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
April 30, 2010
In case anyone missed it, a commenter on this post unearthed a really extraordinary find in the chemical literature. Here's an obscure isolation paper, from an obscure Chinese journal, reporting on a profoundly boring list of marine natural products.
What's so great, you ask? Well, take a look at the list. Dum de dum. . .hold on a minute, bis(2-ethylhexyl) phthalate? From Streptomyces, you say? When it's one of the most common plasticizers in the world, a bulk industrial chemical that, well, notoriously leaches out of labware under solvent exposure? Sure thing, guys. Sure thing.
+ TrackBacks (0) | Category: How Not to Do It
I'm working on breaking out the "Rate The Chemical Supplier" posts into a separate area for reference. But here's another interesting contribution in that area. This paper looks at several of the big compound-library suppliers, and evaluates their collections based on compound uniqueness, physical properties, etc.
The take-home? Suppliers seem to have paid more attention to making unique compounds over the last few years, in attempts to stand out from the herd. The percentage of compounds with roughly drug-like properties has increased a bit since 2006 (with Enamine running high and SALOR running low), although the ones with lead-like properties (smaller, etc.) has gone down a touch over the same period (Chembridge and Enamine are probably two of the best in that regard). And the different suppliers actually vary quite a bit in the diversity of their collections: Life Chemicals and AMRI, for example, tend to have larger clusters of similar compounds, while Peakdale and Oakwood have many more singletons. (Whether these are bugs or features depends on what you're looking for). If you're buying large numbers of diverse compounds for screening, the paper's definitely worth a look.
+ TrackBacks (0) | Category:
Many readers will have heard of Rosetta@Home. It's a distributed-computing approach to protein folding problems, which is certainly an area that can absorb all the floating-point operations you can throw at it. It's run from David Baker's lab at the University of Washington, and has users all over the world contributing.
A reader sends along news that recently the project seems to have come across a good hit in one of their areas, proteins designed to bind to the surface of influenza viruses. It looks like they have one with tight binding to an area of the virus associated with cell entry, so the next step will be to see if this actually prevents viral infection in a cell assay.
At that point, though, I have to step in as a medicinal chemist and ask what the next step after that could be. It won't be easy to turn that into any sort of therapy, as Prof. Baker makes clear himself:
Being able to rapidly design proteins which bind to and neutralize viruses and other pathogens would definitely be a significant step towards being able to control future epidemics. However, in itself it is not a complete solution because there is a problem in making enough of the designed proteins to give to people--each person would need a lot of protein and there are lots of people!
We are also working on designing new vaccines, but the flu virus binder is not a vaccine, it is a virus blocker. Vaccines work by mimicking the virus so your body makes antibodies in advance that can then neutralize the virus if you get infected later. the designed protein, if you had enough of it, should block the flu virus from getting into your cells after you had been exposed; a vaccine cannot do this.
One additional problem is that the designed protein may elicit an antibody response from people who are treated with it. in this case, it could be a one time treatment but not used chronically.
The immune response is definitely a concern, but that phrase "If you had enough of it" is probably the big sticking point. Most proteins don't fare so well when dosed systemically, and infectious disease therapies are notorious for needing whopping blood levels to be effective. At the same time, there's Fuzeon (enfuvirtide), a good-sized peptide drug (26 amino acids) against HIV cell entry. It was no picnic to develop, and its manufacturing was such an undertaking that it may have changed the whole industry, but it is out there.
My guess is that Rosetta@Home is more likely to make a contribution to our knowledge of protein folding, which could be broadly useful. More specifically, I'd think that vaccine design would be a more specific place that the project could come up with something of clinical interest. These sorts of proteins, though, probably have the lowest probability of success. The best I can see coming out of them is more insight into protein-protein interfaces - which is not trivial, for sure, but it's not the next thing to an active drug, either.
+ TrackBacks (0) | Category: Biological News | Drug Development | Infectious Diseases
April 29, 2010
I'm not sure how to interpret this, but my wife just sent me this link. She points out that the item is not only on sale, but that I can get free one-day shipping. Time, however, appears to be running out on that last option, so I must (yes!) act without delay.
I'm thinking of counteroffering with a different allotrope. I'll let everyone know how that goes.
Update: her latest offer is an equitable 50:50 deal - I buy her the ring, and she gets the graphite rod for me. That plan is, I think, that this way I get the shaft twice.
+ TrackBacks (0) | Category: Blog Housekeeping
In keeping with the problem discussed here ("sticky containers"), there's a report that a lot of common spectrometric DNA assays may have been affected by leaching of various absorbing contaminants from plastic labware. If the published work is shown relative to control tubes, things should be (roughly) OK, but if not, well. . .who knows? Especially if the experiments were done using the less expensive tubes, which seem to be more prone to emitting gunk.
We take containers for granted in most lab situations, but we really shouldn't. Everything - all the plastics, all the types of glass, all the metals - is capable of causing trouble under some conditions. And it tends to sneak up on us when it happens. (Of course, there are more, well, noticeable problems with plastics in the organic chemistry lab, but that's another story. Watch out for the flying cork rings!)
+ TrackBacks (0) | Category: Biological News | Life in the Drug Labs
Here's something I never knew: odors can regulate lifespan. Well, in fruit flies, anyway - a group at Baylor published results in 2007 showing that exposure to food-derived odors (yeast smells, in the case of Drosophila) partially cancels out the longevity-inducing effects of caloric restriction. Normally fed flies showed no effect.
That 2007 paper identified a specific sensory receptor (Or83b) as modulating the effect of odor on lifespan. Now comes a report that another receptor has been tracked down in this case, the G-protein coupled Gr63a. Flies missing this particular olfactory GPCR no longer show the lifespan sensitivity to yeast odors. This narrows things down. Or83b mutations seem to broadly affect sensory response in flies, but this is a much more specific receptor, just one of a great many similar ones:
"Unlike previous reports involving more general olfactory manipulations, extended longevity via loss of Gr63a occurs through a mechanism that is likely independent of dietary restriction. We do, however, find that Gr63a is required for odorants from live yeast to affect longevity, suggesting that with respect to lifespan, CO2 is an active component of this complex odor. Because Gr63a is expressed in a highly specific population of CO2-sensing neurons (the ab1C neurons) that innervate a single glomerulus in the antennal lobe (the V glomerulus), these data implicate a specific sensory cue and its associated neurosensory circuit as having the ability to modulate fly lifespan and alter organismal stress response and physiology. Our results set the stage for the dissection of more complex neurosensory and neuroendocrine circuits that modulate aging in Drosophila. . ."
It's going to be very interesting to follow that neuronal pathway - I've no idea where it will lead, but we're bound to learn something worthwhile. To make a wild generalization straight up to humans, this makes me wonder about people who are practicing caloric restriction on themselves - they're still exposed to food odors all the time, right? Does the same reversal apply? For me, I think that the scent of barbecue and fried catfish might be enough to do it right there, but keep in mind that I'm from Arkansas. Your mileage may vary.
+ TrackBacks (0) | Category: Aging and Lifespan | Biological News
Adam Feuerstein schools the Generex folks on what a "Treatment IND" really means, quoting chapter and verse from the FDA. The company's fans have made much of that designation for its flagship buccal insulin product. As has the company's CEO - but that link shows her making statements at investor conferences which are, on the face of them, in flat contradiction to the FDA's own understanding of such matters.
The article's worth reading even if you don't give two hoots about Generex, since it'll give you an understanding of what it means (and doesn't mean) when a company has a product designated for "compassionate use". It can also give you an understanding of what it means when a company misrepresents that status, but I think a lot of people here already know what that must mean. . .
+ TrackBacks (0) | Category: Business and Markets | Diabetes and Obesity | Regulatory Affairs
April 28, 2010
The Wall Street Journal has an article detailing some of Pfizer's plans in the biologics area: stepping in with second-generation versions of current winners from other companies. New versions of Rituxan and Enbrel are in the works, with the improvements mostly coming in how often the drugs need to be given.
