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: email@example.com
February 28, 2011
Past performance (Phase II results) are no guarantee of future success (Phase III). That warning has been proven over and over in this business, and an awful lot of time, effort, and money have gone down the waste chute in the process. To give you an idea, though, of how hard it is to break out of that cycle, consider Renovo.
As the InVivoBlog details, Renovo was founded to try out ideas to reduce scar tissue formation. And their whole strategy was to go into humans as quickly as possible, to firm up the clinical relevance of their candidate therapies. That's a bit easier to do with something like scarring, if you can find patients willing to have small cuts made in their skin. That's just how one of the Phase II trials was run for the company's Juvista (recombinant TGF beta 3) - two cuts, one treated with the drug and one without. And the results looked quite good.
But not in Phase III. Earlier this month, the company announced that Juvista has completely, utterly missed its endpoints in the larger trial, and no one seems to know why. According to the InVivoBlog, investors were reduced on the conference call to asking if somehow the data collection had been messed up - surely some of the placebo group and the treatment group had been, uh, switched somehow? But no.
It's worth remembering, though, that not all the Phase II data were so convincing. In retrospect, the earlier trials that looked bad were predictive, while the impressive numbers appear to have been artifacts. But how do you figure that out in advance? And how do you run only the trials that will be predictive, and how do you know to trust them? I'm tempted to ask Francis Collins to get on this for all of us, but that would be unfair. I think.
+ TrackBacks (0) | Category: Clinical Trials | Drug Development
February 25, 2011
Well, it's been a bit too serious around here this week. So I thought today I'd step back to a period when men were men and chlorine azide was a reactive, toxic, and unstable compound that was only good for finding out what sort of explosion it would set off next. What's that? You say that that's still about all it's good for? Staying power, that's what I call it. If you work with the halogen azides, you work with things whose essential character time does not alter.
"Until they blow up", you say. Ah, but that is their essential character. It's the things around them that alter. Make sure you don't put anything next to them that you're not comfortable seeing altered - you know, all sudden-like.
A reader forwarded this 1943 JACS article, the first comprehensive study of chlorine azide, and it's a joy to read. Part of the fun is, of course, watching these folks set off the fireworks. (The challenge with a substance like chlorine azide is finding something that it won't react with violently):
Owing to the extreme instablity of the compound accurate determinations of the bioing and melting points have not been made as yet. Numerous explosions, often without assignable cause, have occurred during the experiments. . ."
Another thing I always enjoy in these papers is the list of recommended protective gear. No leather suits this time and (interestingly) no earplugs. Nope, it's straight to the Iron Man look. These azidonauts endorse:
". . .masks and breast-plates of sheet iron worn by observers during times of danger. Each mask is provided with a rectangular pane (7 x 3 inches) of shatter-proof glass. Although scores of violent detonations have occurred, with resultant demolition of much apparatus, no personal injury has been suffered."
That last part is sort of a "no graduate students were maimed during the course of this research" statement, which really is good to know. But another nice thing about this paper is the way some parts of it are written, in a style which was a bit formal and archaic even for 1943. A sample:
"If small pieces of yellow phosphorus be added, with stirring, to a solution of chlorine azide in carbon tetrachloride at 0C, the solution gradually becomes turbid, and a succession of slight explosions takes place beneath the liquid. If stirring be omitted until the maximum turbidity is attained, the slightest agitation results in a detonation that demolishes the apparatus. . ."
Do not be omitting the stirring, then. I have to say, not being used to this sort of chemistry, that if I saw these events going on in my fume hood that a series of slight explosions might well take place beneath my iron breastplate. What else doth chlorine azide detonate with? Well, in case you had any doubt, the gaseous reagent "reacts violently" with sodium metal. They had four explosions at -78C, while the fifth run (persistence!) yielded a mixture of sodium chloride and sodium azide. (Actually, the other runs probably yielded that, too, albeit as a fine haze). I really have to salute the dedication involved in finding that out, though - after two or three violent explosions, you or I might be tempted to just say that we couldn't determine the products of the reaction. But they were made of sterner stuff back in 1943.
The date does make me wonder if there was war research money involved; I wouldn't be surprised. But chlorine azide has not been weaponized, nor will it be. It remains, with its chemical relatives, off in a part of chemical science that's safe from human exploitation. It's a spacious game preserve, that territory, and over the gate is the ornate motto Noli me tangere. Take heed.
+ TrackBacks (0) | Category: Things I Won't Work With
February 24, 2011
That's the contention of venture capitalist Kevin Kinsella (of Avalon Ventures) as reported in this piece at Xconomy
“There have been numerous instances of what I refer to as bad behavior—combined with short-sighted, brass-knuckle negotiating tactics—by some pharma companies that really go to the heart of whether this partnership between Big Pharma and biotech can really continue,” Kinsella says. He maintains that the pharmaceutical industry is doing enormous damage to the life sciences venture capital ecosystem. “Their predatory business practices,” he says, “are pushing the sector almost to the point of extinction.”
