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
May 29, 2009
I've been evaluating an interesting and useful piece of equipment the last few days, and getting a lot of things done with it. At about 8:20 this morning, though, I marched into the lab and proceeded to clog, mis-plumb, and generally absurdify the thing, and I've spent the rest of the day trying to get back to the way things were at 8:15. You know, before I laid my magic hands on the apparatus and gave it the healing touch. Honestly, I couldn't have done a more complete job if I'd been wearing a rainbow wig and honking a horn.
At the moment, all seems to be working, but I've labored under that illusion several times today. If this doesn't do the trick, I'm going to bring in a troupe of Pomeranians and train them to jump over the thing. Sheesh.
+ TrackBacks (0) | Category: Life in the Drug Labs
Kyle Finchsigmate of The Chem Blog is starting a wiki site for chemistry lab techniques - have a look here.
Here's an excellent overview of the vaccine/autism stuggles, from PLoS Biology. The take-home message: a lot of people in the general public care about a compelling narrative, and many of them don't give a dirty sock for statistical proofs.
Are solar cells really going to end up looking like this?
+ TrackBacks (0) | Category:
Here's something that I'll bet every bench chemist has experienced: thinking that you've quenched some nasty reagent (it has to be gone by now!) only to find that it's very much still with you. These guests that won't leave can be smelly, corrosive, or downright dangerous when they finally yawn, stretch, and decide that it's time to move off the couch.
Alkylaluminum species, in my experience, take their time for longer than you'd think possible, and then depart in a tearing hurry. I used to use several diethylaluminum-X things (cyanide, alkynes, and so on), and was taken by surprise early on by their lackadaisical response to methanol or water at the end of the reaction. "Surely there's some excess aluminum junk in there", I remember thinking the first time this happened, "but there's nothing happening. Maybe I should just squirt in some more." That last phrase has been the prelude to many exciting chemistry moments, and so it was here. Not long after I acted on that impulse, the reagent caught on the fact that it had lots of methanol surrounding it ("Hey, I react with this stuff, don't I?"), and another geyser was born.
Perhaps the king of the "I thought it was hydrolyzed" bunch is phosphorus oxychloride. That stuff takes forever to get around to reacting with water, although on the face of it, you'd imagine it fizzing and sputtering as soon as it got within range. But no, many chemists who've used this reagent have returned to their fume hoods to find the contents of their sep funnels or waste jars gradually coming back from the dead. Milkshake can tell you all about it at Org Prep Daily, and so can many others: never take this one for granted.
+ TrackBacks (0) | Category: Life in the Drug Labs
May 28, 2009
As a follow-up to the deuterated-drugs idea, I note (courtesy of a co-worker) that Concert Pharmaceuticals has press-released their first issued patents on deuterated analogs of existing drugs.
So apparently the novelty and utility requirements have passed the first major sniff tests. I don't know if the case to be made for these (rimonabant and mosapride) is different than the others that Concert has on their IP assembly line, but I doubt it. If these issued, you'd figure that the others probably will, too. I can't imagine that the rimonabant patent's going to be worth all that much, though, since that drug has failed for reasons that I can't see being addressed by a deuterium analog.
As mentioned here before, though, the IP space here seems to be rather crowded, at least when you look at the number of applications. It's presumably quite a traffic jam at the patent offices - and it'll presumably be some time before that gets sorted out. And that's just at this stage of the game: if any of the companies in this space start to hit it big, it wouldn't surprise me to see lawsuits, requests for re-examination and the like.
+ TrackBacks (0) | Category: Drug Development | Patents and IP
The folks over at the science-and-culture blog 3 Quarks are running a blog award for science writing, to be judged by Harvard's Steven Pinker. I figure that the readership here sees a lot of science blog posts from a lot of sources, so feel free to nominate anything that you've found especially memorable. They're looking for pieces written during the last 12 months, and it looks like their nomination process ends rather soon - wouldn't surprise me if they're working off of Pinker's schedule, which must be rather tightly articulated. . .
+ TrackBacks (0) | Category: Blog Housekeeping
May 27, 2009
I came across this tonight, and had to put up a link. The Guardian newspaper has started a "You Ask, They Answer" feature in its environmental section, and this week a British chain of homeopathic remedies (Neal's Yard) stepped up to the podium. Unfortunately, they weren't prepared for an onslaught of Ben Goldacre fans, who picked up on the opportunity quickly.
About twenty-four hours later, the newspaper had to close down the comments section. The Neal's Yard people had backed out, utterly, refusing to grapple with questions like: "Have you ever been offered a natural remedy that was so obviously without any merit that you refused to bottle it and sell it to your gullible customers, or does pretty much anything go?". But the whole thread is up for your reading pleasure here, even if the ball never does get hit back across the net.
+ TrackBacks (0) | Category: Snake Oil
There are a lot of ways to think about the chemical reagents that we have stirring around in our flasks. But one of the basic ones, and one of the most useful, divides them into classes according to whether they’re in solution or not.
When things are in solution, they may act funny, but at least everything’s starting out on the same footing. If all the components are dissolved (and if everything’s stirring the way it should), then they all have the chance to find each other and do their respective things. But if some reagent is still a solid in there (powder, chips, what have you), that takes you into the nonintuitive world of surface chemistry.
This actually happens quite a bit. Plenty of standard organic reactions involve insoluble things where the chemistry takes place on the surface. There’s formation of a Grignard reagent from magnesium turnings, deprotonation with powdered sodium hydride, hydrogenation over palladium-on-charcoal – these are all classics. And I'm not even mentioning the surface-driven industrial scale catalyst systems today, which is unfair of me, since the economies of the entire industrialized world depend on them. But in all cases, the real details at the molecular level of these reactions are not easy to work out.
People are still arguing, for example, over just how catalytic hydrogenation works on the metal surface, although the general details of the mechanism are known. That one’s complicated by not just being the plain metal, but a weirdo solution of hydrogen in the metal lattice. There’s no dispute, though, that the reaction is taking place on the surface of the metal, and that the higher the surface area the better off you are.
That’s one big variable right there: surface area. Finely divided substances are very different players in these systems, and many chemists find (early in their lab careers) that they’ve unwittingly bought front-row seats for a demonstration of just how different they can be. Finely divided powders have a lot of surface area in them, and if that’s a rate-limiting factor, you can find yourself with something that’s easily a hundred times more reactive just by picking up a different bottle of what appears (at first glance) to be the same substance. I once saw someone substitute lithium powder for lithium sand in a prep without thinking about this issue, and not so much later, I got to see the same guy clean the inside of his fume hood out with a scrub brush.
But there’s more than just surface area affecting some of these reactions. Grignard formation, for example, seems to take place (at least initially) in fresh breaks or cracks on the magnesium surface. That exposes metal that hasn’t had a chance to become coated with anything (like a layer of magnesium hydroxide), and (zooming in) it also may reveal individual reactive magnesium atoms, left out on the edge and insufficiently surrounded by their teammates. Once these react and fly off into solution, the ones around them become exposed, and so on, and the oxidized layers become undermined and flake off. The standard Grignard-initiation tricks are all designed to speed this process along. A drop of iodine will react quickly with any magnesium points or edges, exposing still more fresh rough surface, as will reaching down under the solution and breaking the turnings with a spatula (or, alternately, grinding them with a heavy stir bar).
These days, what’s really complicating things is the ability to generate (and characterize) nano-sized particles. At some point, these things can stop behaving like tiny bits of the bulk substance (which can be enough of a difference in itself, as mentioned above), and start acting like completely new beasts. And the really nano-sized stuff has a better chance of actually being in solution – but that brings on various headache-inducing thoughts about what “being in solution” means on this scale. If you have clumps of (say) palladium a few dozen atoms wide, which manage to be solvated enough to float around, is that a heterogeneous reaction or a homogeneous one? At that size, is that a "surface", or not (and is the reaction really taking place on it?) What if the nanoparticles are immobilized on a solid support - do they stay and react there, or is the reaction driven by the few that escape? (That effect has been noted in the Heck reaction, among others).