They're not alone in this - Merck has announced that they're going to go after the same sorts of markets. And I can see the business rationale, since the original products have been such huge successes. But these new versions are going to be different enough that they're certainly not "biosimilars" or "biogenerics" - they're new substances, which will require their own complete safety/efficacy clinical workup. And by the time they get to market, some of these may be up against (or close to being up against) lower-cost versions of the original therapies, so the insurance companies are going to have to see some real benefit before they switch away.
So while some of these may well work out, not all of them will. It looks like a worthwhile thing to try, but it's not a sure road to riches. That's the thing about this industry these days - all those roads appear to be blocked off and plastered with "Detour" signs. . .
+ TrackBacks (0) | Category: "Me Too" Drugs | Drug Development | Drug Prices
I've had a few requests to make the blog available in a Kindle
version. So after a visit to the innards of Amazon, here it is, for those of you who'd like things delivered in that format. I don't own one of them myself, but I can definitely see the point of one (or something like it).
+ TrackBacks (0) | Category: Blog Housekeeping
Christoph Westphal gave what by all accounts was a very interesting talk at the recent Bio-IT conference. And considering his track record in company formation, he's well worth listening to. But concerning the recent controversy over the compounds and results from his most recent success (Sirtris), I found this part of his speech. . .well, interesting:
"There’s a debate in the academic world,” Westphal acknowledged. “We don’t know the specific molecular mechanism of why you need a specific substrate on the in vitro screen to find Sirt1 activators. Pfizer, Amgen, GSK, Sirtris, everyone in academia agrees on that. Then the question is: Is the mechanism direct on SIRT1 or indirect on SIRT1? Everyone in the field agrees our molecules have beneficial effects in animals, and I hope they will in man soon. The specifics of the mechanism are under debate. This kind of thing will be debated for ten years.”
Emphasis mine. And I emphasize that part because Pfizer specifically tested one of the highlighted Sirtris compounds, SRT1720, and was unable to reproduce the in vivo effects. So no, I wouldn't say that "everyone agrees" on this point. Not quite.
Westphal says that there's another paper in press that might be able to clear things up a bit, so we'll see what that one has to say. And he's right that the clinical results are what will really settle these questions - but we're going to have to wait a while for those. For now, agreement on a lot of key points remains hard to come by. . .
+ TrackBacks (0) | Category: Aging and Lifespan | Business and Markets
I wrote here some time ago about human cells actually making their own morphine - real morphine, the kind that everyone thought was only produced in poppy plants. Now there's a paper in PNAS where various deuterium-labeled precursors of morphine were dosed in rats, and in each case they converted it to the next step in the known biosynthesis. The yields were small, since each compound was metabolically degraded as well, but it appears that rats are capable of all steps of a morphine synthesis from at least the isoquinoline compound tetrahydropapaveroline (THP).
And that's pretty interesting, because it's also been established that rats have small THP in their brains and other tissues - as do humans. And humans, it appears, almost always have trace amounts of morphine in the urine - which leads one to think that our bodies may well, in fact, be making it themselves.
Why that's happening is quite another question, and where the THP comes from is another one. Working under the assumption that all this machinery is not just there for the heck of it, you also wonder if this system could be the source of one or more drug targets (I spoke about that possibility here). What you probably don't want to assume is that these targets would necessarily have to do with pain. We still don't know if there's room to work in here. But it's worth thinking about, if (for no other reason) to remind ourselves that there are plenty of things going on inside the human body that we don't understand at all.
+ TrackBacks (0) | Category: Biological News | The Central Nervous System
April 27, 2010
I've heard that Merck told employees today that the Union site (an old Schering-Plough facility) will be closed. Apparently employees from both the Rahway and Union sites will be part of a pool when it comes to job cuts as a result of this, though - it's not just everyone who was working at Union.
This doesn't surprise me, actually. Union was one of the oldest of the Schering-Plough sites (perhaps the oldest after the company moved out of Bloomfield in 1992?) It always seemed a bit odd to have it and Kenilworth right next to each other, and throwing Rahway into the mix meant that something was probably going to give. . .any more details from the Merck people out there?
+ TrackBacks (0) | Category: Business and Markets
Every year there's a big Cambridge Science Festival, which many companies and institutions around here get involved with. My own company is no exception, and we're holding a "Networking Event" for students in academia tomorrow afternoon. Flyers for it went out a while back to all sorts of institutions around the area, but for anyone who's also a reader of this blog, I wanted to mention that I'll be giving a 30 minute talk at this one. So if you're in the target audience, feel free to stop by (4 PM Wednesday, 200 Sidney Street). I believe that there was an RSVP by last Friday, but drop me an email if you missed it, because I don't think we're going to lock anyone out if you really want to come, either.
+ TrackBacks (0) | Category: Blog Housekeeping
I've said several times that I think that mass spectrometry is taking over the analytical world, and there's more evidence of that in Angewandte Chemie. A group at Justus Liebig University in Giessen has built what has to be the finest imaging mass spec I've ever seen. It's a MALDI-type machine, which means that a small laser beam does the work of zapping ions off the surface of the sample. But this one has better spatial resolution than anything reported so far, and they've hooked it up to a very nice mass spec system on the back end. The combination looks to me like something that could totally change the way people do histology.
For the non-specialist readers in the audience, mass spec is a tremendous workhorse of analytical chemistry. Basically, you use any of a whole range of techniques (lasers, beams of ions, electric charges, etc.) to blast individual molecules (or their broken parts!) down through a chamber and determine how heavy each one is. Because molecular weights are so precise, this lets you identify a lot of molecules by both their whole weights - their "molecular ions" - and by their various fragments. Imagine some sort of crazy disassembler machine that rips things - household electronic gear, for example - up into pieces and weighs every chunk, occasionally letting a whole untouched unit through. You'd see the readouts and say "Ah-hah! Big one! That was a plasma TV, nothing else is up in that weight range. . .let's see, that mix of parts coming off it means that it must have been a Phillips model so-and-so; they always break up like that, and this one has the heavier speakers on it." But mass spec isn't so wasteful, fortunately: it doesn't take much sample, since there are such gigantic numbers of molecules in anything large enough to see or weigh.
Take a look at this image. That's a section of a mouse pituitary gland - on the right is a standard toluidine-blue stain, and on the left is the same tissue slice as imaged (before staining) by the mass spec. The green and blue colors are two different mass peaks (826.5723 and 848.5566, respectively), which correspond to different types of phospholipid from the cell membranes. (For more on such profiling, see here). The red corresponds to a mass peak for the hormone vasopressin. Note that the difference in phospholipid peaks completely shows the difference between the two lobes of the gland (and also shows an unnamed zone of tissue around the posterior lobe, which you can barely pick up in the stained preparation). The vasopressin is right where it's supposed to be, in the center of the posterior lobe.
One of the most interesting things about this technique is that you don't have to know any biomarkers up front. The mass spec blasts away at each pixel's worth of data in the tissue sample and collects whatever pile of varied molecular-weight fragments that it can collect. Then the operator is free to choose ions that show useful contrasts and patterns (I can imagine software algorithms that would do the job for you - pick two parts of an image and have the machine search for whatever differentiates them). For instance, it's not at all clear (yet) why those two different phospholipid ions do such a good job at differentiating out the pituitary lobes - what particular phospholipids they correspond to, why the different tissues have this different profile, and so on. But they do, clearly, and you can use that to your advantage.
As this technique catches on, I expect to see large databases of mass-based "contrast settings" develop as histologists find particularly useful readouts. (Another nice feature is that one can go back to previously collected data and re-process for whatever interesting things are discovered later on). And each of these suggests a line of research all its own, to understand why the contrast exists in the first place.
The second image shows ductal carcinoma in situ. On the left is an optical image, and about all you can say is that the darker tissue is the carcinoma. The right-hand image is colored by green (mass of 529.3998) and red (mass of 896.6006), which correspond to healthy and cancerous tissue, respectively (and again, we don't know why, yet). But look closely and you can see that some of the dark tissue in the optical image doesn't actually appear to be cancer - and some of dark spots in the lighter tissue are indeed small red cells of trouble. We may be able to use this technology to diagnose cancer subtypes more accurately than ever before - the next step will be to try this on a number of samples from different patients to see how much these markers vary. I also wonder if it's possible to go back to stored tissue samples and try to correlate mass-based markers with the known clinical outcomes and sensitivities to various therapies.
