About this Author
College chemistry, 1983
The 2002 Model
After 10 years of blogging. . .
Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases.
To contact Derek email him directly: firstname.lastname@example.org
May 31, 2012
Anonymity is a topic that comes up whenever you talk about commenting on published scientific work. Some people are very uncomfortable with the idea of others being able to take potshots at them from behind convenient rocks, while others think that without that ability, a lot of relevant discussion will never take place.
Similar concerns apply to academic research grants. A big name never hurts - but what if all the names were stripped off the proposals? Many people have wondered this over the years, but now the NSF has been giving it a try:
Known as The Big Pitch and launched 2 years ago by officials in the agency's Molecular and Cellular Biosciences (MCB) Division, the effort aims to find out if making proposals anonymous—and shorter—has an impact on how they fare in the review process. “We wanted to find ways to identify transformative ideas that are getting lost in the regular peer-review process,” says Parag Chitnis, head of the MCB division. “So we asked: What would happen if we strip off the name of the PI [principal investigator] and institution and distill proposals down to just the big question or the core idea?”
What happens is a lot, according to the first two rounds of the Big Pitch. NSF's grant reviewers who evaluated short, anonymized proposals picked a largely different set of projects to fund compared with those chosen by reviewers presented with standard, full-length versions of the same proposals.
They're tried this twice, in two different research areas, each time with some 50 to 60 proposals to work with. Both times, the full-proposal rankings were almost completely different than the anonymous-pitch ones. I can see some problems with drawing conclusions here, though: for one thing, if two different teams of evaluators look over the same set of proposals (in either format), how closely do they agree? I'd like to see the NSF try that experiment - say, three different panels rating each set. And I'd include a third group, the condensed proposals with the names still on them. That might help answer several questions: how much do such panels diverge in general? Is the spread larger or smaller with the condensed proposal format? With the names stripped off? How much of the difference in rating is due to each factor?
These ideas have occurred to the people involved, naturally:
The experiment was not designed to separate out the effect of anonymity, but it may have been a factor. In both Big Pitch rounds, reviewers evaluating the anonymous two-pagers were later told the identity of the applicants. In some cases, Chitnis says, panelists were surprised to learn that a highly rated two-pager had come from a researcher they had never heard of. In others, he notes, reviewers “thought they knew who this person is going to be” only to find that the application came from a former student of the presumed bigwig, working at a small institution.
In their next round, the NSF plans to try to sort some of these factors out. I very much hope that this sort of thing continues, though. There should be a mixture of funding mechanisms out there: programs that fund interesting people, no matter what they're working on, and ones that fund interesting ideas, no matter where they came from.
+ TrackBacks (0) | Category: Academia (vs. Industry)
May 30, 2012
Several people have sent this along, or similar writeups. The claim is that Vioxx actually was responsible for over 500,000 deaths, which would be about ten times the absolute highest (and much disputed) estimate that's been seen to date. Ron Unz, the publisher of the American Conservative who makes these allegations, says that they're obvious in death-rate figures, particularly in the older population:
"We find the largest rise in American mortality rates occurred in 1999, the year Vioxx was introduced, while the largest drop occurred in 2004, the year it was withdrawn," says Unz. "Vioxx was almost entirely marketed to the elderly, and these substantial changes in the national death-rate were completely concentrated within the 65-plus population.">
I found this claim very hard to believe. (For one thing, how could all those patients and lawyers suing Merck have let this get past them?) Looking at the statistics themselves, I can see no evidence for Unz's claim. Here, for example, is the death rate in the US, crude and age-adjusted, over this time span:
And to get more specific, here are the numbers for cardiovascular deaths for people 65 and over. (They're in a chart comparing them to cancer death rates as well):
I do not see the effects that Unz is talking about. Not at all. A single-cause change in the death rate of the magnitude that he's proposing should most certainly show up in these figures (particularly the latter chart), but it isn't there. I see no reason to take this claim seriously.
For those wanting more, there are more arguments against this theory in the comments here).
+ TrackBacks (0) | Category: Cardiovascular Disease
ChemJobber catches a very odd situation, as reported in C&E News. An official at a large R&D organization testifies to Congress about the importance of research funding. No surprises, eh? But get this: it's a VP of Corporate Alliances at WuXi.
Although, actually, it makes perfect sense. The more research funding there is in the U.S., the more contracting work there might be for WuXi, to make those dollars stretch further. Sensible or not, though, it does look strange.
+ TrackBacks (0) | Category: Business and Markets
May 29, 2012
I don't see any alternative. My question from last year is answered, as I'd feared. Word comes of an autism conference featuring the likes of Jenny McCarthy and Andrew Wakefield, which should be all any well-informed person needs to hear.
And Luc Monagnier is there, too. Not content with teleporting DNA molecules and defending homeopathy, he now says that he can cure autistic children with antibiotics, and is decrying the reception that these claims are getting. In fact, all of Montagnier's odd beliefs tend to run together, so in one way, his rubbing shoulders with the likes of the other speakers at this autism meeting is completely fitting. After all, they believe all kinds of weird stuff, too, so why not?
But on another level, it's just sad. Even if one might want to give Montagnier the benefit of the doubt, based on his past work, there's no way that anyone can be taken seriously after sharing a speaker's platform with the likes of Jenny McCarthy et al. The fact that he doesn't seem to realize this, or care, is just another piece of evidence: Luc Montagnier has lost it.
+ TrackBacks (0) | Category: Snake Oil
Update: Immune Response Biopharma CEO David Buswell has left a detailed comment to this point, pointing out that it was his company that ended talks with GSK, and not the other way around. See here for the details.
GlaxoSmithKline has decided not to pursue further development of a potential vaccine therapy for multiple sclerosis, dumping former partner Immune Response BioPharma. We get that sort of headline all the time in this business - deals come, and deals go. What we don't get are press releases like these. The full unaltered text:
"Immune Response BioPharma, Inc. has the first MS Vaccine a first in class and best in class multiple sclerosis drug which restores deficient FOXP3+ T-Regs. GSK has no approved MS drug and probably will never have one they are busy wasting their shareholders money on HGSI and a Lupus drug with poor sales, we don't need them or to give away our blockbuster drug for MS to them which we believe will become treatment of choice" IRBP CEO Mr. Buswell
"IRBP values NeuroVax north of a billion dollar of annual sales once approved. We will find a solid partner or raise capital on our own, we don't need GSK which has zer0 experience in multiple sclerosis or auto-immune diseases. GSK is a joke and seems very ignorant on how multiple sclerosis drugs work and how to develop one, we gave them a chance to develop NeuroVax but their management appears to be very poor. We have decided to terminate any collaboration or development with GSK. GSK is a loser in the MS market and will continue to be a loser" IRBP CEO Mr. Buswell
Y'know, in his way, this CEO is a breath of fresh air. Everyone thinks these things in such situations, but not many people put them out on the PR wires. This release seems to have transcribed directly from Mr. Buswell's (no doubt heated) statements at the time, which I'm sure accounts for the take-a-breath grammar. I'll follow NeuroVax's progress with interest to see who has the last laugh this time. . .
+ TrackBacks (0) | Category: Business and Markets | The Central Nervous System
May 25, 2012
You run into a lot of scientific and medical misconceptions (particularly when you have a blog with a working e-mail address plastered on the front page of it!) There are plenty of harmless ones that are easy to correct, and at the other end of the scale there are major weltanschauung problems (like the "drug companies don't want to find a cure for cancer because it would put them out of business" line). Those involve what Kingsley Amis called "permanent tendencies of the heart and mind", and I'm not sure if they can be fixed at all.
I got to thinking about this subject again after seeing this item, which is pointing out to physicians that a meaningful number of their patients may well opt out of surgery for cancer because they believe that cancer spreads when exposed to air. This turns out to be a common enough belief that it's addressed on many medical sites. It's not one that I'd heard before, and I thought I'd heard quite a few of these.
So, in the spirit of discussions like this one, I'll toss out these questions: what's the farthest-from-reality misconception about medical/pharma topics you've encountered? And what widespread one do you think does the most harm? (Warning about that link: it goes to a hugely long thread, which will soak up your time as you continue running into yet-more-ridiculous beliefs that people have expressed).
