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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png 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: derekb.lowe@gmail.com Twitter: Dereklowe

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In the Pipeline: Don't miss Derek Lowe's excellent commentary on drug discovery and the pharma industry in general at In the Pipeline

In the Pipeline

April 24, 2015

CRISPR Gene Editing in Human Embryos: Not So Fast

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Posted by Derek

As you'll have heard, the rumors that CRISPR/Cas9 experiments had been performed on human embryonic tissue have turned out to be true. The recent calls for a temporary moratorium on such work were said to have been prompted by word that such a paper was being reviewed, and indeed, the paper that has appeared was apparently reviewed and rejected by both Nature and Science.

And what's interesting is that this paper's results are going to actually strengthen the case for such a moratorium. The team from Sun Yat-Sen University in Guangzhou tried to edit the gene involved in beta-thalassemia in human zygotes, but things went awry in several ways:

We found that CRISPR/Cas9 could effectively cleave the endogenous β-globin gene (HBB). However, the efficiency of homologous recombination directed repair (HDR) of HBB was low and the edited embryos were mosaic. Off-target cleavage was also apparent in these 3PN zygotes as revealed by the T7E1 assay and whole-exome sequencing. Furthermore, the endogenous delta-globin gene (HBD), which is homologous to HBB, competed with exogenous donor oligos to act as the repair template, leading to untoward mutations. Our data also indicated that repair of the HBB locus in these embryos occurred preferentially through the non-crossover HDR pathway.

So in short, this process appears to be much harder to realize in human embryos than it is in other cell lines, or even in mouse embryos, and the era of human germ-line manipulation looks like it's going to have to wait a bit. But I would have to think that it's still on the way. Like almost every other big medical advance, though, it's going to be more complicated than it might have looked.

Comments (4) + TrackBacks (0) | Category: Biological News

What Are the Odds of Finding a Drug (And How Do You Stand Them?)

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Posted by Derek

Lisa Jarvis of C&E News asked a question on Twitter that's worth some back-of-the-envelope calculation: what are the odds of a medicinal chemist discovering a drug during his or her career? And (I checked) she means "personally synthesizing the compound that makes it to market". My own hand-waving guesstimate of an upper bound starts with an assumption of around 10,000 people trying to do this, worldwide (which is surely on the high side - see below).

Now, if you start work at 25 (I'm counting master's degrees in there) and go to 65, you've got 40 years of career, but (1) not all of that, as time goes on, is going to be spent full-time cranking away in the lab, in most cases, and (2) God knows that there aren't nearly as many solid 40-year careers in this gig as there used to be. A more realistic count, and still on the high side, might be 25 years. Now, over that 25-year span, how many small molecule drugs are there for a medicinal chemist to score with? A generous count of 20 per year (see here, and note that in the last 20 years you'll need to subtract antibodies/biologics) would give 500 drugs discovered and sent to market during that time, so with the same 10,000 people working over that span, that would give you rough odds of 5%, one in twenty. That is surely an upper bound, by a very substantial amount.

That's because it's not the same cohort of people during that time, of course, so the odds are going to lengthen because of that. The real number of people will be smaller than 10,000, on the average, and the years of lab career will be shorter than 25. It's harder to assign solid numbers at this point, but my own impression is that the real odds are 1% or less. When I think back over my own career, the number of new small-molecule drugs that have come out of the shops I've worked in can be counted easily on my fingers, and I've worked around a lot of medicinal chemists during that span.

Now, this brings up another familiar subject, which comes up whenever I discuss the above topic with anyone outside the whole field of scientific research. "How can you stand that" is not an unusual question. If 99% of the patients a doctor saw were not helped by their medical care, that would be a discouraging way to make a living, for sure. But there are differences, important ones. For one thing, this is science, after all. Even when we find out that something doesn't work, we've found something. I'd rather make a drug that works, but many of the projects I've worked on have added to medical knowledge even when they didn't put a drug on the market. I can tell you, most definitely, that a selective m2 muscarinic antagonist is not going to help Alzheimer's much, nor will a D1 antagonist do much for schizophrenia. Similarly, an inhibitor of hormone-sensitive lipase is not an appropriate therapy for type II diabetes, and you will want to be very careful if you want to take a mixed PPAR ligand on for patients with metabolic syndrome, because they don't all do what you'd expect. And so on. A lot of people got to find out that last one, across several companies and in all sorts of interesting and unusual ways, but I have to say, in those other three examples, my colleagues and I were pretty much up at the front lines, and came up with some of the best compounds you could want (and some of the best ever seen for those targets). And they didn't work, for the usual reasons: failure to understand the disease well enough, failure when hit by toxicity through other mechanisms.

But the only way to find those things out was to make such compounds. So yeah, to invoke the cliché, I've pushed back human knowledge in those areas (and a number of others besides). The projects I'm working on right now are long odds, too, but I have reason to believe that my colleagues and I are again at the very edge of what's known in these areas, right up on the foaming front of the breaking wave. That's where I've always wanted to be. These are important problems, extremely relevant to human disease (as you'd imagine, since a drug company is willing to spend its money on them even though they're very hard indeed). Just getting the chance to work up at that level, to know that no one's ever put a foot down where the next step is going to go, is what does it for me.

Wavefunction has some good thoughts on this question here.

Comments (30) + TrackBacks (0) | Category: Drug Development | Drug Industry History | Life in the Drug Labs | Who Discovers and Why

April 23, 2015

Genervon and ALS: What's Going On Here?

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Posted by Derek

Ever hear of Genervon, and their ALS therapy, GM604? There's not too much to hear about, unless of course you're a desperate patient or relative, looking for something, anything that might help. Genervon is certainly trying to reach those people, with press releases that include phrases such as "dramatic" and "very robust". And they've been giving everyone the impression that this dramatic, robust therapy was already being evaluated by the FDA. But not so fast. As Pharmalot reports, the company is now acting as if it's never said anything of the kind:

. . .Genervon said in an email that it is “at the point of communicating with FDA about whether [the agency] would accept our formal application” for accelerated approval. In other words, the company has not yet submitted a New Drug Application, a step needed to officially set the FDA approval process in motion.

The company's acknowledgement that it has not filed an NDA appears to contradict earlier press releases and statements made by the firm's owners, Winston and Dorothy Ko -- or at least to have sown confusion about the actual status of GM604. In one February press release, for example, the company said that in a meeting with the FDA, "three times during the one-hour meeting we requested that the FDA grant GM604 accelerated approval."

The drug's effects had better have been dramatic: the trial that's causing all this controversy was twelve patients for twelve weeks. That's not a very long time to evaluate a disease like ALS, and you have to wonder just how impressive these numbers are with such a small sample size, and what the FDA is going to think about them. (There's a lot of room to wonder). Genervon isn't doing itself any favors, either, by its response to questions about all this, saying that "Some are crating [sic] an issue out of nothing hoping to discredit Genervon and causing delay to make treatment available to ALS sufferers".

Big red flag there. When you start accusing people of plotting against your company and trying to harm patients, you sound like a crank. Or a fraud. Or a fool, or maybe some of each of those - they're not mutually exclusive. I certainly hope that Genervon's owners are none of the above, and that GM604 will prove to be a useful therapy. But they should realize that they're not making a good case for that so far.

This sort of situation is the beginning of what I fear could develop from "right to try" laws, if they're not carefully written. I certainly understand people wanting access to experimental therapies, especially for a terrible condition like ALS, where there's basically nothing that anyone can do. But figuring out whether a new drug works is really a lot harder than it looks. For the most part, it takes more than twelve people, and it takes more than twelve weeks. We may decide that patients have the right to waste their money and to waste their time chasing such things, but letting them do that without also hurting the chances of finding something real, that's the hard part. A rare disease may wind up with not enough patients around to participate in controlled trials. A small company might end up spending too much of its resources providing its unproven therapy to people who want it now, proof or not. And worst of all, you might end up enabling unscrupulous operators to keep providing "drugs" at "cost" for as long as people are willing to pony up, and the heck with clinical trials.

These aren't the issues with Genervon. But this story shows, I think, how such things could happen. What the issues are with Genervon, though, are hard to say. The FDA has called on the company to release all its data, and the company says it's already sent everything they have (although for the purposes of applying for accelerated approval, not for an NDA package). Someone's confused. Or confusing. Or both - those aren't mutually exclusive, either.

Comments (37) + TrackBacks (0) | Category: Clinical Trials | Regulatory Affairs | The Central Nervous System

April 22, 2015

The Vibrational Theory of Smell: A Counterattack

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Posted by Derek

I've written here a few times about the vibrational theory of olfaction (and Luca Turin's efforts to revive and prove it). This is an attempt to add a new mode to the existing shape/size/polarity ones known to affect the olfactory receptors - the idea is that some of them may actually sense molecular vibrational modes through electron transfer. When I last mentioned this, the theory seemed to have returned serve, with results on human subjects being able to distinguish deuterated forms of musk compounds. Now comes a very strongly worded response in PNAS from a multi-center team. (Here's a good summary in C&E News from Sarah Everts).