I'd also be interested in knowing if this technique is sensitive enough to find small-molecule drugs after dosing. Could we end up doing pharmacokinetic measurements on a histology-slide scale? Ex vivo, could we possibly see uptake of our compounds once they're applied to a layer of cells in tissue culture? Oh, mass spec imaging has always been a favorite of mine, and seeing this level of resolution just brings on dozens of potential ideas. I've always had a fondness for label-free detection techniques, and for methods that don't require you to know too much about the system before being able to collect useful data. We'll be hearing a lot more about this, for sure.
Update: I should note that drug imaging has certainly been accomplished through mass spec, although it's often been quite the pain in the rear. It's clearly a technology that's coming on, though.
+ TrackBacks (0) | Category: Analytical Chemistry | Biological News | Cancer | Drug Assays
April 26, 2010
Last year I wrote about the hideous structure of maitotoxin, with a note about how various groups were kicking around synthetic approaches to it. Now K. C. Nicolaou has a paper out in JACS on the synthesis of a portion of the molecule, which includes the line: ". . .as a prelude to a possible synthesis of large domains of this molecule for biological investigations. . .". Yeah, sure. Betting will now commence on whether or not he'll be able to resist going for the whole thing. As to whether or not that's a good idea, well. . .my views on the subject have already been aired pretty thoroughly.
+ TrackBacks (0) | Category: Chemical News
I don't think we saw this one coming: Charles River Labs has announced that they're buying WuXi PharmaTech. They're paying about a 28% premium over Friday's closing stock price - Charles River's CEO will stay on, and WuXi's founder (Li Ge) will serve as executive VP under him.
Charles River, which is strong in the animal-testing end of the business, has apparently decided that Wu Xi is one of their biggest competitors (I'd agree) and has decided to try to stake out a leading position in the whole contract-research space. It's interesting to me that the folks at Wu Xi bought into this reasoning as well, although (since they're a publicly traded company here in the US), a lucrative stock offer can be its own argument. One now wonders, though, about the company's statements on re-staffing some of their US labs when economic conditions improve. . .
+ TrackBacks (0) | Category: Animal Testing | Business and Markets | Drug Assays | Drug Development
Well, the first thing I can tell everyone is that I think the entire editorial staff at Chemical and Engineering News read every comment to this post. And that includes the nasty ones, for sure. The readership around here is a self-selected lot, and the commentors even more so, but the quick volume of responses got a lot of attention.
I noticed a lot of discussion around the "Do we really need more chemists?" theme. Readers will be interested to know that many people at the magazine share their uneasiness with some of the never-ending "scientist shortage" talk. The ACS's own figures (which many here seem to feel are too low) nevertheless show the highest unemployment rates among chemists they've ever shown.
Outside of the issues that came up here on the site, one of the things I suggested was more focus on smaller companies - both in terms of plain science/business news, but also with reference to where they come from. My point was that chemists reading C&E News see all sorts of items about various companies, but it's as if they've condensed out of the air. If there really is any sort of economic recovery coming on, I think that one of the best chances to lower our profession's jobless rate is through startup formation, and I told the people at the magazine that they should keep this in mind.
I wasn't in the discussion groups that touched on another theme that came up here in the comments, the long-running "Women in Chemistry" articles. And it's probably a good thing - I tend to be pretty much an eye-roller when it comes to corporate diversity programs, but I get the feeling that no one at the ACS (or its publications) feels safe doing so much as that, even if they were so inclined. For the record, I have no problem at all, of course, with women in chemistry, or anyone else in chemistry - it's just the let's-all-join-hands march-of-progress stuff that can get tedious. The people whose march through the ranks I most want to promote are the people who are good at it, whoever that might turn out to be.
One thing I found interesting is that the writers, although almost all of them have chemistry training, seem to feel apart from the actual business of chemistry. That's understandable, I suppose, because their profession is really journalism. I told them that not being a journalist made writing a blog a lot easier. . .
+ TrackBacks (0) | Category: Chemical News | Current Events
April 21, 2010
I note that one of the biggest topics in the "What To Tell the C&E News People" comment thread is chemical employment. And it should be - there are far fewer med-chem jobs out there today than there were five years ago, and it's getting harder and harder to imagine things coming back to the way that they once were.
In fact, I don't see any way that they can, at least if by "the way they once were", you mean the number of well-paid US-based positions at large pharma companies. I hate to sound like this, but I think there's been too much of a shift in recent years for anything to undo it. Costs have gone up, drug-development success rates have (at best) not increased, and there are cheaper ways to get a good amount of work done which used to cost more. Which of these things are going to change back, and how?
We can argue about how effective some outsourcing is, but it's definitely not worthless. And we can certainly argue about whether companies have cut too far back in the current downturn. But (and I've said this before around here), what I really have trouble with are two solutions that get proposed every time this topic comes up.
The first of these is "Cut back on work visas". Well, that's the milder form of it - this point of view has a way of slipping down to "Ship 'em all back" sometimes. Either way, what people who advocate this seem to believe is that companies will gladly hire American-based scientists if they're just, you know, forced to. I can't see it. And as I've said here before, I'm not particularly focused on bettering the lives of American scientists as opposed to those coming in from other countries. Many of them become Americans themselves, and I'm glad to have them. We can use all the intelligent, resourceful, hard-working people here that we can get.
The second solution that gets aired out is "Form a Union!" And I have to say that I have even less patience for this one. I'm not a big union fan in general, actually, and I think that in this case it's an even worse idea than usual. What leverage do employees have? Here's the problem that sinks many such ideas: the US is not an island nation, in any sense of the word. If you force the cost of doing business here up even higher, the jobs will leave even faster. There are now places for them to go, which is the biggest change of the last ten or twenty years. Those places are often not quite as good in some ways (for now), but they're a lot less expensive, and that's where the money will flow if the deal looks reasonable. The only thing that will slow this down is if things get cheaper here (which isn't too likely), or if they get more expensive over there (which is quite likely indeed, actually - a topic for another day).
So to me, both of these proposals boil down to forcing companies to pay more for what they can get elsewhere. In my opinion, they're both unworkable and likely to make the situation deteriorate even faster than it is already.
Update: fixed typos, I think. Views remain the same! As to the "scientist shortage" talk that keeps popping up, I agree with the people who are ticked off about that one. We clearly have no great shortage of scientists at the moment in the fields that I have personal experience of. But this is (or ideally should be) something of a separate topic from immigration, and will be the topic of a future post. . .
+ TrackBacks (0) | Category: Business and Markets | Drug Industry History
April 20, 2010
Still traveling, so not much time to update things. Here are a couple of interesting links, though:
Adam Feuerstein's take on the Rexahn clinical data (which I spoke about here). He's not all that impressed, either, to put it delicately.
Big Pharma bonds getting downgraded - orrg. Smaller companies tend to raise more money with equity, but debt financing gets more and more important as time goes on, so this isn't a good sign.
+ TrackBacks (0) | Category: Current Events
April 19, 2010
Thanks for all the comments to the previous post! And please, non-chemists who read or have a use for the magazine, please feel free to chime in as well.
Just to clear up some confusion, though, this is only an advisory position, and there are plenty of other people from academia and industry who also serve in the same capacity. I'm doing the same job I have been (and writing this blog the same way I have been as well!) Nothing's been affected, but it seems from the comments that some people have thought otherwise.
What will be affected around here this week is posting, which will be irregular. I'll try to get some things up, but it'll be haphazard. And I'll report back on the meeting with the C&E News folks as well.
+ TrackBacks (0) | Category: Blog Housekeeping
April 18, 2010
I'll be traveling Monday, so no new posts during the day. But I'm traveling to something that's of interest to many of the readers here, so I wanted to throw the floor open to questions. I've been invited to be on the editorial advisory board of Chemical and Engineering News, and I'll be meeting with the staff there later this week.
So I wanted to ask the chemists in the crowd: what do you think that C&E News does well, and what do you think it does poorly? Are there topics that you think are covered too much, or some that you think aren't being addressed? Please feel free to add comments - I'll collate them and pass them on to the staff there.