My own candidates: the weirdest one I've encountered might be the person who still believed in spontaneous generation (that old bread just sort of "turned into" living mold, etc.). And the most harmful one, from a drug research perspective, might well be the constellation of "the government does all drug research" beliefs, or the one mentioned above, the "drug companies don't want to cure X" one, which shades into the "drug companies have a cure for X but they don't want to release it" belief.
+ TrackBacks (0) | Category: General Scientific News
May 24, 2012
Bloomberg has an article on Novo Nordisk and their huge ongoing effort to come up with an orally available form of insulin. That's been a dream for a long time now, but it's always been thought to be very close to impossible. The reasons for this are well known: your gut will treat a big protein like insulin pretty much like it treats a hamburger. It'll get digested, chopped into its constituent amino acids, and absorbed as non-medicinally-active bits which are used as raw material once inside the body. That's what digestion is. The gut wall specifically guards against letting large biomolecules through intact.
So you're up against a lot of defenses when you try to make something like oral insulin. Modifying the protein itself to make it more permeable and stable will be a big part of it, and formulating the pill to escape the worst of the gut environments will be another. Even then, you have to wonder about patient-to-patient variability in digestion, intestinal flora, and so on. The dosing is probably going to have to be pretty strict with respect to meals (and the content of those meals).
But insulin dosing is always going to be strict, because there's a narrow window to work in. That's one of the factors that's helped to sink so many other alternative-dosing schemes for it, most famously Pfizer's Exubera. The body's response to insulin in brittle in the extreme. If you take twice as much antihistamine as you should, you may feel funny. If you take twice as much insulin as you should, you're going to be on the floor, and you may stay there.
So I salute Novo Nordisk for trying this. The rewards will be huge if they get it to work, but it's a long way from working just yet.
+ TrackBacks (0) | Category: Diabetes and Obesity | Drug Development | Pharmacokinetics
Here's a note on an ugly situation: when a post-doc publishes a paper without the permission of the principal investigator. Now, this is a fairly rare situation, but still not as rare as you might imagine - the article itself has several citations, and it quotes a journal editor who's seen it happen a number of times.
In most of these cases, there seems to be a more fundamental confusion about ownership of data, with publishing as the sequel. People leave a research group with their piles of results, and decide that since it's theirs, that it's time to get it out into the literature with their name on it. But as the article points out, if work is done under NIH funding, then the results belong to the institution, and the grantee/PI is the person who decides when and where things are published. You may, as a grad student or post-doc, feel that the data you worked so hard to generate are rightfully yours, but most of the time that's just not the case.
In industry we have our own disputes, but this isn't one of them. There's rarely any argument about ownership of data: that's all company property, and you sign documents when you're hired that explicitly spell that out. And publication is rarely as bitter a business as it is in academia (where it's the coin of the realm). We argue about whether a particular project is advanced enough (or dead enough, more likely) to be written up for a journal, but these are secondary questions.
Who gets on the patent is a slightly bigger question, but it's not like you get a cut of the profits based on whether your name is on the list. That's as opposed to Germany, where that's exactly what happens, and I've often wondered if we should try that here. That system leads to some elbow-throwing when it comes to inventorship on a hot project, but it also leads to everyone having a clear idea of the legal requirements to be an inventor. Ownership is, naturally, not in dispute at all. Every invention realized at the company is company property, too (those same documents take care of that back when you're hired on).
So while rogue academic publishing is a known phenomenon, rogue industrial patenting isn't. Well, as far as I know it isn't - anyone have an example of someone who tried to get away with it?
+ TrackBacks (0) | Category: Patents and IP | The Scientific Literature
May 23, 2012
I'm baffled by this abstract. Why would you go to the trouble of putting an unusual group (a ferrocene) on a molecule, and then show that putting it on seems to do little or nothing to the properties and activity of the parent compound? "We put a ferrocene on and it didn't kill the molecule" doesn't seem to be enough grounds for a full J. Med. Chem. paper. Does it?
+ TrackBacks (0) | Category: The Scientific Literature
Several readers sent along a link to this Radio 4 program ("The End of Drug Disocvery") from the BBC on drug discovery. From what I've heard, it's a very good overview of the current state of the field for people outside it, and gets across just how difficult it's been to find good drug candidates.
+ TrackBacks (0) | Category: Press Coverage
For those of you who'd had to explain to colleagues (in biology or chemistry) why you're not enthusiastic about the rhodanine compounds that came out of your high-throughput screening effort, there's now another paper to point them to.
The biological activity of compounds possessing a rhodanine moiety should be considered very critically despite the convincing data obtained in biological assays. In addition to the lack of selectivity, unusual structure–activity relationship profiles and safety and specificity problems mean that rhodanines are generally not optimizable.
That's well put, I think, although this has been a subject of debate. I would apply the same language to the other "PAINS" mentioned in the Baell and Holloway paper, which brought together a number of motifs that have set off alarm bells over the years. These structures are guilty until proven innocent. If you have a high-value target and feel that it's worth the time and trouble to prove them so, that may well be the right decision. But if you have something else to advance, you're better off doing so. As I've said here before, ars longa, pecunia brevis.
+ TrackBacks (0) | Category: Drug Assays | Drug Development
May 22, 2012
The NIH's attempt to repurpose shelved development compounds and other older drugs is underway:
The National Institutes of Health (NIH) today announced a new plan for boosting drug development: It has reached a deal with three major pharmaceutical companies to share abandoned experimental drugs with academic researchers so they can look for new uses. NIH is putting up $20 million for grants to study the drugs.
"The goal is simple: to see whether we can teach old drugs new tricks," said Health and Human Services Secretary Kathleen Sebelius at a press conference today that included officials from Pfizer, AstraZeneca, and Eli Lilly. These companies will give researchers access to two dozen compounds that passed through safety studies but didn't make it beyond mid-stage clinical trials. They shelved the drugs either because they didn't work well enough on the disease for which they were developed or because a business decision sidelined them.
There are plenty more where those came from, and I certainly wish people luck finding uses for them. But I've no idea what the chances for success might be. On the one hand, having a compound that's passed all the preclinical stages of development and has then been into humans is no small thing. On that ever-present other hand, though, randomly throwing these compounds against unrelated diseases is unlikely to give you anything (there aren't enough of them to do that). My best guess is that they have a shot in closely related disease fields - but then again, testing widely might show us that there are diseases that we didn't realized were related to each other.
John LaMattina is skeptical:
Well, the NIH has recently expanded the remit of NCATS. NCATS will now be testing drugs that have been shelved by the pharmaceutical industry for other potential uses. The motivation for this is simple. They believe that these once promising but failed compounds could have other uses that the inventor companies haven’t yet identified. I’d like to reiterate the view of Dr. Vagelos – it’s fairy time again.
My views on this sort of initiative, which goes by a variety of names – “drug repurposing,” “drug repositioning,” “reusable drugs” – have been previously discussed in my blog. I do hope that people can have success in this type of work. But I believe successes are going to be rare.
The big question is, rare enough to count the money and time as wasted, or not? I guess we'll find out. Overall, I'd rather start with a compound that I know does what I want it to do, and then try to turn it into a drug (phenotypic screening). Starting with a compound that you know is a drug, but doesn't necessarily do what you want it to, is going to be tricky.
+ TrackBacks (0) | Category: Academia (vs. Industry) | Drug Assays | Drug Development | Drug Industry History
This article from the Telegraph has nothing to say at all about the drug industry. But you might find it strangely familiar and appropriate, starting with the headline: Bloodless Bean Counters Rule Over Us:
You find this hollowing-out everywhere. In schools, the head who does not teach is now a familiar, indeed dominant figure. University vice-chancellors, instead of being dons who move from their subject into administration for a period of their lives, are now virtually lifelong managers, with hugely increased salaries to match. It is even commonplace for charities to be run by people with no commitment to the charity’s specific purpose, but proud possession of what they call the necessary “skill-sets”, such as corporate governance. . .
. . .These habits are now pervasive across industry and the public services. “Diversity” is always “celebrated”, but it never means diversity of thought. The people who tell you they are “passionate about” X or Y are usually the most bloodless ones in the outfit.
