About this Author
College chemistry, 1983
The 2002 Model
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: firstname.lastname@example.org
April 30, 2009
I have no Facebook presence to speak of (for better or worse), but if you do, and if you're involved in the pharma/biotech area, you might want to check out this report. Someone (or some group) has been setting up a whole network of fake identities there, and you have to wonder just what the motive is. Nature News has more.
+ TrackBacks (0) | Category: Current Events
We now have more data on Dendreon’s results for their prostate cancer therapy Provenge, and the numbers do, in fact, look good. This isn't a cure for refractory prostate cancer, but there seems to be a real statistical improvement in survival, with side effects no worse than the placebo group, and that should be enough for the FDA. In oncology you have to take what you can get.
What’s bizarre is the trading that went on in the company’s stock just before they started presenting on Tuesday. For reasons that are still unclear, a horrendous wave of selling hit within the space of a few minutes, and the stock went down as if hit with a club. Having risen to nearly $25 by about 1 PM, trading was halted in the stock at 1:27, with it now going for $11.81. As the company’s shareholders raved and cursed in utter consternation, the company was detailing exactly the results they’d been hoping to hear.
Wednesday, the stock shot straight back up to its former levels, but that doesn’t help the many people who (prudently, they thought) had put stop-loss orders in and had thus already been sold out. This Bloomberg story has a fellow who was cashed out at $9.31, which must make him wonder (1) just what the hell was going on, anyway, and (2) just what it means to halt trading in a stock, if you’re going to find yourself traded out of it at an even lower price.
I can’t help out with question (1) – I have to say, I’d like to know the answer to that one myself. But as for (2), that’s the problem with stop-loss orders, particularly in a stock that doesn’t have much of a float. Movements, especially downward ones, come suddenly and discontinuously, and the stock doesn't hit all the grace notes on the way down (as Fred Schwed
used to say).
So good luck to Dendreon, and to the patients who will use Provenge. Dendreon's investors, on the other hand, have probably been through the power-wash and spin cycle so many times that they hardly know what's hit them.
+ TrackBacks (0) | Category: Business and Markets | Cancer
April 29, 2009
What a mess! Science has a retraction of a 2005 paper, which is always a nasty enough business, but in this case, the authors can’t agree on whether it should be retracted or not. And no one seems to be able to agree on whether the original results were real, and (even if they weren’t) whether the technique the paper describes works anyway. Well.
The original paper (free full text), from two Korean research groups, described a drug target discovery technique with the acronym MAGIC (MAGnetism-based Interaction Capture). It’s a fairly straightforward idea in principle: coat a magnetic nanoparticle with a molecule whose target(s) you’re trying to identify. Now take cell lines whose proteins have had various fluorescent tags put on them, and get the nanoparticles into them. If you then apply a strong magnetic field to the cells, the magnetic particles will be pulled around, and they’ll drag along whichever proteins have associated with your bait molecule. Watch the process under a microscope, and see which fluorescent spots move in which cells.
Papers were published (in both Science and Nature Chemical Biology), patent applications were filed (well, not in that order!), startup money was raised for a company to be called CGK. . .and then troubles began. Word was that the technique wasn’t reproducible. One of the authors (Yong-Weon Yi) asked that his name be removed from the publications, which was rather problematic of him, considering that he was also an inventor on the patent application. Early last year, investigations by the Korean Advanced Institute of Science and Technology came to the disturbing conclusion that the papers “do not contain any scientific truth”, and the journals flagged them.
The Nature Chemical Biology paper was retracted last July, but the Science paper has been a real rugby scrum, as the journal details here. The editorial staff seems to have been unable to reach one of the authors (Neoncheol Jung), and they still don’t know where he is. That’s disconcerting, since he’s still listed as the founding CEO of CGK. A complex legal struggle has erupted between the company and the KAIST about who has commercial rights to the technology, which surely isn’t being helped along by the fact that everyone is disagreeing about whether it works at all, or ever has. Science says that they’ve received parts of the KAIST report, which states that the authors couldn’t produce any notebooks or original data to support any of the experiments in the paper. This is Most Ungood, of course, and on top of that, two of the authors also appear to have stated that the key experiments (where they moved the fluorescent proteins around) were not carried out as the paper says. Meanwhile, everyone involved is now suing everyone else back in Korea for fraud, for defamation, and who knows. The target date for all this to be resolved is somewhere around the crack of doom.
Emerging from the fiery crater, CGK came up with another (very closely related) technique, which they published late last year in JACS. (If nothing else, everyone involved is certainly getting their work into an impressive list of journals. If only the papers wouldn’t keep sliding right back out. . .) That one has stood up so far, but it’s only April. I presume that the editorial staff at JACS asked for all kinds of data in support, but (as this whole affair shows) you can’t necessarily assume that everyone’s doing the job they’re supposed to do.
The new paper, most interestingly, does not reference the previous work at all, which I suppose makes sense on one level. But if you just came across it de novo, you wouldn't realize that people (at the same company!) had already been (supposedly) working on magnetic particle assays in living cells. Looking over this one and comparing it to the original Science paper, one of the biggest differences seems to be how the magnetic particles are made to expose themselves to the cytoplasm. The earlier work mentioned coating the particles with a fusogenic protein (TAT-HA2) that was claimed to help with this process; that step is nowhere to be found in the JACS work. Otherwise, the process looks pretty much identical to me.