He likens the process to commercial overfishing, and says that some CEOs may not even realize how much damage is being done. He lists several examples of bad behavior (see the article), but the common thread to them (to me) seems to be the attempt to keep every bit of the risk with the smaller company, until there's clearly money about to be made, at which time the money starts flowing to the larger outfit.
Trying to structure things this way, though, is how I've always understood the process to work. I'm not saying it's a good idea, just that it's not a new one. Maybe it's just been getting worse, but the big drug companies have always wanted to jam in those heads-I-win-tail-you-lose clauses. The way I heard it expressed 20 years ago was "So, you need a deal real bad? Well, here's a really bad deal!"
But here's the getting-worse-recently case:
Kinsella sees a confluence of forces that came together after the tech and biotech bubble burst in 2000, and has continued with the mortgage meltdown and ensuing capital crisis. As financial institutions scrambled to save themselves, they shed much of their payroll—including most of the Wall Street banking talent that had focused on the biotech sector. The investment banks that biotech built—Hambrecht & Quist, Robertson Stephens, Montgomery Securities—did not survive, and Kinsella says no “serious” banks remained to serve life sciences startups, or to underwrite biotech IPOs.
Another consequence of the Wall Street meltdown, Kinsella says, is that Big Pharma companies have been hiring the biotech bankers laid off during Wall Street’s financial purges. As he puts it, “The sell-side guys were going to Big Pharma [companies] and saying they can cut better partnerships or buyout deals since they have an ‘inside baseball’ understanding of venture-backed biotechs, and they know how to wring the most concessions from a biotech’s board.”
He may well have a point there, although my first thought after reading that was "GSK should have hired some of those guys before doing the Sirtris deal". But Kinsella goes on to argue that there's not much of an "IPO exit" any more, and hasn't been for several years, so smaller companies are more dependent than ever on doing deals with the larger ones. And his worry is that we're eventually going to end up with fewer small companies, and that disproportionately stocked with outfits trying to go it alone. The chances for mutually beneficial partnerships are, if he's right, going down rather quickly. . .
+ TrackBacks (0) | Category: Business and Markets
February 23, 2011
I have tried several times to get my hands around what NIH head Francis Collins is talking about here (note: open-access article), but I now admit defeat. Allow me to quote a bit, and we'll see if anyone else out there has more luck:
We have seen a deluge of new discoveries in the last few years on the molecular basis of disease. . .(But despite) increasing investments by the private sector, there has been a downturn in the number of approved new molecular entities over the last few years. Also, drug development research remains very expensive and the failure rate is extremely high.
Perhaps in part responding to these factors, and to the downturn in the economy, pharmaceutical companies have cut back their investments in research and development. We can't count on the biotech community to step in and fill that void either, because they are hurting from an absence of long-term venture capital support. So, we have this paradox: we have a great opportunity to develop truly new therapeutic approaches, but are undergoing a real constriction of the pipeline. One solution is to come up with a non-traditional way of fostering drug development — through increased NIH involvement.
Hmm. I may have missed the deluge that he's talking about, but we'll set that concern aside. What might this "non-traditional way" look like? Collins again:
I like to think of this in a broad sense of “what kind of paradigm can we initiate and expand between academic researchers and the private sector to move the therapeutic agenda forward?” . . .By having the NIH more engaged in the pipeline, we can also ask whether we can improve the success rates of drug development. . .We need to re-engineer the process, with a lot more focus on the front end.
Right! Another thick block of wobbling gelatin. Let's see, we're going to get the NIH engaged, and, um, give them the tools, and re-engineer things, and oh yeah, focus. Definitely going to focus. Any more details to add?
There are a lot of moving parts to this set of resources that ultimately need to be synthesized into a smooth process. One of my goals over the next year is to try to identify ways to put these together into a more seamless enterprise.
Good to hear. Please,
those of you with access to (see above) Nature Reviews Drug Discovery, where this interview appeared, take a look and see if you can condense anything more out of it than I did. I mean, King Lear had a more concrete plan of action than this one: "I will do such things - what they are, yet I know not, but they shall be the terrors of the earth."
Update: an NRDD editor has let me know that the interview is open access. He also points out that the piece was done before the official announcement of the NCATS idea. My take is while that might account for a bit of the fuzziness, everything I've seen since then has been similarly soft-focus. . .
+ TrackBacks (0) | Category: Academia (vs. Industry) | Drug Development
A reader from the UK passes along this link. If you're wondering what's going to happen to the former Merck site at Terlings Park, well, here would appear to be your answer. The company is now looking to turn the property into a residential development, having apparently (after several years) given up on the idea of ever shifting it as a research facility. Word has been (see the comments here) that the facilities were deterioring at this point, anyway, making such a sale even less likely.
Having worked at a research site that was later paved over and turned into a Home Depot, among other things, I've seen some definitively repurposed facilities before. But considering the state of pharma research in the UK as a whole, this is another bad sign. Terlings Park seems to have had a much better location than Sandwich for doing R&D, so good luck indeed to these efforts. . .