In such cultures, just as the experts, the professionals and the technicians bitterly resent the managerialists for neither understanding nor caring, so the managerialists secretly detest the professionals who, they believe, get in the way of their rationalisations. They are desperate to “let go” of such people. Very unhappy organisations result.
Or then again, perhaps you haven't encountered anything like this after a few years in the industry. What, after all, are the odds?
+ TrackBacks (0) | Category: Business and Markets | Drug Industry History
May 21, 2012
Here's a good example of phenotypic screening coming through with something interesting and worthwhile: they screened against Entamoeba histolytica, the protozooan that causes amoebic dysentery and kills tens of thousands of people every year. (Press coverage here).
It wasn't easy. The organism is an anaerobe, which is a bad fit for most robotic equipment, and engineering a decent readout for the assay wasn't straightforward, either. They did have a good positive control, though - the nitroimidazole drug metronidazole, which is the only agent approved currently against the parasite (and to which it's becoming resistant). A screen of nearly a thousand known drugs and bioactive compounds showed eleven hits, of which one (auranofin) was much more active than metronidazole itself.
Auranofin's an old arthritis drug. It's a believable result, because the compound has also been shown to have activity against trypanosomes, Leishmania parasites, and Plasmodium malaria parasites. This broad-spectrum activity makes some sense when you realize that the drug's main function is to serve as a delivery vehicle for elemental gold, whose activity in arthritis is well-documented but largely unexplained. (That activity is also the basis for persistent theories that arthritis may have an infectious-disease component).
The target in this case may well be arsenite-inducible RNA-associated protein (AIRAP), which was strongly induced by drug treatment. The paper notes that arsenite and auranofin are both known inhibitors of thioredoxin reductase, which strongly suggests that this is the mechanistic target here. The organism's anaerobic lifestyle fits in with that; this enzyme would presumably be its main (perhaps only) path for scavenging reactive oxygen species. It has a number of important cysteine residues, which are very plausible candidates for binding to a metal like gold. And sure enough, auranofin (and two analogs) are potent inhibitors of purified form of the amoeba enzyme.
The paper takes the story all the way to animal models, where auranofin completely outperforms metronidazole. The FDA has now given it orphan-drug status for amebiasis, and the way appears clear for a completely new therapeutic option in this disease. Congratulations to all involved; this is excellent work.
+ TrackBacks (0) | Category: Academia (vs. Industry) | Drug Assays | Drug Development | Infectious Diseases
Mat Todd at the University of Sydney (whose open-source drug discovery work on schistosomiasis I wrote about here) has an interesting chemical suggestion. His lab is also involved in antimalarial work (here's an update, for those interested, and I hope to post about this effort more specifically). He's wondering about whether there's room for a "Molecular Craigslist" for efforts like these:
Imagine there is a group somewhere with expertise in making these kinds of compounds, and who might want to make some analogs as part of a student project, in return for collaboration and co-authorship? What about a Uni lab which might be interested in making these compounds as part of an undergrad lab course?
Wouldn’t it be good if we could post the structure of a molecule somewhere and have people bid on providing it? i.e. anyone can bid – commercial suppliers, donators, students?
Is there anything like this? Well, databases like Zinc and Pubchem can help in identifying commercial suppliers and papers/patents where groups have made related compounds, but there’s no tendering process where people can post molecules they want. Science Exchange has, I think, commercial suppliers, but not a facility to allow people to donate (I may be wrong), or people to volunteer to make compounds (rather than be listed as generic suppliers. Presumably the same goes for eMolecules, and Molport?
Is there a niche here for a light client that permits the process I’m talking about? Paste your Smiles, post the molecule, specifying a purpose (optional), timeframe, amount, type of analytical data needed, and let the bidding commence?
The closest thing I can think of is Innocentive, which might be pretty close to what he's talking about. It's reasonably chemistry-focused as well. Any thoughts out there?
+ TrackBacks (0) | Category: Academia (vs. Industry) | Business and Markets | Drug Development | Infectious Diseases
May 18, 2012
For those of you interested in the recent work on the diversity of different cancer cell genotypes inside single tumors, there's a review out that covers the field well. The authors also go into some of the major unanswered questions: does having a tumor cell population with a lot of genetic diversity correlate with a poor prognosis for treatment? Can small populations of potentially troublesome cells be identified ahead treatments that might give them too free a field to work in? Can the huge genetic diversity be reduced to a more manageable set of practical phenotypes, to make therapeutic recommendations? This will keep everyone busy for a long time to come.
+ TrackBacks (0) | Category: Cancer
I've read a couple of medical papers recently that show how tricky it is to draw conclusions on what patients would be best helped by a specific therapy. Many of you will have seen the paper in The Lancet on the use of statins in low-risk patients. This isn't something you'd necessarily think would do much good - it all depends on what the benefits are, at the margin, of lowering LDL. But the results appear surprisingly strong:
In individuals with 5-year risk of major vascular events lower than 10%, each 1 mmol/L reduction in LDL cholesterol produced an absolute reduction in major vascular events of about 11 per 1000 over 5 years. This benefit greatly exceeds any known hazards of statin therapy. Under present guidelines, such individuals would not typically be regarded as suitable for LDL-lowering statin therapy. The present report suggests, therefore, that these guidelines might need to be reconsidered.
A note to the conspiratorially minded, should any such come across this: it's worth noticing that this "maybe everyone should take statins" result comes after the major ones have gone off patent. Pfizer, Merck et al. would have greatly enjoyed this recommendation had it occurred ten years ago, but it didn't (and probably couldn't have, since we didn't have as much data as we do now).
Now to another (often related) disease, type II diabetes. It's been found that bariatric surgery improves glycemic control in the very obese patients who are candidates for the procedure. And that makes sense - obesity is absolutely a risk factor for type II in the first place. But as more and more of these surgeries are being done, something odd is becoming apparent:
Clinicians note that bariatric operations can dramatically resolve type 2 diabetes, often before and out of proportion to postoperative weight loss. Now two randomized controlled trials formally show superior results from surgical compared with medical diabetes care, including among only mildly obese patients. The concept of 'metabolic surgery' to treat diabetes has taken a big step forward.
Why this happens is a very good question indeed. Patients seem to benefit greatly within the first two weeks after gastric bypass surgery, well before any significant weight loss has occurred. My first guess is that it's something to do with secretion of hormones from the gut itself, and you'd also have to think that nutrient sensing gets profoundly altered. It's not going to be easy to turn this into an approved therapy, though. Running randomized clinical trials for dramatic surgical procedures (versus noninvasive care) is difficult, as you'd imagine:
Despite these compelling clinical observations, RCTs of surgery versus nonsurgery are sorely needed. Ample precedents exist wherein RCTs reversed longstanding paradigms derived from nonrandomized clinical trials. Some of the best evidence in bariatric surgery, from the Swedish Obese Subjects study (a long-term observation of various operations versus conventional care), is prone to allocation bias because participants were not randomized. Subjects who actively chose surgery may be more motivated overall and generally take better care of themselves. The NIH is unlikely to reconsider its guidelines without pertinent RCTs, and insurance companies are unlikely to pay for operations that are not NIH-sanctioned.
Both of these results point out the completely nonlinear nature of living systems. It can work for good, as in these cases, or for bad. Alzheimer's, the subject of yesterday's post, is a perfect example of the latter: one protein, out of perhaps a few million, has one of its hundreds of amino acids changed in one small way on its side chain. And it's a death sentence. Good to know that things can work in the other way once in a while.
+ TrackBacks (0) | Category: Alzheimer's Disease | Cardiovascular Disease | Diabetes and Obesity
May 17, 2012
The failure of Roche's dalcetrapib has a lot of people wondering just what's going on with HDL as a cardiovascular drug target. And this isn't the first time - there have been a number of puzzling findings in the lipoprotein field that point out to us that we don't know nearly as much about this area as we might think. Many promising therapeutic ideas in it have turned out disastrously.