This group, led by Eric Block at Albany, has several points to make. They've cloned and expressed what is believed to be the human musk receptor, and find that it responds (in vitro, at any rate) no differently to the deuterated and nondeuterated forms of several prototype musks. This looks like careful work - preparing the deuterated compounds and making sure that they're clean enough for such studies is not easy (past reports, positive and negative, have been confounded by small levels of odorous impurities). And there really does seem to be no difference in receptor response.

The authors also have a lot of objections to the vibrational hypothesis in general, and they're not shy about stating them, saying that"While Brookes et al. bring the vibration theory to a more concrete theoretical level, none of the key assumptions has supporting experimental evidence." They go into a detailed list of problems with the idea, which they say have really not been addressed (the amounts of energy needed, the complications of quantum effects swamping the proposed couplings, the effects of dynamical fluctuations on them, and their sensitivity to bonding character in the odorant molecules. There are, they conclude, just too many complication that have to be dealt with, and for a theory that has little empirical support (given their own results), it's just not plausible.

I have to say (as I'm quoted saying in the C&E News piece) that this is the most thorough challenge to the vibrational hypothesis yet. Block et al. have paid Turin and co-workers the compliment of taking them seriously, and this is a serious response. I'll be quite interested in seeing the response to it, and I hope that it's an equally serious one. If there are problems with this new paper's approach (and there could be), then the only thing to do is challenge them head-on, with testable hypotheses and new data. If, on the other hand, the response is vague, ad hominem, or relies too much on special pleading, that's not a good sign.

For example, Turin is reported as expressing doubt that the cloned receptor in this study is the relevant human one. That's the sort of thing, then, that he should press: is it? Can it be shown that Block and co-workers did all the work on the wrong receptor? That would help Turin's case, but what would help it even more is if he (or someone) could show a deuterated-compound effect on any cloned olfactory receptor at all. I realize that in vitro isn't in vivo, but the number of variable that might help the vibrational theory in the latter situation are matched (probably more than matched) by the number of new explanations that become possible for it not to be true at all. You'd think, that if olfactory receptors really can respond in this fashion, that they'd be able to do it in an assay like this. If not, well, there's another strong case to be made, if that one is indeed makeable. Just saying "Well, there has to be such a factor" is not enough. So let's see how things play from here. . .

Update: more from Wavefunction.

Comments (36) + TrackBacks (0) | Category: Chemical News

April 21, 2015

Best And Worst Areas for Drug Discovery

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Posted by Derek

I'm traveling today, with no time to do a full blog post. So I'm going to toss out a couple of questions for everyone:

What diseases or therapeutic areas do you think have the best opportunities now for "traditional" small-molecule drug discovery? And which ones do you think have the worst or fewest? All factors are in play - number and quality of targets, suitability for small molecules to work, market size, etc.

Comments (56) + TrackBacks (0) | Category: Drug Development | Drug Industry History

April 20, 2015

PD-1 Charted

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Posted by Derek

Via AndyBiotech on Twitter, here's a chart from the ongoing AACR meeting on what sorts of tumors are responding best to the PD-1 antibodies that are creating such excitement. You can look at this two ways - what parts of oncology practice are on their way to being transformed, and/or what parts still have a big need for small molecules (!) Here's more from Matthew Herper.

Comments (20) + TrackBacks (0) | Category: Cancer | Clinical Trials

Dr. Oz Under Fire

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Posted by Derek

You'll have heard that a group of physicians has written a public letter to Columbia University asking why Dr. Oz is still on the faculty there. Here's the text, and it includes some heartwarming stuff:

. . .We are surprised and dismayed that Columbia University's College of Physicians and Surgeons would permit Dr. Mehmet Oz to occupy a faculty appointment, let alone a senior administrative position in the Department of Surgery. . .

. . .Dr. Oz has repeatedly shown disdain for science and for evidence-based medicine, as well as baseless and relentless opposition to the genetic engineering of food crops. Worst of all, he has manifested an egregious lack of integrity by promoting quack treatments and cures in the interest of personal financial gain.

Thus, Dr. Oz is guilty of either outrageous conflicts of interest or flawed judgements about what constitutes appropriate medical treatments, or both. . .

It goes on in that vein, and I have to say, I basically agree with every bit of it. I have a good amount of contempt for Oz himself, and that has only increased with time. Columbia, or parts of it, may well be fine with having such a famous, high-profile person associated with the school, but Dr. Oz's fame rests on such a shabby foundation. He spouts nonsense to people who don't know any better - is that such a thing to be proud of?

Columbia is taking an academic-freedom, freedom of speech approach to this request, and Oz himself has said that he'll respond on his show. And I'm sure that we're going to hear oh, so much about bringing in all points of view, and being inclusive, and having an open mind, and providing information to the public (and don't they have a right to that?), and much more in that style. There will probably also be a tone of martyrdom - they're out to get him! - and perhaps a few hints about various "interests" with "agendas" that are behind these baseless attacks.

But I would happily sign a statement requesting that Dr. Oz be shown the door - several doors, at speed - and my only agenda is that I think he peddles sensationalist crap for fame and money. Listening to Dr. Oz is all too often a way to end up less informed than when you started, and full of ideas that have no real basis in fact. Remember, this is the man who told a reporter for the New Yorker that "Cancer is our Angelina Jolie. . .we could sell that show every day". Spoken like a man of medical science!

I'm under no illusions that they're going to get rid of him, though. Hey, Columbia sailed right past that green coffee bean nonsense and the Congressional committee grilling. They're not going to worry about some doctors writing a letter. What would get their attention, though, is if some wealthy donors were to start making some noise. Is that going to happen.

Comments (47) + TrackBacks (0) | Category: Snake Oil

April 17, 2015

Stopped For Efficacy - Again

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Posted by Derek

Well, just weeks after Merck halted a trial of their anti PD-1 antibody Keytruda (pembrolizumab) due to efficacy, Bristol-Myers Squibb has announced that a trial of their own PD-1 antibody, Opdivo (nivolumab) against non-squamous non-small-cell lung cancer has been halted for the same reason: it's working so well that it's unethical to continue. Nivolumab has already shown activity like this before in another lung cancer trial, so there's no doubt that the PD-1 excitement is justified. Oncology is really going through a big change, and we can hope that this is just the start.

Comments (21) + TrackBacks (0) | Category: Cancer | Clinical Trials

You Have One Minute

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Posted by Derek

The European Federation for Medicinal Chemistry has a competition open, for the best one-minute video explaining what medicinal chemistry is and why it's important. Here's the link - the prize is 500 euros, and fame/fortune/etc.

"Why Medicinal Chemistry" is a competition that invites medicinal chemists to make an original video highlighting what medicinal chemists do and why it is important. We want medicinal chemists from any level (eg. students to expert professionals) and affiliation (eg. academia and industry), as individuals or as groups of up to 4 medicinal chemists, to produce an original 1 minute video demonstrating the importance of Medicinal Chemistry to society. The video should be targeted at a non-specialist audience, but otherwise can use any style you like and should be as imaginative as possible.

That's a challenge, but you'd be surprised what you can get across in that length of time with well-chosen words. It's going to be interesting to see what comes out of this one; I hope that they get some good entries.

Comments (12) + TrackBacks (0) | Category: Chemical News

That Can't Be Right

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Posted by Derek

PLoS%20One%20xinghaiamine.jpg
Update: there's more going on here than meets the eye - see the end of the post.

Crazy structure alert! See Arr Oh has pointed out a paper that appeared a few months ago in PLoS ONE, describing a new antibiotic.

Yep, that's it at left. Note that it's a symmetric sulfoxide, with those. . .unusual groups on each side. An acenapthalene in a natural product? Substituted at those positions to make a macrocycle? A macrocycle with that tetracyclic group as part of it, one with two four-membered rings buried in it? Now, there are some truly crazy-looking natural products out there, but this one, were it to be real, would be a strong contender for the craziest.

I don't think it's real. Like See Arr Oh and the folks commenting on his post, I don't see how you can wrench carbon-carbon bonds into those positions. If you tried to make that structure out of one of those nice old metal Dreiding model sets, you'd need a pair of pliers, or perhaps a welding torch. The spectral data in the supporting information, while not at all silly, are nowhere near as extensive as they'd need to be to support such a proposal. This, to me, looks like another case of a structure put out by people who don't realize just how wild it really is. There are quite a few of these in the literature already. And natural product structure assignments do indeed get hosed up at times.