Let’s come up for air, then, and ask how well useful these ideas could be, stipulating (deep breath) that they work. Clearly, there’s some utility here. But I have to wonder how useful this protocol will be for general target fishing expeditions. Fluorescent labeling of proteins is indeed one of the wonders of the world (and was the subject of a recent a well-deserved Nobel prize). But not all proteins can be labeled without disturbing their function – and if you don’t know what the protein’s up to in the first place, you’re never sure if you’ve done something to perturb it when you add the glowing parts. There are also a lot of proteins, of course, to put it mildly, and if you don’t have any idea of where to start looking for targets, you still have a major amount of work to do. The cleanest use I can think of for these experiments is verifying (or ruling out) hypotheses for individual proteins.
But that's if it works. And at this point, who knows? I'll be very interested to follow this story, and to see if anyone else picks up this technique and gets it to work. Who's brave enough?
+ TrackBacks (0) | Category: Biological News | Drug Assays | The Dark Side | The Scientific Literature
April 28, 2009
A minor theme around here recently has been bogus publications and bad conferences. Interestingly, I’ve had three invitations within the past few weeks to speak at meetings in China – once on antivirals, once on antibodies, and most recently on molecular diagnostics. Perhaps it’s my publication record in those areas that recommended me? Nope. I have no publication record in any of those fields. Maybe it’s because of this blog? That’s a lousy reason to invite someone to give a technical presentation, but hey, it’s better than no reason at all, right? Nope, not that either. The letters are make no mention of anything other than the fact that (on behalf of the organizing committee, natch) I’m invited to give a speech.
So let’s go with “no reason at all”, other than (1) I can breathe, (2) I can speak, (3) I can thus fill up a slot in the presentation schedule, and (4) I can presumably pay the conference registration fee. The invitations themselves all come from different contact people, with varying skills in English. The most recent one addresses me as “Dear Dr. Derek”, for example, and goes on through a tangle of subject-verb disagreements and dropped definite articles to invite me to “keep the moment going”. Now, I don’t object to bad grammar on the part of a non-native speaker (the letter’s English is a hell of a lot better than my Chinese), but then again, I’m not organizing a conference by sending out e-mails in the language, either. For which I’m grateful.
But all of the invites are from the same organization, BIT Life Sciences. These folks seem to have a real conference empire going over there, at least for the past two or three years. They have seven big ones scheduled for this year - perhaps I'll eventually be invited to present at all of them. (I wonder if anyone will make the whole circuit like that - do you get a special T-shirt or something?) I note that one of BIT's other sidelines is "Nobel Across China", where they invite various life-science Nobel winners to come and give presentations. I quote from BIT:
"As we all know, Nobel Prize is reputed as an international authorized prize throughout the world, which is a scientific reward for Technology Innovation & Creations. It is designed to bring creative minds as well as exploratory spirits here rightly and stimulate domestic scientists and young generations to pursue new exploration and creation in Life Sciences with surpassing spirits for the crest of Science & Technology."
Well, that's fine. I know, I know: I really shouldn't be making fun of the way that this is phrased. But it's a mystery to me why they don't run these things past a native English speaker. (I notice that James Fallows, a man with plenty of China experience, is baffled by the same thing). And for all I know, it's done some good for people in the audience to attend these presentations. My hopes for BIT's other conferences aren't as high, though, not if they're having to e-mail people like me out of the blue to fill out the program.
Has anyone out there had dealings with BIT, or attended one of their meetings? Are they mostly a chance to make some business contacts in China, or what? First hand experiences welcome. . .
And on the subject of odd Chinese conferences, I'm still looking around for a link to an article I read months ago - I believe on a link from James Fallows, although I can't track it down. A group of expatriates were recruited to attend a steel industry conference in a Chinese city, even though they knew nothing about the field. Bus transportation and free food were provided, along with fake business cards, so long as they spent the day wandering around giving the exhibition an international look. . .
+ TrackBacks (0) | Category: The Scientific Literature
April 27, 2009
Swine flu: is it time to panic yet? Actually, it never is, and this is a particularly useless time to start running in circles, despite the apparent non-stop coverage on the cable news channels. I had some exposure to those during my recent vacation, which only confirmed the complete ban on the damned things in my own house.
I’m reminded of a line from Michael Lewis’s article on New Orleans in the immediate aftermath of Hurricane Katrina. He described a neighbor as suffering from a severe information handicap: his TV was on. But I can’t get all superior about the Internet, either, since Drudge and others are running piled-up red headlines in the same manner. What’s the real situation?
As far as I can make out, it’s this: over the past many weeks, about one thousand cases of influenza have been reported in Mexico, with about seventy of them fatal. Travelers returned from Mexico have shown up ill in several other locations. But none of them have died – in fact, many of them don’t seem to be all that sick, and appear to be recovering without incident. This flu seems to have spread human-to-human in Mexico, but I’m not aware of any reports of that happening in other locations yet.
And here’s what we don’t know: the number of people actually infected in Mexico is unclear and will remain so. Seventy deaths in a thousand cases of flu is a very alarming figure, and that’s what’s driving all the attention. But we don’t know if that number should really be five thousand, or even ten. And we don’t know if all of those seventy patients even had influenza (or this strain of it) at all – the great majority of them don’t appear to have been serotyped.
So no, it’s not time to sound the sirens just yet. Odds are that this will wind down, just like many other outbreaks of influenza do. But we don’t know that for sure. If I had a nonessential trip to Mexico City scheduled, I’d postpone it. (Not that I’m looking to spend a lot of time in the city in general: one factor in the apparently high fatality rate there might be the awful air quality).
One thing an outbreak like this does, though, is to remind everyone that viral epidemics are potentially a real problem. I don’t think that this one is the Pandemic We’ve Been Waiting For, but that one might well be out there, and there’s no way to know when it might appear. If and when it does, we may not have many pharmacological weapons against it, for the reasons I’ve outlined here. For now, keep an eye on whether any of the cases outside Mexico develop into anything more serious than a day or two in bed, and whether any of these transmit to people around them. And don't watch any cable news. Here's the CDC's page on the outbreak, and here's the WHO.