Now there's a new paper in The Lance that underscores this, and how. The authors have done large genome-wide association studies looking for polymorphisms that affect lipoproteins, and they're following those up with clinical data on cardiovascular outcomes. Untangling the effects of HDL, LDL, triglycerides and other factors isn't easy, but they did find one mutation that appears to raise HDL alone. Looking at the people carrying that one, they find that there's no amelioration of risk in them at all. That's as opposed to the mutations that lowered LDL levels, which were consistently associated with lower risks.
This doesn't (necessarily) mean that HDL is useless as a predictor of cardiovascular risk, but it definitely means that it isn't as simple as "HDL = Good Cholesterol!". What this means for things like CETP inhibition is anyone's guess.
+ TrackBacks (0) | Category: Cardiovascular Disease
Just a note: the Breslow origins-of-chirality paper, also known more widely (thanks to some bizarre PR work at the ACS) as the "alien dinosaur" paper, has been withdrawn, and on the correct grounds. The pun in the headline is intended.
+ TrackBacks (0) | Category: The Scientific Literature
Alzheimer's disease is in the news, as the first major preventative drug trial gets underway. I salute the people who have made this happen, because we're bound to learn a lot from the attempt, even while I fear the chances for success are not that good.
A preventative trial for Alzheimer's would, under normal circumstances, be a nightmarish undertaking. The disease is quite variable and comes on slowly, and it's proven very difficult to predict who might start to show symptoms as they age. You'd be looking at dosing a very large number of people (thousands, even tens of thousands?) for a very long time (years, maybe a decade or two?) in order to have a chance at statistical significance. And you would, in the course of things, be giving a lot of drug to a lot of people who (in the end) would have turned out not to need it. No, it's no surprise that no one's gone that route.
But there's a way out of that impasse: find a population with some sort of amyloid-pathway mutation. Now you know exactly who will come down with symptoms, and (unfortunately) you also know that they're going to come down with them earlier and more quickly as well. There are several of these around the world; the "Swedish" and "Dutch" mutations are probably the most famous. There's a Colombian mutation too, with a well-defined patient population that's been studied for years, and that's where this new study will take place.
About 300 people will be given an experimental antibody therapy to amyloid protein, crenezumab. This was developed by AC Immune in Switzerland and licensed to Genentech, and is one of many amyloid-targeted antibodies that have come along over the years. (The best-known is bapineuzumab, currently in Phase III). Genentech (Roche) will be putting up the majority of the money for the trial ($65 million, with $16 million from the NIH and $15 million in private foundation money). Just in passing, weren't some people trying to convince everyone a year ago that it only costs $43 million total to develop a new drug? Har, har.
100 people with the mutation will get the antibody every two weeks, and 100 more will get placebo. There are also 100 non-carriers mixed in, who will all get placebo, because some carriers have indicated that they don't want to know their status. Everyone will go through a continuing battery of cognitive and psychological tests, as well as brain imaging and a great deal of blood work, which (if we're lucky) could furnish tips towards clinical biomarkers for future trials.
So overall, I think that this trial is an excellent idea, and I very much hope that a lot of useful information comes out of it. But I've no firm hopes that it will pan out therapeutically. This will be a direct test of the amyloid hypothesis for Alzheimer's, and although there's a tremendous amount of evidence for that line of thought, there's a lot against it as well. Anyone who really thinks they know what will happen in this situation hasn't thought hard enough about it. But that's the best kind of experiment, isn't it?
+ TrackBacks (0) | Category: Alzheimer's Disease | Clinical Trials | Drug Development
May 16, 2012
How much do we really know about what small drug molecules do when they get into cells? Everyone involved in this sort of research wonders about this question, especially when it comes to toxicology. There's a new paper out in PLoS One that will cause you to think even harder.
The researchers (from Princeton) looked at the effects of the antidepressant sertraline, a serotonin reuptake inhibitor. They did a careful study in yeast cells on its effects, and that may have some of you raising your eyebrows already. That's because yeast doesn't even have a serotonin transporter. In a perfect pharmacological world, sertraline would do nothing at all in this system.
We don't live in that world. The group found that the drug does enter yeast cells, mostly by diffusion, with a bit of acceleration due to proton motive force and some reverse transport by efflux pumps. (This is worth considering in light of those discussions we were having here the other day about transport into cells). At equilibrium, most (85 to 90%) of the sertaline that makes it into a yeast cell is stuck to various membranes, mostly ones involved in vesicle formation, either through electrostatic forces or buried in the lipid bilayer. It's not setting off any receptors - there aren't any - so what happens when it's just hanging around in there?
More than you'd think, apparently. There's enough drug in there to make some of the membranes curve abnormally, which triggers a local autophagic response. (The paper has electron micrographs of funny-looking Golgi membranes and other organelles). This apparently accounts for the odd fact, noticed several years ago, that some serotonin reuptake inhibitors have antifungal activity. This probably applies to the whole class of cationic amphiphilic/amphipathic drug structures.
The big question is what happens in mammalian cells at normal doses of such compounds. These may well not be enough to cause membrane trouble, but there's already evidence to the contrary. A second big question is: does this effect account for some of the actual neurological effects of these drugs? And a third one is, how many other compounds are doing something similar? The more you look, the more you find. . .
+ TrackBacks (0) | Category: Drug Assays | Pharmacokinetics | The Central Nervous System | Toxicology
May 15, 2012
This fine reagent was mentioned here (disparagingly) in the comments the other day, and I knew that it was time to add it to the list. I've had some other selenium entries before, and they're all here for the same reason: their unsupportable stenches. Everyone, even people who've never had a chemistry class in their lives, knows that sulfur compounds are stinky, of course, but it's a problem that continues as you move down Group XVI of the periodic table.
And it's not like plain phenol itself has no odor. It's strong, penetrating, and completely unmistakable. As soon as I get a whiff of the stuff, I'm immediately transported back to the Verser Clinic, the small hospital in the town I grew up in back in Arkansas. Phenol smells like an old-fashioned medical office; it was used for many years as a disinfectant (and was, in fact, introduced as such by Joseph Lister himself). If you move it down a notch to sulfur, you get thiophenol, which is easy to describe: burning rubber - the pure, potent, platonic ideal of burning rubber, bottled up and daring you to open the cap. I can't say that I won't work with thiophenol, since I have (very much to my regret, at times), but I've used it most reluctantly, and probably haven't touched it in at least fifteen years.
Ah, but move down one more element and you have selenophenol, and that's a more exotic reagent. I've never seen any, and after reading the descriptions, I never want to. Actually, let me take that back: I'd look at some from the other end of the lab. What I never want to do is open any of it up. The chemical literature has numerous examples of people who are at a loss for words when it comes to describing its smell, but their attempts are eloquent all the same. A few years ago, Gaussling at the Lamentations on Chemistry blog referred to it as "The biggest stinker I have run across. . .Imagine 6 skunks wrapped in rubber innertubes and the whole thing is set ablaze. That might approach the metaphysical stench of this material." So we'll start with that.
I believe that this lovely compound is commercially available (if you're anywhere close to anyone making it, you'll know about it). But should you wish to prepare it with your own hands, do violence to your own schnozz, and drape yourself out of your own window while you throw up into your own rhododendrons, feel free to use this reliable preparation from Organic Syntheses, circa 1944. This features the note that "it is frequently advisable to work with [selenium compounds] on alternate days", which I suppose is to give them time to work their way out of your nasal passages.
I'm not so sure. When I was a teaching assistant in grad school, I taught three labs a week one semester, and one of those labs, damn it all, was the phenyl Grignard reagent. We had them making it in diethyl ether, outside of the small and inadequate fume hoods, and the solvent fumes were fit to strip paint. By the end of the Monday lab, I was well saturated with ether and had a terrible headache, which returned as soon as I caught my first whiff of the stuff on Tuesday afternoon. I barely made it through that lab, mostly by holding my breath and using a lot of hand gestures, and I took the opportunity on Wednesday to get as much fresh air as I could. But when I came back for the Thursday session, the first first wave of ether vapor washed over me and nearly stretched me out on the tiles. I taught the entire lab from the hallway, shouting and waving like Monty Python's "Semaphore Version of Wuthering Heights". So in my mind, the choice between getting these things over with and stretching them out is still not settled.