When you read the paper, you see that the authors make a big deal out of how extremely unusual it is to find a sulfoxide natural product, but present the rest of the structure as if they're reading the label off of a can of soup. This compound is worth being on the cover of Angewandte Chemie if it's really as drawn - that sulfoxide, while quite weird, is just a decorative ribbon on top of that wild ring system. I'll go ahead and put my marker down: whatever xinghaiamine A is, it isn't that.

Update: several sharp-eyed readers have been looking at the spectral data in the supplementary material of this paper (see the comments section). And there's some troubling stuff. Just to pick one example, the graphic below is a zoom in on one region of the authors' Figure S9, contrast and tints altered from the original. This is supposed to be the HMBC spectrum of the compound, but there are artifacts all over it. You'll note that some of the peaks appear, digitally, to be very different from the others (insharpness, color, and contrast), and there are rectangular bits of noise that may be cutouts as well. I hope that there's a good explanation for this, but it's worrisome, at first glance.

Update 2: Note that the two tan-colored spots at the top of the figure appear to be the same spot (as spotted by another commenter), noise and all, except the left-hand one has a straight clipped edge at the very bottom. And the spot two down from it, in the lower left corner, has what appears to be another clipping artifact on its left side. All of the "tan" spots in this figure appear to have squared-off areas of noise around them, as if they have been cut and pasted into position, and/or the background around them has been cleaned up. Also note that the second spot down on the right-hand side of the figure has stair-step pixel artifacts around its edge, which suggests that it could have originally been much smaller and blown up to this size.

Third update: I've contacted the editorial staff at PLoS ONE about this article. The closer you look at it, the worse it gets.
Figure%209.jpg

Comments (65) + TrackBacks (0) | Category: Chemical News

April 16, 2015

How Many Chemists Have You Seen on a Team?

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Posted by Derek

I'm traveling today to give a talk (at this regional meeting of the AAPS), so I don't have my usual train commute wherein to do the morning blog post. So I wanted to set off a bit of discussion instead. I had an email from someone whose boss was at Merck during the Ed Skolnik R&D era, and he had referred to one "Skolnik Unit" as being approximately 20 medicinal chemists. I found that interesting, because I myself have rarely (if ever) been on a project that had that many med-chem participants. Looking back, I think the maximum I can recall is about 16, and that's been a while. I've seen a couple of projects that I'd say reached the 20 head count in chemistry, but that was a peak that didn't sustain.

So here are a couple of questions: what's the largest number of medicinal chemists (discovery, not process) you've ever seen on one project? (I assume that the people from the large organizations will hold the records here). How long did peak number that go on? My correspondent mentioned a project that was said to have two "Skolnik units" worth of chemists. Has anyone been on one that large? If so, how was it organized - the traditional "this team on the eastern amine part, that team on the central ring, that team on the western heterocycles" way, or something different?

And finally, if there was an era where scores (literally) of medicinal chemists were deployed against a given target, is it over?

Comments (46) + TrackBacks (0) | Category: Drug Industry History | Life in the Drug Labs

April 15, 2015

Using the Same FEP Ruler

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Posted by Derek

With free energy perturbation having its time in the calculational spotlight, thanks to Schrödinger and others, it seems worthwhile to link to this new paper. It's a proposal for a common framework to analyze the results of such work. That's needed, because (as far as I can tell, as a definite outsider) every group seems to have its own idea of how to do that. This situation makes it difficult-to-impossible to compare various approaches, so even if this isn't the best possible set of benchmarking tools (I'm not qualified to say), just getting everyone to use the same ones would be a step up. (Thanks to Ash/Wavefunction on Twitter for pointing this one out).

Comments (13) + TrackBacks (0) | Category: In Silico

Dealing With Cranks

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Posted by Derek

Here's a good article at Vox about what to do with idiots like the Food Babe and Dr. Oz. (OK, perhaps he just plays an idiot on TV, but by this point you have to wonder). Like any scientist with any sort of public platform, I've wondered about this, too. Bash them over the head at every opportunity? Doesn't seem to do any good, and it gets tiresome, both to write and to read. Totally ignore them? Can't stand it. These people are getting so much attention that they have potential to cause a lot of harm, and besides, the sheer level of self-confident ignorance and misinformation is too much to put with sometimes.

So where do you land in between those two extremes? Julia Belluz's suggestion are to not just go after the cranks, but the people who make their career possible. The TV shows that have them, the advertisers that fund them, the publishers that bring out their awful books. You have to make sure that you get the weight of the scientific evidence right (or risk becoming what you behold). And you also have to, as she says, "beware of turning cranks into martyrs", while also not overstating their influence. That's a narrow road, in some cases, but those are indeed the ditches on both sides of it that you have keep from driving into.

The trickiest part is that you don't want to become part of the show yourself:

I've been covering Dr. Oz's promotion of pseudoscience for several years. Recently, my dad made an astute observation about that work. He suggested I was somehow dependent on Oz's shenanigans, benefiting from his erroneous medical infotainment to build an audience. I couldn't deny the charge, and his words made me think of the central conflict in Janet Malcolm's ethics tome, The Journalist and the Murderer, summed up on its first page: "Every journalist who is not too stupid or too full of himself to notice what is going on knows that what he does is morally indefensible."

But given that Oz is, depressingly, the most influential public figure in health in America, I would argue that the coverage is warranted and necessary.

Brendan Nyhan raised this conundrum, calling it a "synergy between people who are pushing these theories and people who are covering them in a kind of freakshow style."

I really think that Dr. Oz is where he finds himself because he really likes to be on television, enjoys being a wealthy public figure, and has convinced himself, as much as he needs to, that he's doing some sort of good along the way. But I also think that if you'd shown him (as a young medical student) where he is today, he'd probably approve of the lifestyle and the fame, but (I hope) be taken aback by what he does to keep it going. He's a performing clown, presiding over a medical and nutritional freak show.

Going after the fools while not being taken for one of them - that's quite a trick to pull off. As I heard growing up in Arkansas, "Never wrestle with a pig - you both get filthy, but the pig enjoys it". That's one reason why I don't spend more time hammering on these people, even though it is sort of fun. Maybe especially because it's sort of fun.

Update: thoughts on the same article from Orac at Respectful Insolence.

Comments (35) + TrackBacks (0) | Category: Snake Oil

Finding Placebo Responders

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Posted by Derek

We all know about the placebo effect - in some therapeutic areas (depression being a classic case), it's so strong that finding a drug that works better is no small feat. And it's been thought for some time that the strength of the placebo response varies from patient to patient, in ways that aren't really understood. But what if there were a genetic component? What if you could tell, beforehand, which people were most likely to respond to just the thought of a drug?

This idea is getting closer to reality. Here's a review in Trends in Molecular Medicine - as the authors show, it's thought that variations in the serotinergic and dopaminergic systems, among others, are likely to be the fundamental differences in varied placebo response. If there are really trends to be discovered, and these can be tracked down all the way to the genetic level, then that will change the way that we conduct clinical trials, for sure. It also has the potential to change medical practice, at least in some areas.

What's more, it opens up a lot of questions that we certainly don't know the answer to. If someone knows that they're a "strong placebo responder", do they continue to be one? Does it wear off over time after repeated applications of self-knowledge, or are the neural pathways involved unconcerned with that sort of high-level activity? When would it be ethical to give one person a placebo and another person a drug substance, just based on their "placebogenic profile"? How do we compensate for these patients in drug clinical trials - leave them out of Phase II, so as to get a clear look at the mechanism, and bring them back in for Phase III as a more real-world test? Do we take more care to remove them from (say) an antidepressant trial, where responses have historically been high, and if so, to what extent is that justified?

And unraveling the mechanisms behind the placebo response itself is bound to produce some interesting information, in an area where we have very little to go on. The slow and gradual clearing of the fog that's covered neuroscience for so long is a very big story that's going to take a long time to completely develop, but in the end, there may not be many bigger ones.

Comments (15) + TrackBacks (0) | Category: Clinical Trials | The Central Nervous System

April 14, 2015

Big Monofluorination Review

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Posted by Derek

Here's a comprehensive and very timely review on monofluorination methods. 84 pages, before you get to the references, and there are 562 of those! It covers the last ten years of the literature, a busy time indeed in the organofluorine field, and no one should be without it who's interested in fluorination. That means pretty much all medicinal chemists - enjoy!

Comments (0) + TrackBacks (0) | Category: Chemical News

*Blog Post Title* Goes Here

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A colleague tells me that he just got a come-on from yet another unknown open-source journal, "Pharmaceutical Chemistry Review". Reproduced below, word-for-word, is the pitch. And it's hard to resist when they butter you up like this:

Dear *name*,
One of your papers has drawn our attention:
Titled: *title*
Published in: *source*.