We need to understand these things better than we do - there are surely a lot of very useful things that could be done if we had better control over catalysis and surface chemistry. It's going to keep a lot of people occupied for a very long time.
+ TrackBacks (0) | Category: Inorganic Chemistry | Life in the Drug Labs
May 26, 2009
With all the recent discussions around here about safety, I think that there's one thing that all of us working chemists can agree on: MSDSs are often the next thing to useless.
They're not supposed to be, at least in theory. The idea is that a materials safety data sheet collects all the relevant toxicity, handling, and disposal information for a given chemical so it can be referenced by users, emergency responders, and so on. But somewhere along the line, things have gone well off track. I refer interested readers to the famous example of the MSDS for sand. Sea sand.
The first thing we find is that it is a cancer hazard. Then we note that "Prolonged exposure to respirable crystalline quartz may cause delayed lung injury/fibrosis (silicosis)". Which is true, but (of course), we have no idea of what "prolonged" means in this context, and we may not realize that sand, in its commonly encountered forms, is not easy to inhale. One should " Wear appropriate protective clothing to prevent skin exposure", but if we were to contact this substance through our own carelessness? We should "Immediately flush skin with plenty of water for at least 15 minutes while removing contaminated clothing and shoes.". We should take care at all times: "Do not let this chemical enter the environment." But that should go without saying, since we've been enjoined to "Use only in a chemical fume hood".
Now, what this thing is trying to tell us is that extensive exposure to finely ground silica dust is bad for the lungs. This is absolutely true, even if lawyers have been trying to make dubious fortunes off of it. A person should take care not to inhale sand dust, and should take particular care if exposure to such dust is a regular feature of one's job.
But there needs to be a way to get this information across without making a bag of sand sound like a weapon of mass destruction. I don't know how many times I've heard of chemical spills being treated like high-level radioactive waste because emergency responders (or local news reporters) read the MSDS and hit the panic button. (A famous example was the closure of the Bay Bridge in California once by a few bags of iron oxide (keep in mind that this happened before the current environment of worries about terrorist incidents). The responders knew what the chemical was: they read the MSDS, which (naturally) told them to wear full protective equipment, avoid exposure, wash copiously and seek medical attention, etc. For a few bags of rust.
There has to be a better way - you'd think, at any rate. But the MSDS is lawyer language, when you get right down to it, and there's the problem. Trying to insulate everyone from liability is not something that can be done simultaneously with trying to inform people in case of an emergency. Very few chemists, in my experience, spend much time with these forms at all, preferring to get their information from almost any other source. There has to be a better way.
+ TrackBacks (0) | Category: Safety Warnings
May 22, 2009
There's an article up at Slate on the UCLA lab accident death. It finishes up by saying:
If Sheri Sangji's death is to mean anything, it must be that no lab chief—and certainly no federal agency—claiming to further human welfare ever again tolerates the risk of harm to lab workers. That means that university administrators from the provost on down must make safety a serious concern and a requirement for career advancement and hiring, and tenure and promotion committees must hold faculty members responsible for seeing that everyone in their labs has the training, skills, and equipment needed to work safely. Funding agencies must make a good safety record and evidence of safety awareness real conditions for getting and keeping grants. Never again should academic research needlessly claim the life of a researcher.
Brave words, but I feel pretty sure that academic research will, in fact, needlessly claim more lives every so often. You've got a lot of people at widely varying levels of experience (and widely varying levels of sense), working all hours of the day and night, often under pressure to produce results. Accidents will happen.
Now, I think that academic labs could be a lot safer than they are, and that they should be. It's worth taking steps to try to realize that. But if you set the standard as "never again should anything bad happen", you will fail. I've worked in an industrial environment that implemented the fiercest, most draconian safety policy I've ever experienced. Multiple, overlapping layers of safety meetings, with an extensive standardized list of topics that had to be covered every time. Incident reports, discussed in detail, every time. Attendance mandatory, and logged on a signup sheet, and tied to bonus payouts. Multiple, overlapping layers of documentation, countersignatures, standard operating procedures, etc. And we still had explosions, due to varying amounts of cluelessness, stupidity, and just plain bad luck.
They will happen. They should be minimized, prepared for, and guarded against. But acting as if there's a policy which will prevent them is foolish, and risks making the perfect the enemy of the good.
+ TrackBacks (0) | Category: Safety Warnings
I’ve been getting a lot of objections to my opinion on Arena’s obesity candidate lorcaserin. Specifically, the first level of the dispute seems to be whether or not the recent clinical trial results met the FDA’s criteria for efficacy or not. So, let’s look at the details. Here’s how Arena press-released the results of the trial:
The hierarchically ordered endpoints were the proportion of patients achieving 5% or greater weight loss after 12 months, the difference in mean weight loss compared to placebo after 12 months, and the proportion of patients achieving 10% or greater weight loss after 12 months. Compared to placebo, using an intent-to-treat last observation carried forward (ITT-LOCF) analysis, treatment with lorcaserin was associated with highly statistically significant (p<0.0001) categorical and average weight loss from baseline after 12 months:
-- 47.5% of lorcaserin patients lost greater than or equal to 5% of their
body weight from baseline compared to 20.3% in the placebo group. This
result satisfies the efficacy benchmark in the most recent FDA draft
-- Average weight loss of 5.8% of body weight, or 12.7 pounds, was achieved
in the lorcaserin group, compared to 2.2% of body weight, or 4.7 pounds,
in the placebo group. Statistical separation from placebo was observed
by Week 2, the first post-baseline measurement.
-- 22.6% of lorcaserin patients lost greater than or equal to 10% of their
body weight from baseline, compared to 7.7% in the placebo group.
Lorcaserin patients who completed 52 weeks of treatment according to the protocol lost an average of 8.2% of body weight, or 17.9 pounds, compared to 3.4%, or 7.3 pounds, in the placebo group (p<0.0001).
Now let’s go to the FDA’s 2007 draft guidance for weight management therapies. Regarding the primary efficacy endpoint in a Phase III trial of such a new agent, the agency says:
The efficacy of a weight-management product should be assessed by analyses of both mean and categorical changes in body weight.
• Mean: The difference in mean percent loss of baseline body weight in the active-product versus placebo-treated group.
• Categorical: The proportion of subjects who lose at least 5 percent of baseline body weight in the active-product versus placebo-treated group.
And here’s the part that people keep wanting me to highlight:
In general, a product can be considered effective for weight management if after 1 year of treatment either of the following occurs:
• The difference in mean weight loss between the active-product and placebo-treated groups is at least 5 percent and the difference is statistically significant
• The proportion of subjects who lose greater than or equal to 5 percent of baseline body weight in the active-product group is at least 35 percent, is approximately double the proportion in the placebo-treated group, and the difference between groups is statistically significant
So lorcaserin showed 47.5% of patients losing at least 5% of their body weight, versus 20.3 for placebo. And yes, that does appear to meet what the FDA's looking for in terms of categorical efficacy, which is why the company highlighted that result in their press release. And yes (here it comes, Arena fans), the FDA does say ("in general") that an agent can be considered efficacious if a compound meets either the mean or the categorical standards.
But (and you knew that this paragraph was going to start with that word). . .but the FDA does not say "efficacious enough for approval". In general, to use their phrase, the agency does approve things that are efficacious and show safety. But they do that on their own terms, and they are (for better or worse) completely within their rights to turn around and ask for more details - for example, how well a compound like this performs as a combination therapy (which is how many physicians would likely wish to prescribe it).
