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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

September 29, 2014

The Case of Northwest Biotherapeutics

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Posted by Derek

There have been a lot of strong words exchanged about Northwest Biotherapeutics (NWBO), a small Maryland-based company developing a brain cancer vaccine. Over at Fierce Biotech, they're wondering why this program was picked by the UK authorities as their first official "Promising Innovative Medicine", given the scarcity of data (and the dismal track record of dendritic vaccines in the field).

Adam Feuerstein has said a bunch of similar things, vigorously, at TheStreet.com over the last few months as well. He's been especially skeptical of the company's own vigorous PR efforts, and in general tends to be unenthusiastic about small go-it-alone oncology programs. The Feuerstein-Ratain rule, that small-cap cancer trials fail, has been hard to refute.

Well, just the other day Washington Post columnist Steven Pearlstein waded into this story with a piece about how evil short-sellers are hurting promising little biotech companies. That's pretty much the tone of the whole thing, and he uses Feuerstein and NWBO as his prime example, with not-quite-stated allegations of collusion with short-sellers.

My belief is that this is a load of crap, from someone who doesn't understand very much about how the stock market works. Small companies that have been unable to interest anyone else in their technologies have a difficult time of it, to be sure. But we don't need to go to conspiracy theories to explain this. There are indeed short-selling investors who are trying to drive stocks down, but they are absolutely overwhelmed in number by the number of people who are trying to drive stocks up. That's what a stock market is: differences of opinion, held strongly enough for money to be put down on them.

If you look at Feuerstein's most recent column on NWBO, you find that only one other company has even applied for the "Promising Innovative Medicine" designation (and that application is in process). So this is not some incredible milestone. And you also find a lot of useful information on the company's debt structure, the exact sort of thing that an investor in the company should be interested in. Will you get these details by reading press releases from Northwest Biotherapeutics? You will not. You will get them from people who are willing to scrutinize a company, its operations, and its pipeline in detail.

Does Steven Pearlstein think that these details about NWBO's debt deal are false? He should say so. But he also talks about short-sellers crippling Dendreon, which ignores completely the fact that what's crippled Dendreon is that their vaccine doesn't work very well. Wonderful drugs don't get buried by short-sellers. Drugs get buried by data.

Comments (19) + TrackBacks (0) | Category: Business and Markets | Cancer | Clinical Trials

2014 Chemistry Nobel Predictions

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Posted by Derek

Well, we're getting close to the Nobel season, so it's time for the yearly "Who's going to win?" post. According to Thomson Reuters, some favorites are Tan/van Slyke for organic light-emitting diodes, Moad/Rizzardo/Thang for RAFT polymerization, and Kresge/Ryoo/Stucky for mesoporous materials. You can see a real materials-science drift to those picks, which would indicate that the Thomson-Reuters folks think that we're not going to get another that's-not-chemistry-that's-biology award this year (nor one in analytical chemistry).

But if they're wrong about that, there are several things that shade over into molecular biology that are queued up. Some sort of prize for nuclear receptors would be plausible, and the CRISPR gene editing technology is surely in line for one. Another surely-that-will-win technique is optogenetics, the photoswitchable gene regulation method that's being used all over biology. They could always give it to Venter (et al.) for gene sequencing, or to Bruce Ames for the Ames test. As usual, these could end up in chemistry, or over in the physiology/medicine prize. In the zone where analytical chemistry blends into physics, there's single-molecule-spectroscopy and SPR. I don't see a flat-out organic chemistry prize in the works, but Sharpless is still plausible as part of a click-chemistry/chemical biology sort of award.

Other predictions can be found at Wavefunction's blog (he has a different top pick) and Everyday Scientist. Add your own guesses to the comments section, and we'll see how wrong we all can be!

Comments (37) + TrackBacks (0) | Category: Chemical News

September 26, 2014

The Deadly Stupidities Around Ebola

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Posted by Derek

It's not all that often that you can say "Now this is a person who's going to get people killed". But I'm willing to say that about Cyril Broderick of Delaware State. He's Liberian-born, and has written an article for a newspaper in Monrovia telling Liberians that the Ebola virus is a manufactured bioweapon from the pharmaceutical companies and the US Department of Defense. And he goes on to say the the WHO, Doctors Without Borders, and the CDC are all in on the plot. Isn't that nice?

This in a region where suspicions run so high that doctors, officials, and aid workers are being killed by angry mobs already. Now Prof. Broderick has given his Liberian countrymen more reason to fear some of the people who are best equipped, of anyone on this suffering world, to actually help them. If GSK's Ebola vaccine actually proves effective, if a rapacious evil pharma company actually comes up with a way to stop the disease and turns it over to people like the WHO and Doctors Without Borders to go into West Africa and administer it, stuff like what Professor Broderick is spewing will make it that much harder to accomplish anything with it. People will hide rather than get vaccinated and attack the people coming in to save their lives. Broderick and Matthias Rath, who's urged HIV patients to throw away their retroviral drugs, are in the same category and I am ashamed to be on the same planet with them.

And all because of a bunch of stuck-together conspiracy theories, chew-toys for halfwits. It would be easier to laugh at if it weren't getting people killed, patients and medical workers alike. Schiller was right: against stupidity, the Gods themselves fight in vain.

Comments (43) + TrackBacks (0) | Category: Snake Oil

PAINS Go Mainstream

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Posted by Derek

Well, I'm back in the Eastern Time Zone after flying in from Basel (and Amsterdam) yesterday. And the first thing I wanted to mention was this article from Jonathan Baell and Michael Walters inNature, on the PAINS compounds. It's good to see the journal cover this issue (and I was impressed that they got New Yorker cartoonist Roz ChastRoz Chast to illustrate it).

PAINS are, of course, nasty frequent-hitting compounds that should be approached with great caution in any sort of screen for activity. This topic has come up many times on the blog (for someone writing about chemistry and drug discovery, there's no way it couldn't have), most recently just a few weeks ago. There are a lot of these things out in the literature (and the catalogs), and they just keep on coming. Now a wider audience gets to hear about the problem:

Academic researchers, drawn into drug discovery without appropriate guidance, are doing muddled science. When biologists identify a protein that contributes to disease, they hunt for chemical compounds that bind to the protein and affect its activity. A typical assay screens many thousands of chemicals. ‘Hits’ become tools for studying the disease, as well as starting points in the hunt for treatments.

But many hits are artefacts — their activity does not depend on a specific, drug-like interaction between molecule and protein. A true drug inhibits or activates a protein by fitting into a binding site on the protein. Artefacts have subversive reactivity that masquerades as drug-like binding and yields false signals across a variety of assays.

That's the problem, all right. It's not like ugly-looking compounds can never become drugs, and it's not like they can't be starting points for research. But the odds are against them, and you have to realize that, and you also have to realize why this "hit" you've just uncovered may well be spurious (at worst) or need a lot of extra work (at best). Far, far too many papers from less experienced research teams seem to be oblivious to these concerns. Compound hits? Compound good!

Appropriately, this piece calls out the rhodanines as perfect examples of the problem:

Rhodanines exemplify the extent of the problem. A literature search reveals 2,132 rhodanines reported as having biological activity in 410 papers, from some 290 organizations of which only 24 are commercial companies. The academic publications generally paint rhodanines as promising for therapeutic development. In a rare example of good practice, one of these publications (by the drug company Bristol-Myers Squibb) warns researchers that these types of compound undergo light-induced reactions that irreversibly modify proteins. It is hard to imagine how such a mechanism could be optimized to produce a drug or tool. Yet this paper is almost never cited by publications that assume that rhodanines are behaving in a drug-like manner.