Yep, personal attention will do the trick every time. The journal says that it publishes papers in (among other subject areas), "Lead Compounds and Enhance the New Drug Research", "Based on Potential Drug Targets for Life Science Research Reveals" (that's what it says, honest), and "The Penetration of Molecular Mechanics and Quantum Chemistry and Pharmaceutical Science". You will not be surprised to find that the go-getters behind this "journal", Biological and Chemical Publishing, are on the list of predatory publishers. And man, with bait like this, they must be reeling them in. . .

Comments (14) + TrackBacks (0) | Category: The Scientific Literature

Looking Back At Merck/Schering-Plough

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Here's Ed Silverman Peter Loftus at Pharmalot, looking back at the Merck/Schering-Plough merger. It has not gone quite like the initial plan:

First, a little history. In November 2008, Schering-Plough Chief Executive Fred Hassan told analysts and investors gathered at the company’s Kenilworth, N.J., headquarters it was developing “five stars” with big sales potential. They were: 1) rheumatoid-arthritis treatment golimumab (with Johnson & Johnson JNJ -1.50%), 2) the antipsychotic Saphris 3) Bridion 4) the anticlotting drug vorapaxar and 5) a hepatitis C treatment called boceprevir.

It was within weeks of Hassan’s stargazing that Merck began courting Schering-Plough, leading to the Merck takeover in 2009. Merck touted the five stars among other Schering drugs, as well as the deal’s potential for big cost cuts.

The five stars did make it to market (in the case of Bridion outside the U.S.). But none has significantly moved the needle for Merck, whose annual sales have fallen each year since 2011—to $42.2 billion last year—hurt by patent expirations for older drugs. . .

Well, a lot of people will tell you that this sort of salesmanship was Hassan's strong point. And drug development is, as we all have had chances to notice, unpredictable. But doesn't everyone sound so confident when they announce these mergers? Isn't the future just laid out there to be marched into and conquered? You don't hear anyone going on about how gosh, you just never know in this business, it might work out and it might not. No, the bold leadership of Company A has stepped up and seized the opportunities provided by Company B, and all manner of things will be well in consequence.

As Silverman Loftus shows, in the Merck/SP case, the bright spot has been Keytruda (pembrolizumab), which was considered to be a roundoff error in the deal compared to all those other big, promising compounds. It's not like Schering-Plough thought a lot of it, either (if they had, you can bet that Hassan would have put a sixth star up there immediately). Keytruda was originally from Organon, and when S-P bought them in 2007, it wasn't even mentioned in the press release or the articles written at the time.

So it's a pretty safe bet that Merck's management would have been nonplussed to hear that Keytruda would turn out to be the best thing that they got out of the deal. And they would probably have had to hold on to the back of a chair or something if you'd shown them what was in store for Fred Hassan's "five stars". As The Clash used to put it, the future is unwritten.

Comments (29) + TrackBacks (0) | Category: Business and Markets | Drug Industry History

April 13, 2015

Better Drinking Through Chemistry

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This is a fascinating article about a guy who's looking into the chemistry of aged spirits - rum, whiskey, cognac, and so on - and trying to find ways, as he puts it, to hack the process. I'm not a drinker myself, but I've watched with interest as the craft spirits movement has become popular. How, I wondered, could anyone start up a business in this area, when you need years in wooden barrels to make the stuff high-quality? Did someone have the idea back when Bill Clinton was running for office that there would be a market for small-volume distilled spirits, and plan accordingly?

Not at all. What happens is that the many of these tiny-label outfits buy their stuff from large-volume distilleries, sometimes doing the minimum possible to get their own brand on it. That might involve running some neutral spirits through another layer of charcoal to make your own "proprietary" vodka, or in the case of the aged liquors, it might just involve slapping a label on whatever showed up on the truck from Lawrenceburg, Indiana, which is where a lot of this stuff really comes from.

But that's not the business model that this new piece is talking about. It's been known for a long time that many of the flavor notes that come into aged spirits are products of extraction from the wood and often subsequent esterification. So do you have to wait twenty years for this to happen, or not?

The trick then is to encourage esterification in a short time period, and that’s the core science behind Davis’s Model 1 reactor. The reactor accomplishes this in three stages, taking white distillate and chunks of oak as inputs. The first stage forces the esterification of short-chained fatty acids in the white spirit, turning them into fruity, short-chained esters. Phase two literally splits apart big polymer molecules in the oak, extracting the compounds needed to complete the esterification process. This pulls out the aldehydes needed for the final step, but also some unpleasant medium-chained acids. In the final stage, those acids and phenolic compounds are forced to esterify, with simple esters being made to bind and combine into longer-chained esters that would normally be associated with a very mature spirit.

What comes out the other side is not necessarily an aged spirit, but rather one that bears the same chemical signature of an aged spirit. Davis uses mass spectrometry to compare old spirits with products put through his process. Spikes on the chromatogram correspond to compounds that appear in the highest concentrations in the spirits.

He's planning to be completely up front about the process, not trying to sell the products as if they've been sitting around for decades, but just tasting as if they do. And it sounds like it could be a successful business, at the right price point. It also sounds like the sort of thing that could bring on a lot of irritated commentary from fans of the traditional methods, naturally. I would doubt that the two techniques produce identical results (and they're not claimed to), but what if they produce equally desirable ones? Blind-taste-test style results? The traditional distillers will always have a market, because some customers will surely always want to pay for the time and effort that goes into making that product (or be seen paying for it, which amounts to the same thing, economically). But if this new technique catches on, they may well not have as large a market as they do now.

It'll be interesting to watch this play out. The same points that get debated around industrially produced foods will surely be argued in this area, too, but the line between nasty, lowbrow "processed food" and high-end "molecular gastronomy" can get pretty blurry, especially if you need an LC/MS to distinguish them from each other, or from a classic preparation. And we're going to see that debate played out in many other food and drink areas in the coming years, too. . .

Comments (32) + TrackBacks (0) | Category: Analytical Chemistry | Chemical News

Hollow Fiber Flow

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Flow chemistry has a lot of potential for catalyzed reactions - just keep flowing your starting materials across the catalyst, and product comes hosing out the other end. Well, in theory. In practice, although this sort of thing is done on gigantic scale in the chemical industry, it can take a fair amount of engineering. You want to have your catalyst firmly immobilized, but still active, and you don't want your reaction gradually fouling it and killing it off, either. That fouling process can lead to clogging, the bane of every flow chemist's life. Just as annoyingly, you don't want the catalyst gradually washing away from the support, contaminating your product stream and deactivating your whole system.

Realizing all of these at the same time is not the work of a moment. For a dedicated plant, it can definitely be worth the time and effort to tweak everything up to concert pitch, but one of the things that holds back benchtop flow experimentation is that most people don't want to face that every time they run a reaction. There are all sorts of solid-supported catalyst products and ideas out there, but here's another one that might have some promise: a joint Emory/Georgia Tech team reports a scheme to use hollow-fiber reactors with imbedded catalysts.

The fibers themselves are made out of cellulose acetate and inorganic oxide particle, a combination that's already well established in industrial gas separation techniques, desalination, water treatment and so on. You pump your reaction stream into the middle of this tube, and the solvent flows radially out through the walls, with the reaction taking place in that transit. A separate flow outside the walls can sweep the product along from there. Acid- and base-catalyzed conditions with two different kinds of hollow fiber worked fine, so they tried tethering a rhodium catalyst for some diazo cyclopropanation and the like. (They'd already worked out how to get the catalyst onto functionalized silica particles). That's a bit more demanding, but it seems to have worked well.

From the data they present, it looks like the rhodium fibers hold up reasonably well, but there is a very small deterioration with time. Hard to say if that's going to keep going, or if it just sort of levels off. The team promises that more work on various metal-catalysed reactions is on the way, so it'll be worth keeping an eye on this stuff as it develops.

Comments (3) + TrackBacks (0) | Category: Chemical News

Teaching Chemistry, According to the Press

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You know how most newspaper articles that deal with chemistry show that the writer didn't know very much about chemistry? Well, it looks as if people know even less about how chemistry is actually taught. Chemjobber has more here. I'll echo his question: do they really not teach anyone at Emory what a bond is until sophomore year? Or did someone garble that part, too

Comments (19) + TrackBacks (0) | Category: Academia (vs. Industry)

April 10, 2015

Acetonitrile. . .In Space!

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You may have seen stories about this paper, which shows that the protoplanetary disk around a (very) young star system is full of HCN, acetonitrile, and other CN-containing compounds. Studies of comets in our own system suggest that these were common materials in our early solar nebula, and this observation strongly suggests that our own situation is not unique. HCN and acetonitrile had already been detected in interstellar dust clouds, but there have been questions about what happens to them during star and planetary system formation. I like how the astronomers call acetonitrile "methyl cyanide" - keep in mind, though, that these are the folks who call everything heavier than helium a metal.