+ TrackBacks (0) | Category: Press Coverage
April 16, 2010
You know, let's just declare this "Sketchy Biotech Day" around here. A reader sends along this intriguing news item from Maryland regarding Rexahn Pharmaceuticals. They recently reported clinical data on their lead compound, Serdaxin,:
On Tuesday, the Rockville company reported the drug performed well in a phase 2a clinical trial for treating patients with one such ailment: major depressive disorder. But the announcement also said "the overall study did not achieve statistical significance," worrying investors and sending Rexahn's stock price tumbling from $3.53 to $1.76 that day.
Wednesday morning, executives felt compelled to issue a follow-up statement, offering "additional commentary, clarifications and insights" to allay investors' concerns. That apparently did the trick — at least somewhat. By the end of trading on Wednesday, the price had rebounded to $2.15. By Thursday morning, shares had climbed to $2.51; they were trading at $2.47 Thursday afternoon.
In its initial statement, Rexahn said that results from the trial, which enrolled 77 patients at several sites in the U.S., "are compelling and warrant further study in a larger phase 2 trial."
Well, to me, "compelling" clinical trial numbers are a hard thing to sell without the statistics to back them up. But that's not slowing these folks down. Here I offer you what is perhaps the most breathtaking rationalization I have yet heard about drug development - and mind you, that is saying a lot. Says Rexahn's CEO:
"Based on the feedback and reaction from our shareholders, stakeholders and other market participants, it is clear that neither the purpose of the Serdaxin trial or its results were well understood.
"The purpose of the Serdaxin Phase IIa trial was to establish, as a proof of concept, that Serdaxin can work as an antidepressant drug for patients suffering from Major Depressive Disorder," Ahn said. "I am happy to say that this is exactly what the study accomplished. The trial results unambiguously reach the conclusion that patients, especially those suffering from severe depression, respond positively to Serdaxin.
"Some market participants have asked us why our overall trial results were not statistically significant," he said. "The answer is simply that the Serdaxin study was never designed to achieve statistical significance as a primary objective, but rather to establish a positive signal among treated patients. This is exactly what the trial succeeded in accomplishing."
So here you have it: a clinical trial that was, apparently, not designed to show statistical significance. And it didn't! Champagne for everyone! Think of how many other drugs have had results just this compelling, but we've all just been too stupid to realize what we had. Throw open the pharma mausoleums and let the dead compounds come forth!
Perhaps some day we'll all look back on this event as the Day the Drug Industry Changed Forever. Or perhaps it's time to ask just what Serdaxin is. . .well, you'll never guess. It's clavulanic acid. (See, I told you that you wouldn't get it). Yep, the beta-lactamase inhibitor that's given as part of Augmentin, to overcome resistant strains of bacteria. Weirdly, it does seem to penetrate the blood-brain barrier, which is not something I would have guessed. And the Rexahn people have done some animal studies that suggest it has anxiolytic effects (as well as effects on sexual arousal, which they're not ignoring: that, friends, is the drug development candidate Zoraxel on their web site. Still clavulanic acid, though, but a rose by any other name. . .).
But none of that means a thing unless you achieve results in humans. And though I hate to contradict such a visionary mind as Dr. Ahn's, I'm afraid I'm going to have to hold out for statistical significance. And wonder, in the meantime, if any of the zillions of people who've taken clavulanate before ever noticed any elevation in their mood. Never happened to me, that's for sure. . .
+ TrackBacks (0) | Category: Clinical Trials | Drug Development | Infectious Diseases | The Central Nervous System
I've been meaning to do another post on Generex, the company that says it's developing an oral spray form of insulin as an alternative to the injected forms. This is the outfit that's suing Adam Feuerstein of TheStreet.com over his dismissive comments on their business, and here I stated that after looking the operation over a bit, that I agreed with him. In short, I have doubts about the real-world efficacy of buccal insulin delivery, doubts about the acceptance of it in the diabetes patient (and physician) population, and doubts that spring from Generex's own statements about the drug's development. A handful of patients in Ecuador does not make for a convincing reason to move into Phase III - not to me - and you don't press-release your Phase III results when you've only enrolled 10% of your targeted number of patients. And so on. . .but who am I to question the buccal spray delivery technology, when (as Generex states on their web site) it's also being used to develop an "energy spray" called Ba-Boom? (Be sure to turn up your speakers so you can hear the theme music; it's going to play when you click that link. And yes, that is Generex - look at the bottom of the page).
It's been a very busy week around here, but what I do have time to do is take a look at the recent infusion of capital the company has experienced. An investment group called Seaside 88 has announced their intention to buy a large amount of Generex stock. Among the Generex investors calling for my head (and other parts of my anatomy), opinion seems divided about Seaside 88 and my relationship to them (which, let me state right up front, is completely nonexistent - I'd never heard of the outfit until this stuff came up). Some of the hardy GNBT folks point to this deal as evidence that I'm a fool, because here's this big investment outfit pouring money into this wonderful company and its promising product. Others seem to think that I'm being paid off by said big investment outfit, that I'm a black-hatted stock-basher out to secure Seaside 88 a better deal as it scoops up this wonderful stock on the cheap.
Which exciting story to believe? Not for the first time, I'm reminded that too many people who invest in small "story" stocks have worldviews that resemble the story lines of profession wrestling. I'd call it Manichean, but that's a bit too elevated. No, it's all Good Guys and Bad Guys, and there's no room for someone like me, a person with no money in the game who finds the whole thing bizarre and amusing. The smaller the stock prices involved, by the way, the crazier the investors seem to be.
So, Seaside 88. If you go do an EDGAR search on them, you find that they've done similar stock-purchase deals with a number of small companies (and other deals show up as you Google for press releases). Flywheel energy storage companies, obscure fuel-cell makers - it's quite a collection. My personal favorite is Ensurge, Inc., and if you'd like to know what business they're in, you'll just have to read the language in their 10-K. If you're not snorting in derision by the time you get to the South-American-gold-mining stuff, then you're a born penny-stock investor. You'd have to use threats of bodily harm to make these things a centerpiece of my own investment strategy - but hey, that's why I'm going to finish up eating off-label cat food in a trailer while the Generex shareholders are sailing their yachts through the Greek islands. These things have a way of evening out.
So, who are these Seaside 88 people, anyway? Well, as is often the case, there's a whole little constellation of related companies. There's your Seaside Analytics, your Seaside Capital Management, your Seaside Capital II, and so on. One person who figures prominently in all of them is William Ritger, who's been in the investment business for some years now. Here's a biography of him from one of the companies he's helped to found.
In fact, he's been in the business long enough for this article from the the New York Times to turn up. It refers to a former venture of his, Research Works, which seems to have issued favorable reports on obscure stocks - causing their prices to jump - but without making much of the fact that he was being paid by the companies involved to write those reports. One hopes that he is no longer in the business of promoting small stocks in this manner.
Another name that shows up when you search the Seaside family of investment partnerships is Denis O'Donnell. Looking over the EDGAR filings featuring his name, you find his ongoing relationship with a company called American Bio Medica, which I note has also been listed as one of the house favorites of a micro-cap "pump and dump" junk-fax operation. He's also been involved with Columbia Laboratories - now of New Jersey, but formerly of Hollywood, Florida, where (interestingly enough) they were mentioned in that same New York Times article as the subject of one of those paid-for investment reports back in the 1990s. One hopes that he is keeping better company now.
So, Generex investors, enjoy your stock, and enjoy the company of the others who have seen fit to invest in it. I will not be putting any of my own money into it, and they won't let a person short companies that trade at 60 cents a share. Which is too bad, in a way, because the great majority of such companies go to zero.
+ TrackBacks (0) | Category: Business and Markets | Diabetes and Obesity | The Dark Side
April 15, 2010
Here's the letter sent out to Novartis employees about the new structure for their US pharma business. Stripped of the biz-speak (aligning priorities, high-growth this, competitive advantage that, you all can fill in the rest), what it says is that (first) the current US pharma head is leaving (replacment to be named soon).
Second, there will be four Business Units: primary care, multiple sclerosis, CNS, and one that looks like a catch-all, respiratory/transplant/infectious disease. The latter ones used to be under the broad heading of "Specialty Medicine" (as opposed to primary care), but now get their own billing.
