of ideas, and basically giving them just enough money to try to prove their worth before doling out any more. They have not been afraid of going after a lot of things that might be considered "out there", which is to their credit. But neither have they been charged with making money, much less reporting earnings quarterly. I don't really know what the intersection of DARPA and a publicly traded company might look like (the old Bell Labs?), or if that's possible today. If it isn't, so much the worse for us, most likely.

Comments (114) + TrackBacks (0) | Category: Alzheimer's Disease | Business and Markets | Clinical Trials | Drug Development | Drug Industry History | Who Discovers and Why

August 4, 2011

Does Anyone Want Axanum?

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Posted by Derek

While we're talking about the cost of drugs, is AstraZeneca really going to be able to sell anyone any Axanum? That's a combination pill of Nexium (esomeprazole) and low-dose aspirin. The FDA didn't go for it last year, but the InVivoBlog details the company's attempts to get it on the market across Europe. Seeing as how AZ's drug is staggering off patent protection in Europe, and seeing as how low-dose aspirin is cheaper than the better grades of dirt, I just don't see how they sell any of this stuff. But desperate times, desperate measure and all that, I guess. . .

Comments (21) + TrackBacks (0) | Category: Drug Prices

Dendreon: Watch the Cost Curve Being Bent

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Posted by Derek

Dendreon has made a lot of news over the last few years with its Provenge prostate cancer therapy. This is the immunological "cancer vaccine" treatment that had such a wild ride through the FDA (and gave DNDR and its investors such a wild ride in the stock market, including some weirdness that I'm not sure ever was explained).

Well, the company is back in the news, and not in a good way. They've been selling Provenge for a while now, but have had all kinds of manufacturing woes (as you might expect from something as complex as personalized immunology). But they've apparently been working through all that, so investors were very much anticipating the company's earnings report yesterday. Unfortunately, they got one.

The company missed all the earnings forecast by an ugly margin, which has really caught everyone by surprise. Worse for them, the reason for the miss is reimbursement. Health insurance companies, in other words, are balking at paying Dendreon's price. And you know, they have a right to. The tug-of-war between drug companies and insurance is the closest thing we have to a free market in the whole drug business, and we might as well get what benefits from it we can.

You can fill in the arguing points: "I'm a prostate cancer patient, and I want to be treated with Provenge" "Fine, but as your insurance carrier, I'm telling you that it's too expensive for what it does. We're not paying for it - if you want it, buy some yourself." "But I can't - you know that - and should my own health be held hostage to how much I can afford to pay?" "Should we be held hostage to how much you want us to spend on you?" "Fine, let's get the government involved - don't I have a right to health care?" "Not seeing that in so many words in the Constitution - but even so, would it give you the right to the most expensive health care there is? Who pays for that? If you want to get the government involved, make them whack the company until they lower their price." And so on.

No, this is what bending the infamous cost curve really looks like. If a company finally prices its products over what the market will bear (and remember, the market in this case is made up of insurance providers), its sales will fall, and it'll either have to persuade its customers that the price is worth it, or it'll have to find a way to offer its good more cheaply (most likely by accepting lower profits). No one wants to give in, no one's particularly happy. But it's probably the only way to arrive at something approaching a right answer.

Update: There's also a theory on Wall Street that the real problem is that demand for Provenge isn't strong enough, and that the company is spinning this as a reimbursement problem. Here's Adam Feuerstein with that take - it'll be interesting to see if that's right. Has the price point at which insurance will balk still not been hit?

Comments (16) + TrackBacks (0) | Category: Business and Markets | Cancer | Drug Prices

August 3, 2011

What the Bottom of the Barrel Looks Like

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Posted by Derek

Want some evil pharma/biotech executives to hate? Don't waste your time on the usual suspects. Go to Immunosyn and Argyll Biotechnologies; they're worth your while. Never heard of them, you say? Well, many of the people that have wish that they hadn't:

"These executives routinely authorized public filings that told investors a story about the status of the company's prized drug that was far different from the behind-the-scenes reality," said Merri Jo Gillette, Regional Director of the SEC's Chicago regional office. "Three of these executives went one step further to illegally profit from their tall tales by selling their company stock and reaping more than $20 million while repeatedly misleading investors about the drug.

Misleading, as in telling people that the lead drug was beginning clinical trials when it wasn't, was in the regulatory process in Europe when it wasn't, and neglecting to mention that its IND actually been placed on hold twice by the FDA and was basically going nowhere. And we haven't even gotten to the $300,000 worth of (undelivered) shares that were flogged to the hapless (and in some cases terminally ill) patients at a Texas "holistic clinic". Oh, these are some fine, fine specimens of humanity we're talking about

Comments (16) + TrackBacks (0) | Category: The Dark Side

A Former Pfizer Executive Finally Trashes Pfizer's Strategy

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Posted by Derek

A number of readers have noted this piece by John LaMattina in Nature Reviews Drug Discovery. He is, of course, a former head of R&D at Pfizer, which makes the title of the article something of an attention-getter: "The impact of mergers on Pharmaceutical R&D". Pfizer, for those of you just returning from a near-lightspeed trip to Alpha Centauri and still adjusting to the effects of relativistic time dilation, has been the Undisputed King of Pharma Mergers over the last ten to fifteen years, growing ever larger and larger in a way that no drug company ever had before. So how has this worked out?