I don't think that enough people realize just how common the small organic building blocks are around the universe. We already have samples from the carbonaceous chondrites (with the Murchison meteorite being the most spectacular example), full of all sorts of compounds. And many small molecules have been detected in nebulae, with many more surely masked by their spectral characteristics. The universe is soaking in the sorts of molecules that life as we know it uses - and literally soaking in water as well, when you consider how much liquid water and water ice is piled up on the outer moons of our own solar system. All those cheapo science fiction movie plots about aliens coming to Earth to steal our water? No way - the ones where they come to steal Earthly women even make more sense than that idea. I should note in haste that no remotely respectable science fiction author has probably used the steal-our-water trope since roughly the 1930s, but movies are another thing altogether. (Not even The Man Who Fell To Earth made sense to me from that angle, but that was mostly social/political satire, anyway).

So life-as-we-know-it would seem not to have any rate-limiting steps that have to do with getting the starting materials together. The rest of it is still an open question, a big one, but if you also make the reasonable assumption that there's probably nothing particularly unlikely about our own solar system, life might well be pretty common. (Note that I'm mostly talking about microorganisms, which were, after all, the only form of life on earth for a huge stretch of time. As for intelligent aliens, I refer you to Where Is Everybody?, an excellent book-length treatment of the Fermi Paradox.

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Sigh

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Swedish%20cover.jpgWell, here you have it again. Thanks to a longtime reader for sending this along: the largest chemistry publication of its kind in Scandinavia, sent out to a large subscriber base of chemists and scientists in general. And what do we have on the cover? Nonsense chemistry drawings from the art department. Sorry, whoever it is who did the cover layout - you don't see aliphatic hydrogens attaching aromatic rings. And you don't usually draw two wedged bonds coming from the same carbon, either, while we're at it. Go ahead and scatter ball-and-stick drawings of ammonium dichromate around in the background, even though it doesn't seem to have anything to do with anything, what the heck. But the big drawing in the foreground, couldn't that at least make sense?

I know, I know. No big deal. Just some art. But do trade magazines for the auto industry ever show cars zipping down the road while missing a wheel? Do the ones for petroleum engineers ever show drawings of people using needle-nose pliers to loosen up hex nuts? It would look nice, you know. Decorative.

Update: I take it all back! Commenter Curt F. noticed what I didn't - that this is an alcohol dehydeogenase reaction, with NAD+ as substrate. I had "organic chemistry reaction" in my head when I was looking at the cover, not "enzyme-catalyzed voodoo", but that's not enough of an excuse. The Swedes are off the hook on this one! I'll leave this post up to make my humiliation complete.

Second update: I just went into the lab and set up a row of amide formations to make myself feel like a real chemist again. Well, a real medicinal chemist, anyway.

Comments (29) + TrackBacks (0) | Category: Chemical News

April 9, 2015

A New Fifty-Year-Old Hepatitis C Drug

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Here's something that might be alarming for the companies that have been piling into the hepatitis C space (Gilead, BMS, Merck and more). But if you're a hepatitis C patient, or the insurance company of one, it might be welcome. A new report suggests that an existing antihistamine, chlorcyclizine (CCZ), could be an effective therapy. Check out that structure - that's a first-generation antihistamine if you ever saw one (the old fuzzy-headed allergy season effect). It's been over-the-counter for dog's years; in the US it mostly seems to be sold as part of the usual combinations for allergy et al.

But this new paper, from NIH and a collaborator at Hiroshima University, makes a good case for it as an antiviral. A cell-based phenotypic assay identified it in a screen of approved drugs, and several related compounds hit as well. Both enantiomers of CCZ seemed to work, so they chose the (S), since it had less histamine receptor activity. It dose-responsed well in assays measuring viral RNA levels in infected cells, and the activity seems to cross all the viral genotypes tested, without any noticeably cytotoxicity. Follow-up assays showed that viral RNA replication doesn't seem to be the target, nor virion assembly. It's back earlier than those, and the best hypothesis now is that it's a cell entry inhibitor. But none of the proteins known to be factors in HCV cell entry appear to be affected, so the target hunt is still very much on.

That unique mode of action would make you think that it would synergize well with the existing HCV drugs, and so it proved - it enhanced the activity of everything on the list. But it's not a pan-viral panacea: tests against a whole list of other disease-causing viruses showed no useful activity, even against another flavivirus like dengue. So far, there's also been an interesting lack of resistant strains developing. Someone's going to uncover some good biology using this compound, that much seems certain.

Pharmacokinetics in mice are reasonable, and (helpfully) the compound attains higher concentrations in the liver than in circulation. It does indeed cross the blood-brain barrier, as all the old antihistamines do, so that would have to be taken into account at the doses needed for an antiviral program. But the desmethyl metabolite, nor-CCZ, seems also quite potent as an antiviral, and doesn't cross nearly as much (as you'd expect; the same thing shows up for other known antihistamines). So that one would have fewer side effects, presumably, but would need to be developed as a completely new drug, whereas chlorcyclizine has been around since the Johnson administration.

In summary, this study provides compelling evidence that CCZ, an over-the-counter allergy drug, has a strong anti-HCV activity in vitro and in vivo in a mouse model of HCV infection. On the basis of these results, a clinical assessment of CCZ alone and in combination with other anti-HCV drugs is warranted. The repurposing or repositioning of CCZ in HCV treatment may provide a more affordable alternative to the current costly options, especially in low-resource settings where chronic HCV infection is endemic. This study also lays the foundation for further structure modification of CCZ to discover more optimal analogs for the treatment of HCV infection.

It also points the way to finding a very interesting new antiviral target, too, as mentioned above. This is just the sort of thing that you run phenotypic screens in order to find - congratulations to the NIH/Hiroshima team for really hitting a good one.

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Not 100%. Not Really.

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I've mentioned Tomas Hudlicky's views on the state of the current synthetic organic chemistry literature here before: he's not very complimentary, and he's good some good reasons not to be. I had an email from him the other day with another example of some of the problems that he's talking about.

Take a look at this paper, which just came out in JOC. It's a total synthesis of a natural product called brazilin, from a group in South Korea. Now, I have no doubt that they have made brazilin. And I have no doubt that they have made it by the route that they detail in the paper. But (like Hudlicky) I do have doubts that six reactions in their synthesis all went with flat 100% yields.

He's shown that if you do a standard workup and chromatography, the odds of you getting 95% and above are very small indeed. You can't even recover weighed amounts of known compounds to 100% with that treatment, much less clean up reaction mixtures. But that's just what happens in this paper. Now, this may seem like a minor point - OK, the yields were high, the reactions worked well, so what's the big deal with saying 97%? Or even 100%?

The big deal is that this is a symptom of a larger problem - the hyping of results, dressing things up to look better than they are. 100% yields are wishful thinking at best, and deception at worst (self-deception, most likely) and none of these are good things to let into the scientific literature, even at very dilute levels. The same impulse and the same tendencies can lead to much worse things. If we're all going to start thinking honestly and clearly about our work, maybe we could start small, and admit that there are no 100% yields after extraction and chromatography. Yes, yes, your hands are great and your technique is awe-inspiringly flawless. But you didn't get a 100% yield.

Comments (61) + TrackBacks (0) | Category: The Scientific Literature

April 8, 2015

Too Many Favorable Clinical Trials? Maybe Not.

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Posted by Derek

Everyone loves a good head-to-head trial of two therapeutic agents - companies want proof that they're better than the competition, physicians want to see what works better, insurance companies want to see which compound they're willing to pay for. They don't always get run, for a lot of reasons (some honorable, some not), and companies don't always get the answers that they want, either. (I'm tempted to link to a version of Fleetwood Mac's "Oh Well" in that last line!)

But how often does that happen? Not, perhaps, as often as it should, according to this paper in J. Clin. Epidemiology. It's from a large team of Italian researchers, and one other co-author, published data scourge John Ioannidis. They analyzed 319 trials that had direct treatment comparisons and were mentioned in the 2011 medical literature, 182 of which were company-funded. The great majority of patients in the overall sample, though, were in the industrial trials, and only randomized trials with more than 100 participants were considered. About 70% of the trials were found in registries such as ClinicalTrials.gov (and 86% of the company-funded ones were).

73% of the trials had a superiority design, while almost all the rest were noninferiority trials. The industry-sponsored ones had a higher proportion (29%) of noninferiority designs, probably because those can be cheaper while still (in some cases) being useful enough for regulatory approval. 68% of the superiority trials reported favorable findings, and 88% of the noninferiority ones did as well (95% of the industry-sponsored noninferiority trials!)