Very occasionally, a PAINS compound does interact with a protein in a specific drug-like way. If it does, its structure could be optimized through medicinal chemistry. However, this path is fraught — it can be difficult to distinguish when activity is caused by a drug-like mechanism or something more insidious. Rhodanines also occur in some 280 patents, a sign that they have been selected for further drug development. However, to our knowledge, no rhodanine plucked out of a screening campaign is in the clinic or even moving towards clinical development. We regard the effort to obtain and protect these patents (not to mention the work behind them) as a waste of money.

Yeah, I wouldn't spend much on trying to stake a claim to these things, either. If you haven't done much screening, you may not appreciate just how many false positives are out there (and for difficult targets, how few real positives there may be). I see people in the literature screening little libraries of a few thousand compounds from a catalog and reporting hit after hit, even in very tricky systems, while in industry we're used to running hundreds of thousands of compounds past some of these things and coming up with squat. Well, after checking the "hits" for purity, aggregation behavior, reactivity, and profiles from past screening campaigns, that is.

Here's the sad truth: If you're doing a small-molecule screen to affect transcription factors, protein-protein targets, or anything in general that doesn't have an evolutionary optimized small-molecule binding site, you'd better assume that the vast majority of any hits you get are false positives. There's almost no way that they can be anything else. The true hit rate for some of these things against any sort of typical compound collection is damn near zero, which means that the ways your compounds can be wrong far outnumber the ways that they can be right.

Every single hit, for any assay, should be regarded with appropriate suspicion. Purity check first, LC/MS and NMR. Is it what it says on the label? You might be surprised how often it isn't (or isn't any more, even if it started out OK). If you have solid material and DMSO stock, check both of them, because things diverge on storage. It's a very good idea to take your interesting hits, run them through a plug of silica gel, and test them again. That's especially true if they have any color to them (but keep in mind, some assay-killing contaminants are completely colorless). The gold standard is resynthesis: if you can make the compound again and purify it, and it still works, you at least know you can trust it that far. If you can't, well, how exactly is this compound going to do anyone any good?

Note that we haven't even gotten to the PAINS yet. There are a lot of clean, accurately labeled compounds that should be chucked into the waste can, too, which is where the Baell PAINS list comes in. You're going to want to check for aggregation: run your assay with some detergent in it, or do some dynamic light scattering or any of several other techniques. A lot of false-positive compounds are aggregators, and you can't completely predict which ones they might be (it varies according to assay conditions).

You're also going to want to run your hits through some other assays. How promiscuous are they? If you have access to data from multiple screening campaigns with the same compound collection, good for you. If you don't, you should strongly consider sending your hot compound(s) out for a commercial screening panel. Don't just pick the similar targets to screen - you want those, of course, but you want all kinds of other stuff. If a compound hits against widely disparate protein classes, it's a PAIN, and is set to cause trouble. Don't assume that they're clean - don't assume that any compound is clean, because it almost certainly isn't. That goes for marketed drugs, too - the question is, does it have selectivity that you can live with, or not?

Those are the big tests, and believe me, they'll clear out your initial list of screening hits for you. If your target is a tough one to start with, they may well clear out everything. Better that, though, than working on (and publishing) crap.

Comments (14) + TrackBacks (0) | Category: Academia (vs. Industry) | Drug Assays

September 25, 2014

En Route

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Posted by Derek

Traveling today, so no time for a blog entry. More science and stuff tomorrow, though!

Comments (4) + TrackBacks (0) | Category: Blog Housekeeping

September 24, 2014

Luc Montagnier Makes His Case in Paris

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Posted by Derek

Well, if you're in Paris next month and want to see some scientific (or perhaps not so scientific?) fireworks at a seminar, here's the event to attend. UNESCO is holding a symposium on the work of Luc Montagnier on his "water memory" studies. I've mentioned this (and some of his other. . .unusual. . .claims) here before, and well. . .it's hard for me to say this, but they are indistinguishable from the work of a crank. Or someone with an unfortunate mental condition. I'm sure that Montagnier gets these kinds of responses all the time, and he obviously is strong enough to keep going with what he believes to be real results, so I have to give him credit for that. But extraordinary claims and extraordinary evidence, you know, and I haven't seen much of the latter.

The mathematician Cédric Villani, who received the Fields Medal in 2010, will propose a synthesis of the various presentations. He will include them in the broader context of Professor Jacques Benveniste’s work (1935-2004) on the "memory of water", which was initiated thirty years ago.

Professor Montagnier’s team is working on electromagnetic waves emitted in the area of very low frequencies and thus of low energy. Different reproducible experiments will be presented at the conference. These experiments show that these waves may play an important role in the pathogenicity of micro-organisms - bacteria and viruses – and also in physiological processes such as stem cell differentiation shown by Professor Carlo Ventura.

The experimental facts will be presented by the two biologists. It appears that water is an important mediator in the transmission of molecular information, such as that carried by DNA. To achieve such transmission, water generates organized structures, which also emit electromagnetic signals. Marc Henry and Giuseppe Vitiello, relying on concepts developed by Italian physicists Giuliano Preparata and Emilio Del Giudice, will explain how quantum physics can elucidate these mysterious phenomena. They will reveal new fields of research that are areas of consistency activating water molecules. Interdisciplinarity (physics/biology) is the conference’s major message.

The promoters of this conference are aware of the critical reactions aroused by this work in parts of the scientific community, so they wish to communicate their results with the utmost rigor. . .

Utmost rigor might not be enough. If anyone makes it to this, please send a report!

Comments (21) + TrackBacks (0) | Category: Snake Oil

See You in Court? Not Likely

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Posted by Derek

There had been talk of some sort of trouble brewing via PubPeer, the open-source post-publication review site, and this appears to be it. There's more on the issue at Science: Farzul Sarkar at Wayne State is suing, if he can find the right people to sue.

The issue first came to light in August, when PubPeer’s (anonymous) moderators announced that the site had received a “legal threat.” Today, they revealed that the scientist involved is Fazlul Sarkar, a cancer researcher at Wayne State University in Detroit, Michigan. Sarkar, an author on more than 500 papers and principal investigator for more than $1,227,000 in active grants from the U.S. National Institutes of Health, has, like many scientists, had his work scrutinized on PubPeer. More than 50 papers on which he is an author have received at least one comment from PubPeer users, many of whom point out potential inconsistencies in the papers’ figures, such as perceived similarities between images that are supposed to depict different experiments.

Recently, PubPeer was contacted about those comments by Nicholas Roumel, an attorney at Nacht, Roumel, Salvatore, Blanchard & Walker P.C. in Ann Arbor, Michigan, who represents Sarkar and spoke to ScienceInsider on his behalf. On 9 June, the University of Mississippi Medical Center announced that Sarkar would join the faculty in its school of pharmacy. Records from a meeting of the Mississippi Board of Trustees of State Institutions of Higher Learning note that he was offered a tenured position and a salary of $350,000 per year, effective 1 July.

But on 19 June, Roumel says, Sarkar got a letter from the University of Mississippi revoking its offer. Science has not seen the letter, but Roumel says that in his view, “it made it crystal clear the PubPeer postings were the reason they were rescinding the job offer.” A representative for the University of Mississippi declined to comment on the case, citing prospective employees’ confidentiality.

Yeah, that would put a person in the mood to sue, for sure: tenure, 350K/year, and a chance to leave Detroit. I'm not in a position to say whether Sarkar's been defamed or not, though: there have been many complaints. And I'm also not sure that he's going to get very far trying to find out who the commenters are, because the folks at PubPeer may well have no idea themselves. (I generally have no idea who the people leaving comments on this site might be!) Under US law (the Communications Decency Act of 1996, it's pretty hard to come after the owners or moderators of a web site for the comments left by its users. So I don't think this is going to get very far, but we shall see.