That Org Syn prep also notes that it can produce small amounts of hydrogen selenide, which is very toxic indeed (and will give you a sore throat, too, apparently, before it kills you). This luckless graduate student from the 1920s got to experience both of these bracing selenium room fresheners in the course of his work:
Berzelius described the poisonous effect of hydrogen selenide quite impressively; "In order ta get acquainted with the smell of this gas I allowed a bubble not larger than a pea to pass into my nostril ; in consequence of its smell I so completely loss my sense of smell for several hours that I could not distinguish the odor of strong ammonia even when held under my nose. My sense of smell returned after five or six hours, but severe irritation of the mucous membrane set in and persisted for a fortnight' The writer has been working on the gas for some time and was also quite seriously affected once, the injury persisting for many days. That it is more poisonous than the hydrogen sulphide is well known."
So you have that to look forward to on your way to selenophenol. And at your destination? Assuming your nose is still attached to your face, you'll experience what few chemists ever have. I'll let this 1908 report from Wisconsin take over:
When benzeneselenonic acid in solution is treated with reducing agents such as hydrogen sulphide, sulphur dioxide, or, best, with zinc and hydrochloric, acid selenophenol is obtained as a yellow oil with an overpowering and most nauseating odor. . .The odor of diphenyl diselenide is extremely disagreeable but is not nearly so bad as that of selenophenol.
. . .The effect of selenophenol on the skin is very similar to that of thiophenol, forming blisters which itch intensely. After a time, these dry up, the skin scales off, and there appears to be a deposit of red selenium beneath it. The odor of selenophenol is very penetrating, and is nauseating beyond description.
Gloves, man, gloves. Unless, of course, you wish to be tattooed with elemental selenium while being nauseated beyond description. Should this be your idea of a fun Saturday night, I will not stand in your way.
+ TrackBacks (0) | Category: Things I Won't Work With
May 14, 2012
Now here's a worrisome thought, if you're doing kinase research. A tyrosine kinase inhibitor in the clinic against Bcr-Abl, bosutinib (SKI-606), is also being used as a research tool in a number of academic groups. But they're probably not using what they think they're using.
This article has the details. The compound has a dichloromethoxy aryl group hanging off of it, and apparently someone has been making (or made one good-sized batch of) the wrong isomer. Instead of 2, 4-dichloro-5-methoxy, many commercial samples appear to be 3,5-dichloro-4-methoxy. This got noticed at first by inspection of an X-ray structure deposited in the Protein Data Bank, 3ZZ2, from a group at Oxford. A postdoc at Stanford saw that something was off, and at the same time, he was having trouble matching his own X-ray data with the known structure of the compound.
The explanation wasn't what anyone wanted to hear, for sure. The two groups had purchased their material years apart, from different vendors. The count of vendors selling the wrong material is now up to thirteen and climbing. That link also suggests a possible earlier source of the problem: some of the commercial supplies of 2,4-dichloro-5-methoxy aniline are not the right material. Whoever made this bosutinib may well have thought that they were right on target.
Odds are, some batch of the wrong stuff has been resold through the supplier community since at least 2006 - this sort of thing goes on all the time. But the tricky part here is that LC/MS wouldn't have told you that there was a problem, unless you had an authentic sample to check the retention times (which would have been pretty darn close, anyway, I'd guess). The mass is, of course, the same. And the NMRs of the authentic and mis-labeled stuff would be different, but not on casual inspection, for sure (same number of aryl protons). No, I would have let this stuff through, I've no doubt about that. Makes a person wonder what else on the shelf is the wrong material, doesn't it?
+ TrackBacks (0) | Category:
A reader sends along this query, which I thought asked a very useful question:
". . .as a member of a growing biopharma company I am tasked with evaluating the effectiveness of industrial post-docs from both a business perspective and the post-doc's experience. Specifically, we are considering adding one for a short-term (2yr) to add headcount to a project. This adds resources without the long term commitment and also gives the scientists on site a chance for a paper they otherwise might not have time to work on. The candidate obviously gets a well-paid post-doc experience, and an industrial foot in the door. But, does this model work? I imagine that if it were that cut and dried you would see more of them."
Good point. Industrial post-docs are still relatively rare, although I've certainly seen a few. Come to think of it, though, those were mostly in biology, as opposed to chemistry. So, what do people think? From my end, I'd say that traditionally, companies have felt that temporary positions are best filled with experienced temporary employees, who presumably don't have to be trained as much. And if you're going to hire someone to learn the ropes, they might as well be good enough to be brought in as a full-time employee.
From the other end, an industrial post-doc has always been seen as less prestigious than an academic one, and there are some hiring managers who probably don't know what to think when one shows up on a c.v. There's often a feeling that if the person did a really good job during the post-doc that the company would have tried to offer them something permanent. And since they didn't, well. . .
Even so, it does seem as if there are situations where an industrial post-doc could be a good fit, and in today's job market, anything looks good. Anyone out there experienced this, from either end?
+ TrackBacks (0) | Category: Academia (vs. Industry)
May 11, 2012
You chemists may have really stretched things to get a reaction to work, but here's a good set of "Conditions You'll Probably Never Be Desperate Enough to Try". Bone meal? Ground carrots? I think he has a point.
+ TrackBacks (0) | Category: Life in the Drug Labs
Drug companies are very attuned to competitive intelligence. There's a lot of information sloshing around out there, and you'd be wise to pay attention to it. Publications in journals are probably the least of it - by the time something written up for publication from inside a pharma company, it's either about to be on the drugstore shelves or it never will be at all. Patents are far more essential, and if you're going to watch anything, you should watch the patent applications in your field.
But there's more. Meetings are a big source of disclosure, as witness the Wall Street frenzies around ASCO and the like. Talks and posters release information that won't show up in the literature for a long time (if indeed it ever does). And there are plenty of other avenues. The question is, though, how much time and money do you want to spend on this sort of thing?
There are commercial services (such as Integrity) that monitor companies, compounds, and therapeutic areas in this fashion, and they're happy to sell you their services, which are not cheap. But figuring out the cost/benefit ratio isn't easy. My guess is that these things, while useful, can be thought of as insurance. You're paying to make sure that something big doesn't happen that you're unware or (or unaware of in enough time).
So here's a question for the readership: has competitive intelligence ever made a big difference for you? Positive and negative results both welcome; "I'm so glad we found out about X" versus "I really wish we'd known about Y". Any thoughts?
+ TrackBacks (0) | Category: Drug Development
May 10, 2012
Here's an excellent article, with copious references, tracing the history of what we now know as the metal-catalyzed coupling field. Victor Snieckus of Queen's University, Thomas Colacot (Johnson Matthey) and co-authors go back to the Wurtz and Glaser reactions of the 1850s and 60s, up through the Ullmann reaction (1891, and still very much with us) and Kharasch and Cadiot-Chodkiewicz couplings (1940s) before breaking into the world of palladium with the Wacker oxidation.
Along the way, one learns that the discoverer of palladium (Wollaston) could never interest anyone in the metal, and almost all of it that he'd extracted was still sitting on the shelf, unsold, at his death. Time vindicated him, and how - it's now perhaps the most essential catalytic metal in the world. The late 1960s were a turning point:
Entry of Richard Heck: Following post-doctoral studies, Heck accepted a position at Hercules Powder Co where he was afforded freedom that is seldom experienced by the modern industrial chemist. Briefed with the task of “doing something with transition metals,” Heck investigated the chemistry of cobalt carbonyl complexes. Although this work generated many interesting observations, finding profitable applications for his research proved difficult. Inspired by his colleague Pat Henry's work on the Wacker oxidation, Heck's attention turned in the direction of arylpalladium chemistry.
He tried Wacker-type conditions with other reagents around to try to intercept the palladium intermediate, and organomercurys obliged with an immediate reaction. The story from there is a trip through a good swath of the periodic table, and the development of an awful lot of knowledge and expertise in metal complexes. Enter then Mizoroki, Kumada, Sonogashira, Negishi, Stille, Suzuki and many others. It's a long, complex, story, but this paper should serve as the definitive overview, and an excellent look at how chemistry (and science in general) go about discovering and developing things.
