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
In the Pipeline:
Don't miss Derek Lowe's excellent commentary on drug discovery and the pharma industry in general at In the Pipeline
May 27, 2015
Remember back when AstraZeneca was fighting off Pfizer's ardent, tax-issue-resolving embrace a year ago? One of their weapons was a pitch to their own shareholders about what potential their own pipeline had, and how much of that would presumably go to waste should the deal go through. Even at the time, people thought that their estimates of what was to come might be a bit optimistic. But I can't really fault them, because if someone were trying to buy me, I'd probably be willing to say all kinds of things to keep it from happening, too.
Well, one of those pipeline assets has just taken a major hit. Brodulamab, targeted against the IL-17 receptor, was part of a 2012 deal between AstraZeneca and Amgen to develop inflammation therapies. Late last November, the companies announced some good clinical results in psoriasis.
But now Amgen has dropped the project, and hard.
The decision was based on events of suicidal ideation and behavior in the brodalumab program, which Amgen believes likely would necessitate restrictive labeling.
"During our preparation process for regulatory submissions, we came to believe that labeling requirements likely would limit the appropriate patient population for brodalumab," said Sean E. Harper, M.D., executive vice president of Research and Development at Amgen.
That really would be a show-stopper - psoriasis is a cruel disease, but suicide is worse. It's surprising, though, that an antibody would have this as a side effect (I'll bet it was surprising to Amgen and AZ, for sure). That's certainly a real side effect of some drugs (it was one of the big factors that scuppered rimonabant, and its competitor taranabant back when). But those were CNS agents, and that's the sort of thing you always look out for in a new CNS drug. What's an antibody to an interleukin receptor doing causing the same problem?
Well, IL-17 certainly has roles in the brain (those recent papers will lead you to others). And given how painfully little we know about what's going on up there, it's certainly possible that these pathways could lead to such a side effect - I mean, how do suicidal thoughts form, mechanistically? Right, it's a black box like all those questions are. But wouldn't brodulamab have to cross the blood-brain barrier for that to happen?
That's very unlikely for an antibody, but (as the various efforts targeting beta-amyloid show), not impossible, either. But if that's what's going on, what it is is hideous bad luck, because no one is looking for a CNS effect to stop a peripheral antibody target. And if it's somehow a peripheral mechanism, feeding back to the brain via who-knows-how, that's hideous bad luck, too. I hope that at some point we find out more about what's going on here, out of sheer scientific curiosity.
+ TrackBacks (0) | Category: Business and Markets | The Central Nervous System | Toxicology
May 26, 2015
David Sackett, epidemiologist and evidence-based medicine proponent, has died this week. I'd heard of him, but I hadn't seen his editorial about being an expert in one's field. Not all experts have had the thoughts that he had about their situation, and even fewer of those have acted on them the way he did:
. . .It then dawned on me that experts like me commit two sins that retard the advance of science and harm the young. Firstly, adding our prestige to our opinions gives the latter far greater persuasive power than they deserve on scientific grounds alone. Whether through deference, fear, or respect, others tend not to challenge them, and progress towards the truth is impaired in the presence of an expert. The second sin of expertness is committed on grant applications and manuscripts that challenge the current expert consensus. Reviewers face the unavoidable temptation to accept or reject new evidence and ideas, not on the basis of their scientific merit, but on the extent to which they agree or disagree with the public positions taken by experts on these matters. . .
. . .Is redemption possible for the sins of expertness? The only one I know that works requires the systematic retirement of experts. To be sure, many of them are sucked into chairs, deanships, vice presidencies, and other black holes in which they are unlikely to influence the progress of science or anything else for that matter. Surely a lot more people could retire from their fields and turn their intelligence, imagination, and methodological acumen to new problem areas where, having shed most of their prestige and with no prior personal pronouncements to defend, they could enjoy the liberty to argue new evidence and ideas on the latter's merits.
But there are still far more experts around than is healthy for the advancement of science. . .
Sackett started his expertise over more than once, but found that he kept becoming an expert again, no matter what. We need more people for whom that could possibly become a problem, and more people who would notice that it had become one.
+ TrackBacks (0) | Category: Who Discovers and Why
Here's an excellent new paper that's appeared in the preprint area of Science, Science Express. Jay Bradner and co-workers at Harvard/Dana-Farber report a new way to control protein function, and this one seems both very effective and startlingly simple.
The engine of destruction is thalidomide, or (more accurately) the way that the pthalimide in that drug binds to CRBN, part of a ubiquitin ligase complex. (This is thought to be the mechanism for that drug's notorious tetratogenicity, but arguments are still going on about that). Many readers here will know ubiquitin well - it was well named, because it shows up everywhere in the cell. One of its main functions (it has others) is to serve as a disposal tag - if a protein gets ubiquitinated, especially multiple times (there are various degrees and pathways), it's like slapping a fluorescent red waste sticker on it. Off it gets dragged to the proteosome, there to be broken up for scrap. There are a variety of ubiquitin ligases doing this job in the cell, and unraveling why there are several and what they do has kept a lot of people working hard for quite a while now.
But it was in 2010 that CRBN (cereblon) was identified by Japanese researchers as a target of thalidomide. Bradner's insight was to use this a a chemical biology handle - this new paper takes a known ligand for some protein, ties a phtalimide off one end of it, and lets the latter go off and bind to CRBN. Then the ligand end goes off and binds to its target, dragging the CRBN behind it, which recruits the rest of its ubiquitin ligase partners. And they set in doing what they do: ubiquitinating away at the nearby protein - the ligand target - which finds itself heading into the shredder.
Bradner's group tried with with the bromodomain (BRD4) ligand JQ1, which they discovered, and it worked perfectly. At the two-hour mark, no BRD4 could be found in the treated cells. A control, with a conjugate of the BRD4 enantiomer, had no effect. And a proteomic analysis showed that the only other proteins affected were the other BRD subtypes, which JQ1 is already known to have some affinity for. The downstream effects on the BRD4 pathways were noticeably stronger than just hitting it with the inhibitor ligand itself. Similar results were found with FKPB and a small ligand for it, SLF.
There are other ways to use the ubiquitin system to target proteins in living cells, such as PROTAC, developed by Craig Crews, Ray Deshaies, and co-workers (recent review). That one started out with a lot of large proteins to hold things together, but has also been skewing towards small molecule ligands. The tricky parts, as often happens in chemical biology systems like this, would seem to me to be (1) having a good ligand in the first place), (2) having an attachment point on it where the phtalimide can be grafted on without messing too much with the target affinity, and (3) cell penetration of the resulting hybrid molecule. All of these worked out here (they even have an X-ray of the modified JQ1 molecule bound to BRD4), but they may not work out all the time. Still, the impressive effects of this system "prompts consideration of therapeutic development", as the paper says.
That'll be worth trying, but it'll be no stroll past the daylilies, either. Anything targeting CRBN would be expected to be at risk of being teratogenic (although, as mentioned above, this mechanism is still being hashed out). And you have the PK of the resulting molecular hybrid to work out, which naturally isn't something that you're going to address in a cell-assay paper like this one. Another big consideration is the specificity of the targeting ligand. This really does look like nuking a protein from orbit ("it's the only way to be sure"), so you're going to want to be careful about where you're dropping the bomb. (GSK has already been working on a collaboration to use the PROTAC system therapeutically, although I have no idea how that's been going, so these problems have already been thought about. ) Similarly, you're going to need a ligand in the first place. That makes the last part of this new paper interesting:
A more general implication of this research is the feasibility of approaching intractable protein targets using phthalimide-conjugation of target binding ligands that may or may not possess target-specific inhibitory activity.
"May or may not"? I'm having trouble seeing how that's going to work, but then, it's the first workday morning of the week around here, and maybe I'm still a bit fuzzy. I very much like the idea of approaching intractable protein targets, but let's say you want to hit, say, p53. That should be intractable enough for anybody. What's your p53 target-binding ligand? There are plenty of others out there. What's your ligand for PTP1B? You could always imagine hooking up the pthalimide to an antibody, I guess, but that brings difficulties of its own, not least the way that it boots you right out of the small-molecule space again. So if anyone has thoughts on that last part, I'd be interested in hearing them.