Reporting favorable results was correlated with whether a trial was industrially sponsored and whether it had a noninferiority design. There are probably several factors at work here:

In conclusion, there is strong dominance of the industry in the influential agenda of head-to-head comparisons, confirming the unbalance between profit and nonprofit sponsored sources of data of current literature. We observed a high prevalence of results that were favorable for the sponsoring companies, which may have several explanations including: (1) industry trials may be conducted more rigorously than nonprofit trials and are thus genuinely more successful; (2) pharmaceutical companies may selectively fund trials that are more likely to yield favorable results (possibly due to the many preliminary phase 1 and phase 2 studies that are conducted before embarking on phase 3); (3) industry trials choose suboptimal outcomes, comparators, and other design features that can secure a favorable result; or (4) trials with unfavorable findings may be less likely to be published by companies. It is currently impossible to determine the relative weight of each of the above. . .

One thing the authors note is that although the drug industry has a reputation for avoiding comparison trials, the great majority of such trials still come from industrial sponsorship, because it's valuable data for approval and subsequent marketing. That second factor in the above paragraph is a key, I think: given the regulatory environment, you're going to have a hard time getting a drug approved these days unless you have something to point at that makes it distinct from the competition. The sorts of compounds that look as if they have a real chance of flunking a head-to-head competition trial just don't get taken that far in many cases, which is as it should be. Comparison trials of this sort come very late in the game - Phase III or post-marketing. So perhaps these results aren't so much evidence of systematic bias, but evidence that drug research is working the way that it's supposed to.

Comments (9) + TrackBacks (0) | Category: Clinical Trials

Colorful Compounds Strike Again

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Here's a paper of the sort that I wish more people would publish: a report of a false positive compound, and why it was a false positive. The authors, from the Helmholtz Institute at Saarland University, were screening for compounds that might directly inhibit bacterial RNA polymerase. That's certainly a worthwhile target, although (like the other bacterial enzymes), it's sure not an easy one. Rifampicin is probably the prototype antibiotic with this mechanism, and not many of us have sent things into the screening collection that look like it does.

pyrrole.jpgBut in a fragment screen, the Helmholtz folks came across the small molecule shown, with pretty decent potency and ligand efficiency. Isomers of the same structure had already been reported as polymerase inhibitors, as it turned out. But when they made some more of the compound, well. . .it wasn't active.

On standing, though, the newly synthesized material began to take on some color, gradually turning redder and redder. Now, you don't get much redder than rifampicin, which can even stain your sweat, but redness is not a necessary property of a polymerase inhibitor. Suspicious, the team aged some of the material by warming it up in an open flask, and sure enough, the activity in the assay was back. And the redder the stuff got, the better it worked. Analysis showed some high-molecular-weight polymeric material forming - their proposal is that the pyrrole is polymerizing and leaving a backbone of carboxyl-substituted aryls poking off in every direction. I can well believe that. I've been on the receiving end of some pyrrole-containing false positives myself, and in several of those cases there was some red-purple stuff that, once removed, killed the activity.

This carboxylate-studded gunk apparently is a good nucleic acid mimic. Gel-shift studies showed that it binds tightly to RNA polymerase, with a Ki in the low nanomolar range. (RNApol, of course, is ready and looking for regular repeated negative charges). A quick check, though, showed that the polymer was a strong inhibitor of a bacteriophase RNA polymerase, but not those from some other species. Still, you could expect that something like this could well tangle up your assay results if your target protein has a net-positive-charge region that's important.

It's tempting to just say "Fine, no pyrroles" after seeing things like this. But it's hard to make rules like that when a pyrrole (albeit a more heavily substituted one) has gone into millions of patients (and pulled in tens of billions of dollars in revenue). Probably the best lesson to draw is to be suspicious of lightly substituted pyrroles, especially if the sample has any color whatsoever, and always be ready to resynthesize/repurify them you start high-fiving anybody.

The Helmholtz group, by the way, did go on to find some things that were more robust. But I'm glad that they published their blind alley along the way - it could do someone some good on some totally unrelated project.

Update: in response to questions in the comments, the authors did try their polymeric stuff against actual cells, but with no effect. It surely has severe problems getting across the membrane, but if you could get it in, I'll bet it would do all kinds of things. . .

Comments (22) + TrackBacks (0) | Category: Drug Assays

April 7, 2015

Phosphorus And Me. Or Maybe You First.

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Posted by Derek

Fosfomycin.jpgA commenter mentioned fosfomycin in this morning's post, which prompts me to put its structure up for those who don't know the compound. Now that's a strange little beast. It's a natural product, as you might well think - who's going to make that on purpose? And it's also a pretty decent antibacterial, as an inhibitor of MurA. That epoxide is indeed part of its mechanism of action; it goes after a particular Cys residue in the enzyme.

fosmidomycin.jpgAnd mentioning that one brings up another creature from that same general lagoon, fosmidomycin. No epoxide, but you still have the phosphonic acid, which very few medicinal chemists have the nerve to explore, and a sort of hydroxamic acid at the other end, which is no one's favorite functional group, either. I'll bet this thing has solubility going for it, anyway.

I like to remind myself of these compounds (and others like them) on a regular basis, for the sake of humility. I never would have wanted to work on either of them, and I never would have picked either of the out as a drug. Which shows that my traditional ideas of drug-likeness are not broad enough, because both of these are being used in humans, which is more than I can say for anything I've ever made myself. I have little to no experience in phosphonic acid chemistry, and have never attempted to add such a group to any compound series. And it's not just me - I'd have to call phosphorus chemistry, in general, relatively unexplored territory for medicinal chemistry. There are a lot of hopeful mentions of pharmaceutical applications in the various reviews and texts on methods in phosphorus chemistry, but outside of the bisphosphonates and the occasional phosphate ester prodrug, you don't find too many. And although I sometimes think that we're missing out on some potential good compounds this way, neither have I done much myself to strike out into the territory. I suspect that most other medicinal chemists feel similarly, and thus the state of things remains. . .

Comments (27) + TrackBacks (0) | Category: Chemical News | Life in the Drug Labs

Countries That Have Developed A Small-Molecule Drug

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Posted by Derek

Writing about Shenzhen Chipscreen got me to thinking: how many countries really have developed a small-molecule drug with their own resources? I'll go with a medium-generous definition of that - you don't have to have discovered the underlying target yourself, for example. As for multinationals, it's a judgment call. I think that Merck Frost should count for Canada, since a lot of the work was done up there. I'm leaving out vaccines, phages, biologics of all sorts, since the development pathways can be so different - traditional small-molecule drugs only, today. So here's an unofficial list, subject (I'm sure) to plenty of correction: The US, Canada, the UK, Germany, Switzerland, France, the Netherlands, Belgium, Denmark, Sweden, Italy, Russia, Japan, and now China. There are several others that I feel sure have done so (Czech Republic, Hungary, Israel), but I don't have examples to hand. And there are others (Australia) that seem plausible, but I can't come up with anything, either. Austria? Former Yugoslavia? Poland? Spain? I await additions in the comments.

Update: here's the list so far, a work in progress.

United States
Canada
United Kingdom
Germany
Switzerland
France
Netherlands
Belgium
Spain
Portugal
Sweden
Denmark
Finland
Norway
Italy
Poland
Hungary
(former Czechoslovakia)
Russia
Austria
Israel
India
China
Japan
South Korea
Australia

Comments (53) + TrackBacks (0) | Category: Drug Industry History

April 6, 2015

China's First Homegrown Pharma

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Posted by Derek

The Wall Street Journal had an article on a new HDAC inhibitor from Shenzhen Chipscreen (full text here from The Australian). It's worth highlighting. Epidaza (chidamide) appears to be the first homegrown drug discovery and development effort to reach regulatory approval in China.

Their founder, Xian-Ping Lu, was working at Galderma before he went back to China in the early 2000s to start his own company. Chidamide is a start-to-finish compound for Chipscreen, and that puts China on a rather short list of countries that have demonstrated the ability to do that in small molecule drug development. You see claims for this sort of thing that don't quite hold up, but this certainly appears to be the real thing, and congratulations to them.

Some thoughts: first off, this would be the fourth (I think) histone deacetylase inhibitor to get regulatory approval somewhere. That class of compounds was a hot topic for development ten or twelve years ago (I was working on some then, not to any great effect). It's the first class of pharmacological agents deliberately targeting epigenetic signaling, and the complexities of that field have made things run slower than people were hoping. As this article in Nature Reviews Drug Discovery put it:

Oncology drug developers have long been interested in the role of HDACs, which can repress gene transcription by modulating chromatin structure, because altered expression of HDAC enzymes is often seen in tumours. HDAC inhibitors, the researchers hoped, could drive the re-expression of silenced genes, including those that encode tumour-suppressing proteins. However, the failure of multiple HDAC inhibitors to show activity in most cancer types, especially in solid tumours, has over the years led to an outbreak of 'HDAC inhibitor fatigue' in the research community — distinct from the physical fatigue many patients experience as a common side-effect of the drugs. “The wave of excitement surrounding this early class of epigenetic drugs has waned and been replaced by a wave of scepticism,” says Jean-Pierre Issa of Temple University in Philadelphia, Pennsylvania, USA, who researches epigenetic mechanisms in cancer.