+ TrackBacks (0) | Category: Current Events | Infectious Diseases
April 20, 2009
Posting will be irregular this week - I'm off traveling again, this time in the Washington, DC area. (This hasn't been the single most scientifically productive April I've ever had, unfortunately). I do hope to get some posts up, but not today - whatever news is happening, I'll catch up on it for tomorrow!
+ TrackBacks (0) | Category: Blog Housekeeping
April 17, 2009
So I see that the headlines are that it’s proving difficult to relate gene sequences to specific diseases. (Here's the NEJM, free full-text). I can tell you that the reaction around the drug industry to this news is a weary roll of the eyes and a muttered “Ya don’t say. . .”
That’s because we put our money down early on the whole gene-to-disease paradigm, and in a big way. As I’ve written here before, there was a real frenzy in the industry back in the late 1990s as the genomics efforts started really revving up. Everyone had the fear that all the drug targets that ever were, or ever could be, were about to be discovered, annotated, patented – and licensed to the competition, who were out there fearless on the cutting edge, ready to leap into the future, while we (on the other hand) lounged around like dinosaurs looking sleepily at that big asteroidy thing up there in the sky.
No, that’s really how it felt. Every day brought another press release about another big genomics deal. The train (all the trains!) were loudly leaving the station. A lot of very expensive deals were cut, sometimes in great haste, but (as far as I can tell) they yielded next to nothing – at least in terms of drug candidates, or even real drug targets themselves.
So yeah, we’ve already had a very expensive lesson in how hard it is to associate specific gene sequences with specific diseases. The cases where you can draw a dark, clear line between the two increasingly look like exceptions. There are a lot of these (you can read about them
in these texts
), but they tend to affect small groups of people at a time. The biggest diseases (diabetes, cardiovascular in general, Alzheimer’s, most cancers) seem to be associated with a vast number of genetic factors, most of them fairly fuzzy, and hardly any of them strong enough on their own to make a big difference one way or another. Combine that with the nongenetic (or epigenetic) factors like nutrition, lifestyle, immune response, and so on, and you have a real brew.
On that point, I like E. O. Wilson’s metaphor for nature versus nurture. He likened a person’s genetic inheritance to a photographic negative. Depending on how it’s developed and printed, the resulting picture can turn out a lot of different ways – but there’s never going to be more than was in there to start with. (These days, I suppose that we’re going to have to hunt for another simile – Photoshop is perhaps a bit too powerful to let loose inside that one).
But I've been talking mostly about variations in proteins as set by their corresponding DNA sequences. The real headscratcher has been this:
One observation that has taken many observers by surprise is that most loci that have been discovered through genomewide association analysis do not map to amino acid changes in proteins. Indeed, many of the loci do not even map to recognizable protein open reading frames but rather may act in the RNA world by altering either transcriptional or translational efficiency. They are thus predicted to affect gene expression. Effects on expression may be quite varied and include temporal and spatial effects on gene expression that may be broadly characterized as those that alter transcript levels in a constitutive manner, those that modulate transcript expression in response to stimuli, and those that affect splicing.
That's really going to be a major effort to understand, because we clearly don't understand it very well now. RNA effects have been coming on for the last ten or fifteen years as a major factor in living systems that we really weren't aware of, and it would be foolish to think that the last fireworks have gone off.
+ TrackBacks (0) | Category: Biological News | Drug Industry History
April 16, 2009
A comment here the other day mentioned Scigen, which I hadn’t seen before. Some folks at MIT have whipped up a bit of code and a database of computer science topics, phrases, and graphs, and developed a quick paper generator. The paper will make no sense at all, of course, but it is quick. And what they’ve found is that making no sense isn’t as much of a handicap as you might think when it comes to some conferences and some journals.
Scigen papers have been accepted for presentation at some of the less prestigious meetings, and have been sent to various cheesy journals, which have cheerfully “reviewed” them once details of payment were cleared up. This is not a good sign for your field when total gibberish can be passed off like this, although one assumes that it says more about the sorts of conferences and journals that are accepting these things.
And yes, a comparison to the Sokal hoax comes to mind immediately. That one was even more damning, though, because the gibberish paper that Sokal came up with wasn’t sent to some sleazy fee-generating publication mill, but to what was considered one of the better journals in the field (Social Text). Who (famously) published it anyway. The editors later backtracked by saying that they thought the paper, you know, lacked originality, that it wasn’t well written, that they (ahem!) just accepted it as a favor to a physicist visiting their rigorous area of study, and so on – but the fact remained (and remains) that an editor should be able to distinguish a valid paper from a sticky pile of superglued nonsense.
The reason the Scigen papers aren’t picked up on, clearly, is that no one’s looking at them, at least no one with any knowledge of computer science. The editors and organizers who let them through are interested in collecting the registration and editorial fees first, and after that, well, that’s not really their department. A perfectly analogous example is the utterly crazed “Atlanta Nights” manuscript, whipped up by a loose team of authors to expose the “editing process” of a pay-to-publish operation (PubilshAmerica) for what it really was. The book is a bit hard to follow. Characters change names and/or genders, die and come back to life, and find themselves doing ridiculous things in impossible tangles of verb tenses. But hey, the manuscript was supposedly read through, and accepted without one solecism out of place. If the credit card number is valid, so’s the syntax. (Don't want to take my word for it? Here it is, under the byline "Travis Tea", published by a print-on-demand house after PublishAmerica hastily backtracked.)