+ TrackBacks (0) | Category: Chemical Biology
May 22, 2015
Phil Baran and group have another big new synthetic methods paper out in Science, and it's well worth a look. It's a radical mechanism, based on some earlier work from the group, as you might guess from the conditions: Fe(acac)2 and
triethylsilane phenylsilane in ethanol. You take the reaction products and run them past some zinc in aq. HCl afterwards, to clear out some N,O-dialkylatedhydroxylamine side product that forms as the nitro group goes down in the first step - that sends everything to the N-alkyl form in the end.
Some of these reactions have been run, the paper says, on scales up to tens of grams, so that's a good sign. (Another good sign, and a rare one for a pure synthesis paper, is a reaction temperature profile for one of those scaleups - no induction period, no real exotherm). A lot of functional groups are tolerated - note the free boronic acid. You can also get away with aryl bromides and iodides, interestingly, as well as thioethers, free amines, aryl triflates and more. But one of the things I particularly appreciate about the paper, and wish that every new methods paper would include, is a section on reaction limitations. Nitroalkanes, for example, give low (but isolable) amounts of product. An ester in the 2-position next to the nitroaryl will tend to get hydrolyzed. You can't get away with a free phenol (or thiophenol), 2-nitropyridines don't seem to work, and styrenes are lousy alkene partners for the reaction.
But the number of things you can do with the reaction seem to well outnumber the things you can't, and there are a lot of variations that people will think of beyond what's been reported here. (That's true even though there are 96 product examples, in 350 pages of supporting information!) This is a mild, versatile reaction that uses cheap reagents and makes a lot of sterically crowded products that otherwise would be a pain to get to, and it's documented out the wazoo. What's not to like?
+ TrackBacks (0) | Category: Chemical News
May 21, 2015
Looks like there are biologists who are getting a chance to figure out what social media can do to communication in their field. Nature News reports on the response to a PNAS paper published late last year from the Mouse ENCODE consortium. That one looked at gene expression profiling in various mouse tissue samples, and concluded that mice were, at that level, not as similar to humans as had been assumed.
Not everyone bought into that conclusion. (This seems to be the destiny of most papers that come out under an ENCODE banner). Yoav Gilad and his co-worker Orna Mizrahi-Man, both at Chicago, re-analyzed that data in the paper and concluded that batch effects invalidated its conclusions. Rather than go the usual route, Gilad opened fire on Twitter, with graphs attached, and the original authors felt, well, ambushed. (That analysis is now published, open-access, in F1000Research).
Michael Snyder, a geneticist at Stanford University in California and co-author of the original paper, stands by his team’s study and its conclusions and says that Gilad broke the “social norms” of science by initially posting the critique on Twitter. Gilad says that he took to social media to highlight his work, which might otherwise have been overlooked. . .
. . .Gilad says that he posted the original critique on Twitter because it would have been difficult to draw much attention to his findings through the traditional channels. “Papers that challenge results from ENCODE or similar large consortium projects are never published in the same glamour journals as the original reports, and these papers are usually largely ignored,” he says.
He's got a point, there. And he may well have a point with his criticism of the original paper; that news article has a number of on-the-record quotes saying that it should be re-examined or retracted. I'm not going to get involved in that fight; there are a lot of far more well-qualified people trading punches. But I did want to comment on the whole peer-review-by-Twitter aspect of things, since that comes up (or will) in every part of the scientific world.
I can understand the original authors feeling blindsided. That's partly because they surely weren't expecting a detailed critique to show up from that direction. And Twitter itself doesn't exactly have a reputation as your go-to place for serious scientific discourse (140 characters and all that). But that said, my sympathies are with Gilad and Mizrahi-Man. I think that if you publish a scientific paper, you are inviting criticism from all comers - the same, in fact, as you are when you publish anything else in a public forum. Complaining that any such criticisms "didn't go through channels" misses the point.
If there really is a problem with a published paper, I think that everyone can agree that it's better to know about it sooner than later, and it's better to get the details of the criticism out there where everyone concerned can read it and come to their own conclusions. Announcing something like this on Twitter, then, actually makes sense in those regards. I like it a lot better than, say, this approach, which was proposed as the reasonable-man method by the editors of ACS Nano after a blatantly faked paper in their journal got splattered all over Twitter and the chemistry blogs. That one only took fourteen months to get cleared up, through the normal channels.
Now, this latest controversy is certainly not about faked data - it's about experimental design and interpretation. One could argue that these more-subtle differences of opinion should be worked out in a more "appropriate" way, while the rough-and-tumble public sphere might be OK to call out papers that are just made up. (Not that the ACS journal editors would have agreed even with that - their take, which I found quaint, was that no one should even comment on such things out in the internet world until journal editors have had a chance to make a decision).
But in this latest case, the critics of the paper are saying that it's wrong, that its conclusions are invalid, because the data were not handled correctly. So it's not all that subtle, when you get down to it. The fact that reasonable observers could read the paper and come to those conclusions is something that everyone looking at the paper should know, and should have a chance to know. Readers can then come to their own conclusions, and that process (thinking hard about the data, and the issues around how it was collected) will do everyone involved some good. Science improves by such a process. Doing it all carefully and quietly, it seems to me, improves it less.
That's not to say that there aren't problems with wrestling out in the public forum. Unfounded reputation-smearing allegations are what everyone worries about when this sort of thing comes up, and it's a legitimate worry. But readers and fellow scientists should have the opportunity to judge the accusers as well. If they come in with solid reasons to question the original work, things that have clearly had thought and effort put into them, then more people will take them seriously. Anonymity has a part to play here, too: note that Gilad and Mizrahi-Man are serious enough, in this case, to do this under their own names, which also counts for a lot. Anonymous criticism needs to exist, but anonymous critics always realize (or should) that they're necessarily starting out with a credibility disadvantage. (Even so, sufficiently strong arguments - flurries of duplicated and swapped gel lanes, obviously cut-and-pasted "photographs" of nanostructures in the supporting information - speak for themselves so clearly that they could be made under any name at all).
So I think it's worth the risk to do this sort of thing out where everyone can see it. And honestly, it's not like we're going to stuff all these snakes, genies, and worms back into their respective cans and bottles at this point, anyway. I think that open, post-publication peer review in science is here, and it's here to stay. We'd better get used to it.
Update: via the comments, here's an analysis that suggests that the criticism of the mouse ENCODE work may well have something to it. And on the topic of post-publication peer review, I should really note that PubPeer is where a lot of this is taking place.
+ TrackBacks (0) | Category: Biological News | The Scientific Literature
I made a brief mention of this article yesterday, but I wanted to highlight it. It's a look, from Nature New, at the broader implications of the antibody problem in research. Antibodies are, of course, universal reagents in molecular biology assays. If you suddenly declared their use illegal, the field would just collapse. But we can't live with 'em, either, because a really significant percentage of the antibodies used are not as good as they should be. A really disturbing percentage of the scientific literature is (at the very least) complicated by this problem, and some of it is flat-out invalidated by it.
As has been mentioned here several times, the same goes for small-molecule chemical probes, too, and how. That problem is, in principle, a bit more solvable (and I've been hearing about some efforts to try to help solve it - more on that as it develops). Small molecules are easier to assay for purity and identity, for one thing, and compared to antibodies, there are a lot fewer of them. The article estimates that there are around 300 companies selling something like two million antibodies. Which of these do what they're advertised to do, and under what conditions, well. . .that's hard to say:
Scientists often know, anecdotally, that some antibodies in their field are problematic, but it has been difficult to gauge the size of the problem across biology as a whole. Perhaps the largest assessment comes from work published by the Human Protein Atlas, a Swedish consortium that aims to generate antibodies for every protein in the human genome. It has looked at some 20,000 commercial antibodies so far and found that less than 50% can be used effectively to look at protein distribution in preserved slices of tissue5. This has led some scientists to claim that up to half of all commercially available antibodies are unreliable. . .
. . .Abgent, an antibody company based in San Diego, California, and a subsidiary of WuXi AppTec in Shanghai, China, tested all of its antibodies about a year ago. After reviewing the results it discarded about one-third of its catalogue.