The biz-speak gets especially thick in this detail-light paragraph, which I suppose will become clear with time:
To maximize investment in high-impact growth areas, we are implementing a brand prioritization approach that will allocate resources based on the brand's growth potential and lifecycle stage. This means we will elevate support for some brands and reduce support for others. We will ensure that critical patient needs are met but we can no longer sustain the old approach to resourcing. You will be hearing more about this from your functional leaders.
The one thing that is made clear in that section is that about 250 people will lose their jobs - "mostly in headquarters", it says. There's also a line about how this is all about "a shift in mindset from doing more with less to prioritizing our focus and resources". If you have some spare time, you can try to work out what the difference might be between those, how you prioritize a focus, and other such questions, but most readers will probably have something more productive to do. . .
+ TrackBacks (0) | Category: Business and Markets
Protip: making slides that refer to your company's drug as "snake oil" and illustrate its use with a cartoon of witches standing around a cauldron is perhaps unwise. Particularly when you're in Marketing. Particularly when you also include unapproved uses for your drug on the slides. Worth noting, Pfizer.
+ TrackBacks (0) | Category: Business and Markets | The Central Nervous System | Why Everyone Loves Us
April 14, 2010
We all hear about the new drugs that have just been approved, and we all keep track of the drugs that are coming off patent. But what about the really old ones, the drugs that made it to the market long before today's regulatory framework? There have long been medicines that are generally recognized as reasonably safe and effective, but have never been through much of the modern process.
The FDA has, for the last few years, been trying to catch up on these things, and has offered exclusivity to any manufacturers who are willing to run clinical trials on older medicines. But this hasn't always worked out the way that it was intended - witness the case of colchicine, a well-known natural product drug that's used for some inflammatory diseases (and used to be a chemotherapy agent, too). The Wall Street Journal has a good story on this.
URL Pharma, a generic manufacturer, took the time and trouble to get fresh data on colchicine for gout attacks, and was granted a three-year marketing exclusivity period. So far, so good - but they then turned around and ran the price up by a factor of fifteen. They also filed suit against other small companies that were selling colchicine in the generic market, with the result that other domestic sources of the drug might dry up (four of the other companies are fighting back in court).
So is this the advent of evidence-based medicine, coming to an area that had little of it before, and therefore a good thing? Is it an abuse of the system by a company that saw an opportunity to suddenly acquire pricing power? Is it just what the FDA should have expected, given that three years of marketing rights have to make up for the cost of the clinical work, with the profits likely to disappear immediately afterwards? I think it's going to be hard to have it both ways. If you expect companies to go back and fill in the clinical profile of older drugs, you do need give them some incentive to do it. But then what's to keep them from pounding that incentive in good and hard, as seems to be happening here?
I'm not sure how to split that difference, especially not with any general rule, because each case will probably be different. The new clinical trials might, in fact, uncover something really useful that was previously unknown - or they might just confirm that the way the drug was being dosed was, in fact, just the way it should be dosed. One of those seems more deserving of compensation than the other, but there's no way of knowing which result you're going to get a priori. I have an aversion to telling a company how much it can charge for a drug, but it's not like URL Pharma discovered colchicine, or had to do any of the risky early-stage work on it. I can justify some pricing moves (although not all of them) by companies that are doing discovery research, because so much of that doesn't lead to anything marketable. (Take, for example, virtually everything I've worked on my whole career). But a generic company that's coming in to dot the Is and cross the Ts on the FDA paperwork is something else again.
Perhaps if the FDA really feels that backfilling the regulatory work on drugs that no one owns in particular is important enough, they should fund the work themselves. But that opens up issues of its own, too.
+ TrackBacks (0) | Category: Business and Markets | Drug Industry History | Drug Prices | Why Everyone Loves Us
April 13, 2010
Now, here's some hardball negotiating: Roche and Novartis, fighting with the UK government over drug pricing and regulations on clinical trials, are threatening to pull their R&D out of the country.
The Swiss drug companies made their threats known in personal meetings with a government minister, according to Whitehall documents seen by the Guardian.
The documents also make clear that cabinet ministers have been conducting a vigorous charm offensive to prevent multinational drug companies leaving Britain. Novartis employs 3,500 people in Britain at nine sites while Roche has 1,500 workers in this country.
The ministers, including business secretary Lord Mandelson, have in recent months visited executives at their headquarters in Japan, the US and Europe in what officials call a "programme of ministerial visits".
The visits have been organised to patch up a relationship strained by ministers' efforts to force the firms to cut the prices of the drugs they sell to the NHS, according to the documents.
In any of these "according to documents obtained by. . ." cases, you have to ask cui bono? Roche and Novartis have not made these threats publicly, so this could be a leak from them to apply more pressure to the government. Or it could be a leak from inside the NHS, in order to make the companies look bad. I would be inclined to not pay attention to any of the public statements on this issue from either side - the real story will take place out of the headlines, unless someone spills some more meeting minutes.
Either way, I think it's unlikely that this would be followed through - but neither is it completely impossible, either, which is what makes it a reasonably effective move.
+ TrackBacks (0) | Category: Business and Markets | Regulatory Affairs
The Tech, the MIT newspaper, has a very interesting account from one of its recent graduates about a stint he did with the Boston Consulting Group in Dubai. It's partly a look at how different the real world is from taking a whalloping course load at MIT (answer: quite different indeed). But it's also a look at how all too many consulting firms end up doing their work. This is only partly the fault of the consultants:
Despite having no work or research experience outside of MIT, I was regularly advertised to clients as an expert with seemingly years of topical experience relevant to the case. We were so good at rephrasing our credentials that even I was surprised to find in each of my cases, even my very first case, that I was the most senior consultant on the team.
I quickly found out why so little had been invested in developing my Excel-craft. Analytical skills were overrated, for the simple reason that clients usually didn’t know why they had hired us. They sent us vague requests for proposal, we returned vague case proposals, and by the time we were hired, no one was the wiser as to why exactly we were there.
I got the feeling that our clients were simply trying to mimic successful businesses, and that as consultants, our earnings came from having the luck of being included in an elaborate cargo-cult ritual. In any case it fell to us to decide for ourselves what question we had been hired to answer, and as a matter of convenience, we elected to answer questions that we had already answered in the course of previous cases. . .
I can't imagine that the BCG people are very pleased about this series of articles, but I don't think there's much they can do about it. As the author details) he walked away from an end-of-employment payment by refusing to sign a nondisclosure agreement. And not to pick on BCG particularly - because there are plenty of other people in this game - I note that they do advise the pharmaceutical industry from time to time. We are, fortunately, not quite Dubai. But here's a description (their own) of some of their work, and I'll leave it up to the reader to decide if it's an inspiring story of teamwork or an example of cargo-cult self-delusion.
At the onset, the BCG team helped provide structure and facilitation for our client's deep content knowledge, then helped them focus on the most important issues. We worked together to develop critical insights about the current and potential marketplace and the roadmap to success, then created and launched an execution plan that rallied the organization around that roadmap and started them down that path.
You might also want to speculate about how many times those phrases have been cut and pasted before.
Update: fixed with link to the story!
+ TrackBacks (0) | Category: Business and Markets | Drug Industry History
April 12, 2010
Everyone who works for a large organization has to wonder about the amount of expertise in it that never gets used. Someone else in the company may have had to solve the exact same problem you're working on, and you may well never know, because there's no way to realize it or track down a person who could help. So there are all sorts of schemes that have been tried to make these connections, but I'm not sure if any of them actually work.
The ones I've seen are e-mail lists (for querying members of the rest of the department), attempts at occasional general-problem-solving meetings, various collaborative software packages, intra-company Wikipedia-type databases, and internal prediction markets. That covers a wide range, probably because these tools are being used against a pretty heterogeneous set of problems.
There's the specific-answer sort of query, such as "Has anyone taken this intermediate that we're all using and done X to it?". A broader form of this one is along the lines of "Does anyone know how to reduce an A group in the presence of a B?". Then there are historical questions, such as "Whatever happened to these Z kinds of compounds? Why did the team that was using them back in 1990 stop working on them?"