No one’s tried (as far as I know) to submit a Scigen paper to a reputable comp-sci venue. I assume (and very much hope) that it would be sent back with a puzzled note attached. The same goes for the chemical literature, or at least it had better. A chemistry-focused version of Scigen would be an interesting experiment, but I think I know what the likely results would be. There are bottom-tier journals and conferences in every field. They’ll bite. As long as that check clears.
+ TrackBacks (0) | Category: The Scientific Literature
Well, this isn't a toxicological side effect so much as an analytical chemistry one. Nature reports that forensic scientists are quite worried about the idea of deuterated drugs catching on, because they use deuterated versions of common pharmaceuticals as analytical reference standards. A lot of common analysis methods for the drugs in question would have to be junked for anyone taking the deuterated compound. And with both versions on the market, toxicologists would always be uncertain about where they stood, particularly by legal evidence standards.
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April 15, 2009
Readers may have seen the recent sting operation on Coast IRB, an institutional review board company that's in the business of monitoring clinical trials. They signed off on a trial of a nonexistent product from a bogus company, which doesn't make them look very good, to put it mildly. Admittedly, they probably weren't expecting things to be faked from top to bottom, but still.
Now, according to the Wall Street Journal's Health Blog, it turns out that the congressional committee that ran this one also was checking out the Department of Health and Human Services to see if they were checking up on IRBs in general:
Rep. Greg Walden, R-Ore., criticized Health and Human Services officials for failing to catch the fictitious IRB and registering it despite numerous red flags. “Nobody picked up on names like Phake Medical Devices, April Phuls, Timothy Witless and Alan Ruse — in the town of Chetesville, Ariz.?” he asked department reps.
Maybe someone should send some identical manuscripts to various peer-reviewed journals, co-authored by Witless and Phuls, and see how many of them get through. . .
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So is Roche already flexing its muscles now that the acquisition of Genentech is complete? Reports are this morning that Genentech's CEO, Arthur Levinson, is moving aside for Roche's Pascal Soriot, and several other top executives are leaving as well.
This does not seem like the way to reassure the Genentech folks that Roche is going to leave them in peace, to put it gently. And the sorts of comments that are out there in the press reports can't be helping, either. As that Bloomberg story has it:
The changes begin the company’s transformation to a team- oriented culture from one that supports individual scientific enterprise, said Stephen Burrill, a venture capitalist who invests in biotechnology companies.
He says that like individual scientific enterprise is a bad thing. Update: out of context, perhaps? See the comments section.)
And if that's indeed what made Genentech what it is, then you'd think we need more of it, because (remember) it's a very successful company indeed. I'm always wary of people talking about "team-oriented culture", too. That sounds too much like HR-speak for comfort. And while drug discovery necessarily has to be done by large teams of people, it's the individuals who come up with the ideas. And it's the individuals that push their ideas forward, sometimes in the face of opposition from other individuals who think that they're completely wrong.
That's how new things get tried, and how we sort out what works and what doesn't. Too often, a lot of talk about "team culture" can be the sign of an organization that doesn't value initiative as much as it should. You don't want a bunch of people shouting at each other all the time and refusing to work together, true - but you don't want a situation where no one can do anything without everyone joining hands. A lot of really good ideas don't seem like good ideas to everyone at the time.
So I can't say that I'm happy to read today's news. We'll see what it really means. If Roche themselves start talking about changing Genentech's culture, then all bets are off.
Update: "It will never work because if we owned all of Genentech we would kill it"
+ TrackBacks (0) | Category: Who Discovers and Why
April 14, 2009
Post updated below - DBL Dendreon is a company that's really been through it, as have their investors. Many will remember the upheaval back in 2007, when the company showed what they felt were impressive results for their autologous prostate cancer immunotherapy Provenge, got a favorable reception from the FDA's advisory panel, but were then hit with an "approvable" letter asking for more data. (Here are three posts on that: before, during, and after).
Well, the company is back with more data, in 512 patients. And initial reports are that the numbers look good. They're doing a conference call as I write, so we'll know more shortly, and I'll update this post as things become more clear.
Update: Hmmm. On the conference call, the company has declined to present any numbers, saying that it's bound by a blackout requirement for its presentation at the American Urological Association on April 28th. Their main statement seems to have been that the drug met its primary endpoint, reducing the risk of death compared to a placebo. There are a lot of other questions about Provenge - whether it slows the progression of prostate cancer or not, for example - but survival is presumably the bottom line. That was the main focus of the whole trial (as opposed to the cancer-progression endpoint of their smaller, earlier one).
So we'll see at the end of the month how impressive the statistics look. The market's reacting well to the news, although you could argue that the stock has pulled back a bit. It closed yesterday at 7 and change, traded over 21 during the morning, and is around 17 now. (Of course, some of that pullback could be from people giddily selling their shares on the news, just as some of the spike could well have been some people rather less giddily covering their short positions).
+ TrackBacks (0) | Category: Business and Markets | Cancer | Regulatory Affairs
I try to keep up with the drug-industry news in general, so once in a while I just hop over to Google News and type "pharmaceutical" into the search box. That generally gets me a barrage of press releases, lucky me, and this morning was no different. But what struck me was that basically the whole page of results was talking about companies that either I only vaguely recognized, or (in most cases) had never heard of at all.
Raptor Pharmaceuticals I remembered from somewhere, mostly because of that bizarre name. But then there's a run of who-they names: Nanobac merging with Eureka Genomics? Osprey? Poniard? Tekmira? Stellar? Kanion? Optimer? Come to think of it, I actually have heard of those last folks, although I can't tell you much about them. Looking closer, I find that several of these are generic producers (Kanion, from China) or seem to be more medical-device companies (Stellar), which makes me feel better. Nanobac seems to be the most way-out-there, supposedly focusing on treatment of nanobacteria-related diseases, which is news to me, since last I heard you could start a major shouting match over the question of whether nanobacteria even exist (or even can).