So that should give you a rough estimate, and I don't think that many experienced assay development folks will be surprised. The people that are surprised, as usual, are the ones who just order out of the catalog and believe what's on the label. As the article mentions, a lot of people shop on price and speed of delivery, which (you'll be shocked to hear) are variables that don't always correlate well with reagent quality. And there are a lot of resuppliers out there, so even if you buy half a dozen antibodies against the same protein from different outfits, you may have only bought two. Or one. Who knows? And if you use up your supply of one that's working for you and re-order, will the new batch be the same as the old one? Who knows?
There are several online resources that are trying to address this problem (they're listed in the article), but many people don't even know about them. And as long people have the attitude that one (now more cautious) scientist expressed in the piece, the crappy reagents will continue to be sold. "I wasn't trained that you had to validate antibodies;" he says, "I was just trained that you ordered them."
+ TrackBacks (0) | Category: Biological News | Drug Assays | The Scientific Literature
May 20, 2015
Here's what looks like a very useful method for turning protein function on and off, reported in a new paper in Nature Chemistry. (This PDF link may work for you). The authors, from the MRC Molecular Biology labs at Cambridge (right there on Francis Crick Avenue), have a neat system for optical switching.
Here we introduce genetically directed bioorthogonal ligand tethering (BOLT) and demonstrate selective inhibition (iBOLT) of protein function. In iBOLT, inhibitor–conjugate/target protein pairs are created where the target protein contains a genetically encoded unnatural amino acid with bioorthogonal reactivity and the inhibitor conjugate contains a complementary bioorthogonal group. iBOLT enables the first rapid and specific inhibition of MEK isozymes, and introducing photoisomerizable linkers in the inhibitor conjugate enables reversible, optical regulation of protein activity (photo-BOLT) in live mammalian cells.
This (to my eyes) is an offshoot of the "tethering" approach that Sunesis used to do. (Dan Erlanson, ex-Sunesis, blogs over at Practical Fragments, and may well have some comment on this). What the Cambridge group has done is to engineer a protein (MEK, in their first example) to incorporate a strained cyclooctyne-containing amino acid (as introduced by the Bertozzi lab), to have a "spring-loaded" partner for cycloaddition. After finding a working MEK variant with this in place, they then took a known MEK inhibitor and hung a spacer group off of it, with a tetrazine on the end (the cycloaddition partner). That's the inverse-electron-demand Diels-Alder bioconjugation system introduced by the Fox lab at Delaware.
So far, this is nicely done (but by now relatively well-worked-out) chemical biology. The authors show that their tagged inhibitor does not work well against native MEK, but that it shows rapid and potent inhibition against the engineered protein. They also make sure that that protein really is covalently labeled, as predicted, and that the tetrazine-containing compound doesn't wander around doing other things to the proteome (it looks clean). They also tried some interesting variations, changing the core inhibitor structure and also changing the linker length. The tethered SAR followed the known inhibitor SAR pretty well, which makes sense. Switching the inhibitor structure to sunitinib (with an added tetrazine) gave a compound that wasn't much of an inhibitor of wild-type MEK, but did indeed go after several of the engineered ones. (Interestingly, the profile of it and the other tetrazine-conjugated inhibitor species were different across several of the enzyme variants, for reasons that are not yet clear). And the linker length didn't affect things much, except the longer linkers were worse (entropic penalty?) I should note that this is in some contrast to what George Whitesides and his group found in a model system a few years ago - they didn't observe much of a dropoff with longer linking groups.
Now comes the funky part. The group put in a linker with an azobenzene group, because azobenzenes are well known to undergo cis/trans isomerization photochemically. And that double bond switch really changes the position of the group out on the end, as you can easily picture. (Here's that same trick being worked on some receptor ligands). Hitting it with 360nm light flips it from the usual trans to the cis - you can flip it back with 440nm light, or wait three or four hours for it to naturally isomerize back on its own.
Six of the group's MEK variants were inhibited by the trans-azobenzene linked compound. One of those also turned out to be switchable via the different wavelengths described above. In live cells, MEK activity could be turned on and off by irradiation, or the normal activity could just be allowed to recover by itself.
The authors then took their sunitinib species and tried it out on LCK. Now sunitinib itself hits a lot of kinase, but LCK isn't one of its better ones (this paper has it as about 1.2 micromolar, compared to single-digit nanomolar on several others). Picking a similar site to put in the cyclooctyne amino acid in LCK as was used for MEK did indeed allow many of these mutants to be inhibited by that species, while that tetrazine compound did not have any activity on wild-type LCK.
I would like to see a profile of the sunitinib/tetrazine compound against a wide kinase panel - if it really is dead, this points a possible way to affect a variety of proteins that don't necessarily have good small-molecule ligands for them. Building in the tethering, and that extra kick of affinity that it gives, might point the way to that. The optical switching is another area with a lot of promise, too. Spatiotemporal control of protein function is the only way we're going to unravel a lot of these networks, and we need all the help we can get to do that. These techniques are not easy - when you read the paper, you see that if you had just given it one reasonable at every step, you probably wouldn't have gotten anywhere. There are a lot of constructs, a lot of mutants, and a lot of shots on goal. But it's a very worthy goal, for sure.
+ TrackBacks (0) | Category: Chemical Biology
The recent revival of interest in the way that the blood from younger animals (and people?) can improve the health of older ones came bundled with a particular protein candidate for the effect, GDF11. Several papers appeared on its effects in vivo, but there were people who found that odd, according to Nature News.
Those results quickly made GDF11 the leading explanation for the rejuvenating effects of transfusing young blood into old animals. But that idea was confusing to many because GDF11 is very similar to the protein myostatin, which prevents muscle stem cells from differentiating into mature muscle — the opposite effect to that seen by Wagers and her team.
For GDF11, “You could imagine that when it came out last year that it helped muscle, it was quite a surprise,” says David Glass, executive director of the muscle diseases group at the Novartis Institutes for Biomedical Research in Cambridge, Massachusetts. “Did we miss something?”
Now in Cell Metabolism, Glass and co-workers are reporting that GDF11 does not, in fact, have the effects ascribed to it. If they're right, this is (yet another) case of antibody trouble, because they report that the antibody used in the recent papers is not as selective as it's supposed to be. Novartis has an anti-myostatin antibody in development as a therapeutic (which explains their immediate interest here) and they're looking into whether it blocks GDF11 as well. Their paper suggests that that would be no bad thing, actually.
Amy Wagers and co-workers at Harvard, though, are apparently sticking to their guns, suggesting that there might be multiple forms of GDF11. That's possible, to be sure, but it's also (I hate to say this) the sort of rationale that one comes up with after one's antibody has been called into question. I wouldn't want to count the number of times that studies (large and small) have come undone because of antibody problems, and it's almost always because they turn out to be less targeted than thought. There are a lot of proteins out there, and a lot of related proteins to any given target. Assaying an antibody against them can be quite tedious, but if you don't, you run the risk of things suddenly getting the opposite of tedious, and not in a good way. We'll see how the dust settles on this one.
If the Glass paper is correct, though, and GDF11 is not the answer, that throws the field wide open for someone to find out what the answer is. I would guess that several groups have held back getting into this area, thinking that the big prize had already been found, but if that's not so, well. . .
Update: and as fate would have it, Nature News now has a feature on the problems of antibody reproducibility! Thanks to a post in the comments section for pointing this out.
+ TrackBacks (0) | Category: Aging and Lifespan | Biological News | Drug Assays
May 19, 2015
Rumors continue to fly around that Pfizer is going to ease its merger hunger and its foreign-cash tax woes by making an offer for GlaxoSmithKline. Lord, what a mess that will be if it happens. Problem is, I can't completely rule that out. I'm a very poor judge of huge pharma M&A deals, because most of them sound insane to me, prima facie, but a lot of them get done regardless of what I think.
For now, though, it seems just to be idle talk, perhaps driven by Wall Street types who dream of the monstrous, massive fees that such a large deal would bring. We'll see if anything more substantial comes of it. I sure hope not.