". . .In this article, it is argued that although mergers and acquisitions in the pharmaceutical industry might have had a reasonable short-term business rationale, their impact on the R&D of the organizations involved has been devastating.

Lest anyone think that he's trying to make excuses for his former employer, LaMattina explicitly advances Pfizer as an example of what he's talking about, going over the company's merger and acquisition history in detail, including research site closure and layoffs. How, he asks, are we supposed to discover new drugs in the face of such cutbacks? And what has been the effect on the scientific health of the industry to have so many fewer organizations there to work on new ideas as they come along?

Good questions. The reaction to LaMattina himself asking them, though, has been varied. My first thought is that I agree with his point of view right down to the ground, and have been publicly inveighing against Pfizer-style mergers for over ten years now for the exact same reasons that he details. (Early next year, in fact, will mark the ten-year anniversary of this blog, which hardly seems possible). All such protests have done nothing, nothing at all, as far as I can tell. Pfizer, up through its acquisition of Wyeth, has getting bigger, buying more companies because it needs their pipelines because now it's so big, slashing and burning these organzations after buying them, and then turning around and buying someone else because now its pipeline needs shoring up, because for some obscure reason people haven't been discovering as many drugs as they used to. Yep, that's about the sorry size of it.

Another reaction, though, has been "How dare someone from Pfizer say that mergers aren't a good idea? Now he tells us!" And while I can understand that, I think that you have to realize that in a company the size of Pfizer, the head of R&D is not perhaps in as exalted a decision-making position as you might imagine. LaMattina alludes to this here:

"Indeed, R&D seems to be especially vulnerable to the negative impact of mergers and acquisitions. Having a sense of how mergers occur in R&D organizations is helpful for understanding this impact. R&D organizations will be the last part of the companies to begin merger discussions before regulatory approval because of the commercial sensitivity of the pipeline and the intellectual property of the company. . .

I would say that in many of these cases, the job of the R&D executives has been to roll over and take it once the higher-ups have decided an acquisition is going to happen. "Your job is to make this work - and if you don't want to do it, we'll find someone that does". After reading that alarming Fortune piece on the goings-on in the upper ranks of Pfizer, I find this view particularly believable. (And I would find LaMattina's view on the events in that article extremely interesting, although I doubt we'll ever hear them).

So, although I don't want to put words in anyone's mouth, my take is that LaMattina finds his part in Pfizer's M&A activities to be regrettable, and that he's now advancing the arguments against them - arguments that never gained any traction inside Pfizer. His own book skirted the topic - the word "mergers" only appears twice in the text, as far as Google Books can tell. But he's not skirting it any more.

Comments (55) + TrackBacks (0) | Category: Business and Markets | Drug Industry History

August 2, 2011

Merck, RNAi, Alnylam, And So On

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Posted by Derek

And while we're on the topic of Merck, I note that they're closing their RNAi facility in Mission Bay, the former Sirna. That was a pretty big deal when it took place, wasn't it? The piece linked to in that earlier post also talks about the investment that Merck was making in the very facility that they're now closing down, but if I got paid every time that sort of thing happened in this industry, I wouldn't have to work.

This isn't going to help the Bay Area biotech/pharma environment, nor the atmosphere around RNA interference as a drug platform. Merck says that they're not getting out of the field, and that they've integrated the technology for use in their drug discovery efforts. But they paid a billion dollars for Sirna, which is not the sort of up-front price you generally see for add-on technologies that can help you discover other drugs. At the time, it looked like Merck was hoping directly for some new therapeutics, and we still don't know when (or if) those will emerge.

There's another player in the field right next door to me here in Cambridge, Alnylam. Not long after I last wrote about the state of the RNAi area, they actually invited me over to talk about what they're up to - a bit unusual, since I'm not just a blogger, but a scientist working at another company, which is a combo that's caused some confusion more than once. But they gave me a nice overview of what they're working on, and it was clear that they understand the risks involved and are doing whatever they can to get something that works out the door. They have several approaches to the drug-delivery problem that besets the RNA world, and are taking good shots in several different disease areas.

But they (and the other RNAi shops) need more money to go on, which in this environment means partnering with a larger company. Merck, Roche, and Novartis have (in various ways) shown that they feel as if they have pretty much all the RNAi that they need for now, so it'll have to be someone else. Maybe AZ or Lilly, the companies with the biggest patent-expiration problems?

Comments (16) + TrackBacks (0) | Category: Biological News | Business and Markets

Merck Moving Research From Rahway?

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Posted by Derek

I've heard from more than one person that Merck has decided to move most discovery research out of Rahway (in favor of the former Schering-Plough site in Kenilworth). Details are welcome in the comments from those with better information. That news does bring on end-of-an-era feelings, since they've been doing medicinal chemistry in Rahway for a long, long time. Kenilworth - well, I joined Schering-Plough when it was still in Bloomfield, and I remember the Kenilworth building site when it was a huge hole in the ground. We migrated into it (the building, not the hole) at the end of 1992, in a massive moving job that involved several convoys of 18-wheel trucks going down a partially-closed-off Garden State Parkway in the middle of the night.