But the others are real drug shops: Tekmira's another RNAi outfit that I'd never heard of, and Poniard seems to be betting on new platinum-based oncology agents. Osprey is working on chemokine fusion proteins. This sort of thing (coming across companies that I'd never realized existed) always cheers me up, actually. I continue to think that one of the US's main strengths is the ability to fund ideas, to try all sorts of things out in the hopes that something interesting will turn up. I want there to be many more companies than I have time to keep up with or even hear of. That, to me, is the sign of a healthy research culture.
Which is what has me worried, given the current economic climate. This is not a particularly good time to get a small company off the ground, to put it mildly. Will there be a notch cut into the startup population as the years go on? How deep and broad will it be?
+ TrackBacks (0) | Category: Drug Industry History
April 13, 2009
We get a lot of surprises in this business, most of them not so good. That's understandable, since there are lot more ways for drugs and their mechanisms to go wrong than there are for them to go right. But once in a while, you do see something that's unexpectedly good news.
That may be what's happened to a small San Diego outfit, Ardea. As Xconomy details, the company (formed out of the remnants of IntraBiotics and Valeant) was testing an HIV compound in the clinic when they noticed significant declines in blood levels of uric acid.
That rang a bell: something that decreases uric acid levels would be useful for gout, and there's only been one new gout drug approved in the last 40 years. Follow-up work showed that the effect seemed to be coming from a metabolite of the original drug, and thanks to the HIV trial data, they already had good hopes for that compound's safety. The new compound, RDEA594, has made it through Phase I and is headed for Phase II, and the trials look to be manageable affairs that the company can afford to run. The market is there: more people have gout in the US than are HIV-positive (although the two diseases clearly aren't comparable in other respects!). But the state of HIV research now means, weirdly, that the serious medical needs in that population are actually being met more completely than those in many other disease areas. (Ardea's HIV compound is progressing as well).
So good luck to them, on both fronts. It's a reminder to always look through all your data, and to be alert for whatever opportunities might be hiding in there. We don't get as many as we'd like, so we can't let any of them slip away.
+ TrackBacks (0) | Category: Drug Development | Infectious Diseases
April 9, 2009
It's been some time since I've written about Ariad and their NF-kB patent. This has been a very long story, full of legal twists and turns, but I believe that it's finally come to an end.
Back in 2002, Ariad was issued an extremely broad patent on the uses of agents that affected the NF-kappaB pathway. And since it's basically impossible to talk about inflammation without talking about NF-kB at some point, the company believed that it had the legal means to claim that many other companies were infringing their intellectual property. Among the first to be sued was Eli Lilly - here was my reaction at the time. Short form: I was not pleased. I found it potentially catastrophic that one could lay claim to fundamental biochemical pathways and then assert that this naturally gave you a piece of the action for any compound that affected them. Update: it's worth noting that even as late as last month, Ariad's boilerplate at the bottom of their press releases included basically that process as part of their corporate strategy.
Well, the case finally was argued before a court in 2006, and to my surprise and disgust, a jury found for Ariad. Part of that surprise was a financial one, since (as I noted at the time) I'd gone short Ariad stock in anticipation of a more sensible verdict. (Note that I have no position in their stock or options now. They've significantly underperformed the market since 2006, which is no mean feat).
Every time I wrote about the company I would get beaten up on various message boards by its fans. I was a tool of Eli Lilly, Amgen (another of Ariad's legal opponents), or just of the Monied Interests in general. I was a shill, a moron, you name it. The glee was especially pronounced after that court case in 2006. A separate bench trial took place afterwards on whether the Ariad patent was enforceable at all, partly on the issues of its subject matter and possible inequitable conduct, but Ariad won that round as well.
The case then went to the Court of Appeals for the Federal Circuit, which is where all tough patent cases are going to end up eventually (a very small number go on from there to the Supreme Court). And last week the CAFC ruled: Ariad's key patent claims, they find, are in fact invalid. Lilly was right. The jury was wrong, and so was the verdict in the bench trial:
"Ariad claims methods comprising the single step of reducing NF-κB activity. Lilly argues that the asserted claims are not supported by written description because the specification of the ’516 patent fails to adequately disclose how the claimed reduction of NF-κB activity is achieved. The parties agree that the specification of the ’516 patent hypothesizes three classes of molecules potentially capable of reducing NF-κB activity: specific inhibitors, dominantly interfering molecules, and decoy molecules. Lilly contends that this disclosure amounts to little more than a research plan, and does not satisfy the patentee’s quid pro quo as described in Rochester. Ariad responds that Lilly’s arguments fail as a matter of law because Ariad did not actually claim the molecules. According to Ariad, because there is no term in the asserted claims that corresponds to the molecules, it is entitled to claim the methods without describing the molecules. Ariad’s legal assertion, however, is flawed.
I've been waiting to hear someone say that since 2002. I have never been able to figure out how the company could lay claim to such huge swaths of cellular biology with no real enablement, no demonstration that they could actually do what they were asserting the rights to. Well, in the end, they can't:
"Regardless of whether the asserted claims recite a compound, Ariad still must describe some way of performing the claimed methods, and Ariad admits that the specification suggests only the use of the three classes of molecules to achieve NF-κB reduction. Thus, to satisfy the written description requirement for the asserted claims, the specification must demonstrate that Ariad possessed the claimed methods by sufficiently disclosing molecules capable of reducing NF-κB activity. . .