These, at least, probably only need to go to a certain list of people. Tougher are the problems where insights might come from anywhere in the company, and this is where the advertising copy for the software packages starts to wax lyrical. Then you have the wisdom-of-crowds approach, where you're not looking for a specific answer to a specific problem, but are interested in the opinions of a wide range of people on some question, hoping to find out more about it than you'd realize on your own. That's where the prediction market stuff comes in.
And I'm interested in the latter idea, although I can see some problems with it. For one thing, I'm pretty sure that you'd want to have anonymity as an option. If the Big Honcho proposes an idea, how many people will vote it down under their own names? (Although any Big Honcho should realize that some of the most valuable feedback they can get is when their own name and position aren't yet attached to a proposal). Then you have the whole participation problem - people have to feel that it's somehow worth their time to use these things. Depending on free-floating altruism is, in my experience, not going to work out very well (and I'm not so sure how it worked out for Blanche DuBois in the end, either).
And with any of these systems, you have to be sure that you're asking the right questions, in the right format, to the right people. A prediction-market question inside a company on the lines of "When do you think we're going to file the NDA for Compound X?" doesn't seem all that useful, because there are only a few people really in a position to know (and they're not supposed to talk about it). But it would be interesting to put up the best screening hits for a nascent program, or the three or four most advanced compounds for a later-stage one, and throw the question open to the whole company of which ones they think are best. You'd want to track the results, though, to see if your crowd has any particular wisdom or not.
I think that the line you're trying to walk with such systems is the one between solidifying groupthink and getting past it. To that end, I'd recommend (in many cases) that people not be able to see how the voting is going while it's in progress, for fear that some participants would just jump on one bandwagon or another to save time. But I have to think that if, say, Pfizer had asked more people about the prospects for Exubera (their catastrophic inhaled-insulin product), that it might have given them the ghost of a clue that there was a chance for failure. (Or maybe not!)
Of course, now that I think about it, Pfizer has one of the more widely publicized internal idea-and-prediction-sharing efforts in the industry. (Lilly is also known for talking about this sort of thing). And I'd be interested in people who have actually experienced these, or those in other shops. Have you ever gotten any use out of these things? Or is it just something that sounds good on paper?
+ TrackBacks (0) | Category: Business and Markets | Lowe's Laws of the Lab | Who Discovers and Why
April 9, 2010
Boy, do the Generex fans love me over at Seeking Alpha, where some of my articles are reposted. I am apparently in the pay of The Hidden Interests (although there are contradictory opinions as to who They may be), and there are calls to have the SEC, the IRS, and all those other fun agencies come and sort me out.
That increases my interest in the company even more, now that I see what high-caliber fans it has. Look for an article on Generex here next week. From what I've been able to find already, I should have something the company's cheering section will enjoy.
+ TrackBacks (0) | Category: Business and Markets | Diabetes and Obesity
I've had some follow-up with the people at Dundee who reported those compounds for sleeping sickness recently. As mentioned, one of the key points in making these a viable therapy will be brain penetration, since trypanosomes in the central nervous system are a hallmark of the most serious phase of the disease.
The group has a patent application out (WO2010026365), and you can see from it that they've been addressing this problem. Their Table 5 has blood and brain concentrations after dosing in mice, and there's a compound on it (DDD73490) with a brain/blood ratio of 6. That one, as the med-chem audience will have no trouble believing, has an N-methyl on the sulfonamide - getting NH sulfonamides into the brain is often a losing battle. And there are a number of other compounds on the list with fluorinated N-alkyl groups on the sulfonamide, which suggests that the plain N-methyl solved one problem but created another. The tables in the patent also suggest some other therapeutic areas that these NMT inhibitors could be used in, and I'm sure that these are being investigated as we speak.
Stephen Brand at Dundee tells me that they're definitely in the market for something else that can provide the "cis kink" that the sulfonamide gives their structures, so if anyone has any ideas, please feel free to suggest them. My thoughts turn to seeing if a fragment-based approach might work here - perhaps there's a ligand-efficient piece to these compounds that could be used as a new starting point to build out to something with a lower molecular weight and better properties?
Antitrypanosome compounds are never going to make anyone rich, but if they work out, they could relieve a tremendous amount of pain and suffering in the tropics. They're being developed in partnership with the Drugs for Neglected Diseases Initiative, and the group is also looking into partnering opportunities to go after Chagas Disease. That'll be harder, but well worth a look.
+ TrackBacks (0) | Category: Infectious Diseases
I had some correspondence with the people at MassHighTech about their "New England Patent Rankings" chart (which I spoke about here). That's the one that shows Pfizer with only three patents in 2009, which didn't make a whole lot of sense, considering the size of the operation in Groton/New London.
A look through the patent databases (which several readers also confirmed) showed that something was apparently off, since there were numerous Pfizer patents where the inventors all were from Connecticut. But as it turns out, the MassHighTech people say that their consultant looks at the states of the assignees, and filters out any that don't contain CT, VT, ME, NH, MA, or RI. So that means that many Pfizer patents, which are assigned to the company at its global HQ in New York, don't make the cut.
That seems like an odd way to do things, but maybe it's just me. The people at MassHighTech say that they're looking specifically for "New England-based companies" on their list, but in that case, you wonder how even three Pfizer patents made it in.
+ TrackBacks (0) | Category: Patents and IP
April 8, 2010
Since I'm on the editorial board, I should point out that the first full issue of ACS Medicinal Chemistry Letters is up, with free access for the occasion. I note with approval Dennis Liotta's lead-off editorial, which mentions that the journal will be introducing a section to highlight key patents - as far as I can tell, this is the first time a med-chem journal has explicitly acknowledged that this is where the real cutting-edge stuff often first appears in the field. (And no, I didn't have anything to do with the current batch of papers, in case anyone's wondering).
+ TrackBacks (0) | Category: The Scientific Literature
A very weird news item: multicellular organisms that appear to be able to live without oxygen. They're part of the little-known (and only recently codified) phylum Loricifera, and these particular organisms were collected at the bottom of the Mediterranean, in a cold, anoxic, hypersaline environment.
They have no mitochondria - after all, they don't have any oxygen to work with. Instead, they have what look like hydrogenosome organelles, producing hydrogen gas and ATP from pyruvate. I'm not sure how large an organism you can run off that sort of power source, since it looks like you only get one ATP per pyruvate (as opposed to two via the Krebs cycle), but the upper limit has just been pushed past a significant point.
+ TrackBacks (0) | Category: Biological News | General Scientific News | Life As We (Don't) Know It
For people who've done work on metabolic disease, this paper in PNAS may come as a surprise, although there was a similar warning in January of this year. Acetyl CoA-carboxylase 2 (ACC2) has been seen for some years as a target in that area. It produces malonyl CoA, which is a very important intermediate and signaling molecule in fatty acid metabolism (and other places as well). A number of drug companies have taken a crack at getting good chemical matter (I'm no stranger to it myself, actually). A lot of the interest was sparked by reports of the gene knockout mice, which seem to have healthy appetites but put on no weight. The underlying reason was thought to be that fatty acid oxidation had been turned up in their muscle and adipose tissue - and a new way to burn off excess lipids sounded like something that a lot of people with excess weight and/or dyslipidemia might be able to use. What's more, the ACC2 knockout mice also seemed to be protected from developing insulin resistance, the key metabolic problem in type II diabetes. An ACC2 inhibitor sounds like just the thing.
Well, this latest paper sows confusion all over that hypothesis. The authors report having made some selective ACC2 knockout mouse strains of their own. If the gene is inactivated only in muscle tissue, the animals show no differences at all in body weight, composition, or food intake compared to control mice. What's more, when they went back and inactivated ACC2 in the whole animal, they found the same no-effect result, whether the animals were fed on standard chow or a high-fat diet. The muscle tissue in both cases showed no sign of elevated fatty acid oxidation. The authors state drily that "The limited impact of Acc2 deletion on energy balance raises the possibility that selective pharmacological inhibition of Acc2 for the treatment of obesity may be ineffective."
Yes, yes, it does. There's always the possibility that some sort of compensating mechanism kicked in as the knockout animals developed, something that might not be available if you just stepped into an adult animal with an inhibiting drug. That's always the nagging doubt when you see no effect in a knockout mouse. But considering that those numerous earlier reports of knockout mice showed all kinds of interesting effects, you have to wonder just what the heck is going on here.