+ TrackBacks (0) | Category: Chemical News
For those of you following Arena Pharmaceuticals and their long-running efforts to get lorcaserin approved by the FDA, there's a committee hearing on that matter today. Adam Feuerstein is live-blogging the event here. The big issues, now with fresh data: tumors in rat models, and possible heart-valve damage, versus efficacy. The FDA has until June 27 to make a decision.
+ TrackBacks (0) | Category: Diabetes and Obesity
More disruption in the scientific publishing model: the UK government has announced that it will set up an open-access system for papers that are generated through its funding, similar to the system in the US. The details are still being worked out, and the government is still making noises about not "ruining the value provided by academic publishers", but it's that value that's at issue, isn't it?
A statement from Wiley said that "Publishers enable content digitisation, rigorous peer review, strong editorial infrastructure and support and investment in an effective online platform for dissemination." And yes, they do those things. But how well do they do them? And how well do they do them for the prices they charge? I'm glad that these arguments are finally out on the table.
+ TrackBacks (0) | Category: The Scientific Literature
I mentioned the other day that Human Genome Sciences had turned down an offer from GSK, feeling that they could do better. Well, if they can, now's the time: GSK is now offering the same deal ($13/share) on the open market in a hostile takeover attempt. One of these companies is wrong about that price, and now I guess we'll find out which one of them it is. . .
+ TrackBacks (0) | Category: Business and Markets
May 9, 2012
I've received another e-mail from Prof. Fathi Moussa, lead author of the C60 longevity paper that's been discussed around here. I'd sent a list of the critiques that had shown up in the comments sections, and here's the reply:
An erratum with the right figures 3 and 4 will be published soon in Biomaterials. The right lifespan values after the beginning of the treatment are given in the original text without any change. To sum it up, the extensions of lifespans are twenty months and sixteen months with respect to water-treated controls and olive-oil-treated controls, respectively.
Our original objective was not to study lifespan extension but the toxic effects of C60 at reiterated doses. Lifespan extension by C60 is not really surprising, all the more so as it had already been shown by others that some C60-derivatives can prolong lifespans in several experimental models, albeit moderately.
What is really surprising in our results is that C60 acts at very low doses, which means that the effect is very strong, and that this effect lasts for a long time after the end of the administration. A possible explanation is that some C60 precipitated inside the reticulo-endothelial system and then slowly dissolves and diffuses.
Of course we understand that non C60 specialist readers are incredulous about these results, as it could be expected.
We hope now that others will try and confirm our results. If our results are confirmed by others, which we firmly believe, it will be then necessary to try to reproduce these experiments on bigger samples including other species and of course to optimize the dose and the duration of the treatment.
I share that hope that others will try to confirm the results. It'll be a while, most likely, before we hear about anything in this area, but when something comes up, I'll blog about it.
+ TrackBacks (0) | Category: Aging and Lifespan
I've written here before about reaction discovery schemes, and the reaction to those reactions has been, well, mixed. I like them, some other people like them, but some other people are quite offended by the "random search" mentality behind these ideas.
Well, prepare yourselves for another technology for exploring the wild blue yonder. A new paper in Angewandte Chemie from a group at the CEA (Gif sur Yvette, France) outlines an immunological detection scheme. They have antibodies to an imidazole derivative, and antibodies to a phenolic moeity as well. So both structures are attached to a range of functional groups and combined with heat and/or metal catalysts to see if anything happens. A sandwich assay at the end with the different antibodies gives you a yellow color only if a compound has been formed that has both ends present; that is, if a coupling reaction of some sort has occurred.
They ran 3360 reactions, each on a 100 nmol scale (there's the sensitivity of the antibodies for you). Two new reactions were discovered - an isourea synthesis (which can lead to benzoxazoles) and an alkyne reaction leading to thiazole derivatives. Neither of those is going to set the world of organic chemistry ablaze, but as a proof of concept, I'm convinced that this technique can work. So what do you do with it next?
One plan looks to be discovering new bioorthogonal reactions, couplings that can take place either inside or on the surface of living cells. The immunological detection is so sensitive that products can be teased out of all sorts of messy mixtures, apparently even cell lysates. I'd also encourage them to try some other conditions, such as various photochemical setups, to see what might be out there - it's a much less explored field than copper-catalyzed coupling reactions.
Like it or not, I think we're going to be seeing more of this sort of work. We might as well make the most of it!
+ TrackBacks (0) | Category: Chemical News
A number of people have sent me this article about the number of people with Master's and PhD degrees who are receiving food stamps. And while it's undeniable that the numbers have grown, I'd ask for everyone to keep their statistical glasses on. According to the chart at the end of the piece, the percentage of doctorate holders receiving assistance went from 0.05% in 2007 to 0.15% in 2010. (For MS/MA degree holders, it went from 0.5% to 1.3% over that same time).
So it can't be said that this is a widespread phenomenon. One would also want to see the numbers broken down by age cohort, and (especially) by field of study. The examples in the article are all history and English types. Also, if those figures are correct, the headline could have just as easily read "Master's Degree Holders Ten Times More Likely To Be On Food Stamps".
Honestly, the number I find most alarming in that chart is the total number of advanced degree holders. We went from 20 million in 2007 to 22 million in 2010 - two million more in only three years? The population of the country went from 301 million to 313 million during that time, so that's a pretty good crop of degree holders. Given what the economy has been like during that period, I'm surprised the food stamp figures aren't even higher.
Looking at advanced degrees as a percentage of the population, we have 4.3% in 1970, 7.2% in 1980, 8.8% in 1990, 8.6% in 2000 (a decrease I'm at a loss to explain), and 10.6% in 2009. Those figures don't quite add up with the ones in the food stamp article, but the trend certainly is in the same direction. We have figures in the growth in bachelor's degree or higher going back to 1940, and they show the relentless uptrend you'd expect.
So it shouldn't come as a surprise that well-educated people are participating more in some of the downsides that hit the rest of the population. Well-educated people are becoming more and more of the population.
+ TrackBacks (0) | Category: Business and Markets | General Scientific News | Graduate School
May 8, 2012
You'll remember the Sanofi chemist who was caught selling proprietary compounds through her own Chinese outsourcing company. Now, via Pharmalot, comes word that Yuan Li has been sentenced to 18 months in prison, along with paying $131,000 in restitution. This foolproof business plan has turned out not to perform up to expectations. Perhaps this example will keep another fool from trying it?
+ TrackBacks (0) | Category: The Dark Side
I've received a reply from Dr. Fathi Moussa at Université Paris-Sud, lead author of the C60 longevity paper that I blogged about here, which turned out to have a duplicated figure. With permission, here are the main points of the e-mail:
Of course, you are right: in the published figure 4 the GAog and GAip panels are identical. These two panels were meant to represent the well-known effect of intra-peritoneally (i.p.) administered CCl4 on rat livers. The mistake was obviously due to the fact that the pretreatment of control animals with water either orally (GAog) or i.p. (GAip) cannot influence the effects of CCl4 on livers. Therefore the effects on liver are identical and the corresponding figures are expected to be closely alike. Anyway we sent to the Editor an erratum that will be published soon.
We are very grateful to you for warning us about this figure. We are very furious against ourselves. We still do not understand how such error could have escaped our notice during the revision process. While this mistake has not any influence on the validity of the results described in the text, this could raise a certain amount of doubt over the work. The extension of the lifespan of rats is real and we fear that our error could delay or even prevent control experiments we are expecting to be made by others.
We have published on C60 toxicity since 1995 and all our results have been confirmed by several independent teams. . .
That point in the second paragraph is an important one: if these results are real, they're quite important and interesting. But, as with any other scientific result, they won't be accepted as real until they've been replicated, and replicating this experiment is already a substantial undertaking. The mistake with the figures doesn't help to get these started. (I should note that I've also called the authors' attention to the other points raised here in the comments).
My hope is that other groups studying longevity effects in rodents (and having already made the commitment that entails) will be able to add a C60 arm to their experiments as a comparison.
+ TrackBacks (0) | Category: Aging and Lifespan
May 7, 2012
A couple of notes: in the previous post, I forgot to include the link to Wavefunction's article on the "negative rate constant" brouhaha - it's here, and well worth a look.
And I wanted to note that the post that discusses the Dobson and Kell theories about how compounds make their way into cells now has a comment from Douglas Kell himself, which is also worth a look if you're into this topic.