. . .The ’516 patent discloses no working or even prophetic examples of methods that reduce NF-κB activity, and no completed syntheses of any of the molecules prophesized to be capable of reducing NF-κB activity. The state of the art at the time of filing was primitive and uncertain, leaving Ariad with an insufficient supply of prior art knowledge with which to fill the gaping holes in its disclosure. . .
Ariad sought and obtained the broad claims we now hold to be invalid. For its own reasons, Ariad maintained the breadth of these claims through claim construction and into trial. As Judge Rader observed, the situation presented in this case should not often occur, because “[i]n simple terms, a court would properly interpret the claim[s] as limited.” Univ. of Rochester v. G.D. Searle & Co., 375 F.3d 1303, 1312 (Fed. Cir. 2004) (dissenting from denial of petition for rehearing en banc). Nonetheless, as it stands, Ariad chose to assert claims that are broad far beyond the scope of the disclosure provided in the specification of the ’516 patent. Cf. Liebel-Flarsheim Co. v. Medrad, Inc., 481 F.3d 1371, 1380 (Fed. Cir. 2007) (“The motto, ‘beware of what one asks for,’ might be applicable here.”)."
On the other hand, the CAFC did not side with Lilly in their arguments about inequitable conduct or inherent anticipation of the patent's claims, finding that there was no clear evidence of intent to deceive on Ariad's part. But since they find that the key claims of the patent are invalid anyway due to lack of written description, it hardly matters. Ariad's patent is dead. And this ruling should deter anyone from trying another idiotic IP power grab like this in the future. Good news, and it only took seven years of constant legal wrangling to emerge. . .
+ TrackBacks (0) | Category: Patents and IP
April 8, 2009
So Pfizer's announced its post-Wyeth structure, and on the face of it, the plan makes as much sense as you can make of such a massive organization. The big divide is between small molecules and biologics, which makes sense - the two of them have different R&D, manufacturing, and regulatory issues in many ways. Besides, that's how most companies already divide things up internally if they do both.
There's a lot of brave talk in the press releases about how Pfizer has learned from its past mergers, how this organization will be ready to take wing just as soon as the last signature is put on the last form. I'm not buying it. It's good to hear that the company realizes that the previous mergers led to so much disruption and lost time, but I don't see how good intentions will help that much. There is no way, as far as I can imagine, to integrate ten billion dollars worth of R&D in an orderly fashion. The best that they can hope for is "not as hideous as the last couple of times", but I suppose the lawyers wouldn't sign off on that language as appropriate. And even that's a fairly ambitious goal.
We won't know for years if they've succeeded, either. The final measure is the productivity of the new organization, and for some time they'll be running on what was already in the works at both companies before. That, as I've said before, is one of the hardest things about the drug business: the lag time before you see results. You can change the early R&D, and see in a year or two if you've started more projects than you used to. But you won't know if they were good projects (or better ones, anyway) until they've run for a while. Maybe you just lowered your standards and initiated a bunch of stuff with a higher failure rate?
For that to resolve itself, you have to see how many of these new-regime projects make it all the way to the clinic. But then you'll have to wonder if you've just thrown some exhausted, just-barely-there stuff over the wall to declare victory - everyone who's worked in a big pharma organization has seen that one. The real measure of success in this industry is how many things come out of the clinic alive, and that's so dependent on luck (since we don't understand enough about toxicology and drug mechanisms), that those numbers may not reflect anything you're doing particularly right or wrong. No one at Pfizer saw torcetrapib's horrible failure coming, for example.
But hold on - another real measure of success in this industry, when you get right down to it, is money. Did those projects you started, took to the clinic, got through human trials, took to the FDA, and got out onto the market ever pay for themselves? There's always the possibility of an Exubera, to pick another example from Pfizer's recent past. And now we're up to ten or twelve years since you overhauled basic R&D. How many overhauls have you done since? Who's to say what thing had which effect and how? Pfizer can tell you about that, too - the dust hadn't settled from the Warner-Lambert deal when the Pharmacia one went through.
So, yes, we'll see about all this. But we won't see for a while, and when we finally do see, it'll probably be impossible to say just what we're looking at.
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April 7, 2009
Biogen Idec has continued to fight off Carl Icahn, opposing his nominees to the company's board and setting up a fight at the annual meeting later this year.
But this morning (as a correspondent has just pointed out to me) the company's stock has been taking off. It's up about 7%, with the broad market down, and all of this rise seems to have been since 11 AM. Someone's stepping up and buying a good amount of BIIB, for some reason. But who, and why?
Update: ah, here we go - rumors of Sanofi-Aventis or some other non-Ichan entity stepping in. We'll see if there's anything to it. . .
+ TrackBacks (0) | Category: Business and Markets | Current Events
There's an interesting article that showed up in the Financial Times about the leadership of drug companies. Specifically, the number of them that are run by scientists (always lower than you would have thought) is dropping even further.
"Only one large western pharmaceutical company will be run by a scientist (John Lechleiter of Lilly) following completion of the current round of acquisitions, in spite of the growing need for strengthened innovation to develop new medicines. . .
The changes reflect a shift for the scientists who once dominated senior pharmaceuticals positions to give way to executives with backgrounds in marketing, legal or other more general business backgrounds.
The evolution mirrors growing legal and marketing expertise required to operate in the US, which remains the world’s largest medicines market, although its recent sluggish growth and renewed demand for greater innovation and science-based assessment of drugs may suggest different skills will be required in future."