Then we have the issue of "efficacious to interest a partner". Arena is surely looking to do that, since (as noted the other day) it does not appear that they have the resources to push the product through on their own. Given the potential size of the market for an effective obesity drug, we can be sure that a number of potential partners have been approached, and have taken a meaningful look at the data. So far, no one has taken them up on it. And whatever one thinks about the press coverage that lorcaserin has received (or the reaction from analysts who follow the stock, which has also not been good), it's for sure that these opinions don't count for much when it comes time for two companies to do a deal. Put more directly, if Arena sits down with Merck or Pfizer, what I say on this blog means nothing at all once the door closes. Heck, what they say at JP Morgan means nothing at all, either, because we're all outsiders. Potential partners are getting a chance to look over Arena's prospects, and if the numbers look convincing, someone will bite. If no one bites, we can assume that no one was convinced.
Or perhaps they're waiting for Arena to get even more cash-strapped and desperate. That isn't a very nice way to do business, but isn't unheard of, either, and I can tell you that these aren't very nice times in the drug business. At any rate, for those Arena fans who have been waiting for me to say something about all this, well, here you are. This is as good as you'll get from me - but really, you're wasting your time. You need to be hoping to persuade the people who can initiate nine-figure wire transfers.
+ TrackBacks (0) | Category: Business and Markets | Clinical Trials | Diabetes and Obesity | Regulatory Affairs
May 21, 2009
As predicted here (and everywhere else that's looked at this deal), Johnson & Johnson is not sitting back and letting Schering-Plough "take over" Merck - not when that would mean billions of dollars of lost revenue, they're not. Today the company has filed a notice of intention to arbitrate.
"As the public statements make clear, Merck is acquiring Schering-Plough", the company says, and that triggers an arbitration hearing under their agreement with them for sales of Remicade (and the newer agent, Simponi). Merck continues to insist that their strategy is bulletproof, and I guess we'll find out who's right. It could take months, unless Merck is willing to walk away from that revenue stream (and they're probably not).
Interestingly, that Wall Street Journal link quotes a "person familiar with the matter" as saying that Schering-Plough turned to J&J after Merck made its initial overtures. J&J passed on the chance to acquire the whole company, though, leaving Schering-Plough no choice but to act as if an offer from Merck was the answer to one of their most longstanding prayers.
+ TrackBacks (0) | Category: Business and Markets
The NIH has announced that they're going to start up a preclinical drug discovery effort to address rare diseases. I find this interesting for several reasons. For one thing, it's worth a try for conditions where no company has seen a way to fund research, and there are quite a few of them. Treating rare diseases can be quite profitable in the industrialized world (ask Genzyme, among other companies), but if the conditions are localized in poorer areas no one's likely to take a crack at them. So my first reaction is "Good, and the best of luck to you". The NIH has been getting closer to doing preclinical drug discovery in recent years, so this is a logical next step.
The second thought I have is that this will be an interesting experience for the researchers involved. There's nothing quite like drug discovery, and if they do it right, everyone will come away with an appreciation of just how complicated a process it is. The only way to make it simple and reasonable is to cut corners. I notice that the press release says:
Typically, drug development begins when academic researchers studying the underlying cause of a disease discover a new molecular target or a chemical that may have a therapeutic effect. Too often, the process gets stuck at the point of discovery because few academic researchers can conduct all the types of studies needed to develop a new drug. If a pharmaceutical company with the resources to further the research does get involved, substantial preclinical work begins with efforts to optimize the chemistry of the potential drug. This involves an iterative series of chemical modifications and tests in progressively more complex systems — from cell cultures to animal tests — to refine the potential medicine for use in people. Only if these stages are successful can a potential treatment move to clinical trials in patients.
Unfortunately, the success rate in this preclinical process is low, with 80 to 90 percent of projects failing in the preclinical phase and never making it to clinical trials. And the costs are high: it takes two to four years of work and $10 million, on average, to move a potential medicine though this preclinical process. Drug developers colloquially call this the "Valley of Death."
. . .If a compound does survive this preclinical stage, TRND will work to find a company willing to test the therapy in patients. There are several stages to the clinical trials process that can take several years before the safety and efficacy of a new drug is determined. FDA will only approve a drug for general use after it passes these trials. The clinical trials process is also expensive, but the failure rate is lower at this stage.
Well, a tiny bit lower. I think that the general clinic-to-market failure rate is still somewhere around 90%, but it varies by therapeutic area. And that 80 to 90% failure rate that they quote for preclinical is a bit lowballed, I'd say, because you'd want to subtract that things that get recommended to the clinic (but really should never have been). But overall, this is a reasonably clear-eyed look at the difficulties involved. If they can get some things to the point that a company or foundation is willing to take on the (now somewhat reduced) risks, that'll be great.
The last thought I have (for now) is that I feel like writing a bunch of people and asking them why the NIH is doing this, since they've been telling me for years that this is what the NIH already does, anyway. The "Big Pharma does nothing but rip off NIH" meme hasn't surfaced for a little while, but it's always out there.
+ TrackBacks (0) | Category: Drug Development | Drug Industry History
May 20, 2009
Isis Pharmaceuticals has had a long, tough history developing antisense-based therapeutics. I've lost count of the number of promising candidates they've had (and promising deals they've signed). But the latest one seems to be progressing: mipomersen, designed to block production of the ApoB lipoprotein.
That should lower LDL, and help with several other cardiovascular risk factors at the same time. Isis and their partner Genzyme have just announced that a trial of the drug in patients with homozygous familial hypercholesterolemia showed significant LDL reductions (25 per cent). These people are already maxed out on statin therapy, and still have huge LDL levels, so this does seem to represent an advance.
And Genzyme knows all about getting drugs through for very small patient populations (and charging accordingly) - they're definitely a good partner for this sort of drug. But both they and Isis would like for mipomersen to be used more widely. The next target are patients with the heterozygous form of hypercholesterolemia, and then they'll try to move on to various other statin-intolerant patients with risky LDL levels.
Isis could use a success. They were the first to get an antisense therapy approved (Fomiversen), but it really has never brought in much revenue. Mipomersen, as an injectable, is never going to go out and take over the world like the stating drugs, but it could still be a winner in its own (larger) niche.
+ TrackBacks (0) | Category: Cardiovascular Disease
Well, we can all study biochemical mechanisms in tumor cells every day of the week. And we can crank out tens of thousands of potential clinical candidates to hit them, run the assays, and then turn around and do it again. We can send things through all sorts of tox testing, take them to the clinic, try them against all sorts of terrible cancers, and amass enough data to make it through the FDA. Then we can let the oncologists continue to try variations, combinations, and regimens in the continuing search for something that works.
And every so often, we actually succeed. Childhood Hodgkin's lymphoma has one of the highest cure rates of all cancers. We can actually do something about that one (as opposed to, say, pancreatic cancer, which we can't do much about at all). Children who would otherwise die - and die slowly - now get a chance to live, to grow up.
But we can't, apparently, convince everyone of this. Many readers will have heard over the last few days of the case of Daniel Hauser of Minnesota, a 13-year-old diagnosed with Hodgkin's a few months ago. Instead of going in for rounds of chemotherapy, the boy (who has said that he doesn't believe that he's sick) and his family have opted for "Native American alternative therapy", and have fled from a court order. The boy's mother, who apparently does believe that he's sick, has said that she's treating him with "herbal supplements, vitamins, and ionized water".
These will, almost certainly, allow the lymphoma to kill him. Chemotherapy and radiation, on the other hand, will very likely allow him to live. If someone is bleeding to death from an arterial wound, anyone trying to heal them by invoking spiritual powers or alternative therapies would (and should) be shoved aside by any onlooker with a tourniquet. Daniel Hauser is bleeding to death as well: just more slowly, and in front of many more onlookers.