Comments (48) + TrackBacks (0) | Category: The Scientific Literature

September 23, 2014

Thoughts on Fragment-Based Drug Discovery

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Posted by Derek

I've been enjoying the FBLD fragment conference in Basel. There have been many good talks, and it's been instructive to talk shop with people as well. Some things that various participants (and I) have noted:

(1) There are a lot of industry people here, from all over. Fragment-based methods have clearly made a big impression across drug discovery - academia finds it a low-barrier way to get into compound screening, and the industrial groups clearly find it useful as well. This has already lasted longer than the combichem boom of the 1990s (a point I'll be mentioning in my talk here tomorrow), and at this point, it would appear to be not a fad at all. Fragment-derived compounds are marching along through the clinic as we speak.

(2) The number of instrumental and biophysical techniques to do fragment work is still growing. There are always NMR screens, SPR, and X-ray crystallography (and many variations on each of these), calorimetry and thermal shift experiments, and so on. But there are mass spec methods, chromatographic ones, thermophoresis and electrophoresis, and more where those came from. Which is good - as anyone who'd done this can tell you, you need orthogonal ways of looking at the compounds.

(3) Several of these technique are, though, still a bit "operator-dependent". SPR, just to pick one, needs someone experienced at the controls for the trickier experiments, because there are a lot of things that can give you funny-looking data (aggregation, compounds that bind to the chip surface, super-stoichiometric binding, and more). It's not a good part-time occupation. You can say the same thing about a lot of other screening techniques that are used for traditional high-throughput screening, though, as anyone who's troubleshooted FRET, FP, or AlphaScreen assays will tell you at length.

(4) There are still a lot of important and interesting things we don't quite know about fragment collections and fragment binding. Some of these are just beginning to get sorted out - what are the physical characteristics of a good fragment screening set (beyond the obvious ones of size and solubility)? Are there different sorts of collections that could give you better hit rates against targets like protein-protein interactions (there have been many examples of these at the meeting). What are the relationships between selectivity at the fragment level and selectivity in the eventual optimized compounds? The answers the questions like these are still being written.

I have more thoughts, naturally, but some of those my employer has first call on. I have a talk to give tomorrow (one of those 30,000-foot-overview things), right at the end of the conference, and I'll probably unburden myself of a few opinions then.

Comments (9) + TrackBacks (0) | Category: Chemical News | Chemical News | Drug Assays

Seaborgium hexacarbonyl

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Posted by Derek

If you want to really push the frontiers of analytical chemistry, try making compounds of the superheavy elements. Science is reporting the characterization of seaborgium hexacarbonyl, which gives us all a chance to use Sg in an empirical formula. We're not going to be using it too often, though, because this work was conducted on eighteen atoms of Sg, and that's at least as hard as it sounds. You have several seconds in which to do all your work, and then it's back to the gigantic particle accelerator to see if you can make another atom or two. Separating these from the various decay products and other stuff is one of the hardest parts of that process, and was a key step in getting this experiment to work at all.

The reason for going to all this trouble was the predicted behavior of the valence electrons. Elements of this size are rather strange in that regard, in that the outer inner-shell electrons (corrected: jet-lag, I think - DBL) are relativistic - Sg's have velocities of about 0.8c, which leads to some unusual effects. The element itself doesn't differ as much from its other periodic relatives (as opposed to 104 Rutherfordium and 105 Dubnium), but compounds leaving some outer-shell electrons free were still calculated to show some changes. In this case, the hexacarbonyl had similar behavior to the molybdenum and tungsten complexes, but its properties only come out right if you take the relativistic effects into account. So both Mendeleev and Einstein come out well in this one.

Irrationally, this makes seaborgium more of a "real" element to me (there have been a couple of other compounds reported before as well). Single atoms seem to me to be the province of physics, but once you start describing compounds, it's chemistry.

Comments (25) + TrackBacks (0) | Category: Analytical Chemistry | Chemical News

The Stock Buybacks Roll On

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Posted by Derek

We've had a couple of vigorous discussions about share buyback programs around here, but for those who'd like some more, let me recommend this comment thread over at Marginal Revolution. The starting point was this article in the Financial Times.

One of the interesting points made is that management may well prefer buybacks to dividends because they tend to hold options. The tax treatment of the two has become more similar since 2003, but buybacks have increased, so taxes alone don't seem to be the key factor. But if you pay a dividend, it's out the door, whereas if you prop up the stock price, your future option transactions are disproportionately affected. (Balancing that, the stock price should, in theory, reflect expected future dividends, but this is one of the points that's argued in the comments thread).

And as mentioned here before, I think that another big factor in approving buyback programs is that no one has ever been fired for doing it. Whereas spending that money on something turned out not to work - people have lost their CEO positions for that sort of thing, so who needs it?

Comments (9) + TrackBacks (0) | Category: Business and Markets

September 22, 2014

Chemical Space

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Posted by Derek

chemical%20space.jpg
I'm listening to Jean-Louis Reymond of Bern talking about the GDB data set, the massive enumerated set of possible molecules. That's the set of chemically feasible molecules at or below a certain heavy atom count - the first iteration was GDB11 (blogged about here), and it's since been extended to GDB13, which has nearly one billion compounds with up to 13 C, N, O, S and Cl atoms. (Note, as always, that huge vast heaps of poly-small-ring compounds, especially concatenations of 3-membered rings, are pre-filtered out of these sets, because otherwise they would overwhelm them completely). They're working now on GDB17, which is a truly huge mound of data.

I was particularly taken with the image shown (from this paper), an artificial set of compounds (up to heavy atoms counts of 500) from several main classes of real molecules. It's a 3-D principle components analysis plot, which tunes things up to emphasize the differences, of course, and there's what chemical space looks like from this angle. There go the proteins and nucleic acids, off into their own zones, and similarly the linear alkanes and diamond-like lattices, beaming off in separate directions. In the middle are drug-like compounds - and don't imagine for a minute that any substantial number of those have actually been prepared, either. This is where we live, all of us organic chemists.

Comments (4) + TrackBacks (0) | Category: In Silico

A Free Online Med-Chem Course

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Posted by Derek

Erland Stevens at Davidson is going to be running an online med-chem course on EdX, the MOOC platform founded by Harvard and MIT. It starts in October, runs for 8 weeks, can be audited for free, and covers these topics:

(1) The drug approval process (early drugs, clinical trials, IP factors)
(2) Enzymes and receptors (inhibition, Ki, types of ligands, Kd)
(3) Pharmacokinetics (Vd, CL, compartment models)
(4) Metabolism (phase I and II, genetic factors, prodrugs)
(5) Molecular diversity (drug space, combi chem, libraries)
(6) Lead discovery (screening, filtering hits)
(7) Lead optimization (FG replacements, isosteres, peptidomimetics)
(8) Important drug classes (selected examples)

So if you know someone who would like to have a better understanding of the basics of med-chem and has been looking for an opportunity, this might be the answer. Stevens taught this one in the spring on the same platform, and had 14,000 people sign up at the beginning.

Update: from the comments, there's another med-chem course starting on Coursera shortly, from UCSD: https://www.coursera.org/course/drugdiscovery.

Comments (14) + TrackBacks (0) | Category: Pharma 101

Merck KgaA Buys Sigma-Aldrich

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Posted by Derek

Well, I didn't see this one coming: Merck KGaA (Merck-Darmstadt) is buying Sigma-Aldrich. So that's Merck/Millipore/Sigma-Aldrich, which will be a big life sciences company indeed. It's a $17 billion dollar deal, which goes off at at 37% premium to SIAL's close on Friday. Doesn't look much like any news of this offer leaked out, either, since the company's stock went down on Friday, and I don't see anything particularly weird in the options activity, either.

Merck KGaA has had a rough time of it recently trying to be a biotech company - perhaps they've decided that there's more stability in services?

Comments (16) + TrackBacks (0) | Category: Business and Markets

Astex's Financial History

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Posted by Derek

I'm at the FBLD conference in Basel today through Wednesday, and I'll be blogging some of the things I hear there. This morning we had an overview from Harren Jhoti of Astex, looking back over the company's history (they were recently bought by Otsuka for about $900 million).