I wonder, though, how many of the background assumptions here are true. I don't think that the large drug companies have been dominated by scientific leadership for some time. This (to me) isn't a recent shift, although it may well have accelerated. And we've gotten into discussions around here a couple of times (most recently on the news of Lechleiter's appointment) about whether you even want a scientist in the top job. Opinions, to put it mildly, are divided on how much difference that makes, and (if it does) which way you'd rather go.
My take, for what it's worth, is that scientific training can be desirable in a drug company CEO, but it's not sufficient, or always even necessary. The skills needed don't overlap as much as you might think between science and management, even in a company that makes its living from science. The problem is, I don't think that the particular skills associated with law and MBA degrees are sufficient, either. Being good at running a large organization is a rather rare quality. And it's not always easy to recognize: some companies have issues (good ones or bad!) that will swamp most of the signals you might try to get about the qualities of their CEO.
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April 6, 2009
Thanks to the readership for all the suggestions. Today I managed to survive on fish tacos for lunch and a fearsome bacon burger at Hodad's over in Ocean Beach for dinner. Good thing the hotel has a gym. No one's going to mistake Newport Street there for La Jolla, are they? Tomorrow I'm having a working lunch, a light one, I should hope, and at some point I'll do my Mexican thing over on University Avenue (Super Cocina has come highly recommended).
And yes, for the folks back at the shop who read the site, I am doing something here other than plow through the local food. Honest. I have witnesses that I was in every single talk at the meeting today, and y'all know from experience how rare that is.
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Most of my last 24 hours have been spent in travel mode, of one sort or another, so I doubt if I'll have a full blog post this morning. I'm out in San Diego for a conference, so if any of you are doing the same, perhaps I'll run into you.
I won't be blogging the meeting itself. I'll be taking a lot of incoherent notes for my own use, naturally, and putting them into immediate readable sentences takes a lot of mental overhead. And naturally, proprietary concerns might well keep me from revealing which parts of the meeting I find most important. Of course, you could say that about the literature that I mention here on the blog as well. It's something that crosses my mind, but I try to arrange things so that I'm not giving away much. I also make sure to talk about fields about which I have no (current) professional irons in the fire, so that evens things out a bit.
But daily blogging will continue here during the week, just at odd times as my schedule and scrambled time zones allow.
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April 3, 2009
We use a lot of automated equipment in the drug discovery business. There’s an awful lot of grunt work involved, and in many cases a robot arm is better suited to the task – transferring solutions, especially repetitive transfers of large numbers of samples, is the classic example. High-throughput screening would just not be possible if you had to do it all by hand; my fingers hurt just imagining all the pipetting that would involve.
But I wouldn’t say that the process of medicinal chemistry is at all automated. That’s very much human-driven, and a lot of the compounds on most med-chem projects are made by hand, one at a time. Sure, there are parallel synthesis techniques, plates and resins and multichannel liquid handlers that will let you set up a whole array of reactions at once. But you do that, typically, only after you’ve found a hot compound, and that’s often done the old-fashioned way. (And, of course, there are a lot of reactions that just don’t lend themselves to efficient parallel synthesis).
But I remember the first time I saw an automated synthetic apparatus, back at an ACS meeting in the mid-1980s. There was a video in the presentation (a real rarity back then), and it showed this Zymark arm being run to set up an array of reactions, assay each of them after an overnight run, and report on the one that performed the best. “Holy cow”, I thought, “someone’s invented the mechanical grad student”. Being a grad student at the time, I wasn’t so sure what I thought about that.
This all comes to mind after reading a report over at Wired about a robotic system that has been claimed to have made a discovery without much human input at all. “Adam”, built at Aberystwyth University in Wales, seems to have been set up to look for similarities in yeast genes whose function hadn’t yet been assigned, and then (using a database of possible techniques) set up experiments to test the hypotheses thus generated. The system was also equipped to be able to follow up on its results, and eventually uncovered a new three-gene pathway, which findings were confirmed by hand.
And Ross King, leading the project at Aberystwyth, is apparently extending the idea to drug discovery. Using a system that (inevitably) will be called “Eve”, he plans to:
. . .autonomously design and screen drugs against malaria and schistosomiasis.
"Most drug discovery is already automated," says King, "but there's no intelligence — just brute force." King says Eve will use artificial intelligence to select which compounds to run, rather than just following a list.
Well, I won't take the intelligence comment personally; I know what the guy is trying to say. I’ll be very interested to see how this is going to be implemented, and how it will work out. (I'll get an e-mail off to Prof. King asking for some details). My first thought was that Eve will be slightly ahead of a couple of the less competent people I’ve seen over the course of my career. And if I can say that with a straight face (and now that I think about it, I believe that I can), then there may well be a place for this sort of thing. I’ve long held that jobs which can be done by machines really should be done by machines.
But how is this going to work? The first way I can see running a computational algorithm to design drugs would be some sort of QSAR, and we were just talking about that here the other day – most unfavorably. I can imagine, though, coding in a lot of received wisdom of drug discovery into an expert system – Topliss tree for aryl substituents, switch thiophene for phenyl, move nitrogens around the rings, add a para-fluoro, check both enantiomers, put in a morpholine for solubility, mess with the basicity of your amine nitrogens, no napthyls if you can help it, watch your logD - my med-chem readers will know just the sorts of things I mean.
Now, automating that, along with feedback from the primary and secondary assays, solubility, PK, metabolite ID and so on. . .mix it in with literature-searching capability for similar compounds, some sort of reaction feasibility scoring function, ability to order reagents from the stockroom, analyze the LC/MS and NMR traces versus predictions, weight the next round of analogs according to what the major unmet project goals are. . .well, we're getting to the mechanical medicinal chemist, sure enough. Now, not all of these things are doable right now. In fact. some of them are rather a long way off. But some of them could be done now, and the others, well, they're certainly not impossible.