+ TrackBacks (0) | Category: Cancer | Current Events | Snake Oil
May 19, 2009
I've heard that Pfizer is doing something unusual with its proprietary compound collection: they're offering to let other people screen it.
Now, that's quite a step. Most companies guard their compounds pretty closely, considering them to be key assets. But I'm told that Pfizer has been meeting with several other (mostly smaller) companies, offering their (entire?) compound library as a screening resource. As I understand it, you need to come to them with a reasonably formatted HTS assay, and there's a fee in the high hundreds of thousands to run the screen.
That doesn't seem like much of a moneymaker, to be honest. The whole thing appears to me to be a way for Pfizer to strike deals with a number of other companies, since the compounds that come out of the screen will (likely as not) be covered by Pfizer's own patents. I haven't heard of how the IP issues are to be worked out in these deals, but that's the first thing that occurs to me. Anyone have more details?
+ TrackBacks (0) | Category: Drug Assays
Some emails and discussions with colleagues have raised an important point to be learned from the recent TMS-diazomethane tragedies. Many people are probably taking some of these reagents less seriously than they should.
As organic chemists know, the trimethylsilyl group is a strange beast, and can often substitute for a proton in small reagents. That often gives such compounds new and useful properties along the way – for example, hydrazoic acid (hydrogen azide) is an extremely dangerous substance because of its unpredictable explosive qualities. It should never be generated except in very dilute solution (that is, unless you’re prepared at every moment for a serious detonation, and not many people are). But the corresponding trimethylsilyl azide is an article of commerce – you can pick up the phone and order a bottle. No one in the history of the fine chemical industry, as far as I know, has been crazed enough to offer hydrazoic acid for sale. How could it be delivered - by trained hummingbirds?
But the two reagents can do many of the same transformations, since the TMS group is often just about as easy to lose at the end of the reaction as a proton is. The exact same situation obtains with trimethylsilyldiazomethane: no one’s ever tried to sell or ship the parent compound, but solutions of the TMS derivative are ready to be ordered at your convenience.
But that's only because they're less explosive. All the TMS reagents are just as poisonous as their proton counterparts. And that's where I think some chemists aren't making the connection. We treat diazomethane gingerly because we don't want it to explode, but we should also be handling it like the volatile toxin it is. The same goes for hydrazoic acid. If you have to deal with the stuff, you're mostly thinking every second about how it could go off on you. But you should also be thinking about how it's a potent, poisonous vasodilator. It doesn't have to blow up: a good deep gust of it will relax your arterial walls permanently by killing you, and TMS azide will do the exact same thing.
These compounds are intrinsically toxic, and they're also toxic because they'll hydrolyze back to the parent compounds in a warm, wet environment - like the inside of your lungs. I think that people treat another one of the series, trimethylsilyl cyanide, with more respect. That's because HCN gets a lot of respect for its inhalation toxicity (and with damned good reason), and opening an ampoule of TMS-CN is (or should be) a reminder that it's just as nasty. And since it doesn't explode, that's the main thing that you think about.
So spread the word: these reagents, though extremely useful, are not to be handled lightly. They're volatile and they're just as poisonous as their parents. The ease of ordering and handling them, in fact, may make them even more of a potential hazard. Treat 'em with respect.
Note: for those looking for a thorough reference work on the subject, this seems like an up-to-date choice.
+ TrackBacks (0) | Category: Safety Warnings
May 18, 2009
I wrote in March about lorcaserin, Arena Pharmaceutical's serotonin ligand for obesity. Their clinical data had come out, and things (at least to me) didn't look good. They didn't quite make the minimum threshold for efficacy, and the FDA isn't in a mood to take a flyer on on things that don't quite work.
Well, according to Ruthanne Roussel at Obesity Investor, the company looks like it could be running out of cash. So far, at any rate, no partner is appearing. Obesity has always been a tough area to work in, and this economic environment isn't making it any easier for the smaller companies to survive. Arena's done some interesting work over the years, and I'd hate to see them collapse. But it sure looks like a possible outcome at this point. . .
Update: note that not everyone agrees with my take here. On the other hand, others are even more harsh. . .we'll see what comes out in the end. And as always, since I've said nothing about having a position in Arena's stock, that means that I have none.
+ TrackBacks (0) | Category: Business and Markets | Diabetes and Obesity
I've got a piece coming up today at The Atlantic Monthly's business site on the state of the biotech industry out in the Bay Area. Since the Genentech takeover fight broke out, a persistent theme in the comments here (and in e-mail that I've received) has been how well the industry is holding up out there. Opinions range from "basically fine" (a minority, to be sure), to "incipient disaster" (also a minority, but a loud one). The consensus view is that there may well be room to worry.
So let's start the discussion explicitly (here as well as over at The Atlantic. How healthy is the original biotech cluster? And how many of its current problems are due to secular reasons (the general economy, the general state of the drug industry), and how many are home-grown? I'd be very interested to hear from people out there, although I guess it'll be mostly us Eastern types for the next few hours here. . .
+ TrackBacks (0) | Category: Business and Markets | Drug Industry History
May 15, 2009
Sean Cutler, a biologist at UC-Riverside, is the corresponding author of a paper in a recent issue of Science. That’s always a good thing, of course, and people are willing to go to a lot of trouble to have something like that on their list of publications. But Cutler’s worried that too many scientists, especially academic ones are willing to do a bit too much for that kind of reward. He tells John Tierney at the New York Times that he approached this project differently:
” Instead of competing with my competitors, I invited them to contribute data to my paper so that no one got scooped. I figured out who might have data relating to my work (and who could get scooped) using public resources and then sent them an email. Now that I have done this, I am thinking: Why the hell isn’t everyone doing this? Why do we waste taxpayer money on ego battles between rival scientists? Usually in science you get first place or you get nothing, but that is a really inefficient model when you think about it, especially in terms of the consequences for people’s careers and training, which the public pays for. . .
. . .Obviously there is a balance between self and community interests, but as it stands there are very few metrics of scientific “niceness” and few ways to reward community-minded scientists (some grants consider “broader impact,” but that is not the same thing). What is even worse, is there are even fewer mechanisms for punishing selfish (sometimes horribly so) scientists. If it were their own money or private money they were spending on their research — fine, they can be as selfish as they want and hold others up. But 99 times out of 100, it’s not their money- it’s the public’s money and it drives me absolutely crazy that there is no meaningful oversight of behavior.
That brought in a flood of comments, and Teirney followed up a couple of days later. Addressing the general issue of scientific competition, which is where many of the comments took issue, Cutler added:
” I am in full favor of competition. My message is: Compete ethically. Sadly, there is a lot of unethical competition that goes on in science. This year alone, I have heard of cases that are the scientific equivalent of insider trading, where reviewers of important papers exploit their access to privileged data to gain unfair advantages in the “race” to the next big discovery. I have heard of researchers being ignored when they request published materials from scientists.
Not sending materials described in papers or exploiting privileged information is a clear violation of journal policies, but unethical behavior of this kind is common in science and is usually perpetrated with a proud smile in the name of “competition. . .”
Well, he’s right that this sort of thing goes on all the time in academia. I don’t know how many tales I’ve heard of pilfered grant application ideas, shady conduct when refereeing papers, and so on. To tell you the truth, though, you don’t see so much of that in industry, at least not in the discovery labs. It’s not that we’re just better human beings over here, mind you – it’s that the system doesn’t allow people to profit so much by that particular sort of conduct. Patent law is one big reason for that, as are the sheer number of lawyers that corporations can bring to bear on someone if they feel that they’ve been wronged. There’s more money involved, in every way, so the consequences of being caught are potentially ruinous.