The move had to be done; Bloomfield was at the limits of its capacity. And while it was nice to move into a completely new facility, I realized as time went on that Bloomfied had had charms of its own that I hadn't recognized at the time. But I left Kenilworth in 1997, when the building was comparatively new, so no doubt it's acquired some character by now. Do they still have the stark white socialist-realist statue of Sir Derek Barton down in the lobby?

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

August 1, 2011

Laquinimod Fails For Multiple Sclerosis

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Posted by Derek

If you haven't been reading carefully, you might have had trouble figuring out Teva's oral therapy for multiple sclerosis, laquinimod. After all, earlier this year, the company was blowing the horn for the compound at neurology meetings, touting how safe and effective it was, its advantages over existing therapies, and its potential in the market. You'd hardly know that the compound actually didn't perform as well as many people were hoping. And of course, that very article does mention, near the end, that the company was going to have some more results later in the year. . .

. . .and that day has arrived. Unfortunately. Laquinimod missed its primary endpoint of reducing relapses in MS patients, and unless Teva and its Israeli Swedish partner company (Active Biotech) have some real surprises to unveil, you'd have to presume that the compound is dead. Or if not dead, destined to never make much of an impact in the market, for sure. This program has had a long history, with an earlier version of the structure (roquinimex) running into severe cardiovascular issues ten or twelve years ago.

Teva is a huge player in the generic world, and in recent years has been trying to break into the research end of the drug business. (Their first was Copaxone (glatiramer acetate), also for MS, a compound with a tangled history). Enjoy the experience, guys. If you're used to dealing with compounds whose value has already been proven, this sort of thing must come as even more of a shock than usual.

Comments (19) + TrackBacks (0) | Category: Clinical Trials | The Central Nervous System

Chinese Research: Not Quite the Juggernaut?

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Posted by Derek

A perennial topic around here has been the state of scientific research in China (and other up-and-coming nations). There's no doubt that the number of scientific publications from China has been increasing (be sure to read the comments to that post; there's more to it than I made of it). But many of these papers, on closer inspection, are junk, and are published in junk journals of no impact whatsoever. Mind you, that's not an exclusively Chinese problem - Sturgeon's Law is hard to get away from, and there's a lot of mediocre (and worse than mediocre) stuff coming out of every country's scientific enterprise.

But what about patents? The last couple of years have seen many people predicting that China would soon be leading the world in patent applications as well, which can be the occasion for pride or hand-wringing, depending on your own orientation. But there's a third response: derision. And that's what Anil Gupta and Haiyan Wang provide in the Wall Street Journal. They think that most of these filings are junk:

But more than 95% of the Chinese applications were filed domestically with the State Intellectual Property Office—and the vast majority cover "innovations" that make only tiny changes on existing designs. A better measure is to look at innovations that are recognized outside China—at patent filings or grants to China-origin inventions by the world's leading patent offices, the U.S., the EU and Japan. On this score, China is way behind.

The most compelling evidence is the count of "triadic" patent filings or grants, where an application is filed with or patent granted by all three offices for the same innovation. According to the Organization for Economic Cooperation and Development, in 2008, the most recent year for which data are available, there were only 473 triadic patent filings from China versus 14,399 from the U.S., 14,525 from Europe, and 13,446 from Japan.

Starkly put, in 2010 China accounted for 20% of the world's population, 9% of the world's GDP, 12% of the world's R&D expenditure, but only 1% of the patent filings with or patents granted by any of the leading patent offices outside China. Further, half of the China-origin patents were granted to subsidiaries of foreign multinationals. . .

The authors are perfectly willing to admit that this probably will change with time. But time can make things worse, too: as this editorial in Science last year made clear, the funding of research in China has some real problems. The authors of that piece are professors at two large Chinese universities, and would presumably know what they're talking about. For the biggest grants, they say:

. . .the key is the application guidelines that are issued each year to specify research areas and projects. Their ostensible purpose is to outline “national needs.” But the guidelines are often so narrowly described that they leave little doubt that the “needs” are anything but national; instead, the intended recipients are obvious. Committees appointed by bureaucrats in the funding agencies determine these annual guidelines. For obvious reasons, the chairs of the committees often listen to and usually cooperate with the bureaucrats. “Expert opinions” simply reflect a mutual understanding between a very small group of bureaucrats and their favorite scientists. This top-down approach stifles innovation and makes clear to everyone that the connections with bureaucrats and a few powerful scientists are paramount. . .

Given time, this culture could be changed. Or it could just become more entrenched as the amounts of money become larger and larger and the stakes become higher. China could end up as the biggest scientific and technological powerhouse the world has ever seen - or it could end up never living up to its potential and wasting vast resources on cargo-cult theatrics. It's way too early to say. But if many of those Chinese patents are just being written because someone's figured out that the way to get money and prestige is to file patents - never mind if they're good for anything - then that's not a good sign.

Comments (31) + TrackBacks (0) | Category: Patents and IP | The Scientific Literature | Who Discovers and Why