+ TrackBacks (0) | Category: Business and Markets
As long as there's been organized scientific research - that is, more than one person working on a problem - there have been timeline disconnects. Something takes longer than expected, throwing everything off, usually. That's the basic disconnect, and there are ways to deal with it, but there's a larger one that I don't think that anyone's ever found a way to deal with.
That's the problem that larger discoveries have of coming infrequently and on no one's schedule at all. Scientists have been complaining about this for as long as anyone's tried to manage scientists. There's a conservation law at work here, I think: the harder the task you ask a team to accomplish, the less able you are to say when they'll accomplish it. Straightforward tasks can be planned out to the day. Harder ones can be roughly estimated by quarter. Really big ones. . .well, there's just no damn way of knowing.
There are several problems that follow this one around, probably wearing the same color shirts and the same brand of shoes. One of those is the way that progress on tough problems comes in irregular fits and starts. If you're budgeting for steady, regular accomplishments that can be listed every quarter, you're going to have a bad time. Long periods will go by without much concrete evidence that anything useful is happening. That's because the team has been trying things out that didn't work. Even worse, part of the time some of them may have been trying those things out mostly in their heads, trying to get a better handle on the problem. A run of negative results is (on first approximation) hard to distinguish from people just messing around, but a run of unproductive thinking is hard to distinguish from someone just staring out a window. It doesn't look so great come performance review time.
In the extreme cases, you get people like Claude Shannon, who did tremendous, revolutionary work near the beginning of his career, and is hardly remembered for anything in the years afterwards. (This story is told in many places, but William Poundstone's Fortune's Formula is a good place to find it. Shannon is an indelible figure in the history of science, but he would have had some pretty rough quarterly progress reports to turn in.
What to do about this? The only advice I have is to keep that relationship above in mind, difficulty versus predictability. If you want someone (or some group) to aim high, be prepared for that uncertainty principle to kick in. It's not possible just to leave everyone alone forever, but checking in enough to see that real thought and effort is being expended is probably all that a manager can do. Not every organization is going to be open to that.
+ TrackBacks (0) | Category: Who Discovers and Why
May 18, 2015
Ah, the good old nitric acid/sulfuric acid nitration conditions. A classic reaction if ever there was one. But you don't want to let it spray all over your lab coat - you really don't.
I have a shirt like the coat in that photo, one that I got from a sulfuric acid splashback in 1984 or so. I still keep it in my drawer, to remind me. I stripped it off pretty fast once the acid solution sprayed on me, I can tell you, then reached for a bottle of saturated sodium bicarb and just turned it upside down over my chest. I came out fine; the shirt was never the same. I'll bet whoever was wearing the coat in that link above got out of it pretty fast, too. But it's a lot better to have that stuff hit your lab coat than it is to have it hit your skin.
+ TrackBacks (0) | Category: How Not to Do It
To my surprise, there has apparently been a sighting of the "Natavis Voyager" device in the wild. Nativis, as long-time readers will recall, is the company that claims to be able to record "RF signatures" of drugs in solution, which can then be played back at other solutions or organisms to generate the effect of the original drug. No, I'm not making that up, that's pretty much what they're saying. And no, I can't see any way that can possibly work or even make sense, either.
When last heard from, the company had apparently moved on from veterinary applications and was preparing for some sort of clinical trial in glioblastoma. And thanks to an alert reader, here is a news report of the first patient who is trying the thing:
This time, in order to help hope, Doug decided to try a new piece of technology. It is a device he would have to wear on his head more than 20 hours a day: A thin blue headband called the Nativus Voyager. (sic)
The coach was the first human to try the device, which is designed to block cancer cells from multiplying.
"What is does is tells the cancer cells not to divide, not to grow," he said. "It's a frequency that disrupts everything."
The experiment has led to one stable MRI after another so far.
"I feel like, at times, I can feel it working," he said.
I certainly hope that Coach Doug Corta survives glioblastoma multiforma. It's an awful disease, and those afflicted with it need all the help that they can get. There's a very tough call to make in these situations, though, about offering hope. You want to be able to help patients, and you want to be able to offer then something. But I have never been able to understand how the Nativis device can be more than an interesting-looking placebo. As a chemist, their rationales for it and the technology behind it have never made sense to me.
I'm aware that there is an RF device (from NovoCure) that has been used in glioblastoma multiforma patients. I'm not the biggest fan of that one, either - the rationale behind it is apparently membrane disruption of the dividing tumor cells. The NovoCure device was tried in GBM patients with recurrent disease, and is "intended as an alternative to standard medical therapy for recurrent GBM after surgical and radiation options have been exhausted". The prognosis for recurrent GBM is very poor indeed, and the fact that the NovoTTF/Optune device was similar to standard-of-care in these patients probably tells you more about the standard of care than it does about NovoCure's technology, which remains the subject of much disagreement.
But Novocure's supposed mechanism of action still looks more plausible to me than the Nativis Voyager's. But that's on a relative scale. On the absolute scale, in case you're wondering, I rank the former as "unlikely to be real", and the latter as "don't see any possible way it can be real". Interestingly, Nativis appears to be going for the same market. Their Clinicaltrials.gov page says that "This feasibility study will assess the effects of the Nativis Voyager therapy in patients with recurrent GBM who have either failed standard of care or are intolerant to therapy". The inclusion criteria are that patients have failed (or are intolerant to) radiation therapy and temozolomide, which are really the only things that can be offered to GBM patients. That news article I linked to, though, makes it sound as if Coach Corta is receiving some sort of chemotherapy (up near the beginning of the piece), although that doesn't sound like a temozolamide dosing schedule, either. So I'm not sure what's going on. All I can say is that the Swedish Neuroscience Institute in Seattle (and three other research centers - see that clinical trial link) are involved in some very unusual treatment options indeed.
+ TrackBacks (0) | Category: Cancer | Clinical Trials
May 16, 2015
This web site has been acting oddly the last day or two - redirects are showing up to totally unrelated domains and so on. But there is indeed a move to a new location coming - archives are being migrated now, and I should be testing out the first version of the new site shortly. So these problems are going to resolve themselves, and pipeline.corante.com will redirect to the new site. It will be far more stable than this one, I can promise you that!
Update: the redirect problem seems to be with Sitemeter, so I've deleted that from the web site. Things should hold together long enough now!
+ TrackBacks (0) | Category: Blog Housekeeping
May 15, 2015
Last time I mentioned Mannkind and their inhaled-insulin product (Afrezza) around here was when Oliver Brandicourt was announced as taking over at Sanofi. But I've had unkind things to say about them over the years, and their retail-investor cult is one of the most bizarre I've ever seen.
So now that Afrezza is launched, and Sanofi-fied, how's it doing? Not so great. Here's a look from Buyer's Strike (admittedly not disinterested observers of this sort of thing), but it's hard to put a good face on things. This reminds me of what Pfizer went through with their own inhaled insulin, Exubera, back in 2007. When that one hit the market, and it was like watching an Olympic dive into a dried-out swimming pool. No one wanted it. And so far, it doesn't look like many people want Afrezza, either, which is what I (and others) have always wondered about. Is there any reason why people are going to start buying it?
+ TrackBacks (0) | Category: Diabetes and Obesity
You may remember the MRI accident in India, where someone brought an oxygen tank into the imaging room. The consequence were not good ones - not only did two people get pinned to the machine by said tank, it took hours for them to kill the magnet because the emergency quench circuit was deactivated.
A longtime reader sends along the news that GE (maker of the MRI machine involved) has asked for all its installed machines to be checked to make sure that the quench circuits are operational. One would assume that this is being done both for safety and for legal/liability purposes (being able to come into a court and say that every other GE machine in the world has a working quench circuit, so how come this one didn't, and to forestall any other such problems). It's basically a short instruction list - press this button, make sure that this light comes on, and so on.
If you're not an NMR user, it might come as a surprise to find that the quench circuit is really little more than a heater. All these NMR magnets are superconductors; it's the only practical way to get that kind of magnetic field. (Note that "practical", for these purposes, means finely machining a bunch of expensive rare-metal alloy and cooling it down with liquid helium - that should tell you what the other options must be like). Also note that "MRI" (magnetic resonance imaging) is merely the consumer-friendly acronym tacked onto what the rest of the scientific world calls an NMR. The phrase "nuclear magnetic resonance", though, gave some patients the willies, since they thought it involved nuclear isotopes and radiation, so a less threatening phrase was quickly dreamed up.