One of the most striking slides was not from the scientific side - it was a plot of the company's financial position over the years. They had several deals with larger companies over the years (GSK, Novartis, J&J among others), and you could see that these, in many cases, were very timely indeed. In fact, Jhoti said, the company was more than once in the position of running out of money within a few months.

I think that many small companies could show a similar slide - well, the ones that survive could. The others would show a graph, if there were anyone left to show it, where that line came down and crossed the X-axis, and that was that. You hear a lot about these little tech companies, especially social media and the liek, that just take off and soar ever higher, but that doesn't happen much in biopharma. You can go for years dodging disaster until something works, which can make it a tough sell to investors, since you can also go for years and have nothing that works at all.

Comments (3) + TrackBacks (0) | Category: Business and Markets

September 19, 2014

Peter Thiel's Uncomplimentary Views of Big Pharma

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Posted by Derek

See what you think of Peter Thiel's characterization of the drug industry in this piece for Technology Review. Thiel's a very intelligent guy, and his larger points about technology stalling out make uncomfortable reading, in the best sense. (The famous quote is "We wanted flying cars; instead we got 140 characters"). But take a look at this (emphasis added):

You have to think of companies like Microsoft or Oracle or Hewlett-Packard as fundamentally bets against technology. They keep throwing off profits as long as nothing changes. Microsoft was a technology company in the ’80s and ’90s; in this decade you invest because you’re betting on the world not changing. Pharma companies are bets against innovation because they’re mostly just figuring out ways to extend the lifetime of patents and block small companies. All these companies that start as technological companies become antitechnological in character. Whether the world changes or not might vary from company to company, but if it turns out that these antitechnology companies are going to be good investments, that’s quite bad for our society.

I'd be interested in hearing him revise and extend those remarks, as they say in Washington. My initial reaction was to sit down and write an angry refutation, but I'm having second thoughts. The point about larger companies becoming more cautious is certainly true, and I've complained here about drug companies turning to M&A and share buybacks instead of putting that money back into research. I'd say, though, that the big drug companies aren't so much anti-technology as they are indifferent to it (or as indifferent as they can afford to be).

Even that still sounds harsh - what I mean is that they'd much rather maximize what they have, as opposed to coming up with something else. Line extensions and patent strategies are the most obvious forms of this. Buying someone else's innovations comes next, because it still avoids the pain and uncertainty of coming up with your own. There's no big drug company that does only these things, but they all do them to some degree. Share buybacks are probably the most galling form of this, because that's money that could, in theory, be applied directly to R&D, but is instead being used to prop up the share price.

But Thiel mentions elsewhere in his interview that we could, for example, be finding cures for Alzheimer's, and we're not. Eli Lilly, though, is coming close to betting the company on the disease, taking one huge swing after another at it. Thiel's larger point stands, about how more of the money that's going into making newer, splashier ways to exchange cat pictures and one-liners over the mobile phone networks could perhaps be applied better (to Alzheimer's and other things). But it's not that the industry hasn't been beating away on these itself.

I worry that the Andy Grove fallacy might be making an appearance again, given Thiel's background (PayPal, Facebook, LinkedIn). That link has a lot more on that idea, but briefly, it's the tendency for some people from the computing/IT end of the tech world to ask what the problem is with biomedical research, because it doesn't improve like computing hardware does. It's a good day to reference the "No True Scotsman" fallacy, too: sometimes people seem to identify "technology" with computing, and if something doesn't double in speed and halve in cost every time you turn around, well, that's not "real" technology. At the very least, it's not living up to its potential, and there must be something wrong with it.

I also worry that Thiel adduces the Manhattan project, the interstate highway system, and the Apollo program as examples of the sort of thing he'd like to see more of. Not that I have anything against any of those - it's just that they're all engineering projects, rather than discovery ones. The interstate system, especially: we know how to build roads, so build bigger ones. The big leap there was the idea that we needed large, standardized ones across the whole country, with limited entrances and exits. (And that was born out of Eisenhower's experiences driving across the country as the road network formed, and seeing Germany's autobahns during the war).

But you can say similar things about Apollo: we know that rockets can exist, so build bigger ones that can take people to the moon and back. There were a huge number of challenges along the way, in concept, design, and execution, but the problem was fundamentally different than, say, curing Alzheimer's. We don't even know that Alzheimer's can be cured - we're just assuming that it can. I really tend to think it can be cured, myself, but since we don't even know what causes it, that's a bit of a leap of faith. We're still making fundamental "who knew?" type discoveries in biochemistry and molecular biology, of the sort that would totally derail most big engineering projects. The Manhattan project is the closest analog of the three mentioned, I'd say, because atomic physics was such a new field (and Oppenheimer had to make some massive changes in direction along the way because of that). But I've long felt that the Manhattan project is a poor model, since it's difficult to reproduce its "Throw unlimited amounts of money and talent at the problem" mode, not to mention the fight-for-the-survival-of-your-civilization aspect.

But all that said, I do have to congratulate Peter Thiel on putting his money down on his ideas, though his investment fund. One of things I'm happiest about in today's economy, actually, is the way that some of the internet billionaires are spending their money. Overall, I'd say that many of them agree with Thiel that we haven't discovered a lot of things that we could have, and they're trying to jump-start that. Good luck to them, and to us.

Comments (58) + TrackBacks (0) | Category: Business and Markets | General Scientific News | Who Discovers and Why

A Day of Irreproducibility In Cambridge

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Posted by Derek

I wanted to mention that there's an interesting symposium on "Irreproducibility in Target Validation" taking place at Novartis (Cambridge, MA) next month, October 23. This is a topic that many an industrial biopharma researcher can relate to, and as academic centers get into more drug research, they're joining the rueful party, too. There are a number of good speakers from both academia and industry on the schedule, so if you're in the area, it's worth a look. More information here.

Comments (3) + TrackBacks (0) | Category: Academia (vs. Industry) | The Scientific Literature

Prison Sentences in the GSK China Scandal

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Posted by Derek

The GSK/China bribery case has come to some sort of ending. The company has been fined the equivalent of nearly $500 million, and Mark Reilly, the former head of that part of their operations in China, has been sentenced to prison for "two to four years". No further details seem to be available about the sentence. There are so few particulars, in fact, that although several other people are reported to have also been sentenced, we don't know who they are or what prison terms they've received. China's press (and government, same difference) are working on the usual need-to-know basis, and they've decided that no one else needs to know.

Update: the latest report is that Reilly has been given a suspended sentence and has been deported back to the UK. Certainly beats time in the Chinese prison system.

Comments (16) + TrackBacks (0) | Category: Business and Markets | The Dark Side

Big Journals, Big Retractions

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Posted by Derek

Big high-impact journals have more retractions, it seems. I can see how that would be, because there are several forces at work. People want to publish their splashy, cutting-edge results in the big-name journals, and a higher percentage of those papers are wrong to start with, as opposed to more incremental ones. And the big papers in the big journals get more scrutiny, so they're more likely to be picked apart when there's something wrong with them. I would have been surprised if this correlation had come out any other way, actually.

Comments (1) + TrackBacks (0) | Category: The Scientific Literature

September 18, 2014

The Worst Seminar

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Posted by Derek

Thinking of good seminars and bad ones reminds me of a story, which I'm surprised that I haven't told here, because it's a favorite memory of mine from grad school. Like everyone else, I've attended some pretty deadly talks over the years - some of them had decent subject matter, but were presented murderously, while others had such grim content that they would not have been redeemed by substituting the best speaker available. Combine those two, and you have a section of the Venn diagram that makes you wonder what you've done with your life (or with a previous one) to be sitting through the thing.