Update: does this mean I've never worked with sleazeballs? Not at all! Credit-stealing and the like does happen in industrail research labs; they're staffed with humans. But direct theft of someone else's work - that's rare, because being inside an organization is the academic equivalent of being inside the same research group, and it's harder to get away with blatant theft. Academic lab vs. academic lab, though, is more the equivalent of "company vs. company", and (at least in the researchstage of things) we have far fewer opportunities for chicanery in industry at that level.
Anyway, unethical conduct in industrial research, when it happens, tends to occur closer to the sources of the money – over in the marketing department, say, or perhaps regulatory affairs. In academia, grants are the source of money, with high-profile publications closely tied to them. The sharp operators naturally tend to concentrate there, like ants around honey.
Cutler’s proposed solution is to go right to that source:
My call to scientists, journals and granting agencies is this: What I’d like to see implemented are rewards for ethical behavior and consequences for unethical behavior. If you knew you might not get a grant funded because you had a track record of unethical practices, then you’d start behaving. It is not much more complicated than that. The journal Science has a “reviewer agreement” that bars the unsavory behavior I described above. After my discussion of the matter with Bruce Alberts, editor in chief of Science, it is clear to me that Science considers the matter very important, but that the journal currently lacks a written policy on the consequences for ethical violations of the reviewer agreement. Without clearly advertised consequences, why behave?
My take is that two issues are being mixed here, which is the same difficulty that led to Tierney having to address this story twice. The first issue is unethical behavior, and I’m with Cutler on that one. There’s too much of that stuff around, and the reason it doth prosper is that the risk/benefit ratio is out of whack. If there were stiffer (and more sure) consequences for such things, people would act on their underhanded impulses less frequently. And for the kinds of people who do these things, the only factors that really matter to are money and prestige, so hit ‘em there, where they can feel it.
But the second issue is competition versus cooperation, and that’s another story. Prof. Cutler’s points about wasting grant money don’t seem to me to necessarily have anything to do with unethical behavior. It’s true that holding back cell lines and the like is slimy, and does impede progress (and waste public money). But without going much further, you could talk about waste when you have multiple research groups working on the same problem, even when they’re all behaving well.
That’s what went on here, if I understand the situation. Cutler basically went out to several other groups who were pursuing the same thing (abscisic acid signaling) through different approaches, and said “Hey folks, why don’t we get together and form one great big research team, rather than beat each other up?” I certainly don’t think that he was expected these other labs to do something sleazy, nor was he trying to save them from temptation.
And the problem there is (as many of Tierney’s commentors said) that competition is, overall, good for scientific progress, and that it doesn’t have to involve unethical conduct. (More on this in a follow-up post; this one’s long enough already!) That’s why Cutler had to go back and clarify things, by saying “Compete, but compete ethically”. The difficulty with talking about all this at the same time is that the groups he ended up collaborating with were (presumably) doing just that. They’re two separate issues. Both topics are very much worth discussing, but not tangled together.
+ TrackBacks (0) | Category: Academia (vs. Industry) | The Dark Side | Who Discovers and Why
May 14, 2009
I've been contacted by several people over the last few weeks about the TMS diazomethane-linked fatality in Nova Scotia (first written about here). Many more details are emerging about the case, chief among them that the fume hoods in the lab were apparently down for maintenance during this time.
Here's a newspaper article that's just appeared. I'm quoted in it as saying that I would have refused to work under such conditions, and I stand by that. But that's not surprising: in every industrial lab I've ever worked in, when the fume hoods go down, people roll their eyes and walk out the door. I most especially cannot recommend working with something like TMS diazomethane in such a situation.
+ TrackBacks (0) | Category: Chemical News
And while we're on the subject of clinical trials, and the headaches associated with them, this is a neat little article over at Slate on the subject. Darshak Sanghavi from UMass does a good job of explaining the surrogate-endpoints problem in clinical results, relating it to reality TV:
. . .In the federal Multimodal Treatment Study, hundreds of kids with ADHD, whose families were desperate enough to enroll them in a randomized study, entered a well-funded and highly supervised National Institute for Mental Health program complete with specialized therapy, regular evaluation by developmental experts, and careful drug prescription—a setup that's about as realistic as a date on The Bachelor. Within that very unusual, closely monitored environment, as reported in 1999, stimulant medications caused modest improvement after about a year. In response, use of these products surged nationwide, and Ritalin and its peers became household brands. But in March, the researchers described what happened after the lights went out. In their subsequent years in the real world, the drug-treated kids ultimately ended up no better off than the others.
Epidemiologists call this the problem of "surrogate endpoints," and it's no surprise to fans of reality television. Garnering the greatest number of text-messaging votes after a brief performance doesn't always mean you'll be a successful pop star; winning the final rose after an on-air courtship doesn't mean you'll have a happy marriage; and getting higher scores on a simple rating scale of attention-deficit symptoms doesn't mean you'll later succeed in school. In medicine, this problem happens all the time.
He doesn't shy away from some of the big surrogates in the clinical world, the biggest of which are cholesterol levels. That one, as he says, is at least considered a validated marker (with some relation to real-world mortality and morbidity), but there's plenty of room to argue about that, too. Ask Gary Taubes, who has a lot of provocative things to say about the whole low-fat idea. And if that one is still worth arguing over, what about the less validated endpoints?
In the end, I agree with Sanghavi that we really don't have any good alternatives yet. The real endpoints, in most cases, just take too long to measure. No one can finance a twenty-year clinical trial, and no one would put up with one even if it were feasible. We're stuck with what we have, and we just have to make it work the best we can.
+ TrackBacks (0) | Category: Clinical Trials
Late last year, I wrote about a possible new way to fund drug discovery, a private-equity model that seemed to be in the works at Goldman Sachs. The driving force behind the idea seemed to be Jon Symonds, former CFO at AstraZeneca.
Well, as the InVivoBlog noted yesterday, Symonds has suddenly decamped to Novartis. He’s press-released as their new CFO (after the current one retires), which makes you wonder what’s happened to that drug funding plan. Given the current environment for new financing schemes, and for banking in general (not to mention the current environment at Goldman Sachs), has the whole idea just been shelved?
As the In Vivo folks go on to say, financing clinical candidates in this way isn’t necessarily a bad idea – it just might be a bad time to try it out. There are a lot of issues to be worked out, but it’s looking more and more like no one’s going to be working them out any time soon. . .
+ TrackBacks (0) | Category: Business and Markets | Clinical Trials | Drug Development
May 13, 2009
This may be just the Japanese equivalent of HR-speak, but I would like to know what it means:
Takeda Pharmaceutical Co., Asia’s biggest drugmaker, will change its research and development policy by providing compensation to scientists based on the quality of their work.
“We focused too much on the quantity and speed of research and development, which didn’t necessarily bring results,” company President Yasuchika Hasegawa told reporters at a briefing in Tokyo. “I want to change everyone’s mindset.”
The problem is, evaluating the quality of individual scientific performance is notoriously difficult. Or was the problem that Takeda was too focused on the numbers, and has decided to back off on that? (I think I could be behind that initiative). Perhaps some one at Millennium could comment on whether they've heard anything about this?
+ TrackBacks (0) | Category: Who Discovers and Why
Now, this is an example of an idea being followed through to its logical conclusion. Here’s where we start: the good effects of exercise are well known, and seem to be beyond argument. Among these are marked improvements in insulin resistance (the hallmark of type II diabetes) and glucose uptake. In fact, exercise, combined with losing adipose weight, is absolutely the best therapy for mild cases of adult-onset diabetes, and can truly reverse the condition, an effect no other treatment can match.
So, what actually causes these exercise effects? There has to be a signal (or set of signals) down at the molecular level that tells your cells what’s happening, and initiates changes in their metabolism. One good candidate is the formation of reactive oxygen species (ROS) in the mitochondria. Exercise most certainly increases a person’s use of oxygen, and increases the work load on the mitochondria (since that’s where all the biochemical energy is coming from, anyway). Increased mitochondrial formation of ROS has been well documented, and they have a lot of physiological effects.