Well, the authors of the present paper are wondering the same thing, as are, no doubt, the authors of that January Cell Metabolism work. They saw no differences in their knockout animals, either, which started the rethinking of this whole area. (To add to the confusion, those authors reported seeing real differences in fatty acid oxidation in the muscle tissue of their animals, even though the big phenotypic changes couldn't be replicated). Phrases like "In stark contrast to previously published data. . ." make their appearance in this latest paper.
The authors do suggest one possible graceful way out. The original ACC2 knockout mice were produced somewhat differently, using a method that could have left production of a mutated ACC2 protein intact (without its catalytic domain). They suggest that this could possibly have some sort of dominant-negative effect. If there's some important protein-protein interaction that was wiped out in the latest work, but left intact in the original report, that might explain things - and if that's the case, then there still might be room for a small molecule inhibitor to work. But it's a long shot.
The earlier results originated from the lab of Salih Wakil at Baylor (who filed a patent on the animals), and he's still very much active in the area. One co-author, Gerry Shulman at Yale, actually spans both reports of ACC2 knockout mice - he was in on one of the Wakil papers, and on this one, too. His lab is very well known in diabetes and metabolic research, and while I'd very much like to hear his take on this whole affair, I doubt if we're going to see that in public.
+ TrackBacks (0) | Category: Biological News | Diabetes and Obesity
April 7, 2010
I'm not sure I'd use this sort of language myself, but here we go: Pfizer's Martin Mackay is telling Bloomberg that the company is in a "golden age of drug discovery".
As of the end of last year, Pfizer had 26 drugs in phase-three trials. . .compared with eight at the end of 2007, Mackay said. That doesn’t include the treatments it got from Wyeth, he said at a briefing at the company’s research unit in Singapore.
Following the acquisition, Pfizer cut its research portfolio to 500 projects from 600, as it focuses on accelerating the development of drugs with a “big, early” effect in patient studies while weeding out the losers earlier in the process, Mackay said.
He says that Pfizer's pipeline is basically just running over with candidates in cancer, Alzheimer’s, pain, inflammation, and infectious diseases. And I've been hearing for years and years about weeding out the losing compounds earlier in the process, but as far as I can see, Phase III failures are either the same or going up as a share of total clinical dropouts.
At any rate, these assertions are subject to proof. For the sake of the patients that these drugs could help, and for the sake of Pfizer's patient shareholders, I hope that this golden-age talk is right. But there are a lot of ex-Pfizer people out there who have reasons of their own to dispute the statement.
+ TrackBacks (0) | Category: Business and Markets | Drug Development
I haven't written anything about Generex, a company developing an oral insulin spray for Type I diabetes, although they have come up in the comments here once or twice. I'm now regretting my lack of coverage, since if I'd said something uncomplimentary about them (an even bet), I might have had my chance to get sued by them as well. That's what's happening to Adam Feuerstein of TheStreet.com.
Feuerstein wrote two recent columns about the company. The first one was quite skeptical of the company's prospects, saying that he thought the company's Oral-lyn was "a total bust". Said Feuerstein:
"Common sense should tell you that an insulin spray like Oral-lyn is more fiction than science. If Oral-lyn was real, Big Pharma would have snatched up the technology a long time ago. Instead, Pfizer lost millions with an insulin bong, and Al Mann, billionaire healthcare entrepreneur and MannKind's founder, is spending hundreds of millions of dollars of his own money to build another inhalable insulin device. For that kind of money, Mann could have bought Generex several times over. He didn't."
There were also some unkind comments about the way the company touts its regulatory approvals in Ecuador, India, Lebanon and Algeria. (You'll notice that India is by far the most serious regulatory and financial market in that list - read on!) He also had things to say about the size of the company's potential market, given the effectiveness of insulin injections for Type I patients. But his second column (written in response to a flood of e-mail and a hostile legal letter from the company about the first one) was even more blunt:
"The more I dig into Generex Biotechnology(GNBT) and its insulin spray for diabetics, the more preposterous the story becomes. . .it becomes apparent almost immediately that the company is using science and the quest to develop an alternative insulin delivery method not to actually help diabetics but as a ruse to perpetuate a 15 year-long stock promotion scheme. In the process, investors are getting fleeced while Generex management earns millions of dollars in compensation."
Read the rest of his article to get the story on the clinical data, which include things like a ten-day trial in two dozen patients in Ecuador. Actually, that's the centerpiece of the clinical story, come to think of it. The company recently press-released "Successful Phase III Data", although they only had data on 60 patients out of the targeted 750. And so on. No, something seems odd about all this.
If you ask me, Feuerstein's likely in the right here. I, too, have trouble believing that an oral insulin spray can reliably treat the type I diabetes population, for whom careful insulin dosing is crucial. And I think that if there were a realistic chance of that happening, that the likes of Novo Nordisk and Eli Lilly would probably have at least looked into the possibility. And even if they'd missed out, if Generex were the company to discover a real opportunity here, I don't see how they wouldn't be able to raise more money (or do a co-development deal) with more convincing clinical data, if they had any. Why treat a handful of people in Ecuador and let your stock value sit at 60 cents a share, if you have the chance to raise the serious money needed to get a real diabetes therapy through some convincing Phase III trials instead? That's not how this business tends to work.
Generex, though, decided after the second Feuerstein column that they'd had enough, and has sued. For two hundred and fifty million dollars, yet. The company has some very vocal defenders, and I believe that they're completely sincere, but this lawsuit makes me think even less of Generex than I did after reading about their product. Why are they wasting time and money on this sort of thing? These kinds of lawsuits have virtually no chance of going anywhere - the only reason I can see for filing one (if indeed they have) is to get more publicity (and look noble and beleaguered).
The same day the lawsuit was announced, Feuerstein dropped another article into the mix, returning to that regulatory-approval-in-India issue. As it happens, the Indian government revoked the approval a year ago, only three months after the product was offered for sale. You can search (and Feuerstein does, gleefully) through all of Generex's press releases, conference call transcripts, and regulatory filings for any mention at all of this material event. There's nothing. Now, the original approval in India was covered extensively by the company, as you'd imagine, but the withdrawal seems to have passed in total silence - with even a denial last fall that there were any delays or problems in India at all. According to Feuerstein, Generex has completed several financing deals without apparently getting around to mentioning this little detail.
Wagering may now commence as to whether either the lawsuit or the oral insulin spray are going anywhere. If the company really has failed to disclose a material event, though, they may be going somewhere themselves.
+ TrackBacks (0) | Category: Business and Markets | Diabetes and Obesity | Press Coverage
April 6, 2010
In keeping with my Modest Literature Proposal from earlier this year, I would like to briefly point out a Journal of Medicinal Chemistry paper on potential Alzheimer's therapies. Whose lead compound has a nine-carbon alkyl chain in the middle of it. And weighs 491. And has two quaternary nitrogens. Which structural features will, in all likelihood, lead to said compound demonstrating roughly this amount of blood-brain barrier penetration, assuming it reaches sufficient blood levels to get that far. That is all.
+ TrackBacks (0) | Category: Alzheimer's Disease | Pharmacokinetics | The Scientific Literature
A reader sends along a note about this patent application from the University of Rochester. The inventor, David Goldfarb, seems to have used an assay (the subject of a previous application) to screen a library of commercially available compounds for potential life-extending properties in model organisms. Here's some detail on the screen from PubChem.
The abstract of the application makes it sound worse than it is: "A method for altering the lifespan of a eukaryotic organism. The method comprises the steps of providing a lifespan altering compound, and administering an effective amount of the compound to a eukaryotic organism, such that the lifespan of the organism is altered. . ." That sounds like one of those "Oh, get real" applications that the patent databases are cluttered with. But when you get to the claims, you find that a list of compounds is specifically given, with more- and most-preferred ones as you go down. And I don't have a problem with that, as far as it goes - the inventor has an assay, has run a bunch of compounds through it, and finds that some of them have utility that apparently no one else has recognized.
The compounds themselves, though. . .well, here are the specifically claimed ones on the list. I don't necessarily see aliphatic triketones extending my life, but perhaps I'm cynical.