So you have a big round superconducting magnet, with a ridiculous amount of electric current ripping around it, forever. Well, or until it warms up, whichever comes first. Sometimes, when you're getting these things running for the first time, some anomaly will cause a small domain in the magnet to decide that it's tired of the superconducting lifestyle (I am bypassing the more technical explanation). It finds itself, then, suddenly exhibiting electrical resistance, and it has plenty of current to exhibit it with, too. That part of the magnet heats up very quickly, and that heating throws the regions around it out of superconductivity, and they heat up just as fast, and then. . .well, what you get, as a bystander, is a loud, clanging thump, followed traditionally by a very expensive geyser of helium vapor. No one is pleased.
Unless they're pinned to the damned magnet by an oxygen cylinder, of course. Then you definitely want to be able to slap a big red knob, artificially heat the magnet, and have all the larger stray ferromagnetic objects suddenly drop to the floor. These knobs are generally mounted behind a cover of some sort, to prevent someone from leaning up against them or putting a philodendron on top of them, because (1) that aforementioned geyser can represent thousands to tens of thousands of dollars of helium these days, and (2) quenching is Not Good for the integrity of the magnet, and in the worse case you might find yourself with a lot of high-quality scrap metal. (I've long thought that a magnet housing itself could be turned into a real conversation piece of a barbecue pit, perfect for departmental get-togethers).
Helium has become a lot more expensive over time, with some rather large price fluctuations along the way due to the small number of suppliers. This has led the market to supply various sorts of helium-recycling devices for NMR facilities, which were once too expensive to make sense, but now pay for themselves pretty handily - unless someone stumbles on another big helium-rich natural gas field, anyway.
+ TrackBacks (0) | Category: Analytical Chemistry
May 14, 2015
I've recently been adding to my list of elements I've worked with, which is a nice effect of my current side project. I'll do an updated post once I total things up; there are some more on order, but I can tell you that I've already checked off a number of the ones mentioned in the 2009 post. Looking over the pile of stuff in my hood, though, I'm prompted to wonder what I haven't ordered. What is the least useful non-radioactive element for the synthetic organic chemist (we'll leave the noble gases out of this one)?
There are some strong contenders. Not many of us have ever had call to break out any gallium or germanium reagents, and some of the lanthanides are pretty obscure (and pretty indistinguishable in some applications). But I'm going to vote for beryllium. I think it gets a multiplier, in my mind, for being so far back up the periodic table, next to all those fundamental building blocks of the universe. And what do you get with Be? A silvery toxic metal, one that the physicists and metallurgists are willing to handle, but which no synthetic chemist of my acquaintance has ever bothered with. I have seen the occasional paper on beryllium reagents, but even those seem to be a bit self-conscious: "There has to be some use for this stuff, right?" Update: as pointed out in the comments, beryllium is essential for a lot of X-ray crystallography hardware, but I think that's about as close to the organic chemistry bench as it gets.
So for organic chemistry, that's my choice. Nominations are welcome for other contenders in the comments.
+ TrackBacks (0) | Category:
To go along with the recent calls for Andrew Witty to step down at GSK, here's John LaMattina wondering if he's the right guy for the job as well:
. . .the bigger issue with Witty’s stance is the direction that he is taking GSK. His company has a long and proud history of delivering new drugs to patients. Unfortunately, he has seemed to have lost his appetite for the difficult challenges faced in drug discovery. Sure, vaccines and consumer health care product are necessary and important. But so are new drugs for cancer, rare diseases, Alzheimer’s disease, etc. For a major company like GSK to deemphasize this type of research, especially given all of its R&D experience and capabilities, will correspondingly decrease the amount of innovation devoted to curing these diseases. That’s a shame.
He's referring to Witty's statements recently on drug pricing, and his calls to move GSK out of areas that depend on pricing power. I have long-term worries about this myself, but at the same time, if you come up with a really groundbreaking drug, you do indeed get to price it at what you think it's worth. That's your reward for taking on those substantial risks. (If you come out with a drug that makes your flu symptoms five per cent better for the last two days of the flu, on the other hand, you're not going to get many takers at $50k per course of treatment).
So if Witty is saying that the industry needs to be careful with its pricing, because we can't use that tool forever, for everything, I think he's right. But if he's saying that a fifty-thousand-dollar drug that saves the healthcare system a hundred thousand dollars is not a good deal, then that's harder to support. (You do, of course, have to make sure that the hundred thousand in savings are real!)
+ TrackBacks (0) | Category: Business and Markets | Drug Prices
There's more news on Puma Biotechnology and their drug, neratinib. It's been quite a story over the last couple of years, and it's not getting any less convoluted.
The initial results in breast cancer looked promising, and Puma's stock jumped tremendously. Then (as that link above details) things got murkier. Now (last night) new clinical results were released for the upcoming ASCO meeting, and the survival benefit is down to 2.3 months, which is not what people had been hoping for. Pumas's stock went down 25% in after-hours trading, and will not have a good day today.
Here's Matthew Herper's email exchange with the company's CEO. (As the headline mentions, he himself saw a good deal of personal wealth vanish last night). There are possible mitigations in the data, but not nearly enough (I think) to take the drug back to the status it used to have.
+ TrackBacks (0) | Category: Cancer | Clinical Trials
May 13, 2015
If you're an imaginative organic chemist, you can probably think of some interesting things to do with the never-before-described reagent, difluorodiazomethane. That paper will tell you how to generate it in situ without blowing yourself up, which is mighty handy, and it looks as if should do all the synthetic transformations you'd want from a diazomethane derivative. The key is to avoid aqueous and/or basic conditions: t-butyl nitrite and a catalytic amount of acetic acid in chloroform do the trick nicely from difluoroethylamine. Thanks to Pavel Mykhailiuk of Enamine for making this technique available to the rest of us!
+ TrackBacks (0) | Category: Chemical News
We turn now to Orexigen, one of the small companies trying to make headway in the obesity market. Earlier this year, a patent application from them published, claiming that their drug (Contrave, a sustained release formulation combining the known drugs naltrexone and bupropion) had cardiovascular benefits above and beyond its weight-loss effects. Problem was, they based that claim on the first 25% of the data from an ongoing clinical trial. You're not supposed to go around doing that. The disclosure led to a public fight with researchers at the Cleveland Clinic (including well-known cardiologist Steve Nissen) about whether the trial had been compromised, and whether Orexigen was misleading its shareholders.
Now, as Matthew Herper reports, the trial has been halted, on the grounds that it has indeed been compromised by that premature data release. The FDA had also stated that they would not accept the trial results for that very reason. Orexigen and their partner, Takeda (who must be wondering how they got into this) announced this yesterday morning, followed a half-hour later by the release of the (half-completed) trial data by the Cleveland Clinic team. (Takeda is also talking breach-of-contract). The cardiovascular benefit that had been noted at the quarter-way mark had slipped below statistical significance, and the best bet is that it was on its way to disappearing entirely, had the trial actually completed.
It's been ugly. Orexigen released a statement, trying to make their case. Read it at that link and see what you think. I have trouble believing, myself, that they're really pleased that the study is being terminated, and that it's yielded important information nonetheless.
The company also seems to be trying (obliquely) to blame the USPTO for disclosing the data, but they're glossing over the fact that (1) everyone knows the schedule for publication of patent applications, and (2) the PTO is only publishing what you put into your own patent application that you wrote yourself. So this is not even as plausible as blaming the "Reply All" button in an e-mail application. They also seem to be blaming Matt Herper for merely reporting the ways in which the company seems determined to super-glue a clown wig onto its head.
I'll gladly stand by that opinion, in case Orexigen's people get around to reading this, and I'll throw in another one: they would have had trouble paying someone to mess up that trial as throughly as they managed to mess it up themselves. For all the talk in the Orexigen statement about all the tensions and problems with disclosure of clinical data, it's really not all that hard: you shut up about your interim data, unless you've already (from the beginning) planned to disclose something, and the trial has been designed with that in mind. Otherwise, unless the numbers are enough to halt the trial (in either a good or bad way), you just sit tight and see what happens. Because interim data are, well, interim. You run a full trial to see what the real numbers are - until then, they aren't the real numbers.