Of course, ROS are also implicated in many theories of aging and cellular damage, which is why cells have several systems to try to soak these things up. That’s exactly why people take antioxidants, vitamin C and vitamin E especially. So. . .what if you take those while you’re exercising?
A new paper in PNAS askes that exact question. About forty healthy young male volunteers took part in the study, which involved four weeks of identical exercise programs. Half of the volunteers were already in athletic training, and half weren’t. Both groups were then split again, and half of each cohort took 1000 mg/day of vitamin C and 400 IU/day vitamin E, while the other half took no antioxidants at all. So, we have the effects of exercise, plus and minus previous training, and plus and minus antioxidants.
And as it turns out, antioxidant supplements appear to cancel out many of the beneficial effects of exercise. Soaking up those transient bursts of reactive oxygen species keeps them from signaling. Looked at the other way, oxidative stress could be a key to preventing type II diabetes. Glucose uptake and insulin sensitivity aren't affected by exercise if you're taking supplementary amounts of vitamins C and E, and this effect is seen all the way down to molecular markers such as the PPAR coactivator proteins PGC1 alpha and beta. In fact, this paper seems to constitute strong evidence that ROS are the key mediators for the effects of exercise, and that this process is mediated through PGC1 and PPAR-gamma. (Note that PPAR-gamma is the target of the glitazone class of drugs for type II diabetes, although signaling in this area is notoriously complex).
Interestingly, exercise also increases the body's endogenous antioxidant systems - superoxide dismutase and so on. These are some of the gene targets of PPAR-gamma, suggesting that these are downstream effects. Taking antioxidant supplements kept these from going up, too. All these effects were slightly more pronounced in the group that hadn't been exercising before, but were still very strong across the board.
This confirms the suspicions raised by a paper from a group in Valencia last year, which showed that vitamin C supplementation seemed to decrease the development of endurance capacity during an exercise program. I think that there's enough evidence to go ahead and say it: exercise and antioxidants work against each other. The whole take-antioxidants-for-better-health idea, which has been taking some hits in recent years, has just taken another big one.
+ TrackBacks (0) | Category: Aging and Lifespan | Biological News | Cardiovascular Disease | Diabetes and Obesity
May 12, 2009
For those who are interested, I have a review up at Nature Biotechnology of Reasonable Rx: Solving the Drug Price Crisis, a book that proposes an. . .interesting solution for reworking the drug industry.
And as Fate would have it, I also have a review in the latest issue of Nature Chemistry of Drug Truths: Dispelling the Myths About Pharma R & D, from Pfizer's John LaMattina. The only reason these are showing up at the same time is that I took an unconscionably long time to come to grips with Reasonable Rx - it wasn't something that I could just dismiss, but it has (I think) a lot of things wrong with it.
+ TrackBacks (0) | Category: Drug Industry History | Drug Prices | Regulatory Affairs
Time, regrettably, for some politics. In case anyone’s wondering, my take on yesterday’s health care announcement by the Obama administration is perfectly stated here. I could not agree more.
In other words, I see the “historic announcement” as nothing more than political theater. Everyone got together, held hands, and pledged to voluntarily do some not-all-that-painful things to reduce costs, some of which (cost savings through better record keeping?) have already been underway for years. Even so, the chances of all of these being followed through are still low. And even if they were, the amount of money being saved is only a small fraction of what would be needed to pay for the administration’s stated health care goals.
None of this would bother me all that much, under normal circumstances. A lot of what goes on in Washington, at least in front of the cameras, is an elaborately choreographed dance. It’s related to real political dealing in the same way that a synchronized swimming exhibition compares to the 1956 Olympic water polo match between the Hungarians and the Soviet Union. But (like Megan McArdle in the Atlantic link above), I worry that the administration will now pretend that these savings are real. When they turn out to be (gasp!) insufficient, a crisis will be declared (you should never waste one, you know), and more persuasive measures will be used. You know, just as in the recent Chrysler “bailout”, a term I can only put in quotes. (Mickey Kaus perfectly sums up my feelings about that one, in that link and here).
Why should I care? After all, my industry should be more or less in the clear, since prescription drug spending is only about ten per cent of the nation’s health care costs, right? Well, my worry is that we’re a very visible (and often disliked) ten per cent, a nail that sticks up and that may well get hammered down pour encourager les autres. I hope I'm wrong. But I think that the Chrysler deal was just a curtain-raiser for an even bigger one in the same style for General Motors, and I hope I'm wrong about that one, too.
+ TrackBacks (0) | Category: Business and Markets | Current Events | Drug Prices
May 11, 2009
+ TrackBacks (0) | Category: Blog Housekeeping
I've been meaning to write about the latest advance in salesmanship, pioneered by Merck and Elsevier. As most of you will have heard, the two collaborated to produce something called "The Australasian Journal of Bone and Joint Medicine". This appears to have looked like a real journal, complete with the Elsevier logo and a board of review editors, but it apparently featured nothing but articles (complimentary article, needless to say) about Merck products.
Update: It appears that Merck and Elsevier actually set up a whole publishing division, Excerpta Medica, to handle these things. More here and many more details here.
The news broke about a month ago in The Australian, and the story has been rolling downhill ever since, getting larger all the way. Now Elsevier has issued a public apology for their part in the whole affair, as well they should.
As Orac points out, there are a lot of "throwaway" journals out there, particularly in the medical field. These are sort of once-over-lightly review journals, condensing the literature down into short reads. And that's not all bad, although you wouldn't want a physician to be getting all his or her news that way. But this latest venture was designed to look like a real journal, and was, in fact, full of real articles which had been reprinted from other Elsevier journals. That's well over the line.
I'm not sure who to be more mad at here: Merck or Elsevier. This one really looks like a team effort. If Merck wants to assemble a bunch of previously peer-reviewed studies and put them out under some banner to show how wonderful their drugs were, well, that's fine by me. But that banner shouldn't be something that's deliberately designed to look like a peer-reviewed journal itself. And the collection should have a disclaimer on the cover that it's being paid for by Merck, and the first page of every article should have another box: "As originally reported in (journal citation) - brought to you as a service by Merck". I wouldn't have a problem with that at all.
But that (completely above-board) style seems to be just what the company wanted to avoid, and they got Elsevier, a large and (apparently spottily) respectable scientific publisher to say "Yes, indeed!". Merck's marketing people should be ashamed of themselves, but they should be ashamed for doing what they're paid to do too vigorously. Elsevier, on the other hand, shouldn't be doing this sort of thing at all.
+ TrackBacks (0) | Category: Business and Markets | The Dark Side | The Scientific Literature
May 8, 2009
I've finally, at long last, updated the blogroll to include a lot of sites I should have included. . .well, a long time ago. No doubt I've missed some, so let me know. For now, welcome new additions (and re-linked old sites) On Pharma, The Science Business, , Kinase Pro, Synthesizing Ideas, ChemCafe, Chemical Sabbatical, Computational Organic Chemistry, Depth-First, Henry Rzepa, Peter Murray-Rust, Periodic Tabloid, Useful Chemistry, ChemSpider Blog, SimBioSys, The Loom, No Name No Slogan, Fetz the Chemist, Atomchuxky, Realm of Organic Synthesis, Kilomentor, Realizations in Biostatistics, Generally Chemistry, Business|Bytes|Genes|Molecules, Pharma Blog Review, Pharma's Cutting Edge, C&E News Blog, and The Wall St. Journal Health Blog.
+ TrackBacks (0) | Category: Blog Housekeeping
Kary Mullis is an outlier among Nobel Prize winners. Attendees some of his invited talks in the years after his award will know what I’m talking about. These were famously random affairs, with the audience never knowing quite what to expect when the next slide came up on the screen. And his own book, Dancing Naked in the Mind Field, will give you about as much flakiness as you can stand.