+ TrackBacks (0) | Category: Aging and Lifespan | Drug Assays | Patents and IP
For what it's worth, here's a report that tallies up the layoff numbers in the industry so far this year as compared to 2009. And even though the first two months of the year featured plenty of job cuts, we're still well off last year's horrendous pace. March had the lowest number of layoffs in some time.
How you look at this news depends on whether you're a glass-half-full type or not. Perhaps there just aren't so many people to cut any more, at least not at early-2009 rates. But it may be that things have bottomed out. The real question will be whether the industry can get back to adding jobs in the US.
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April 5, 2010
Last summer a paper was published (PDF) showing rapamycin dosing appeared to lengthen lifespan in mice. (In that second link, I went more into the background of rapamycin and TOR signaling, for those who are interested). Now comes word that it also seems to prevent cognitive deficits in a mouse model of Alzheimer's.
The PDAPP mice have a mutation in their amyloid precursor protein associated with early-onset familiar Alzheimer's in humans, and it's a model that's been used for some years now in the field. It's not perfect, but it's not something you can ignore, either, and the effects of rapamycin treatment do seem to be significant. (The paper uses the same dose that was found to extend lifespan). The hypothesis is that rapamycin allowed increase autophagy (protein digestion) to take place in the brain, helping to clear out amyloid plaques.
What I also found interesting, though, was the rapamycin-fed non-transgenic control animals. In each case, they seem to show a trend for increased performance in the various memory tests, although they don't quite reach significance. This makes me wonder what the effects in humans might be, Alzheimer's or not. After that lifespan report last year, it wouldn't surprise me to find out that some people are taking the stuff anyway, but it's not going to be anywhere near enough of a controlled setting for us to learn anything.
This report is definitely going to start a lot of people thinking about experimenting with rapamycin for Alzheimer's - there are a lot of desperate patients and relatives out there. But together with that lifespan paper, it might also start some people thinking about it whether they're worried about Alzheimer's or not.
+ TrackBacks (0) | Category: Aging and Lifespan | Alzheimer's Disease | Biological News
What to make of the case of Becky McClain? She's a former Pfizer scientist who sued the company, claiming that she had been injured by exposure to engineered biological materials at work. She's just won her case in court, although Pfizer may well appeal the verdict. It's important to note that her most damaging claim, that the company engaged in willful misconduct, was thrown out at the beginning. The jury found that Pfizer had violated whistleblower laws and wrongfully terminated McClain as an employee.
But what I'd most like to know is whether the claim at the core of her case is true, and I don't think anyone knows that yet. McClain says that she was exposed to embryonic stem cells and to various engineered lentiviruses (due to poor lab technique on the part of co-workers, if I'm following the story correctly), and that this gave her a chronic, debilitating condition that has led to intermittent paralysis. More specifically, the theory that I've seen her legal team floating is that the lentivirus caused her tissues to express a new potassium channel, and that she has improved after taking "massive doses" of potassium. (Query: how massive are we talking here?).
Now, that's a potentially alarming thing. But that should also be potentially subject to scientific proof. This trial didn't address any of these issues, and McClain has been unable to get any traction with the court system or with OSHA on these claims. Looking around the internet, you find that some people are convinced that this is a cover-up, but (having seen OSHA in action) I'm more likely to think that if you can't get them to bite, then you probably don't have much for them to get their teeth into. I also note that the symptoms that have been described in this case are similar to many that have been ascribed in the past to psychosomatic illness. I can't say that that's what's going on here, of course, but it does complicate the issue.
The other problem I have is that such human illness from a biotech viral vector is actually a very rare event, with every case that I can think of being a deliberate attempt at gene therapy. Industry scientists don't work with human-infectious viruses without good cause, but there's still an awful lot of work that goes on with agents that most certainly can infect people (hepatitis and so on). And although I'm sure that there have been cases (accidental needle sticks and the like), I don't know of any research infections with wild-type viruses, much less engineered ones.
Well, we may yet hear more about this, and I'll rethink the issue if more information becomes available. But for now, I have to say, whatever the other issues in the case, I'm inclined to doubt the engineered-viral-infection part of this story.
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April 2, 2010
I'll be taking advantage of the fact that it's not actually raining today, and adding a day to the weekend. The rising rivers around the Boston area have made me glad that I live on a hill! Regular posting returns for Monday. . .
+ TrackBacks (0) | Category: Blog Housekeeping
April 1, 2010
As a commenter here has noted, something odd happened to Exelixis stock today at about 1 PM EDT. A sudden, sustained jump of about 10% is certainly possible without a huge expenditure of money in a stock this size - but what caused it? The delayed options quotes at the CBOE show what looks like a big spike in $7.50 calls with several expiration dates. You can bet the the SEC will be watching closely to see if the company makes any announcements in the next few days. And if they do, they'll be checking to see if those option orders were placed before or after 1 PM. . .
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Science and Nature finally decide to stop beating each other up in chasing after hot papers. The problem with the announcement is that it quotes magazine consultant Rick Rolling, but neglects to link to the video where he explains things in detail.
+ TrackBacks (0) | Category: The Scientific Literature
Nature has a very encouraging paper out today on some potential treatments for trypanosomiasis (sleeping sickness). The mechanism is protein N-myristoylation (catalyzed by an enzyme abbreviated as NMT) which is a process that's important for membrane targeting and trafficking. NMT has been shown to be essential for trypanosome survival by siRNA experiments, so it's a pretty well-validated target.
And now there's some chemical evidence for that idea. This groups screened a compound library, found some micromolar-level hits, and optimized these through good old-fashioned medicinal chemistry down to nanomolar-level compounds. The compounds aren't that bad - they're all pyrazole sulfonamides, a bit bulky and aromatic, but everyone who's done med-chem has seen a lot uglier compounds than these. Here's an X-ray structure of the lead bound to the target enzyme.
And more to the point, that lead compound actually works. In two models of sleeping sickness infection in rats, it cured every single animal in the test group. There's a lot of evidence presented that the compound is working on-target; it certainly convinces me. It's also good news that it doesn't seem to be showing toxicity, because human cells use NMT of their own. All in all, this compound is an excellent start, and may well be a drug candidate all by itself.
But if it is, it's only going to be useful in the earlier stages of the infection. The nastiest part of the disease is when the parasites make it into the central nervous system, but these compounds don't seem to penetrate into the brain. The paper mentions that further optimization is underway to try to address this, and I wish them good luck, and quickly. And I hope that this report stimulates other people to look through their own compound collections for NMT inhibitors that might do the same thing.
+ TrackBacks (0) | Category: Infectious Diseases
We're all going to be hearing a lot about nanoparticles in the next few years (some may feel as if they've already heard quite enough, but there's nothing to be done about that). The recent report of preliminary siRNA results using them as a delivery system will keep things moving along with even more interest. So it's worth checking out this new paper, which illustrates how we're going to have to think about these things.
The authors show that it's not necessarily the carefully applied coat proteins of these nanoparticles that are the first thing a cell notices. Rather, it's the second sphere of endogenous proteins that end up associated with the particle, which apparently can be rather specific and persistent. The authors make their case with admirable understatement:
The idea that the cell sees the material surface itself must now be re-examined. In some specific cases the cell receptor may have a higher preference for the bare particle surface, but the time scale for corona unbinding illustrated here would still typically be expected to exceed that over which other processes (such as nonspecific uptake) have occurred. Thus, for most cases it is more likely that the biologically relevant unit is not the particle, but a nano-object of specified size, shape, and protein corona structure. The biological consequences of this may not be simple.
Update: fixed this post by finally adding the link to the paper!
+ TrackBacks (0) | Category: Biological News | Pharmacokinetics
Ardea's serendipitous gout drug RDEA594, which I wrote about here last year, is still alive. Phase IIb results had the compound meeting its endpoints (although not at the lowest dose), so on it goes to Phase III. Since we've been talking all week around here about how Phase III is a different world, it's worth noticing that the primary endpoint is still a biomarker (reduction of serum urate levels), not a real clinical outcome. But in the case of gout, that association is probably strong enough to be optimistic. Good luck to 'em.
+ TrackBacks (0) | Category: Clinical Trials