Update: more on the data release.
+ TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Diabetes and Obesity | How Not to Do It
May 12, 2015
Now here's someone with optimism to burn, compost, and scatter to the winds. According to FierceBiotech, Vivek Ramaswamy has started a company called Axovant Pharmaceuticals, and their asset is a 5-HT6 antagonist from GSK. It goes back to the SmithKline days, when it was known as SB742457. It was in development for Alzheimer's, apparently going through at least five clinical trials of one sort or another (Phase I and II), before being shelved in 2012.
Ramaswamy picked it up for $5 million up front, with various payments back to GSK for milestones if it can get approved. But those are picayune - $35 million for US approval, for example. If Axovant can actually get a compound on the market for Alzheimer's, they'll make $35 million in the first twenty minutes. But as the Ephors of Sparta said to Phillip II. . ."If". Phase III is where Alzheimer's compounds have traditionally gone to die, and it's an expensive death indeed, given the size and length of the trial.
Axovant, for its part, has already filed for an IPO, valued at about $172 million. Optimism indeed, and a comment on the current state of the IPO market. It will be a matter of interest to see how this flies when the time comes. . .
+ TrackBacks (0) | Category: Alzheimer's Disease | Business and Markets | Clinical Trials
Time for another roundup of the chemistry journals. . .let's see what we have in the current issues:
JACS: "Science Rejected It, and Angewandte Couldn't Think Up a Bad Enough Joke, So Here We Are"
"A Paper Mentioning the Jahn-Teller Effect in the Title, So You May Scroll Right Along Without the Slightest Pang of Guilt"
Ang. Chem.: "A Metal-Organic Framework With Nanostructured BODIPY Ligands, Published Without Review on the Basis of the Title Alone"
"A Paper Mentioning the Jahn-Teller Effect in Its Title, Providing an Opportunity For a Brow-Furrowing Joke in the Abstract About Yawning Bank Tellers"
JOC: "A Piece of Organic Chemistry So Solid and So Reasonable That Even the Authors Are Bored With It"
"Someone Will Look Up This Paper, For Some Reason, About Ten Years From Now. But Until Then, Keep Scrolling."
J. Med. Chem.: "This Project Looks Good, But It Did Not Work. And 18 Out of the 23 Authors have Typographical Symbols Behind Their Names, Because The Work Took Place During Bush's First Term"
"We Hooked Two Totally Different Kinds of Drug Together With a Chain of Methylenes. Bet You Big Drug Companies Never Thought of That One!"
Nature Chemistry: "Whiplash-Inducing Subject Change From the Last Paper Before This One. You Only Get That in the Best Journals, Right?"
Org. Lett.: "Catalytic Photochemical Fluorinations of Photochemical Fluorination Catalysts"
Tet. Lett.: "Arrows Are All the Experimental Details You Need, Because You're Never Going to Run These Reactions, Anyway"
ACS Med. Chem. Lett.: "Holy Cow, Is This Ever Easier Than Writing a Full J. Med. Chem. Paper or What?"
Bioorg. Med. Chem. Letters: "Come For the Mini-Reviews, Stay For the. . .Well, Come For the Mini-Reviews, Anyway."
+ TrackBacks (0) | Category: The Scientific Literature
May 11, 2015
Now this is a neat synthetic trick. The authors demonstrate various standard reactions with acetylene (copper-catalyzed triazole formation, Sonogashira coupling, three-component condensation). And the first thing that many chemists will thing is "Yeah, acetylene, pain in the rear to use". So it is, which is why many people use trimethylsilylacetylene instead, and then deprotect.
But here's a way around that: this paper generates the acetylene in situ from calcium carbide (the good old-fashioned way!) and uses a multiphase system to keep everything where it should be. The acetylene gas comes up and saturates the organic phase on top, where the synthetic chemistry is occurring, and you have no cylinders and no worries. Worth thinking about next time you're into alkyne chemistry.
+ TrackBacks (0) | Category: Chemical News
I like scientific progress a lot. And we've had quite a bit of it in recent years in immunotherapy and gene editing; no one can doubt it. But there still seems to be something a bit off with the quotes below. These are the CEOs of Bluebird and Agios, speaking at the National Venture Capital Association conference in San Francisco:
Messrs. Leschly and Schenkein said the surge of biotech IPOs and the rise in the stock of many of those companies doesn’t mean the sector is in a bubble.
What once seemed like science fiction–for example, using a virus to deliver new genes to a patient’s body–is now reality, and investors want to be part of it every bit as much as dangerously sick patients do.
“A decade ago, stuff just didn’t get to market,” Mr. Schenkein said. “In the 2000s, most drugs failed because they didn’t work. But the science has changed dramatically.”
Well, some things have changed dramatically. But some things are still the same, and I don't think we've quite cleared out all the development risks yet, even when compared to such ancient, dusty efforts as those drug projects with the misfortune to have taken place before 2010. (Those poor people!) Though we've learned a lot, there's still a lot to learn. The money coming from those venture capitalists is still very much at risk, and to suggest otherwise is. . .well, the sort of thing that people say during an investment bubble.
That's not to take away from the sorts of results that have been reported in the fields mentioned. It's true - there are patients who have been almost literally pulled out of the grave by CAR-T and PD-1 therapies. But there are others who haven't, and we still need to find out why, and there are risks associated with even the successful examples. (There are also, naturally, plenty of other disease areas where these techniques, so far, avail not). As we push such ideas further, we're sure to have some dramatic successes, and some equally dramatic failures. A lack of those failures would, in fact, argue that we aren't pushing things hard enough: they're inevitable, or they should be.
We're in a very exciting period for drug discovery. But it's not, unfortunately, the Era When New Drugs Just Work. I don't expect to ever see that one.
+ TrackBacks (0) | Category: Drug Development | Drug Industry History
May 8, 2015
Three years ago, a Federal appeals court ruled that restraints on off-label promotion of drugs by pharma companies is a violation of the freedom-of-speech provisions of the Constitution. At the time, there was a lot of talk about where this might lead (with some betting on another court challenge to try to settle the issue).
Here's an update from Ed Silverman. The court case is here:
The FDA did not challenge the decision. And since then, the pharmaceutical industry has been lobbying the agency to revise its guidelines, because the ruling only applied to three states. The FDA has not indicated when it will take action, but plans to hold a meeting this summer to review the contentious topic.
Now, one drug maker is trying to force the issue. Amarin yesterday filed a lawsuit hoping to convince a federal court that the FDA prohibition on off-label promotion violates the company’s First Amendment rights, and that its reps should be able to convey truthful and “non-misleading” information to doctors.
Won't this be interesting to watch? I'm no constitutional lawyer, but the FDA seems to have lost a few decisions in this area already, and I'm betting that they'll lose this one, too. If they do, then we'll have a pretty lively time of it, sorting out what can and can't be said, but the "can" side will be on top.
+ TrackBacks (0) | Category: Regulatory Affairs
May 7, 2015
Ah, the dietary supplement industry. Where faked-up ads blatantly rip off every big media organization you can name, and claim that all sorts of billionaires and celebrities take the wonder pills. But they've never heard of the stuff. And all sorts of writers and reporters get their names added to the fakery, but they've never heard of the stuff, either, until someone asks them what the heck they're doing promoting brain pills. And faked-up clinical trial reports and images get thrown in, too, but when you contact the university where all this supposedly took place, they're never heard of the stuff. And when you finally track down the company, they say that this all must have been affiliate marketers, darn them all, and that they've never heard of such things. And when you finally track down the marketer himself, it turns out to be a phone number for a guy who runs a carpet cleaning service. He sends you to someone else - who's never heard of the stuff.