But although he's been way off base about a lot of things, he may not be that way about everything. I notice (h/t Biotechniques) that he gave a lecture recently at San Jose State, and instead of hearing about the discovery of PCR, the students got an update on Mullis’s company Altermune, whose website website is intertwined with Mullis's own. The site is worth a look. Mullis has a vigorous writing style, and the rest of the front page is his pitch for his company’s approach to immunotherapy for infectious disease:
We have been slowly developing chemistry- the art of dealing, using instruments we devise, with things that are much too small for us to see. They have plus and minus charges on them that we can't feel; they have oily places on them much too tiny for us to notice oil and they have water-loving patches too small for us to see oil droplets beading up on the water. Microbes need all of these things, specific types of them, in fact, to survive, and none of them are beyond the scope of our instruments and our synthetic tools. That's our advantage. Just in this last century we have come to know these things the way we used to know javelins and swords.
How can we help our immune system? Altermune has a shot at it.
Give its antibodies - its workhorse molecules - bionic arms. That's right, little chemical extensions that allow an old antibody to do new tricks. Altermune, LLC, in collaboration with Biosearch in Novato, CA, this summer, fitted up some antibodies whose job used to be binding to something called galactose-alpha-1,3-galactosyl-beta-1,4-N-acetyl glucosamine, with new bionic arms, synthesized on an Applied Biosystems ABI 3900, arms that can tightly sieze an influenza virion, shake it a little bit for emphasis, and turn it over to a hungry human macrophage for further processing. The change was accomplished with a swallowed drug. No need to send the antibodies back to the factory. Viruses never saw the ABI 3900 coming.
It looks like he’s using DNA aptamers as recognition elements for specific pathogens, which are used to bring on a response from the ubiquitous antibodies that target 1,3-Gal-Gal antigens. Here's the patent on the technique. And I have to say, that’s not necessarily a crazy idea at all. That epitope has been suggested before as a way to boost immune response, and marrying that to an aptamer could work. (Other aptamer conjugates are under investigation). Of course, the problem (as with all nucleic-acid based things) is, how do you dose it (and how long does it hang around once you do?)
Mullis seems to be talking about oral delivery, which is a real challenge. But that makes me wonder about a report from a company called RXi, which claims to be having some success in delivering their RNAi therapy to macrophages through the gut. They're packaging things in beta-glucan particles and taking advantage of a transport system (and of the fact that there are macrophages in the gut wall waiting for whatever comes out of the food supply). Perhaps something like this would do the trick for a immunological approach like Altermune's?
The immune system scares me, to be honest. I think that evolutionarily we've always walked a narrow path between "strong enough to fight off threats" and "touchy enough to get you killed". Versions of the machinery that threw their hosts into anaphylactic shock too easily have been weeded out by strong selection pressure - you probably wouldn't live long enough to pass that blueprint on. But it's still a tricky thing to mess with (ask TeGenaro). Using existing antibodies might be the most sensible way to do it. . .
+ TrackBacks (0) | Category: General Scientific News | Infectious Diseases
May 7, 2009
Now, here’s something to think about: can angiogenesis inhibitors, the famous class of tumor-starving cancer drugs, actually make some kinds of cancer worse?
This unnerving thought comes courtesy of two recent studies on VEGF pathway inhibitors which present what calls "intriguing, almost perplexing evidence" of just that. One team studied the effects of an anti-VEGF-receptor antibody or the VEGF kinase inhibitor Sutent (sunitinib) in mouse models of pancreatic cancer or glioblastoma multiformis. These are two very nasty tumors, and they’re just the sort of thing that people would like to be able to treat when a new drug comes along. But treatment with either the antibody or the small molecule significantly increased the number of metastatic cancers in the animal models, and I mean significantly: like 6% highly invasive tumors in the controls versus over 50% in the treated group. Admittedly, those numbers were in immune-compromised animals, but in mice with normal immune function, the numbers of metastatic tumors still rose by two- to four-fold.
The other study looked at injections of either metastatic breast cancer cell lines or melanoma lines in mouse models. The authors reproduced the effects of Sutent on the former – it inhibits growth of locally placed tumors, as it should (on past evidence). But if you inject cells into the bloodstream, the story is different. Pre- or post-injection treatment of the mice with Sutent led to an increase in metastatic tumors and a decrease in survival relative to untreated mice. Similar results were obtained with Nexavar (sorafenib), which also hits the VEGF kinase, among others.
That “among others” might be significant. The antibody study does make you think that this is a VEGF-driven effect, but it’s important to remember that both Sutent and Nexavar hit a famously wide variety of kinases. And as a Nature item on these results points out:
It is important to emphasize that both studies clearly recapitulate the clinical data that anti-angiogenic therapies can have significant, albeit transitory, effects on localized tumour growth. However, they raise interesting questions about the timing of anti-angiogenic therapy and whether combining these agents with chemotherapy or other targeted agents can counteract the observed unfavourable effects.
Oh, yes. Among these questions are whether the other VEGF-targeting drugs (like Genentech's Avastin) have this effect. You'd have to presume that they would. And what about other therapies directed at other anti-angiogenic targets?. They might, if the effect is brought on simply by low oxygen levels in tumor cells, or it might be something specific to VEGF. We also don't know, in general, which sorts of tumors respond in this way and which don't. But these findings should have effects on clinical practice, and soon. They didn't quite come out of the blue - it's been known since the anti-angiogenic drugs were developed that they didn't actually seem to cure cancers so much as knock them down for varying lengths of time. And in many cases, patients only survive a few months longer after treatment.
Every time I write something like that, though, I'm tempted to quote Peter Altenberg and say "What's so only"? But there still seems to be so much more potential in the idea - the same potential that led to a lot of hype and craziness a few years ago - and perhaps we're beginning to see where things went wrong. Can they be put right, or not?
And you know, perhaps it's for the best that Judah Folkman himself isn't still around to see these latest results. I don't think he would have despaired, but it wouldn't have been easy news for him to hear. . .
+ TrackBacks (0) | Category: Cancer
May 6, 2009
Here's a good example of why all of us in the industry tiptoe into Phase I trials, the first-in-man studies. A company called SGX, recently acquired by Eli Lilly, has been developing a kinase inhibitor (SGX523) targeting the enzyme cMET. That's a well-known anticancer drug target, with a lot of activity going on in the space.
SGX's specialty is fragment-based design, and they've spoken several times at meetings about the SGX523 story. The starting point for the drug seems to have come out of X-ray crystallographic screening (the company has significant amounts of X-ray synchrotron beamline time, which you're going to need if you choose this approach). They refined the lead, in what (if you believe their presentations) was a pretty short amount of time, to the clinical candidate. It seems to have had reasonable potency and pharmacokinetics, very good oral bioavailability, no obvious liabilities with metabolizing enzymes or the dreaded hERG channel. And it was active in the animal models, however much you can trust that in oncology.
So off to the clinic they went. Phase I trials started enrolling patients in January of last year - but by March, the company had to announce that all dosing had been halted. That was fast, but there was a mighty good reason. The higher doses were associated with acute renal failure, something that most certainly hadn't been noticed in the mouse models, or the rats, or the dogs. It turns out that the compound (or possibly a metabolite, it's not clear to me) was crystallizing out in the kidneys. Good-looking crystals, too, I have to say. I can't usually grow anything like that in the lab; maybe I should try crystallizing things out from urine.
Needless to say, obstructive nephropathy is not what you look for in a clinical candidate. There's no market for instant kidney stones, especially when they appear all over the place at the same time. The patients in the Phase I trial did recover; kidney function was restored after dosing was stopped and the compound had a chance to wash out. But SGX523, which was (other than its unlovely structure) a perfectly reasonable-looking drug candidate, is dead. It didn't take long.