I'm not planning on being replace any time soon. But the folks cranking out the parallel libraries, the methyl-ethyl-butyl-futile stuff, they might need to look over their shoulders a bit sooner. That's outsourcing if you like - from the US to China and India, and from there to the robots. . .
+ TrackBacks (0) | Category: Drug Development | Drug Industry History | General Scientific News | Life in the Drug Labs
April 2, 2009
There are a lot of recommended mediations for people at cardiovascular risk. ACE inhibitors and diuretics for blood pressure, a bit of aspirin for anti-thrombotic activity, most likely a stain for cholesterol levels. There are plenty of people who are taking all of these at once, and millions are taking some subset of them. So why not combine them into one good-for-what-ails-you pill?
This idea came up a few years ago, and there’s no point in pretending that I wasn’t a bit skeptical of it:
This is a touchingly linear approach to drug therapy. It's actually kind of sweet. Since the authors clearly mean well, I won't wave my fists around too much. But I would like to point out that these things may well work a bit differently in combination than they do in less crowded company. I realize that many people take subsets of these, which is a good starting point, but taking all six at once will be a new adventure. Drug interactions aren't easy to predict, and that's putting it mildly. Some people are going to feel more effects of one part of the mixture, and some will get hit by another. Some of the people taking this monster will also be taking (for example) diabetes medication, which sets off a whole new set of possible interactions.
As I went on to mention in that post, though, the comments that came in to the British Medical Journal, where the original proposal appeared, were (in many cases) a lot nastier than what I had to say:
Some of the responses are favorable, but there are many that really unload on the authors and their idea. Phrases like "one the most egregious presentations that I have ever come across," "it is very dangerous to take bits and pieces of research and cobble it together," "I would like to add my voice to those who are truly dumbfounded," "total disregard for scientific principles" and "It is almost impossible to know where to start" are flying around over there.
Well, that was in the days before I had comment functions on this blog, so no one told me what they thought about my opinion. But now there are some results from just this sort of formulation, and I have to say, they’re not bad. Most of the beneficial results were about the same as the individual drugs (except for lowered triglycerides, where the effect was only about half as strong). And rather more surprisingly, there weren’t any complicating side effects or interactions. Cardiologists are quoted in the news articles as expressing surprise, and although I Am Not a Cardiologist, you can count me in there, too.
My biggest worry was actually getting all these things to absorb properly from the same pill – this thing must be interesting to manufacture. Medicinal chemists like me tend not to think much about excipients, binders, coatings, and the other issues that go into making solid pill formulations, but that stuff is not easy. There’s a lot of voodoo in it, too, since (after all) you’re trying to affect oral absorption, which is not a really well-understood process.
There's still no guarantee that the polypill, or some variation thereof, will make it. This is a first clinical look, and that's still a long way from the end. But it's already made it a bit further than I thought.
+ TrackBacks (0) | Category: Cardiovascular Disease
April 1, 2009
This has been forwarded on to me - if you find the idea of a gene sequence being sponsored by IKEA unusual, you should give the press release (and its associated links) a close look. . .
+ TrackBacks (0) | Category: Current Events
Thanks to a comment on this post, I’ve had a chance to read this interesting article from Stephen Johnson of Bristol-Myers Squibb, entitled “The Trouble with QSAR (Or How I Learned to Stop Worrying And Embrace Fallacy)”. (As a side note, it’s interesting to see that people still make references to the titling of Dr. Strangelove. I’ve never met Johnson, but I’d gather from that that he can’t be much younger than I am).
The most arresting part of the article is the graph found in its abstract. No mention is made of it in the text, but none has to be. It’s a plot of the US highway fatality rate versus the tonnage of fresh lemons imported from Mexico, and I have to say, it’s a pretty darn straight line. I’ve seen a lot shakier plots used to justify some sweeping conclusions, and if those were justified, well, then I’m forced to conclude that Mexican lemons have improved highway safety a great deal. The vitamin C, maybe? The fragrance? Bioflavanoids?
None of the above, of course. Correlation, tiresomely, once again refuses to imply causation, even when you ask it nicely. And that’s the whole point of the article. QSAR, for those outside the business, stands for Quantitative Structure-Activity Relationship(s), an attempt to rationalize the behavior of a series of drug candidate compounds through computational means. The problem is, there are plenty of possible variables (size, surface area, molecular weight, polarity, solubility, charge, hydrogen bond donors and acceptors, and as many structural representation parameters as you can stand). As Johnson notes dryly:
” With such an infinite array of descriptions possible, each of which can be coupled with any of a myriad of statistical methods, the number of equivalent solutions is typically fairly substantial.”
That it is. And (as he rightly mentions) one of the other problems is that all these variables are discontinuous. Some region of the molecule can get larger, but only up to a point. When it’s too large to fit into the binding site any more, activity drops off steeply. Similarly, the difference between forming a crucial hydrogen bond and not forming one is a big difference, and it can be realized by a very small change in structure and properties. (Thus the “magic methyl” effect).
But that’s not the whole problem. Johnson takes many of his fellow computational chemists to task for what he sees as sloppy work. Too many models are advanced just because they’ve shown some (limited) correlations, and they’re not tested hard enough afterwards. Finding a model with a good “fitness score” becomes an end in itself:
”We can generate so many hypotheses, relating convoluted molecular factors to activity in such complicated ways, that the process of careful hypothesis testing so critical to scientific understanding has been circumvented in favor of blind validation tests with low resulting information content. QSAR disappoints so often, not only because the response surface is not smooth but because we have embraced the fallacy that correlation begets causation.”
+ TrackBacks (0) | Category: In Silico