+ TrackBacks (0) | Category: Blog Housekeeping
Over at The Curious Wavefunction, there's a great post looking back at the infamous "negative rate constant" affair (Breslow, Menger, Haim). If you're not familiar with that one, give it a look. I remember this one while it was going on, and in retrospect, you have to imagine what it would have been like if there had been a chemical blog world at the time. It's an extraordinary chapter in chemical (and chemical literature) history.
To that end, there's this opinion piece from yesterday's New York Times. Author Jack Hitt is talking about the tail of comments that now follows any notable article, in any field:
Almost any article worth reading these days generates some version of this long tail of commentary. Depending on whether they are moderated, these comments can range from blistering flameouts to smart factual corrections to full-on challenges to the very heart of an article’s argument. . .
. . .the comments section of any engaging article is almost as necessary a read as the piece itself — if you want to know how insider experts received the article and how those outsiders processed the news (and maybe to enjoy some nasty snark from the trolls).
Should this part of every contemporary article be curated and edited, almost like the piece itself? Should it have a name? Should it be formally linked to the original article or summarized at the top? By now, readers understand that the definitive “copy” of any article is no longer the one on paper but the online copy, precisely because it’s the version that’s been read and mauled and annotated by readers. (If a book isn’t read until it’s written in — as I was always told — then maybe an article is not published until it’s been commented upon.) Writers know this already. The print edition of any article is little more than a trophy version, the equivalent of a diploma or certificate of merit — suitable for framing, not much else.
I think this is exactly what science is about, and exactly what it needs. People should be able to read the latest results, add their opinions and criticisms to them, and those comments in turn should also be available for everyone to see. There's going to be noise in there, but I'll take some noise as the price that gets paid for figuring things out more quickly and more completely than we ever could before. As far as I'm concerned, the "peer" in "peer review" means "Everyone who can read and understand the paper".
+ TrackBacks (0) | Category: The Scientific Literature
Roche has halted trials of its CETP inhibitor dalcetrapib. Many will remember the Pfizer compound in this class, torcetrapib, which went down catastrophically in Phase III back in 2006. In that case, deaths in the treatment group were higher than the placebo group, which will bring you to a screeching halt every time. The generally accepted story is that the compound's effects on blood pressure (and possibly electrolyte balance) negated its beneficial effects on lipoproteins. But was torcetrapib actually working? It certainly raised HDL levels - but is that enough?
You have to wonder. Dalcetrapib wasn't taken out by toxicity - it was dropped because of "a lack of clinically meaningful efficacy". Analysis of several Phase II trials seems to have shown no beneficial outcome in cardiovascular mortality and mobidity. So what is it that we don't know about CETP, about HDL, and about lipoprotein roles in cardiovascular disease in general? Quite a bit, is my guess.
Two companies that are very, very much pondering that question are Merck and Eli Lilly, both with competing CETP inhibitors in the clinic. Expect statement from each of them that they continue to have confidence in their clinical candidates. But behind the scenes, expect a lot of very intense re-evaluation.
+ TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials
May 4, 2012
Now these are the funkiest structures I've seen in quite a while. I won't spoil the surprise; if you're an organic chemist, go ahead and click on the link. This is one of those "No one's made compounds like this, so let's see if they do anything" papers, and I'd say that if you're going to do that sort of thing, you should go pretty far off the beaten path. That they have.
These compounds are - not surprisingly - said to be cytotoxic, with activity against a range of cancer cell lines. A couple of passes through the paper, and I haven't found any normal cells used as controls for all that cytotoxicity. Sad to say, the betting would be that there's no window at all. But at least I've seen a class of compounds that I'll bet has never made it into J. Med. Chem. before.
+ TrackBacks (0) | Category: Cancer | Chemical News
Benlysta got approved for lupus last year, as the first new drug in the field in decades. But as noted at the time, it didn't exactly blow the doors out at the FDA, nor in the clinic. Now it's having a rough time in Europe, which makes things interesting for both Human Genome Sciences and their partners at GlaxoSmithKline.
Both the British (NICE) and German (IQWiG) agencies responsible for assessing the cost/benefit of new drugs have recommended against Benlysta's use. This adds some drama to GSK's recent offer of $2.6 billion for HGSI, which the smaller company turned down out of hand. Their case for a higher bid seems to be based on the market potential of Benlysta, but the arguing has begun over how realistic those hopes are. This is the sort of issue that gets settled with a sales price - or perhaps, in this case, just an upper bound. . .
+ TrackBacks (0) | Category: Business and Markets
Here's a Reuters headline for you: "GSK rejects idea of buying AstraZeneca".
In other news, Delta Airlines has rejected the idea of making its new fleet of long-range passenger jets out of bamboo and stale Fig Newton bars. There are also reports this morning that Burger King has rejected the idea of buying Birkenstock and cramming their sandals into buns in lieu of hamburger patties. More business news as it become available.
+ TrackBacks (0) | Category: Business and Markets
May 3, 2012
Here's an excellent piece by venture capital guy Bruce Booth, looking back at the heady days of 1991-1994. I can tell you that they weren't so heady in Big Pharma, but there were a lot of startups coming along. Included are some really big names of today, but also a lot of outfits that no one even remembers any more. And how have investors fared? That depends:
Only a subset of the 1991-1994 IPO window have accrued real value over time. There were certainly a few big winners in there – Gilead probably being the biggest, up over 100x since its IPO in 1992. MedImmune also fared quite well with its $16B acquisition (though AZ is not thrilled about it now), and Vertex is up 10x.
But let’s take the prior two examples, Isis and Amylin, which represent “successful” 20-year old mid-cap biotechs. Both have gone from preclinical stage companies around their IPOs to having products launched or filed with the FDA. But they haven’t really created any shareholder value over 20 years. Isis today trades at $8 per share, but it went public at $10 per share. Amylin went out at $14, but closed on the end of its first day of trading in 1992 at $21 per share. It now trades at $25. So for 20 years, these companies (and many, many others in the 1991-1994 cohort) have underperformed not only all major equity indices, but also treasury bills, and consumed billions in equity capital. And recall that many more companies from this window, probably at least half, ended up dying long whimpering deaths like long-forgotten Autoimmune Inc and Alpha-Beta Technology.
And that's a big reason why you don't see so many big biotech/small pharma IPOs any more. The markets are a different place, twenty years on:
The current reality, shaped by a couple decades of lackluster performance, is that the public markets aren’t open for business in biotech. While they are much less tolerant of the value-destroying tactics of the past (which is a good thing), they have also set the bar so high as to discourage even great, innovative companies from considering it as a viable option. In this new world, the old company building models just don’t work: it’s hard to back a startup today with an investment thesis around “we’re building the next Gilead” – the capital markets are just so different.
Small companies have to act differently, raise money differently, and sell themselves differently these days. Stay private, do as much virtually/outsourced, sell out to Big Pharma earlier than before. . .it's worth another post or two to talk about some of those models, but the "Let's Have an IPO!" one isn't going to be on the list. Not for some time to come, anyway.
+ TrackBacks (0) | Category: Business and Markets | Drug Industry History
Has the last shot been fired, very quietly, in the COX-2 discovery wars? Here's the background, in which some readers of this site have probably participated at various times. Once it was worked out that the nonsteroidal antiinflammatory drugs (aspirin, ibuprofen et al.) were inhibitors of the enzyme cyclooxygenase, it began to seem likely that there were other forms of the enzyme as well. But for a while, no one could put their hands on one. That changed in the early 1990s, when Harvey Herschman at UCLA reported the mouse COX2 gene. The human analog was discovered right on the heels of that one, with priority usually given to Dan Simmons of BYU, with Donald Young of the University of Rochester there at very nearly the same time.
The Rochester story is one that many readers will be familiar with. The university, famously, obtained a patent for compounds that exerted a therapeutic effect through inhibition of COX-2, without specifying what compounds those might be. They did not, in fact, have any, nor did they give any hints about what they'd look like, and this is what sank them in the end when the university lost its case against Searle (and its patent) for not fulfilling the "written description" requirement.
