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
September 30, 2008
Today brings the news of which areas Pfizer has decided to bail out of: obesity, most cardiovascular (it seems), anemia, osteoporosis and some osteoarthritis, liver disease, and muscle. They're concentrating on oncology, pain, Alzheimer's, and diabetes, which the company seems to have identified as the best intersection of their pipeline and the associated profits.
This will probably fuel speculation that the company is Imclone's mystery bidder - that name will supposedly be revealed at midnight on Wednesday, if I'm reading these reports correctly. If so, that makes me want to groan and roll my eyes. I'm waiting for Carl Icahn to tell everyone that they'll have to say the secret password to find out.
That news item linked to above also mentions that Pfizer has shed ten thousand employees since January of last year. Yikes. And on that subject, I hear from several sources that GlaxoSmithKline is cutting preclinical development hard today. People seem to have known that it was coming today, and roughly how bad it would be, but today is supposedly the day that names are read off the list. Good luck to people there. The contractions continue.
There's no longer any doubt, in case anyone was wondering, that this is the worst stretch for research employment at the big pharmaceutical companies in at least twenty years (to my certain knowledge) and very likely much longer than that, from what longer-serving colleagues tell me. Frankly, I'm not sure we've ever seen anything quite like this - which makes further prediction impossible. . .
+ TrackBacks (0) | Category: Business and Markets
September 29, 2008
For the most part, the biologists on a drug discovery project expect us in the med-chem labs to be able to make pretty much anything we need to make. Actually, I don’t have to go that far – the other chemists more or less expect that, too. Chemistry’s a big field, with a lot of reactions and techniques, and if you want some particular structure badly enough, there are usually ways to get to it.
But not always, and not always by routes that you’re willing to put up with. That’s especially true early in a project when you need some robust chemistry to turn out a lot of diverse analogs quickly, so you can have some idea of which parts of the molecule are most important. Synthetic trouble at this stage is frustrating for everyone involved.
I was on a project a few years ago that ran into this exact problem. Compounding the pain was the way the lead compound looked when it was up on a screen during a meeting: small, perfectly reasonable, easy to deal with. Hah! It was a werewolf, that thing. None of the ideas that we had ever worked out the first time, and many of them never worked out the last time, either. Meeting after meeting would take the same format when there were outside managers or other chemists present: “But why don’t you just. . .” “We did. It doesn’t work.” “But then you should try. . .” “We know. We tried that. It doesn’t work.” “Well, OK, but then you could always come around and. . .” “We could. If it worked. But it doesn’t.”
New chemists would be added on to the program to try to get things moving, and they’d always come in rolling up their sleeves, muttering “Do I have to do everything myself around here. . .” How do I know? Because I was one of them. Within a month or two, though, I was in the same shape as everyone else on the project, looking at a bunch of NMRs and mass spec traces and trying to figure out what went wrong. Meanwhile, helpful folks would wander past the whiteboard and ask me how come we hadn’t tried the reaction that had just failed for the eleventh time. Eventually we learned to offer the more persistent questioners a supply of our starting material so they could solve the problem themselves and be heroic, but nothing ever came of that.
The project managed to stagger to a clinical candidate, but ran into mechanistic problems in the more advanced animal models. (That was really the hot fudge topping on the whole sundae – this was one of those therapeutic areas whose definitive animal models were too complex and costly to run until you were absolutely sure you had The Compound). I haven’t run into one quite like this since, and with any luck, I never will.
+ TrackBacks (0) | Category: Life in the Drug Labs
September 26, 2008
I wrote back in the summer about the FDA's delayed decision on Lilly's potential anticoagulant blockbuster Effient (prasugrel). Well, those three months have zipped right by, and the agency is supposed to rule today.
Prediction, for what it's worth: I think the drug will be approved, but with label restrictions for the group(s) that seemed to respond best to it in trials - who may have been. at least partly, the groups that could put up with the associated bleeding the best, too. So no elderly patients, no low-weight ones, and no one with a history of stroke or TIA. That'll cut down the market for the drug, definitely, but not as much as if it doesn't get approved at all, right? I think the FDA will require Lilly to keep a careful eye on how Prasugrel performs in the real world while they wait on the results of the next trial to come in, with a possible label-language change to come at that point.