I don't know if I've quoted this part from Martin Amis's London Fields or not, but it's appropriate here, I think. Here's Keith Talent, a lout at the heart of the novel, at work:
Yet no one seemed to have thought through the implications of a world in which everyone cheated. The other morning Keith had bought five hundred vanity sachets of Outrage, his staple perfume. At lunchtime he discovered that they all contained water, a substance not much less expensive than Outrage, but harder to sell. Keith was relieved that he had already unloaded half the consignment on Damian Noble in the Portobello Road. Then he held Damian's tenners up to the light: they were crude forgeries. He passed on the notes without much trouble, in return for twenty-four bottles of vodka which, it turned out, contained a misty, faintly scented liquid. Outrage!”
I should note, off topic, that while London Fields has its moments, it already seemed when I read it to be a distorted echo of my favorite (Martin) Amis novel, Money. And The Information, which followed next, seemed only like a distorted echo of London Fields. And so it's gone since, for the most part.
+ TrackBacks (0) | Category: Snake Oil
Here's a very good review in J. Med. Chem. on thermodynamics and drug discovery. That topic has come up at this site several times over the years, and I've been wondering if anyone's reached a consensus yet. What I take away from this new article is "Nope. Not yet." Update: see also this review, also from earlier this year.
The hope, fanned by the work of Ernesto Friere and others, has been that there would be some sort of thermodynamic signature of compound binding that would help pick better compound series to work on. That's easier said than done. For one thing, you have to be able to do good calorimetry on your binding target, which isn't always possible. But even if you have plenty of protein and have the system well worked out, there are complications, and that's what this new article goes into.
Wavefunction has a good post on those, in response to this same article. One problem has been that we medicinal chemists have tried to oversimplify things, to work down to rules of thumb, and I don't think that ligand binding is amenable to that sort of thing. (Most of the really important topics in drug discovery - think toxicology - aren't reducible in that way, either, as it turns out). There is no useful textbook titled "Thermodynamics: A Hand-Waving Approach", unfortunately, because that approach doesn't work so well.
The hand-waving rules, in this case, have been "Pick the enthalpic-driven compounds", "Displace water molecules to pick up favorable entropy", among others. But there are too many exceptions. I gave a talk on entropic factors here at my workplace a few years ago, and as I dug into the topic, I found that water molecules could (and have been) assigned to every category possible, which is what everyone who takes a close look at the field discovers. Sometimes, indeed, you can displace one, and it goes flying off into entropic heaven and gives you a better T-delta-S term. But sometimes you displace one and it ends up more ordered out there in solution than it was in the protein binding site, which is counterintuitive. And sometimes (probably more often) it's the enthalpic effects of its hydrogen bonding, on both the protein and out in the bulk phase, that really determine the energetics. Thinking that displacing a water is always a good thing is just too reductionist, because the self-evident truth about water molecules is that they are not all created equal.
This is only the beginning of the complications. As the paper illustrates, in detail, similar ligands in the same SAR series (to the eyes of a medicinal chemist) can work through very different sorts of thermodynamics. Networks of water molecules, subtle effects on protein structure and stabilization, variable hydrogen-bonding networks, entropic and enthalpic penalties or bonuses from the bulk solvent, the localized water molecules, the ligand molecule, and the protein itself are all in play. You can't generalize - that's the message.
No one particularly likes to hear this. As scientists, we want to generalize, to discover trends and rules that we can use to cover more ground more quickly. As employees in hierarchical organizations, many of us would like to be able to report that we have found such things, through our own valuable keenness, and are now exploiting them (and deserve to be gainfully employed for doing so). "We've got a handle on this" is what we'd like to tell ourselves and to tell others. But when it comes to the thermodynamics of ligand binding, no, I don't think we have a handle on it yet. There may be rules and trends that will help us out, but they're not going to be as broadly applicable and wide-ranging as we'd once hoped.
+ TrackBacks (0) | Category: Analytical Chemistry | Chemical News | Drug Assays
May 6, 2015
So Eli Lilly is opening a research center in Cambridge (specializing in drug delivery). This prompts several questions.
Which big drug companies have not taken the Massachusetts Plunge, at least a little bit? (GSK and Roche don't have much of a presence, to pick two). What finally made Lilly decide that they were missing out, and what exactly do they feel that they're missing out on? Is putting a 50-head-count unit inside the magical environs of Kendall Square enough, especially when whatever they come up with is going to have to make it through the rest of Eli Lilly? And so on. . .
+ TrackBacks (0) | Category: Business and Markets
Via FierceBiotech, here's an odd story about a small company you've probably never hears of, Symbiomix. They were launched just a couple of years ago, and are now heading into Phase III with an antibiotic. How, you ask, is that remotely possible?
Well, it's an antibiotic (secnidazole, a nitroimidazole) that's been sold in other countries for so many years that it's gone generic, but was never taken to the FDA over here. So that does speed things up. The company says that the compound has a real advantage in treating bacterial vaginosis (single-dose versus longer course of treatment), and plans to market it accordingly. What insurance companies will think about this as an advantage worth paying for it yet to be seen.
This looks like a one-shot regulatory arbitrage play. For some reason, this compound was never marketed here, so even though it's an older generic drug overseas, it gets to be turned into a New Drug here, with New Pricing. It's safe to say that no one is going to be holding their breath waiting to see if Symbiomix's Phase III trial goes as expected - of course it's going to go as expected. Everyone else has already done all that work. Symbiomix just gets to put together as much of a package as they need for the FDA, and then they can go try to make money with it.
It'll be worth watching to see if they do. I dislike regulatory arbitrage, as many posts around here have made clear. That's partly because, as someone who's spent all his time in new drug research, it feels to me like cheating, like pulling a fast one. Hah-hah, someone forgot to cross their fingers and stand on their right leg back in 1991, which means that I get to price my drug today as if I'd done the work of discovering it myself! Suckers! But this isn't quite as airtight a case as the odious ones of companies who pick some obscure one-supplier drug and ratchet the price up on it. There are alternatives to secnidazole out there - specifically metronidazole, one less methyl group at the cost of faster clearance and a few more pills. Symbiomix will be devoting as much time to figuring out their price point as they will to their clinical trial.
+ TrackBacks (0) | Category: Business and Markets | Infectious Diseases | Regulatory Affairs
May 5, 2015
Here you are: a public call for the head of GlaxoSmithKline's CEO, Andrew Witty:
Witty, who’s led Britain’s largest drugmaker since 2008, is facing criticism for Glaxo’s lagging share performance and a depleted pipeline of promising medicines. A bribery scandal in China that led to a $489 million fine last year and sluggish U.S. sales also eroded support.
“Mr. Witty is running out of time,” said Stephen Bailey, a fund manager at Liontrust Asset Management Plc in London, which holds Glaxo shares. “He’s either got to deliver in the next 12 months or step aside.”
It has been rough over there recently, to say the least. Here's one analyst's take on what they should do:
Hampton should reinvest in research at Glaxo, which is failing to produce drugs capable of boosting earnings, said Laura Foll, a fund manager at Henderson Global Investors Ltd. in London, which owns about 7.6 million shares in Glaxo.
Profits are still tied to the aging asthma drug, Advair, while demand for two new respiratory medicines, Breo and Anoro, remains sluggish. The company is considering a spinoff of its HIV medicines, although it has few compounds capable of replacing them. Foll recommends cutting the dividend to fund research, a move some investors might resist.
Now, I like the sound of that very much. But I'll be surprised if anything like that happens. After all, the company says itself that "We are committed to using free cash flow to support increasing dividends, share repurchases or, where returns are more attractive, bolt-on acquisitions." Do you see anything in there about using any of the free cash flow to do more research of their own? A cynical investor might say that GSK got itself into the fix it's in now by all that R&D stuff, so why would you want them to do it even harder? But more seriously, Merck also tried to tell investors to stop pestering them while they're discovering drugs, and that didn't seem to last for long, either.
My guess is that if GSK were to pop up with an announcement that they're cutting the dividend and dialing back the share buybacks in order to do more R&D, the stock would get hammered, and a lot of high-level people would end up losing their jobs for having made such unpopular decisions. It's a shame.
+ TrackBacks (0) | Category: Business and Markets
Wavefunction has a good look at Peter Thiel's Zero to One. As he puts it, "Thiel has said some odd things about chemistry and biotech before, so I was bracing myself for encountering some naiveté in his book." I don't blame him; I'd be the same way. But it wasn't quite as bad as he feared.