But there was legal action on the BYU end of things, too. Simmons and the university filed suit several years ago, saying that Simmons had entered into a contract with Monsanto in 1991 to discover COX2 inhibitors. The suit claimed that Monsanto had (wrongly) advised Simmons not to file for a patent on his discoveries, and had also reversed course, terminating the deal to concentrate on the company's internal efforts instead once it had obtained what it needed from the Simmons work.
That takes us to the tangled origin of the COX2 chemical matter. The progenitor compound is generally taken to be DuP-697, which was discovered and investigated before the COX-2 enzyme was even characterized. The compound had a strong antiinflammatory profile which was nonetheless different from the NSAIDS, which led to strong suspicions that it was indeed acting through the putative "other cyclooxygenase". And so it proved, once the enzyme was discovered, and a look at its structure versus the marketed drugs shows that it was a robust series of structures indeed.
One big difference between the BYU case and the Rochester case was the Simmons did indeed have a contract, and it was breach-of-contract that formed the basis for the suit. The legal maneuverings have been going on for several years now. But now Pfizer has issued a press release saying that they have reached "an amicable settlement on confidential terms". The only real detail given is that they're going to establish the Dan Simmons Chair at BYU in recognition of his work.
But there may be more to it than that. Pfizer has also reported taking a $450 million charge against earnings related to this whole matter, which certainly makes one think of Latin sayings, among them post hoc, ergo propter hoc and especially quid pro quo. We may not ever get the full details, since part of the deal would presumably include not releasing them. But it looks like a substantial sum has changed hands.
+ TrackBacks (0) | Category: Drug Development | Drug Industry History | Patents and IP
May 2, 2012
There's a new paper out in Cell Metabolism on resveratrol and SIRT1, and the press release from Elsevier (Cell Press) is just a tiny bit optimistic. "Study resolves controversy on life-extending red wine ingredient, restores hope for anti-aging pill", says the headline, but believe me, no one paper is going to do that. (This entry has links back to some of the history of the compound and the target, as covered here, but it's a convoluted story indeed). The EmbargoWatch web site calls it a "truly appalling" press release, and while I can't disagree with that, I don't think it particularly stands out: a lot of press releases are appalling.
And I disagree with them when they say that studies like this "probably don't deserve any coverage at all". It's actually a very interesting paper, even if it's not going to resolve any major controversies all by itself. It's from David Sinclair and co-workers (a large international team), and it presents the results of a long-running effort to see if what resveratrol does in animals that don't have the SIRT1 protein at all. That's a good experiment, which cuts right to the question of whether resveratrol's effects are SIRT1-driven or not. Problem is, the traditional knockout mouse model is almost always embryonic lethal in that case, so it's not so simple that generate such animals. The team was able to develop inducible whole-body conditional knockout adult mice, though, and set about dosing them with resveratrol to see what happened then.
Well, quite a few things did. From what I can see, the marquee items are these: normal mice fed a high-fat regimen showed beneficial effects on their mitochondria when given resveratrol, but the knockouts didn't, so that might be a clear connection to SIRT1. Resveratrol's effects on AMPK appear to be SIRT1-dependent (there are several links in this post about that connection, some of which led to papers that hypothesized a SIRT1-independent effect). But resveratrol treatment had good effects on glucose levels in mice, whether or not they had SIRT1 present, so that part seems to be going through some other pathway.
Sinclair's quoted in this Nature News piece as saying that this reflects the nature of resveratrol as a compound. “Resveratrol is a dirty, dirty molecule, very non-specific", he says. I think that's a very fair characterization, which is one of the reasons why I wouldn't take it myself. (That does shed an interesting light on the 2010 controversy when two former Sirtris executives set up their own reveratrol distribution effort, though, doesn't it?)
It would be quite interesting, for the sheer science of it, to take one of the later (apparently cleaner and more targeted) SIRT1 activating compounds that have come out of the GSK/Sirtris work and run it through the same animal model. You might expect the same sorts of SIRT1-driven effects, and perhaps much less of an effect on blood glucose, if that's really some off-target resveratrol thing. But since we're talking about epigenetic enzymes here, prediction is a chancy business. I wonder if this experiment is being done somewhere?
+ TrackBacks (0) | Category: Aging and Lifespan
May 1, 2012
Just another nitpicking note: if you're going to publish a paper on glucose conjugates of drugs (aspirin, in this case), you might want to be sure to draw the glucose as the correct enantiomer. I had to do a little head-scratching with this one, since the sugar ring is drawn from a perspective that no carbohydrate chemist would ever use, but as far as I can tell, that's L-glucose instead of D. . .
This is not as big a deal in the grand scheme of things, but it particularly gets to me, as someone who worked with sugars as chiral starting materials for 4 1/2 years. And then, every chemical drawing program extant will draw you the correct stereochemistry. . .
+ TrackBacks (0) | Category: The Scientific Literature
Let's file this one under "Cultural Differences Between Chemists and Biologists". Have any of my chemistry colleagues out there noticed the difference in presentation detail between the two disciplines?
It's struck me several times over the years. Biologists seem, on average, to go into much more granular detail about their experiments when presenting to a mixed audience than do most chemists. Buffers, buffers that worked a little better, buffers that worked a bit worse, the brand of the sizing column, western blot after western blot. The usual chemistry comment was always "Hey, I don't show pictures of my TLC plates", but eventually I suppose we'll need to come up with another line as LC/MS takes over the world.
Even presenting among their own tribe, most chemists don't (to me) seem to go to the level of detail that I often see from protein purification people or pharmacologists. My theory is that most forms of biology still have so many hidden variables in them (since it's an intrinsically more complex and less understood science) that all the details need to be specified. Organic chemistry, for all its troubles, still tends to be more reproducible, on average, than molecular biology, and at a less picky level of detail
That's why chemists don't often feel the need to go into details even in a room full of chemists: "We had the bromide, so we made these coupled products, and then we made these by reductive amination. . ." substitutes for "We had the aryl bromide, so we reacted it with a list of boronic acids under palladium-catalyzed coupling conditions to give these products, each of which still has the aldehyde in the 3-position, which we purified by chromatography in an ethyl acetate/hexane gradient over 8-gram ISCO silica gel cartridges. We then reacted them with a list of amines using sodium triacetoxyborohydride in dichloromethane at room temperature, followed by a chromatography in 1 to 5% methanol/dichloromethane. . . ". Each of those steps has plenty of other options - different reagent combinations, solvents, etc., and if some colleague needs to reproduce your work, they'll check your notebook or ask you "Hey, what did you guys use for those Suzukis? Dppf? Yuck."
We certainly won't go into that level of detail in a room half full of biologists - it's mostly "We made these, and these, and these", which spares everyone. No TLC plates, no LC/MS traces, no NMR spectra. But they're available if you want 'em.
+ TrackBacks (0) | Category: Life in the Drug Labs
John LaMattina has a good piece up on the FDA, where they might be trying to have it both ways. About a recent speech by Janet Woodcock, he has this:
But Dr. Woodcock begins to stray into areas where I think she is off base. For one thing, she asserts that “many late stage [clinical] failures are due to efficacy problems.” That’s not exactly true. It is only when companies take compounds into late stage development with little or poor proof-of-concept data where this happens. The majority of phase 3 clinical trial failures are due to unforeseen, unpredicted side-effects or else due to finding that, in direct comparison to existing therapy, the new drug doesn’t show the superiority necessary to be successful commercially. Dr. Woodcock goes on to advocate for the generation of “evaluative tools,” new methodologies that can better predict the performance of a compound in late stage studies.
Of course, those tools are a good idea, and would be worth a lot (which is why everyone's been spending time and money trying to find them). But the FDA will not approve drugs based on them. They probably shouldn't - as LaMattina says, there have been quite a few drugs in recent years that looked like they would work based on one secondary endpoint or another, only to come up short in the real world. Woodcock is right to call for such approaches, but they won't necessarily shorten the time until approval. The hope is that they'll save time and money another way, in letting us kill projects earlier, with some hope of being right. Anything that spares us an unnecessary Phase II, or especially an unnecessary Phase III, is a good thing. But the eventual drug is going to have to jump through all the hoops, same as before.
+ TrackBacks (0) | Category: Regulatory Affairs