+ TrackBacks (0) | Category: Cancer | Clinical Trials | Toxicology
May 5, 2009
Back when I joined the first drug company I ever worked for, the group in the lab next door was working on an enzyme called ACAT, acyl CoA:cholesterol acyltranferase. It’s the main producer of cholesterol esters in cells, and is especially known to be active in the production of foam cells in atherosclerosis. It had already been a drug target for some years before I first heard about it, and has remained one.
It hasn’t been an easy ride. Since 1990, several compounds have failed in the clinic or in preclinical tox testing. The most recent disappointment was in 2006, when pactimibe (Daiichi Sankyo) not only failed to perform against placebo, but actually made things slightly worse.
Lipid handling is a tough field, because every animal does is slightly differently. There are all sorts of rabbit strains and hamster models and transgenic mice, but you're never really sure until you get to humans. Complicating the story has been the discovery that there are two ACATs. ACAT-1 is found in macrophages (and the foam cells that they turn into) and many other tissues, and ACAT-2 is found in the intestine and in the liver. Which one to inhibit is a good question - the first might have a direct effect on altherosclerotic plaque formation, while the second could affect general circulating lipid levels. Pactimibe hits both about equally, as it turns out.
Now a second study of that drug has been published this spring. This one was going on at the same time as the earlier reported one, and was stopped when those results hit, but the data were in good enough shape to be worked up, and the company paid for the continued analysis. The new results look at patients with familial hypercholesterolemia, who got pactimibe along with the standard therapies. Unfortunately, the numbers are of a piece with the earlier ones: the drug did not help, and actually seemed to increase arterial wall thickness. I think it's safe to say, barring some big pharmacological revelation, that ACAT inhibitors are a dead end for atherosclerosis.
I bring this up for two reasons. One is that the group that was working next door to me on ACAT was the same group that discovered (quite by accident) the cholesterol absorption inhibitor ezetimibe, known as Zetia (and as half of Vytorin). Although its future is very much in doubt, it's for sure that that compound has been a lot more successful than any ACAT inhibitor. The arguing goes on about how helpful it's been (and will go on until we see the next trial results for another couple of years), but it's already made it further than ACAT.
And that's actually my second point. I suspect that almost no one in the general public has ever heard of ACAT at all. But it's been the subject of a huge amount of research, of time and work and money. And while we've learned more about lipid handling in humans, which is always valuable, the whole effort has been an utter loss as far as any financial return. I have no good way of estimating the direct costs (and even worse, the opportunity costs) involved with this target, but they surely add up to One Hell Of A Lot Of Money. Which is gone, and gone with hardly a sound outside the world of drug development. And this happens all the time.
+ TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Drug Development | Drug Industry History | Toxicology
May 4, 2009
I’ve written before about the copper-catalyzed triazole formation (often referred to as “click chemistry”). It’s turned into a very useful way to stick all sorts of molecules and structures together, and is showing up in materials science, biochemistry, organic synthesis and other fields.
Now Fraser Stoddart’s lab has a new variation on the technique, using atomic force microscopy (AFM) equipment. If you’re not familiar with that machinery (invented in the 1980s), it’s rather startling. An AFM rig uses a very fine metal tip (fine, as in “down to one atom or so at the end” fine), which is brought down very close to a solid surface. And that’s close as in “within the size of a molecule or so” close. Once you’re ranged in, you can run these tips around in any direction you choose, and a lot ingenious measurements can be obtained. Both modern surface and solid-state chemistry live off this family instruments, with good reason.
One thing you can imagine doing is lowering some sort of active catalyst down near the surface and doing chemical reactions. If you want to tear up the surface below in some controlled fashion, that’s a bit easier, through straight oxidation or reduction. Forming bonds is a bit trickier, but that’s been achieved with some palladium reactions. Now Stoddart’s group has gotten it to work with the triazole chemistry, and in very straightforward fashion.
If you take an azide-functionalized silicon wafer (and these are well known), you can then dissolve some acetylene compound up in ethanol and put a drop of it on the surface. And lowering an AFM tip which has simply been coated with copper metal down to the surface is enough to initiate the reaction. As the tip moves, it “writes” a path of triazoles. The conditions are very mild, the resolution of the lines is very high (down to about 50 nanometers wide), and it turns out that the reaction is so fast that the tip can be moved at relatively high speed.
This opens up a potential way to stick all sorts of molecules to solid surfaces. There are a lot of ways known to do that, of course, but this one could have some real advantages. The selectivity and high resolution seen here could allow for very dense and complicated arrays of complex molecules to be laid down. Since the triazole reaction is compatible with all sort of biomolecules, this could provide a way to produce functionalized chips that would currently be rather hard (or nearly impossible) to make. And now that we can make them, we can start thinking up unusual things to do with them.
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May 1, 2009
Science has a short interview with Richard Scheller, who will be running R&D now at Genentech. A highlight:
Q: How do you plan to maintain the famous Genentech culture?
R.S.: By making sure that scientists continue to have time to work on their own projects that aren't translational, that aren't governed in any specific way, and that scientists have time to think and imagine and invent, not just do routine things.
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One of Merck’s less wonderful recent experiences was the rejection of Cordaptive, which was an attempt to make a niacin combination for the cardiovascular market. Niacin would actually be a pretty good drug to improve lipid profiles if people could stand to take the doses needed. But many people experience a burning, itchy skin flush that’s enough to make them give up on the stuff. And that’s too bad, because it’s the best HDL-raising therapy on the market. It also lowers LDL, VLDL, free fatty acids, and tryglycerides, which is a pretty impressive spectrum. So it’s no wonder that Merck (and others) have tried to find some way to make it more tolerable.
A new paper suggests that everyone has perhaps been looking in the wrong place for that prize. A group at Duke has found that the lipid effects and the cutaneous flushing are mechanistically distinct, way back at the beginning of the process. There might be a new way to separate the two.
Niacin’s target seems to be the G-protein coupled receptor GPR109A – and, unfortunately, that seems to be involved in the flushing response, since both that and the lipid effects disappear if you knock out the receptor in a mouse model. The current model is that activation of the receptor produces the prostaglandin PGD2 (among other things), and that’s what does the skin flush, when it hits its own receptor later on. Merck’s approach to the side effect was the block the PGD2 receptor by adding an antagonist drug for it along with the niacin. But taking out the skin flush at that point means doing it at nearly the last possible step.
The Duke team has looked closely at the signaling of the GPR109A receptor and found that beta-arrestins are involved (they’ve specialized in this area over the last few years). The arrestins are proteins that modify receptor signaling through a variety of mechanisms, not all of which are well understood. Wew’ve known about signaling through the G-proteins for many years (witness the name of the whole class of receptors), but beta-arrestin-driven signaling is a sort of alternate universe. (GPCRs have been developing quite a few alternate universes – the field was never easy to understand, but it’s becoming absolutely baroque).
As it turns out, mice that are deficient in either beta-arrestin 1 or beta-arrestin 2 show the same lipid effects in response to niacin dosing as normal mice. But the mice lacking much of their beta-arrestin 1 protein show a really significant loss of the flushing response, suggesting that it’s mediated through that signaling pathway (as opposed to the “normal” G-protein one). And a known GPR109A ligand that doesn’t seem to cause so much skin flushing (MK-0354) fit the theory perfectly: it caused G-protein signaling, but didn’t bring in beta-arrestin 1.
So the evidence looks pretty good here. This all suggests that screening for compounds that hit the receptor but don’t activate the beta-arrestin pathway would take you right to the pharmacology you want. And I suspect that several labs are going to now put that idea to the test, since beta-arrestin assays are also being looked at in general. . .
+ TrackBacks (0) | Category: Biological News | Cardiovascular Disease | Toxicology