Nevertheless. . .there is a grain of truth in Thiel's diagnosis of many biotech and pharma companies. For some reason the pharmaceutical industry has lost the kind of frontier spirit that once infused it and which is now largely the province of swashbuckling Silicon Valley inhabitants. Whatever the hurdles and naiveté intrinsic to this spirit, it doesn't seem unreasonable to imagine that the industry could benefit from a bit more can-do, put-all-your-chips-on-the-table, entrepreneurial kind of spirit.
Still, you'll need to be ready for the phrase "high-salaried, unaligned lab drones" - just warning you. Another part of the blog post mentions a good reason for the more cautious approach that you see in biopharma as opposed to software, though: higher chances of failure via factors outside of your control. That gets back to the humans-didn't-make-this argument that I make in this situations - you really do have a better chance of bulling your way through in an IT startup by sheer skill and hard work. Whereas in drug discovery, skill and hard work are necessary, but nowhere near sufficient. We get our heads handed to us more often, and for reasons that couldn't always be anticipated by a reasonable person.
That's why the avoidable errors are so annoying in this business. Our failure rates are high enough already without own goals!
+ TrackBacks (0) | Category: Who Discovers and Why
Biocentury has a roundup of reactions to the recent human CRISPR paper:
There's no dispute that because the technology is in its infancy, much more work needs to be done to establish its safety. Stakeholders also agree that no experiments should be done, at least for now, in clinical programs that would involve modifying germline DNA and creating gene-edited embryos.
However one camp argues that research to understand the technology better and establish its safety in human cells should be permitted under appropriate regulatory controls. That means gene editing would be performed on human germline cells, but that any products would be discarded. Advocates for that position believe it's worth considering whether there are therapeutic situations where using gene editing might be beneficial.
The other school of thought is that there will never be a justifiable use related to human germline cells, and that no experiments should be done for either research or clinical applications. The argument is not just that it's a slippery slope from establishing safety and methods for well-meant therapeutic uses to providing a roadmap for eugenics.
Over the whole discussion, though, seems to be an air of "Well, someone's going to be doing it; it's just a matter of when". That's how I see it, and that makes the job how to have it happen in the least crazy way possible.
+ TrackBacks (0) | Category: Biological News
May 4, 2015
Ed Silverman at Pharmalot has a piece on a perennial source of confusion for anyone outside the drug industry (and too many inside it): the difference between Merck and Merck. One of them gets called "Merck-Darmstadt" or just "German Merck" by some people - I've never heard "Merck KGaA" used in spoken English. The other, when needed, is differentiated by saying something like "You know, Rahway".
There's history behind this, of course, dating back to World War I and before. Back when there was a Schering-Plough, and back when there was a Schering in Berlin, the same sort of confusion piled up around them, but now we're down to just the Merck case. "German Merck's" CEO, Karl-Ludwig Kley, is apparently wanting the company's name to be better known, and better differentiated from "New Jersey Merck", which could prove tricky.
So if anyone - former employees, especially - would like to suggest names for either company that might be more distinctive, memorable, or appropriate, please feel free to do so in the comments. Just don't expect to see either company take any action!
+ TrackBacks (0) | Category: Drug Industry History
in 2013 I mentioned the efforts by the Reproducibility Initiative to redo studies in the field of experimental psychology. That's a timely idea, since there have been many questions recently about the rigor of some of its results - for a fresh example, see here.
Now the results are in for the first 100 studies (here's an article at Nature News). This effort is being written up as a paper, and will probably change around a bit during that process, but the general points seem to be pretty clear. It depends on how you look at them, though, and what your priors were.
The majority of studies could not be reproduced. That's one way to interpret things. Based on the preselected criteria, the results of 61 of the 100 papers examined did not repeat. But 24 of those produced results, which while not on the mark, were "broadly similar" to what was originally reported, and here begins the arguing. How "broadly" do we mean? And is that enough? According to the Nature News piece, a number of psychology researchers have been taken aback by these figures, so the answer to the last question might well be "No, not really". Between one-third and two-thirds of the recent experimental psychology literature does not hold up to replication, and no one is very happy with either end of that range.
The very next questions that readers around here will have, then, is what would happen if we tried that out in our own fields. The famous "Amgen paper" on the irreproducibility of the oncology literature comes to mind. There have been arguments over that paper's methods and its interpretation, but we're eventually going to get a more in-depth look at things. As that last link mentions, the Reproducibility Initiative is also taking a look at the "fifty most impactful" recent papers in cancer biology. So we can have that discussion with some solid data when the time comes.
How about organic chemistry? I think that the rate of reproducibility would be solidly over fifty per cent, but beyond that, I'm not prepared to say. Depends on a lot on the journal you're getting the papers from! But if you pick the same sort of level that the two Reproducibility Initiative projects have for those fields - say, a list of papers from JACS and the like, I would like to think that we would come out better than experimental psychology, and probably better than cancer biology. This isn't some moral superiority at work - we just have fewer variables in chemistry. That's not to say that there aren't some fiendish complications hidden inside our work; there certainly can be. But overall, we have a lot better time of it proving that our reagents and products are what we think they are compared to those other areas.
But how would it go, reproducing 100 papers from Organic Letters? From Tetrahedron Letters? From Synthetic Communications? Not as well, I feel sure. I think that comparable journals in psychology or biology would fare even worse, but that thought is of limited comfort.
+ TrackBacks (0) | Category: The Scientific Literature
May 1, 2015
Here's a paper on recent clinical trials in Nature Reviews Drug Discovery that reports some changes. It's just concentrating on the trials that began in the 2005-2009 period, and in case you're wondering, over 14,000 trials started during that period. There was a steady increase in the percentage of those that were sponsored by industry (from just under 60% to over 70%). The two biggest classes, by therapeutic area, were oncology and CNS, but (to my surprise) the former decreased by small but steady amounts over this period. On the other hand, anti-infectives moved up each year, overtaking the cardiovascular category, some of which was no doubt due to all the work on Hep C. Trials in metabolic disease also increase a bit each year.
Clinical trial lengths (all three phases) also decreased during this time, for reasons that are not completely clear. Phase I trials saw the biggest decrease in length, but the change wasn't as steady as in those other factors mentioned above - 2008 and 2009 were about the same, and the authors speculate that whatever it was making trials run faster might have reached its limits by then. (The authors did all sorts of fancy regression analysis, but couldn't assign the trial length changes to any particular factors - therapeutic area, type of sponsoring organization, phase of trial, etc.) All of these had some influence, but none of them were enough of an explanation by themselves.
If that decrease is real (and it seems to be) it'll be worth knowing if it's continued. I'll bet, though, that this hasn't, for just those reaching-the-limits reasons mentioned above. There's only so much you can do to speed things up. It's also worth thinking about the effect on costs. In general, a shorter clinical trial should cost you less money, but setting one up to run that way might be more expensive. So I'm not sure how those two balance out!
+ TrackBacks (0) | Category: Clinical Trials | Drug Industry History
In the long-running saga of getting a stapled peptide to work as a drug, Aileron Therapeutics was last heard from raising money for their p53 candidate. Now comes word that the company is basically going all-in with that one, raising yet more cash and gearing up for some definitive human trials.
I wish them luck. p53 is one of those great targets that no one's ever been able to make anything out of, so a completely new approach (like a stapled peptide) is a reasonable thing to try. And the whole stabilized-helical-structure approach that the stapled compounds represent needs to be given a real-world test, too. From one perspective, you might say that such a different technique should be tried out on a well-validated target, so you at least cut the risk down that way. But that's not how things go. Exotic techniques get used on the problems that other methods have failed on. But on the other hand, p53 is (biologically) about as well-validated as you can get, total lack of clinical success aside.
This will be exciting to watch, although I can't help but wonder if it's a death-or-glory move for Aileron. They've raised a fair amount of money over the last few years, and you can't go back and fill that bucket too many times. Good luck to them!
+ TrackBacks (0) | Category: Cancer | Chemical Biology | Clinical Trials