I'll give that option about a 70% chance. The 30% chance is that they delay things yet again, since the agency has been in a delaying risk-averse mood these days. We'll know soon. This new policy of not issuing those irritating "approvable" letters has made this sort of thing rather more tense, hasn't it?
+ TrackBacks (0) | Category: Cardiovascular Disease | Regulatory Affairs
So it seems that Bristol-Myers Squibb took my advice (yeah, sure) and made an insultingly incremental counteroffer for Imclone, raising their $60/share all the way to. . .$62. I was hoping for something more like $60.25 myself, but you can’t have everything. (I should send them a bill for consulting services and see how far that gets me).
Carl Icahn has replied in yet another public letter, saying that there must be more productive ways for BMS to enrich its lawyers. I notice that the folks at the Wall Street Journal’s Health Blog are getting tired of the extended correspondence between Icahn and BMS’s Jim Cornelius. Although I’m still enjoying the show, I can see where it will eventually pall.
Icahn claims that his mystery $70/share bidder is doing due diligence, which should be completed this weekend. You’d think that any due diligence worth the name would tell someone not to pay $70/share for Imclone while Erbitux is still tied up with Bristol-Myers Squibb and its successor’s status is still very much in doubt. Wouldn’t you? Just how long does it take to run those numbers, anyway? Especially in this financial market, with credit tightening and the investment banking community in chaos? Or is the whole thing just a load of. . .no, no, Carl Icahn wouldn’t stoop to tactics like that. And I am Marie of Rumania.
My prediction: 64% chance that the companies agree, with much face-saving theater, at a price of about $65 per share. 35% chance that the whole business falls apart for now, due to the uncertainly about IMC-11F8. And that leftover 1% chance is that there really is a $70/share bidder.
+ TrackBacks (0) | Category: Business and Markets
September 25, 2008
I'm hearing reports that Pfizer is telling employees in various therapeutic areas right now that there will be deep cuts coming, and that more details will be coming out in about two weeks (individual-level layoff notices, etc.) I gather that obesity research is being hit hard, and some others as well - but any details from people in a position to know would be appreciated.
This is a heck of a time to be laid off, that's for sure. Here's hoping that things aren't as bad as I'm hearing. . .
+ TrackBacks (0) | Category: Business and Markets | Current Events
Want a hard problem? Something to really keep you challenged? Try protein folding. That'll eat up all those spare computational cycles you have lounging around and come back to ask for more. And it'll do the same for your brain cells, too, for that matter.
The reason is that a protein of any reasonable size has a staggering number of shapes it can adopt. If you hold a ball-and-stick model of one, you realize pretty quickly that there are an awful lot of rotatable bonds in there (not least because they flop around while you're trying to hold the model in your hands). My daughter was playing around with a toy once that was made of snap-together parts that looked like elbow macaroni pieces, and I told her that this was just like a lot of molecules inside her body. We folded and twisted the thing around very quickly to a wide variety of shapes, even though it only had ten links or so, and I then pointed out to her that real proteins all had different things sticking off at right angles in the middle of each piece, making the whole situation even crazier.
There's a new (open access) paper in PNAS that illustrates some of the difficulties. The authors have been studying man-made proteins that have substantially similar sequences of amino acids, but still have different folding and overall shape. In this latest work, they've made it up to two proteins (56 amino acids each) that have 95% sequence identity, but still have very different folds. It's just a few key residues that make the difference and kick the overall protein into a different energetic and structural landscape. The other regions of the proteins can be mutated pretty substantially without affecting their overall folding, on the other hand. (In the picture, the red residues are the key ones and the blue areas are the identical/can-be-mutated domains).
This ties in with an overall theme of biology - it's nonlinear as can be. The systems in it are huge and hugely complicated, but the importance of the various parts varies enormously. There are small key chokepoints in many physiological systems that can't be messed with, just as there are some amino acids that can't be touched in a given protein. (Dramatic examples include the many single-amino-acid based genetic disorders).