I remember coming back upstairs after one of those. Like most grad students, I didn't have the nerve to just bail on a speaker if they turned out to be horrible (heck, I sometimes don't have the nerve now). So I'd sat through a real forced march, or forced stagger, though a bunch of uninteresting stuff delivered at dictation speed in a nasal monotone. At this remove, I couldn't tell you what it was about even for a large reward; all I remember was the pointlessness.

So I was back in front of my hood when my labmate at the time appeared in the doorway. "That was the WORST seminar I have EVER heard in my LIFE!" he proclaimed, and I could only agree with him, which I did with a strange expression on my face. "Why are you grinning like that?" he asked. "Because the seminar speaker just walked behind you when you said that", I told him (truthfully). "No!" he said in horror, and looked off to his right down the hall. "Oh my God! Oh, well. He's heard it before." And maybe he had. Nominations for your own worst seminar experience are welcome in the comments, if you haven't blocked them out of your mind by now.

By the way, I checked to see if I'd told this story on the site by a Google trick, which is useful for searching the site as a whole. Just start your query with site:pipeline.corante.com, and you'll search only within that domain. It works quite well, but to be sure, I went and checked a text backup of the site (I make one from time to time, via an "Export" command. In case you're wondering, the whole site (posts and comments) rendered in 10-point Courier with standard margins on letter-sized paper, now comes to over 28,000 pages. Dang. I did a search for "worst seminar" and didn't find the phrase, but at this point you'd have to do a search for "Swann" to find the text of "Rememberance of Things Past" in there.

Comments (92) + TrackBacks (0) | Category: Blog Housekeeping | Graduate School

Conference in Basel

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Posted by Derek

I wanted to let people know that next week I'll be attending the FBLD (Fragment-Based Ligand Design) meeting in Basel, Switzerland. I'm looking forward to it - there are a number of good talks on the agenda, and it's always nice to attend a specialized conference where you're interested in the great majority of what's on offer. (Sitting through bad or irrelevant talks, as I've mentioned, becomes harder and harder for me every year). I hope to do some blogging from the conference itself as interesting topics come up.

If there are folks in Basel who'd like to meet up while I'm in town, it looks like I'll be free on Monday and Wednesday evening, so drop me an e-mail and maybe we can find a place to meet.

Comments (4) + TrackBacks (0) | Category: Blog Housekeeping

September 17, 2014

Messed-Up Clinical Studies: A First-Hand Report

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Posted by Derek

This makes for a very disturbing read. The author details his participation in a clinical trial for an asthma therapy being developed by Amgen at a clinic in Newport Beach (CA). He doesn't say what the drug was, but my guess is that it's brodalumab, an anti-IL17 antibody which has been in trials for asthma and psoriasis.

What he recounts is very disturbing. Here's a sample:

Moment of Truth #2 came during one of the many whispering sessions they gave me. The lead technician had a disturbing habit of frequently pulling me into a corner or another room and whispering things like “We’re just going to say that you take this medication.” I had to fill out numerous questionnaires, and she would often stand over me and whisper which answer I should mark. At last, one day after a battery of breathing tests, questionnaires, and vital-sign checks, it was required that the doctor (listed as the principal investigator on this study) verify all this, personally examine me, and sign off on it. Amgen was very clear on that point. “But he’s not here today,” she whispered, “so we’re just going to mark this off and send it through. We’ve already done everything he was going to do anyway.” By now I knew this contractor was willfully and knowingly giving Amgen invalid data, and I resolved to stick with it only long enough to see what more I could learn. I’d already decided I would not complete the trial and contribute bad data to a medical clinical trial.

It gets worse from there. The comments to Brian Dunning's post are already starting to fill up with the expected "Yeah, that's what Big Pharma does" stuff. So I'd like to help provide an antidote to that: Hey Amgen! Hey FDA! Check out this Newport Beach trial center! Dig into these allegations, and do something about them. And tell everyone what you've found!

Update: some readers are asking how anyone can be sure that this description is real. We can't, although it's certainly a detailed description, and attached to the name of someone with a good bit of internet traffic and associated notoriety. Mind you, some of that associated notoriety is a conviction for wire fraud. But in a "cui bono" sense, I don't see any reason for someone to make up the details in this account.

And how accurate it is should be an immediate concern for Amgen. In this business, we not only have to be death on clinical trial fraud, but we also have to be seen to be death on clinical trial fraud, so that (1) other people won't get the impression that it's a good idea, and (2) the general public won't get the impression that we're a bunch of crooks. So one way or another, these allegations have to be looked at, pronto.

Second update: see the comments section. Adam Feuerstein reports that Amgen has told him that they're already investigating this, which is just what the company should be doing. Glad to see them moving this quickly!

Comments (23) + TrackBacks (0) | Category: Clinical Trials | The Dark Side

Pharma and Ebola

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Posted by Derek

So, Ebola. A terrible virus, with a high mortality rate. And although that percentage is raised by the poor public health infrastructure in the areas where it's endemic, it's still very bad news indeed, a major medical challenge anywhere it might show up. The current outbreak in West Africa is by far the largest yet, which makes prediction of its course difficult. One can hope that the virus will mutate to a less ferocious form, as often happens with host/pathogen systems, but (1) that could take a long time, and (2) there's no guarantee that it would help much. After all, polio and smallpox had been infecting humans for a long time, and were still awful enough. There's also a small (but non-zero) chance that a mutation could go the other way, and make the virus easier to spread by airborne routes, to pick one worrisome possibility, in which case we're all going to long for the good old days when Ebola was only as bad as it is now.

With those cheerful thoughts in mind, what does the biopharma industry have to offer against the disease? As I mentioned regarding avian influenza several years ago, we can probably cross off most small-molecule therapies. Not very many antiviral drugs have a broad enough mechanism to go after Ebola as well as their designed targets, and there are no small molecules on the market that have been aimed at Ebola itself. As with many infectious diseases, immune-system therapies are a better bet - antibodies and the like for acute treatment, and vaccines as the best hope for prevention. Famously, there is a potential Ebola antibody in development (more on this in another post, and as we get some more details on the work itself), but there is (equally famously) no such thing yet as an Ebola vaccine yet, although there's a GSK/NIH venture that not many people had heard about until this latest outbreak.

You can realize all this, as the Independent newspaper did in England, and write a big story about how Big Pharma has been callous and negligent. But once you scroll down that one, you'll find in the comments section that the main source for the article is quite unhappy with it:

his article claims that I, Adrian Hill, have “ launched a devastating attack on Big Pharm, accusing drugs giants including GlaxoSmithKline (GSK), Sanofi, Merck and Pfizer of failing to manufacture a vaccine, not because it was impossible, but because there was no business case.” I did no such thing.

I simply explained to Mr Cooper what is widely known in the biomedical research and development community: that vaccine development is extremely expensive, usually takes a very long time and the market is dominated by some very large pharma companies. Because outbreaks of diseases such as Ebola are rare and unpredictable and, until now, have afflicted small numbers of people in very poor countries, it is widely understood that that is no business case for a private company to invest tens or hundreds of millions of dollars in vaccine development for such diseases. It may be the Independent’s view that this is a telling indictment of the global pharmaceutical industry, but it is not mine and I am unhappy that the first paragraph of this report wrongly attributes that view to me.

Adrian Hill is completely correct. Until this latest outbreak, there have been far, far larger pubic health problems in Africa than Ebola. Not even the deepest-pocketed NGO or most open-hearted charity would have been able to make a good case for putting large amounts of money behind an Ebola vaccine effort - in fact, such a project would almost certainly have been a criminal misuse of funds. There are just too many other things that have caused (and are causing) death and disease in these areas - until this year, the number of people killed by Ebola was trivial compared to the number being killed by a host of other factors. In fact, the number of people being infected now by Ebola is pretty damned small compared to the other public health problems in the poorest parts of West Africa - just to stick with the infectious diseases alone, you have malaria, yellow fever, schistosomiasis, dengue, typhoid, hepatitis A, meningococcus, and just plain diarrhea (a killer for young children). Ebola doesn't deserve the current level of attention just because of the number of people it's killed - the number of people in Liberia who've died before their time over the last ten or twenty years is horrific, and it wasn't Ebola that killed them. It deserves attention because we don't know how bad this outbreak is going to get, and because it's already (and understandably) causing huge amounts of fear and disruption, given its high mortality rate. If cases continue to show up inside the larger cities, things could get out of control pretty quickly.