As these mechanisms get more worked out, the hope is that the HDAC compounds can get on a more sound footing, but for now, they're minor players in the oncology world. (I have no feel for how well chidamide compares to the other marketed compounds).

The second thought is whether Chipscreen plans to seek approval to market the drug anywhere outside China. I hope so - it would be good for Chipscreen and good for the global reputation of the Chinese drug industry. What would be good is if China becomes another market like the US, EU and Japan, where companies from each region get drugs approved in the others. There are (or can be) some slightly different requirements in each, and sometimes regulatory authorities will let something through in one that doesn't fly in the others, but the serious drugs end up in all of them and other markets (Canada, South America, Australia, Israel and so on) besides. (I'm excluding some of the no-efficacy-just-safety compounds from Japan from that category). What China does not need is to become a sort of regulatory backwater. The sheer size of the market there argues against that happening, but if the drug industry there continues to develop, the government could conceivably start tipping the scales towards China-discovered compounds. Getting chidamide out into the rest of the world would help to get things off to a good start.

The last thought comes from the statement in the article that the drug cost about $70 million to develop. That is indeed cheap, as little as ten per cent of what it would cost to do that in the US or the EU. And why is that? One's first thought is cost of labor, but although it can be cheaper to outsource some parts of drug research to China, it does not save you 90% by any means. Most of the money spent in a drug project is spent in the clinic, so my guess is that Chipscreen was able to get their clinical trials done for much less money than it would cost over here. Just how and where those savings came in, though, I couldn't tell you. If that's a real effect, though, and if those are real figures, then the Chinese companies would appear to have a huge cost advantage on the rest of their worldwide competition, which makes you wonder why it's taken until 2015 for the first locally-produced small molecule to show up. I should note as well that the other big multinational drug companies have not swarmed into the Chinese clinical trial space, not to the degree you'd expect if there were really 90% savings to be realized by doing so. This part will remain an open question for now.

But all of that aside, I'm glad to see Chipscreen make it through with their own compound. I'm glad to see any small company do that, Chinese or not, but their position as the first to do it in China is something that no one can take away from them. People have been waiting for it to happen, and here it is.

Comments (24) + TrackBacks (0) | Category: Business and Markets | Cancer | Drug Development

Levels of Data

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Posted by Derek

Here's a brief article in Science that a lot of us should keep a copy of. Plenty of journalists and investors should do the same. It's a summary of what sort of questions get asked of data sets, and the differences between them. There are six broad data analysis categories:

1. Descriptive. This is the simplest case, where you're just summarizing a data set and describing the totals in it.

2. Exploratory. The next step - you search through the descriptive analysis looking for trends or relationships, with which to develop new hypotheses. No guarantees, of course - you'll have to confirm these with more work.

3. Inferential. This one looks at an exploratory treatment and tried to determine whether those trends are likely to hold up. As the authors say, this is probably the most common statistical workup in the literature - better than randome chance, or not? But it can't tell you why something is happening, of course.

4. Predictive. An inferential study is necessarily done on a large sample (well, it had better be, at any rate, if you're going to infer with much confidence). A predictive analysis uses some subset of the data to predict how individual cases will go. The example from drug development would be the use of biomarkers to predict whether a given patient in a trial will respond to some new investigational drug.

5. Causal. At this level, you're trying to see what the magnitude of changes are across the system when you start changing things - what often gets called the "tone" of the system. What are the most important variables, and what has little effect on the outcome?

6. Mechanistic. With the information at the causal level available, now you can really get down to the nuts and bolts. Change A causes effect B, through this detailed mechanism. We don't see this as much with anything involving biology - there always seem to be exceptions. This is more the realm of engineering and physics, although a lot of time and money is going into trying to change that.

It's only at the causal and mechanistic levels that you can start doing detailed modeling with confidence. That's where everyone would like to be with computational binding predictions, but we don't understand them well enough yet. And think how far we have to go to get predictive toxicology to those levels! We can do that sort of thing on a small scale - for example, saying that a compound that (say) inhibits angiotensin-converting enzyme, to this degree, and with that average half-life in vivo, will be expected to lower X% of a random population's members blood pressure by at least Y%. That's after decades of experience and data-gathering, keep in mind.

But that's not aeronautical engineering. Those folks don't tell you that wing design A will provide at least so much lift on a certain percentage of the airframes it gets bolted on to. Nope, those folks get to build their airframes to the same exact specifications, not just take whatever shows up at the factory needing wings, and those airframe/wing combinations had better perform within some very tight tolerances or something has gone seriously wrong. This is just another way of stating the "built by humans" difference I was talking about the other day.

So some of that data analysis hierarchy above is, well, aspirational for those of us doing drug research. The authors of the Science article are well aware of this themselves, saying that "Outside of engineering, mechanistic data analysis is extremely challenging and rarely achievable.". But that level is where many people expect science to be, most of the time, which leads to a lot of frustration: "Look, is this pill going to help me or not?" We should remember where we are on the scale and try to work our way up.

Comments (12) + TrackBacks (0) | Category: Clinical Trials | Drug Development | General Scientific News | In Silico

April 3, 2015

Researchmanship

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Posted by Derek

Stuart Cantrill's blog pointed me to an online copy of this article, "Researchmanship". I was given a copy of it from the (now defunct) ACS Chemtech in the 1980s, while I was in grad school, so it had a great effect on me. It recounts the techniques of one James J. Pudvin for getting through his degree program:

All professors expect a student to have an all-night session in the lab once in a while. Perhaps they feel that if they as students did so, the present generation should suffer in a like manner. Do not disappoint your professor! Pudvin "worked nights" at least twice a month, and his simulation of suffering was so successful that often his professor told him to "go home and get some sleep before you have an accident." Pudvin’s approach, which is by no means the only one to take, was as follows.

In the afternoon Pudvin would announce his intention "to make a night of it." He would sign up for the preparative GLC unit for the hours 8 p.m. to 5 a.m. (How else can I get 25g of starting material?"), and would decline all invitations to go to the movie, play bridge or pool etc., preferably when the professor was within hearing distance. When everyone was getting ready to go to supper, the professor included, Pudvin was seen carrying flasks, GLC receivers, syringes, coffee pot, radio and a green eyeshade to the GLC room. Next morning at 9.00 when the professor arrived, Pudvin would be found, haggard, pale, noticeably thinner, proudly displaying a 50 ml. flask of colourless liquid. "100% pure" he’d cheerfully tell the professor. After such concentrated devotion to duty it was not unexpected that Pudvin was not seen in the lab for the next two days.

Actually Pudvin’s nightly exertions were spent in strenuous, but pleasurable activities not related to chemistry in the remotest way. At 8.30 the previous evening he had left the laboratory, being careful to leave the lights on and a sign on the door ("BACK IN A MINUTE". The radio played all night, and the coffee pot remained on "reheat" until Pudvin’s return at 8.00 a.m. The flask that he so proudly displayed was filled with 100% pure ethyl acetate.

Some of the advice is a bit outdated - waiting for the JACS to come back to the bindery, for example - but a lot of it is (for better or worse!) timeless.

Comments (27) + TrackBacks (0) | Category: Graduate School

Sanofi Bets on Schrödinger

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Posted by Derek

Sanofi has signed an expanded deal with Schrödinger, the computational chemistry folks. Here's something from the press release:

Schrödinger has made a number of key scientific breakthroughs in recent years in the areas of protein and ligand structure determination and potency prediction that promise to have a transformative impact on the discovery of drugs. The collaboration with Sanofi aims to deploy this and related technologies at a level that is unprecedented in the pharmaceutical industry.
.

I'd guess that this is going to involve the FEP calcuations that they've been talking about (blogged here). Schrödinger is also very strong in doing molecular dynamics simulations (for similar reasons), although, as with everything in this field, there's room to argue about what that can do for you. So this will be very interesting to watch. I'm glad that Schrödinger's technology is being given such a thorough real-world test, because that's the only way to see what it can do.

Comments (36) + TrackBacks (0) | Category: In Silico

April 2, 2015

Review of Reviews

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Posted by Derek

Several papers of interest, in the "catching up with the literature" vein. For you stapled peptide fans, here's a review of their possible therapeutic uses, with what's been accomplished so far. And for people interested in therapeutic editing of the human genome, and that's a large group of people, here's a new overview from Nature Medicine. People interested in late-stage modifications to complex drug structures (and that's a lot of us, too) will want to take a look at this short review. If you're into pharmacokinetics, this minireview on strategies to alter volume of distribution will be worth a look, and if you're tired of trying to understand what's going on in the whole animal, you may want to read up on the progress in organ-on-a-chip models.