But perhaps the way to look at it is that the complexity is actually an attempt to overcome this nonlinearity. Otherwise the system would be too brittle to work. All those overlapping, compensating, inter-regulating feedback loops that you find in biochemistry are, I think, a largely successful attempt to run a robust organism out of what are fundamentally not very robust components. Evolution is a tinkerer, most definitely, and there sure is an awful lot of tinkering that's been needed.
+ TrackBacks (0) | Category: General Scientific News | In Silico
September 24, 2008
Over the years on this blog, I’ve written quite a few times about Ariad Pharmaceuticals and their quest to assert some rather sweeping patent rights. For background, see here and search for "Ariad" - there's a lot to read, in you're in the mood. The short version is that the company is the licensee of a patent which was issued with extremely broad claims around the NF-kappaB pathway in cells. Dozens and dozens of claims – the thing just drones on and on about compounds, methods, techniques that affect, inhibit, modulate, fill-in-your-verb anything that regulates, changes, modulates, etc. anything to do with NF-kappaB.
My problem with that is I think that claiming such broad swaths of biochemical mechanism is counterproductive. It’s bad for drug research, bad for patent law, and bad for the enterprise of science in general. For example, the company had no compounds to actually enable a lot of these claims when the patent was issued. A lot of other people did, though, because that pathway is tied up with all sorts of cellular processes, especially those dealing with inflammation and immune response. So Ariad immediately went after other companies with profitable drugs whose mechanism of action went, at least partly, through their newfound patent rights. I find it perverse that a company, rather than patenting their drug, could be able to patent the idea of how a yet-to-be-found drug might work, or retroactively, having had no role in the process at all, claim the rights to other drugs that had already been developed and marketed by someone else.
Of course, all this ended up in litigation, which has gone on for years now. There are all sorts of issues – you have the separate court cases with Lilly and Amgen, for one, and then there’s the question of whether Ariad’s patent is valid at all. I’ve chronicled some of the twists and turns – Lilly, for example, lost the first round in court (to my, and no doubt their, disbelief).
But the latest news is much more to my liking. Here’s the background: Amgen struck first in 2006, fearing a lawsuit by Ariad over the use of Enbrel – hey, it goes through NF-kappaB, so it’s fair game, right? Amgen asked for a declaration that all 203 claims of the Ariad patent were invalid. Ariad wanted that dismissed, naturally. But in September of 2006, the court turned them down, saying that Amgen did indeed have grounds to sue, since internal Ariad presentation documents specifically mentioned targeting Enbrel (and another Amgen product, Kineret) as part of their business strategy. (The court also took a moment to point out that had these documents not turned up, Ariad would have gotten its desired dismissal right there).
Ariad followed up by saying that they’d done no work related to whether the Amgen drugs infringed its patent, but they were going to do so now, by gosh, and in April 2007 they added a counterclaim that Amgen had indeed infringed 22 of the claims. (They later revised that down to nine). By January of this year, they’d dropped the Kineret part of the case and cut the list of claims down to seven.
But court found, in a summary judgment, that Amgen had indeed not infringed the Ariad patent. The use of Enbrel, they ruled, falls outside the scope of Ariad’s claims – mainly because all of Ariad’s claims related to reducing NF-kappaB activity inside the cell, and Enbrel acts on TNF-alpha exclusively outside the cell and never enters cells at all. Ariad has no case for infringement.
But there was another ruling, which I found quite interesting, and want to go into in detail. During this litigation, Amgen had proposed a broad covenant with Ariad not to sue them, and Ariad responded that sure, they’d sign that – but only covering Enbrel and Kineret. They reserved the right to sue at some future date about something else, you see.
Amgen rejected this idea, but Ariad went ahead and publicly declared that they’d abide unilaterally by their proposal – and then they turned around and asked the court to butt out of the original Amgen motion to invalidate all 203 claims of their patent, on the grounds that their covenant deprived the court of jurisdiction to consider the request. After all, they said, the only issues here were Enbrel and Kineret, and they’d promised not to sue Amgen over those, anyway! (Now you see why Ariad would go to the trouble of entering into a covenant with, basically, themselves).