The NIH (specifically, the NIAID) has funded a number of Ebola research programs in the US, and I would guess that many of these have been directed, at least partly, to possible bioterror threats. It's also worthwhile to figure out how to develop a vaccine against a class of viruses that no one's tackled before, since there are bound to be some lessons learned that can be applied again. Okairos, a small Swiss-based company spun out of Merck, has been working on a vaccine along with the NIH as well, and they were recently acquired by GSK. (This one is the focus of a great deal of suddenly accelerated work).

But no, the big companies have not spent time working on an Ebola vaccine until now. And as Hill says, this should not come as a surprise. By the WHO's count, from 1976 through 2012 there had been a total of 1590 human fatalities from Ebola, with whole years going by without a single case. There is not enough research money in the world to work on everything at this level, or at least, not without taking away from everything else.

Comments (21) + TrackBacks (0) | Category: Infectious Diseases

September 16, 2014

Lilly Steps In for AstraZeneca's Secretase Inhibitor

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Posted by Derek

Today brings news of a deal with AstraZeneca to help develop AZ's beta-secretase inhibitor, AZD3293 (actually an Astex compound, developed through fragment-based methods). AZ has been getting out of CNS indications for some time now, so they really did need a partner here, and Lilly lost their own beta-secretase compound last year. So this move doesn't come as too much of a shock, but it does reaffirm Lilly's bet-the-ranch approach to Alzheimer's.

This compound was used by AZ in their defense against being taken over by Pfizer, but (as that link in the first paragraph shows), not everyone was buying their estimated chances of success (9%). Since the overall chances for success in Alzheimer's, historically, have ranged between zero and 1%, depending on what you call a success, I can see their point. But beta-secretase deserves to have another good shot taken at it, and we'll see what happens. It'll takes years, though, before we find out - Alzheimer's trials are painfully slow, like the disease itself.

Update: I've had mail asking what I mean by AZ "getting out of CNS indications", when they still have a CNS research area. That's true, but it's a lot different than it used to be. The company got rid of most of its own infrastructure, and is doing more of a virtual/collaborative approach. So no, in one sense they haven't exited the field at all. But a lot of its former CNS people (and indeed, whole research sites) certainly exited AstraZeneca.

Comments (29) + TrackBacks (0) | Category: Alzheimer's Disease | Business and Markets | Drug Development

Update on Alnylam (And the Direction of Things to Come)

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Posted by Derek

Here's a look from Technology Review at the resurgent fortunes of Alnylam and RNA interference (which I blogged about here).

But now Alnylam is testing a drug to treat (familial amyloid polyneuropathy) in advanced human trials. It’s the last hurdle before the company will seek regulatory approval to put the drug on the market. Although it’s too early to tell how well the drug will alleviate symptoms, it’s doing what the researchers hoped it would: it can decrease the production of the protein that causes FAP by more than 80 percent.

This could be just the beginning for RNAi. Alnylam has more than 11 drugs, including ones for hemophilia, hepatitis B, and even high cholesterol, in its development pipeline, and has three in human trials —progress that led the pharmaceutical company Sanofi to make a $700 million investment in the company last winter. Last month, the pharmaceutical giant Roche, an early Alnylam supporter that had given up on RNAi, reversed its opinion of the technology as well, announcing a $450 million deal to acquire the RNAi startup Santaris. All told, there are about 15 RNAi-based drugs in clinical trials from several research groups and companies.

“The world went from believing RNAi would change everything to thinking it wouldn’t work, to now thinking it will,” says Robert Langer, a professor at MIT, and one of Alnylam’s advisors.

Those Phase III results will be great to see - that's the real test of a technology like this one. A lot of less daring ideas have fallen over when exposed to that much of a reality check. If RNAi really has turned the corner, though, I think it could well be just the beginning of a change coming over the pharmaceutical industry. Biology might be riding over the hill, after an extended period of hearing hoofbeats and seeing distant clouds of dust.

There was a boom in this sort of thinking during the 1980s, in the early days of Genentech and Biogen (and others long gone, like Cetus). Proteins were going to conquer the world, with interferon often mentioned as the first example of what was sure to be a horde of new drugs. Then in the early 1990s there was a craze for antisense, which was going to remake the whole industry. Antibodies, though, were surely a big part of the advance scouting party - many people are still surprised when they see how many of the highest-grossing drugs are antibodies, even though they're often for smaller indications.

And the hype around RNA therapies did reach a pretty high level a few years ago, but this (as Langer's quote above says) was followed by a nasty pullback. If it really is heading for the big time, then we should all be ready for some other techniques to follow. Just as RNAi built on the knowledge gained during the struggle to realize antisense, you'd have to think that Moderna's mRNA therapy ideas have learned from the RNAi people, and that the attempts to do CRISPR-style gene editing in humans have the whole biologic therapy field to help them out. Science does indeed march on, and we might possibly be getting the hang of some of these things.

And as I warned in that last link, that means we're in for some good old creative destruction in this industry if that happens. Some small-molecule ideas are going to go right out the window, and following them (through a much larger window) could be the whole rare-disease business model that so many companies are following these days. Many of those rare diseases are just the sorts of things that could be attacked more usefully at their root cause via genomic-based therapies, so if those actually start to work, well. . .

This shouldn't be news to anyone who's following the field closely, but these things move slowly enough that they have a way of creeping up on you unawares. Come back in 25 years, and the therapeutic landscape might be a rather different-looking place.

Comments (18) + TrackBacks (0) | Category: Biological News | Business and Markets | Clinical Trials | Drug Development

September 15, 2014

There Must Have Been Multiple Chances to Catch This

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Posted by Derek

Battery%20abstract%20figure.jpgIt's time for a hang-heads-in-shame moment. This is another off the Twitter feed, and the only place to see the figure in its native state is to go the the Chemical Reviews table of contents and scroll down to the article titled "Aqueous Rechargable Li and Na Ion Batteries". A perfectly reasonable topic, but take a look at the graphical abstract figure. Oh, dear.

Comments (31) + TrackBacks (0) | Category: The Scientific Literature

Weirdly, Tramadol Is Not a Natural Product After All

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Posted by Derek

Last year I mentioned a paper that described the well-known drug tramadol as a natural product, isolated from a species of tree in Cameroon. Rather high concentrations were found in the root bark, and the evidence looked solid that the compound was indeed being made biochemically.

Well, thanks to chem-blogger Quintus (and a mention on Twitter by See Arr Oh), I've learned that this story has taken a very surprising turn. This new paper in Ang. Chem. investigates the situation more closely. And you can indeed extract tramadol from the stated species - there's no doubt about it. You can extract three of its major metabolites, too - its three major mammalian metabolites. That's because, as it turns out, tramadol is given extensively to cattle (!) in the region, so much of it that the parent drug and its metabolites have soaked into the soil enough for the African peach/pincushion tree to have taken it up into its roots. I didn't see that one coming.

The farmers apparently take the drug themselves, at pretty high dosages, saying that it allows them to work without getting tiree. Who decided it would be a good thing to feed to the cows, no one knows, but the farmers feel that it benefits them, too. So in that specific region in the north of Cameroon, tramadol contamination in the farming areas has built up to the point that you can extract the stuff from tree roots. Good grief. In southern Cameroon, the concentrations are orders of magnitude lower, and neither the farmers nor the cattle have adopted the tramadol-soaked lifestyle. Natural products chemistry is getting trickier all the time.