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February 22, 2011
During the most recent Avastin controversy (with its conditional approval for metastatic breast cancer being pulled by the FDA), the role of follow-up studies in oncology became a big point of discussion.
Now there are reports that some companies aren't exactly following up in the way that they're supposed to. This isn't good. Conditional approvals are granted under the banner of "better to help people now than wait for more data", but eventually the numbers have to show up. After all, not all of these treatments are going to confirm when they're looked at more closely.
Not all of this can be put down to foot-dragging on the part of the companies. In some cases, it's proven hard to round up enough patients for further trials, and in others, the trial protocols themselves have become outdated. But there needs to be some way to review these things more regularly (as seems to be the case in the EU) to keep the process from getting tangled up.
You'll note from the article that opinions are all over the place on how lenient the FDA's approval process really is. You have people who say that the agency is dragging its feet on life-saving treatments, and people (looking at the same data set) who say that they're letting too much stuff through on the flimsiest grounds. We're not going to resolve that argument any time soon. But can we at least agree that we're going to require evidence at some point?
+ TrackBacks (0) | Category: Cancer | Clinical Trials | Regulatory Affairs
GIven everything that's happening across North Africa and the Middle East, I thought a quick geopolitical note might be in order. This is very far from being a world politics blog, but there is a connection to science.
Specifically, it's been notable for some time how under-performing these regions of the world are, scientifically. I last wrote about this topic here, with a link to this map. That's ten-year-old data, but the main changes would be shifts among the bigger players. From roughly the western border of India over to the Atlantic ocean, things haven't changed much - the only country in that swath that's made a serious R&D mark is Israel.
In some cases, that's perfectly understandable. No one expects a country at Afghanistan's level of development to have much of a research culture; they've got plenty of other priorities. But you hit some pretty gaudy GDP/per capita numbers when you cross the oil-rich regions, and that money has not been plowed into science and technology. That's in spite of the funding that Saudi Arabia, for one, has thrown into various King-This and Prince-That institutions. Maybe they're going for more applied training - I absolutely cannot recall seeing any notable research result out of the Saudi system. Examples welcomed in the comments, if there are any. And the other oil-rich states are even further out in the wilderness, scientifically. The UAE? Kuwait? You'd have to do some real digging to find much of anything, as far as I can tell. Science, research, and invention have just not been priorities for these places, and changing that isn't easy.
Then you hit countries like Egypt, which are in the broad and sad category of "countries that really should be doing better than they are". I'd put Iran on that list, too. Scientifically, nations in this category have some infrastructure, but it's usually not enough to produce anything noteworthy. Their expatriate scientists and engineers, though, have flourished. There's clearly a lot of talent going to waste inside these places. Algeria and Morocco, too? They don't look so bad, though, when opposed to the next category, the Syrias and Libyas of the world. There's some GDP in these places (although nowhere near as much as there could be), but scientifically, they're absolutely off the map.
So now we get to asking why this should be so. Some of it can be put down to development, as mentioned above, but even the countries in this region that are better developed still aren't making much of a mark. I realize that I may be coming across as culturally insensitive here, because I'm assuming that R&D is the sort of thing that any society with enough money and talent would choose to do. But I'm willing to defend that assumption. I think that these activities really are a key part of a modern economy, and provide a productive outlet for a lot of brainpower. Instead, we have countries that are too poor to even think about these things (Afghanistan), too occupied in keeping the boot pressed down (Syria), several that have decided to sit back and enjoy their money (the oil sheikdoms), and a few that would like to do this sort of thing but aren't getting so much out of their efforts, like Iran.
And that brings us to the volatile topic of religion. Most of the region we're talking about is Islamic, of course. And while it led the world for a good while in mathematics, astronomy, and other sciences, it's also been clear for a long time that it later adopted a different attitude towards homegrown advancements in science and engineering. And this could well have something to do with the religious character of society. The pursuit of secular knowledge can, in some religious environments, seem like at best a distraction from more important matters, and at worst an active source of evil and discord. The present-day countries have all sorts of varying amounts and styles of religious observance, but this is always going to be a factor to consider.
And now we have revolutions ongoing in a lot of these places, and you have to assume that there are more to come - if not right now, then eventually. My own interest in Iran leads me to think, for example, that the lid is going to come off there at some point - and the longer the wait is, the worse the boilover will be. The question that everyone has, though, is what will replace the former regimes, once the lids have blown off? I would like, naturally, to see an Egyptian Republic (for example) that has a chance to get its act together. But that's not going to be easy, to put it very mildly. There are a lot of problems to solve, and a shortage of people who've had to opportunity to try solving them under the former regime of the Big Boss Leader. I fear that the most likely result is the advent of a new boss - who may be wearing a uniform, or robes, or even a nice suit, but who has the same ideas in mind as the last guy. I very much hope I'm wrong about that. Doors are opening; let's hope that many of them don't just slam shut again.
+ TrackBacks (0) | Category: Current Events
February 21, 2011