Amgen didn’t go for that at all, saying that they were trying, once and for all, to settle the issue of whether Ariad could sue them on any ground related to the original patent – neglecting, as far as I can tell, to append the phrase delenda est Cartago to their filing. They disparaged Ariad’s maneuver as a last-ditch attempt to avoid arguing about invalidity and unenforceability, and said that they had no interest in leaving Ariad’s patent issues open and being sued later on at Ariad’s convenience. I’m paraphrasing here from the court documents, but not by very much, I have to tell you. There’s a distinctly irritated tone to most of the filings in this case.
The court went for Ariad on part of this, saying that Amgen’s potential pipeline of drugs and Ariad’s possible lawsuits didn’t amount to a real controversy – not compared to the other two products, which after all had been specifically mentioned in Ariad’s internal documents. Amgen’s attempts to go on with its invalidity claims were no longer on the table. But, as the latest document goes on to say, “The court reaches the opposite conclusion with regard to Amgen’s declaratory judgment claim of unenforceability”. The court held that it did indeed have jurisdiction to hear that part of the case.
Amgen’s line of argument was inequitable conduct – that when Ariad’s patent was filed, that the parties involved had not met the “candor and good faith” requirement to disclose all known information related to patentability. They claimed this both for the initial filing and for the PTO’s re-examination of the patent, but it’s the latter that was an issue in this latest ruling. Ariad had filed declarations by two expert witnesses, Inder Verma and Thomas Kadesch, during that process. Amgen claims that Verma’s statement is misleading, and that Ariad didn’t point that that he’d published articles that appear to contradict his own statements. And as for Kadesch, he was deposed by Amgen in the course of another trial that they were involved in (vs. Roche), and they claim that he recanted testimony that he’d given for Ariad in the Lilly trial, which was used by Ariad in their dealings with the PTO. (Amgen apparently had to pry the Kadesch’s reversal documents out of Roche with a subpoena).
Ariad did finally get around to submitting all these details to the PTO, but only during the course of 2007 and 2008, after the Amgen legal wrangling was underway. And Amgen claims that they dumped most of the really hot stuff in with a pile of other things, so as not to call attention to any of it.
As it turns out, the court found that Ariad had behaved properly with respect to the Kadesch documents – but the Verma stuff was another matter. In his statement for Ariad, Verma said several times that the actions of glucocorticoids through NF-kappaB were poorly understood, not known, etc. But his own articles concluded that glucocorticoids repressed NF-kappaB-mediated transcription, making those statements hard to reconcile.
If this was indeed evidence of inequitable conduct, the case all turned on the criteria worked out in a previous case (Rohm and Haas) on whether Ariad had voluntarily submitted this later evidence to the PTO. The court found that there was no evidence for that, that Ariad had only disclosed these documents under threat of Amgen’s litigation, and that Amgen’s motion for (partial) summary judgment on equitable conduct was thus granted.
So not only does Ariad have a ruling that interprets its claims in a way it doesn't like (and lets Amgen off the hook, besides), it also has one that raises significant concerns about inequitable conduct, and calls the entire enforceability of its patent into question. Not a good day for them - but a good day for common sense.
+ TrackBacks (0) | Category: Patents and IP
September 23, 2008
Over the years, when some puzzling feature of a drug candidate’s binding to a target came up, I’ve often said “Well, we’re not going to know what’s happening until some lunatic builds a femtosecond X-ray laser”. Various lunatics are now pitching in to build some. I’m going to have to revise my lines.
The reason I’d say such a mouthful is that we already, of course, get a lot of structural information from X-ray beams. Shining them through crystals of various substances can, after a good deal of number-crunching in the background, give you a three-dimensional picture of how the unit molecules have packed together. Proteins can be crystallized, too, although it can be something of a black art, and they can be either crystallized with or soaked with our small molecules, giving us a picture of how they’re actually binding.
There are, as mentioned earlier around here, plenty of ways for this process to go wrong. For starters, a lot of things – many of them especially interesting – just don’t crystallize. And the crystals themselves may or may not be showing you a structure that’s relevant to the question you’re trying to answer – that’s particularly true in the case of those ligand-bound protein structures. And the whole process is only good for static pictures of things that aren’t moving around. It used to take many days to collect enough data for a good crystal structure. That moved down to hours as X-ray sources got brighter and detectors got better, and now X-ray synchrotrons will blast away at your crystals an