Comments (18) + TrackBacks (0) | Category: Analytical Chemistry | Chemical News | Natural Products

September 12, 2014

Thiola, Retrophin, Martin Shkrell, Reddit, and More

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Posted by Derek

Well, it was not a dull evening around the In the Pipeline headquarters last night. I submitted a link to Reddit for my post yesterday about Retrophin and Thiola, and that blew up onto that site's front page. The Corante server melted under the impact, which isn't too surprising, since it's struggling at the best of times. (A site move really is coming, and no, I can't wait, either, at this point.)

But then, to my great surprise, Martin Shkreli (CEO of Retrophin) showed up in the Reddit thread, doing an impromptu AMA (Ask Me Anything), which I have to say takes quite a bit of aplomb (or perhaps foolhardiness - I don't think too many other CEOs of any publicly traded corporations would have done it). But not too long after that, the entire thread vanished off the front page, and off of r/News, the subreddit where I'd submitted it.

Then I got a message from one of the moderators of r/News, saying that I'd been banned from it, and going on to say that I would likely be banned from the site as a whole. After having been on Reddit for seven years, that took me by surprise. As best I can figure, the thread itself was reported to r/Spam by someone, and the automated system took over from there. Over the years, I've submitted links to my blog posts, and Reddit, or some parts of it, anyway, has been notoriously touchy about that. The last time I submitted such a link, though, was back in February (and before that, August of 2013), so I'm not exactly a human spam-bot. We'll see what happens. Update: I was banned for some hours, but I've been reinstated.

But back to Retrophin, Thiola, and Martin Shrkeli. The entire Reddit thread can still be read here, via a direct link, although it can't be found in r/News any more. If you look for a user named "martinshkreli", you can see where he gets into the fray (I'm "dblowe" on the site, or perhaps I was?). You'll note that he gives out his cell phone, office phone, and e-mail, which again is not your usual CEO move - you have to give him that, although it does seem a bit problematic from a regulatory/compliance angle. So what arguments does he make for the Thiola price increase?

From what I can see, they boil down to this: patients themselves aren't going to be paying this increased price - insurance companies are. And Retrophin is actually going to be working on new formulations for the drug, which no one has done previously. He seems to have implied that the previous company (Mission Pharmacal) was reluctant to raise the price and take the public outcry, and stated (correctly) that Mission was having trouble keeping the drug in supply. He claims that the current price is still "pretty low", and that he does not expect any pushback from the eventual payers. There was also quite a bit about the company's dedication to patients, their work on other rare diseases, and so on.

He and I didn't cross paths much in the thread. I tried asking a few direct questions, but they weren't picked up on, so my take on Shkreli's answers will show up here. He's correct that the drug's availability was erratic, and he may well be correct that its price was too low for a company to deal with it properly. But if so, that does make you wonder what Mission Pharmacal was up to, and how they were sourcing the material.

He's also correct that Retrophin is planning to work on new formulations of the drug. But when you look at the company's investor presentation about Thiola, all that comes under a slide marked "Distribution and Intellectual Property". The plan seems to be that they'll introduce 250mg and 500mg dosages, at which time they'll discontinue the current 100mg formulation. Later on, they'll try to introduce a time-release formulation, at which time they'll discontinue the 250mg and 500mg forms. You can argue that this is helping patients, but you can also argue that it's making it as difficult as possible for anyone else to show bioequivalence and enter the market as well, assuming that anyone wants to.

And as I mentioned yesterday, the company does seem to care about someone else entering the market. My questions to Shkreli about the "closed distribution" model mentioned on the company's slides went unanswered, but the only interpretation I can give them is that Retrophin plans to use the FDA's risk management system to deny any competitors access to their formulations, in order to try to keep themselves as the sole supplier of Thiola in perpetuity. Patents at least expire: regulatory rent-seeking is forever.

Also left out of Shkreli's comments on Reddit are the issues on the company's slide titled "Pharmacoeconomics", where it says (vis-a-vis the other drug for cystinuria, penicillamine):

Current pricing of Thiola® - $4,000 PPPY
– Penicillamine pricing- $80,000-$140,000
• Thiola could support a significant price increase

Personally, I think that's the main reason for Retrophin's interest. You'll note that the price hike takes Thiola's cost right up to the penicillamine region (the price of that one is another story all its own). But to a first approximation, that's business. I've defended some drug company pricing decisions on this site before (although not all of them), so what's different this time?

I've been thinking hard about that one, and here's what I have so far. I think that pricing power of this sort is a powerful weapon. That's the reason for the patent system - you get a monopoly on selling your invention, but it's for a fixed period only, and in return you disclose what your invention is so that others can learn from it. And I think that this sort of pricing power should be a reward for actually producing an invention. That's the incentive for going through all the work and expense, the (time-limited) pot of gold at the end of the rainbow. I have a much lower opinion of seeing someone ram through a big price increase just because, hey, they can. Thiola has nothing to do with the patent system - it's off patent. What this situation looks like to me is regulatory rent-seeking. Celgene seems to be doing that too, with thalidomide (as mentioned yesterday), which is why they're being taken to court. Retrophin is betting that Thiola just isn't a big enough deal for anyone to go to that trouble, once they tell them to buzz off by using Celgene's strategy.

Businesses can, though, charge what they think the market will bear, and Retrophin's contribution to cystinuria therapy so far is to have realized that the market will bear a lot more than people had realized. But in an actual market, it would be easier for someone else to come in and compete on price. What Retrophin is planning is to use regulatory loopholes to keep anyone else from doing so, with no time limit until someone at the FDA does something about it. Cloaking this in a lot of noble-sounding talk about being the company that really cares about cystinuria patients is a bit stomach-turning. In my opinion.

Comments (29) + TrackBacks (0) | Category: Business and Markets | Drug Prices | Why Everyone Loves Us

September 11, 2014

The Most Unconscionable Drug Price Hike I Have Yet Seen

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Posted by Derek

There's a drug called Thiola (tiopronin) that most people have never heard of. It's on my list of "smaller than aspirin" drugs, and I'd never heard of it until I put that one together. But thanks to a little company called Retrophin, we all get to hear about it now.

It's used to treat cystinuria, a rare disease that causes painful kidney complications, namely unusual kidney stones of pure cystine. And until recently, tiopronin (as a small, nearly forgotten drug for an orphan indication) was rather cheap. It was sold by a small company in Texas, Mission Pharmacal, until Retrophin bought the marketing rights earlier this year (a move complicated by the company's CEO, investor Martin Shkreli, who may have let the news of the deal leak on his Twitter account).

That link mentions part of Shkreli's business plan as "acquiring the rights to obsolete remedies Shkreli says can be put to new and lucrative purposes", and by gosh, that's certainly accurate. Retrophin is increasing the price of Thiola from $1.50 per pill to over $30 per pill. Because they can - they stated when they bought the drug that their first move would be to raise the price. New dosages are formulations are also mentioned, but the first thing is to jack the price up as high as it can be jacked. Note that patients take several pills per day. Shkreli is probably chortling at those Mission Pharmacal hicks who didn't realize what a gold mine they were sitting on.

Now, there have been somewhat similar cases in recent years. Colchicine's price went straight up, and (infamously) so did the progesterone formulation marketed as Makena. But in both those cases, the small companies involved took the compound back through the FDA, under an agency-approved program to get marketing exclusivity. I've argued here (see those last two links) that this idea has backfired several times, and that the benefit from the clinical re-evaluation and re-approval of these drugs has not been worth their vastly increased cost. I think that drug companies should be able to set the price of their drugs, because they have a lot of failures to make up for, but this FDA loophole gives people a chance to do minimal development at minimal risk and be handed a license to print money in return.