There, that should get everyone through lunch. I'm reminded of the old George Booth cartoon, with the guy looking at a newscaster on his TV set: "And I'm John Harmon saying "That's all there is, there is no more". Until tomorrow, when there will be more."

Comments (2) + TrackBacks (0) | Category: Biological News | Chemical News

Silicon Valley Sunglasses

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Posted by Derek

The intersection between Silicon-Valley-style tech and biotech is getting a lot of attention these days. Some of it looks like it could be a productive synthesis: 23andMe hiring Richard Scheller of Genentech (update: and Robert Gentleman, today) as it starts its own efforts in drug discovery and Google bringing on Art Levinson (Genentech's former CEO) to run its Calico subsidiary. (They recently signed a big deal with the Broad Institute and one with the University of California system). You'll have noticed that I'm defining "productive" as "listening to people who've done it before", and I make no apologies for that.

That's because, as I've gone on about before, drug discovery is a very different world than hardware and software. People working in those areas have gotten used to the key capabilities of their work improving wildly and constantly getting cheaper, tendencies that have rippled out to affect everything than has a data-crunching rate-limiting step in it. And it turns out that all kinds of things do (or can be reconfigured to). But living in this environment can give a person an unusual perspective on the world.

Some of that perspective is welcome - the idea that there are always huge opportunities out there waiting for someone with enough speed and nerve to go after them, for one. That's very Silicon Valley (and it's also very American) and I think it's great. But if along the way you pick up the idea that the world of apps, code, and processor speed is the default setting for the world, you can start to see everything that doesn't advance that way as defective. That's the Andy Grove fallacy, as I've called it (referenced in those links above), the idea that understanding human disease and its treatments should be pretty much like designing a new chip or writing a new app.

There's another problem that's not unique to the Valley, although it does tend to give people a bad case of it. That's the "Clearly I'm smart and successful, so clearly I have something to offer in this other field over here" one. We all succumb to that one now and then; it's human nature. You can watch Mark Cuban display it here, with respect to medical testing.

But here are a couple of recent examples of the more localized problem. I wrote last year about Emerald Therapeutics, an outsourced-lab-assay company backed by Peter Thiel (who may also be interested in their antiviral therapy ideas). Here's another article on them, and it asks, in so many words, "Why is new drug development so comparatively torpid when app development is so torrid?". I couldn't provide a more succinct version of the Silicon Valley/biopharma disconnect if I tried.

According the article, the folks at Emerald ". . .think it comes down to the difficulty of running experiments in the life sciences". But I'd like to propose that this difficulty, at least for early-stage work like Emerald is proposing to do for people, is largely a matter of contrast. If you're used to being able to sit down and bang out code, any time, anywhere, with all kinds of tools (libraries, compilers, virtual machines, what have you) at your fingertips, then yeah, working up a new assay protocol in a cell line is going to seem agonizingly slow. Multibillion dollar ideas can be cranked out in the coding world very quickly, if you hit the right place at the right time, but just you try that in the lab. Now, I have no problem with Emerald running assays for people, although it may yet be harder than they're thinking. But they're not removing as much of a bottleneck as they might think. The real bottlenecks are figuring out what assay to run, and what to do with the data once you have it. Can't outsource those.

Then we have this piece on genomics at TechCrunch. Experienced readers will get a very 1999 vibe from it; it's full of the wonders-of-the-genome stuff that was so thick on the ground back then. (That makes it simultaneously cute and annoying to see it all again, of course). "One App Away" is a headline from the article, which is suffused with the next-big-thing attitude that you'd find from someone who's figured out how to social-gameify the process of splitting the check at a bar, complete with a three-second clip of everyone hoisting drinks with the amount they chipped in hovering over their heads. That probably already exists.

But you know, I don't really disagree that much with many of the conclusions in the genomics piece - just the pace at which things will happen. That's what I think has been Valley-ized there, the idea that very, very soon now something will just wildly, exponentially take off. As much as I might like to see something like that happening in biopharma, though, I can't quite make myself believe it. Technology, Silicon Valley style technology, is human-designed and human-optimized for other humans. As human beings, we're playing on our home turf there. But the biology of disease is an away game if there ever was one. The inner workings of cells and the ways that they work together are flat-out alien compared to anything we've ever built ourselves. People who are used to coding up apps have never experienced anything like it, and many of them don't seem to realize that they haven't. Expecting the sorts of behavior that you get from human-built technologies, and expecting the same effects from the techniques that work to optimize them, is an expensive accident waiting to happen.

Comments (35) + TrackBacks (0) | Category: Drug Assays | Drug Development | Drug Industry History

April 1, 2015

Trouble with Sovaldi, Or Not?

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Posted by Derek

I wish that this were some sort of April Fool's entry, but it isn't. There appears to be an outside chance that Gilead's huge-selling Sovaldi (sofosbuvir) for hepatitis C has some cardiovascular problems. There have been a few reports from the field, and the FDA has asked for a label change when the drug is used in patients who have taken amiodarone. But this commentary at Medscape is arguing that the problem might be bigger.

The amiodarone interaction could be explained by inhibition of PGP, changing the pharmacokinetics of Sovaldi in some susceptible patients. (Amiodarone has odd PK and a particularly long half-life, raising the chances that you might see something). And/or there could be something intrinsic to sofosbuvir, and that's the open question (the kind of question you can really only answer once a drug's on the market). There's a large patient population taking the drug, and getting larger all the time, so if there's something out there to be seen, the adverse events should show up. But for now, Gilead is just waiting to see what happens - if anything.

Comments (9) + TrackBacks (0) | Category: Infectious Diseases | Toxicology

Rotten Rottlerin

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Posted by Derek

Here's one of the problems with the various schemes to do "deep learning" using the published scientific literature: a fair proportion of that literature is junk. This is not news, of course, and to some extent I feel that that's always been the case. The pressures to publish, and the corresponding rise of publishing fraud, aren't helping much, though. And there's a lot of plain old sloppiness out there, too.

For a small example, consider the polyphenol compound rottlerin. It's isolated from a plant in India and the surrounding area (and named after the botanist who first described the genus in the European literature). Rottlerin itself was isolated in the 1800s as a tan, crystalline substance, and in the early 1990s it was identified as a PKC-delta inhibitor, for which purpose it has been used in uncounted studies in the literature.

Problem is, though, like a lot of such compounds, it's not anywhere near as selective as advertised. And it has all sorts of other activities in cells, too, as one can well imagine, looking at its structure. In fact, as that link shows, the original PKC activity reported for the compound may well have been due to an impurity - other papers have found no real PKC inhibition at all, much less anything selective (not that the original selectivity was anything to jump around about, either). So rottlerin, as a tool compound, is useless. It does too many thing to untangle, and the the thing that it's most well-known for doing it probably doesn't do at all.

So no one uses it any more, right? Har de har. That link will take you to the latest list of rottlerin papers, and on it you'll find this paper from this year, using it as a PKC-delta control. And this 2015 paper. And this one. And this one. You can pick out more of them, all the way down the list.

Now, some of the papers you pull up are more defensible, since they're more like "Here's something rottlerin does phenotypically to cells, and we're going to unravel what it is". Fair enough. But why is anyone using it as a PKC-delta inhibitor, a good dozen years (at least) since that activity was called into question? I wouldn't trust it as a pan-PKC inhibitor either, not when it does so many other things. Rottlerin is useful if you're studying rottlerin, but getting it to illuminate something else for you is going to be a tricky business. Watching people just blithely treat it as if it were some automatic selective switch you can drop into an assay is disturbing.

That broad phenomenon has come up in discussions around here before, though. There's a persistent lack of examination in the biological world when it comes to small-molecule tool compounds. Too many people seem willing to believe that there are all sorts of those perfectly selective compounds out there, ready to reach into cells and do exactly what it says in some catalog or some old paper. There are some, but nowhere near as many as you might imagine, or as many as people will sell you. Tocris is more up front about what the compound does, but here's EMD/Millipore/Calbiochem, selling rottlerin as " cell-permeable and reversible protein kinase C inhibitor that exhibits greater selectivity for PKC-delta (IC₅₀ = 3-6 µM) and PKC-theta". So how can I blame some biologists for not trusting that sort of thing?

Update: from the comments, here's a complaint about the use of this very compound from 2007. It spells it out in the title ("An Inappropriate and Ineffective Inhibitor"), and it appeared in what a colleague of mine once called "An obscure journal called Cell"). But rotterlin itself marches on, and neither editors nor reviewers seem to care, in many cases.

Comments (27) + TrackBacks (0) | Category: Biological News | Chemical News | Drug Assays