But this isn't even one of those cases. It's worse. Retrophin hasn't done any new trials, and they haven't had to. They've just bought someone else's old drug that they believed could be sold for twenty times its price, and have put that plan right into action. No development costs, no risks whatsoever - just slap a new sticker on it and put your hands over your ears. This is exactly the sort of thing that makes people go into fist-clenching rages about the drug industry, and with damn good reason. This one enrages me, and I do drug research for a living.

So thank you, Martin Shkreli. You've accelerated the progress of the giant hammer that's coming down on on all of us over drug pricing, and helped drag the reputation of the pharmaceutical industry even further into the swamp. But what the hell do you care, right? You're going to be raking in the cash. The only thing I can say about Shkreli and Retrophin is that they make the rest of the industry look good in comparison. Some comparison.

Update: There are some interesting IP aspects to this situation. As pointed out in the comments section, this compound has no exclusivity left and is off patent. So what's to stop someone else from filing an ANDA, showing bioequivalence, and competing on price (since there seems to be an awful lot of room in there)?

Simon Lackner on Twitter sent me to this presentation from Retrophin on their purchase of the Thiola license. In it, you can see that their plan for this: "Similar to Chenodal, Retrophin will move Thiola into closed distribution". Chenodal was the company's previous brainstorm of this sort, when they bought Manchester Pharmaceuticals, details of which can be seen on this presentation. What they say on that one is "Closed distribution system does not allow for generics to access product for bioequivalence study. ANDA filings are impossible unless generic company illegally penetrates specialty distributor. Recent Celgene v. Lannett case establishes precedent." So let's go back and take a look at Celgene v. Lannett.

That was a long-running dispute between the two companies over Lannett's desire to market a generic equivalent of Celgene's thalidomide. Lannett brought suit, accusing Celgene of using the drug's Risk Evaluation and Mitigation Strategy (REMS) improperly to deny potential competitors access to their product (which is needed to do a head-to-head comparison for an ANDA filing). As you can imagine, the REMS for thalidomide is pretty extensive and detailed! But there was no court decision in the case. The companies reached an out-of-court settlement before it went to trial in 2012, although I have to say that that Retrophin slide makes it sound like there's some sort of legal precedent that was set. There wasn't. The limits of REMS restrictions to deny access to a given drug are still an open question.

In late 2012, Acetelion and Apotex went at it over the same issue, this time over access to Tracleer (bosentan). The Federal Trade Commission filed an amicus brief, warning that companies could be abusing the REMS process to keep out competition. That case was also dismissed, though, after the two companies reached an out-of-court settlement of their own, removing another chance for a legal opinion on the subject.

But the issue is very much alive. Earlier this year, Mylan went after Celgene, also over thalidomide (and its follow-up, lenalidomide). Their complaint:

Celgene, a branded drug manufacturer, has used REMS as a pretext to prevent Mylan from acquiring the necessary samples to conduct bioequivalence studies, even after the FDA determined that Mylan’s safety protocols were acceptable to conduct those studies. In furtherance of its scheme to monopolize and restrain trade, Celgene implemented certain distribution restrictions that significantly limit drug product availability.

And this is the plan that Retrophin has in mind - they say so quite clearly in those two presentations linked above. What their presentations don't go into is that this strategy has been under constant legal attack. It also doesn't go into another issue: the use of REMS at all. Thalidomide, of course, is under all kinds of restrictions and has plenty of hideous risks to manage. Bosentan's not exactly powdered drink mix, either - patients require monthly liver function tests (risk of hepatoxicity) and monitoring of their hematocrit (risk of anemia). But what about Thiola/tiopronin? It's not under any risk management restrictions that I can see. Its side effects seem to be mainly diarrhea and nausea, which does not put it into the "This drug is so dangerous that we can't let any generic company get ahold of our pills" category. So how is Retrophin going to make this maneuver work?

Update: more on this issue here.

Comments (39) + TrackBacks (0) | Category: Business and Markets | Drug Prices | Why Everyone Loves Us

September 10, 2014

Clinical Trial Fraud

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Posted by Derek

Bizarre news from Evotec - see what you make of this press release:

Evotec AG was informed that US company Hyperion Therapeutics, Inc. ("Hyperion") is terminating the development of DiaPep277(R) for newly diagnosed Type 1 diabetes.

In a press release published by Hyperion on 08 September 2014 at market opening in the US, the company states that it has uncovered evidence that certain employees of Andromeda Biotech, Ltd. ("Andromeda"), which Hyperion acquired in June 2014, engaged in serious misconduct, involved with the trial data of DiaPep277. Hyperion announced that it will complete the DIA-AID 2 Phase 3 trial, but will terminate further development in DiaPep277.

Here's the Hyperion press release, and it details a terrible mess:

The company has uncovered evidence that certain employees of Andromeda Biotech, Ltd., which Hyperion acquired in June 2014, engaged in serious misconduct, including collusion with a third-party biostatistics firm in Israel to improperly receive un-blinded DIA-AID 1 trial data and to use such data in order to manipulate the analyses to obtain a favorable result. Additional evidence indicates that the biostatistics firm and certain Andromeda employees continued the improper practice of sharing and examining un-blinded data from the ongoing DIA-AID 2 trial. All of these acts were concealed from Hyperion and others.

The Company has suspended the Andromeda employees known to be involved, is notifying relevant regulatory authorities, and continues to investigate in order to explore its legal options. Hyperion employees were not involved in any of the improper conduct.

What a nightmare. All biomedical data are vulnerable to outright fraud, and it gives a person the shivers just thinking about it. I can only imagine the reactions of Hyperion's management when they heard about this, and Evotec's when Hyperion told them about it. What, exactly, the Andromeda people (and the third-party biostatistics people) thought they were getting out of this is an interesting question, too - did they hope to profit if the company announced positive results? That's my best guess, but I'm not sleazy enough (I hope) to think these things through properly.

Comments (17) + TrackBacks (0) | Category: Business and Markets | Clinical Trials | The Dark Side

Grinding Up Your Reactions

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Posted by Derek

I'd seen various solventless reactions between solid-phase components over the years, but never tried one until now. And I have to say, I'm surprised and impressed. I can't quite say which literature reference I'm following, unfortunately, because it might conceivably give someone a lead on what I'm making at the moment, but it's a reference that I found as a new technique for an old reaction. Doing it in solution gives you a mess, but just grinding up the two solid reactants and the reagent, in a mortar and pestle, gives you a very clean conversion. The stuff turns into a sort of ugly clay inside the mortar, but it looks are deceiving. I feel like an alchemist. Consider me a convert to the solventless lifestyle - I'll try this again on some other reaction classes when I get the chance. Anyone else ever ground up some solids and made a new product?

Comments (40) + TrackBacks (0) | Category: Life in the Drug Labs

Peer Review, Up Close and Personal

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Posted by Derek

Retraction Watch has a rare look behind the peer review curtain in the (now notorious) case of the STAP stem cell controversy. This was the publication that claimed that stem-like cells could be produced by simple acid treatment, and this work has since been shown to be fraudulent. Damaged reputations, bitter accusations, and one suicide have been the result so far, and there are still bent hubcaps wobbling around on the asphalt.

The work was published in Nature, but it had been rejected from Science and Cell before finding a home there. That's not unusual in itself - a lot of groundbreaking work has had a surprisingly difficult time getting published. But the kinds of referee reports this got were detailed, well-argued, and strongly critical, which makes you wonder what Nature's reviewers said, and how the work got published in the form it did, with most (all?) of the troublesome stuff left in.

Retraction Watch has obtained the complete text of the referee comments from the Science submission process and published them. Here are some highlights from just the first reviewer:

. . .This is such an extraordinary claim that a very high level of proof is required to sustain it and I do not think this level has been reached. I suspect that the results are artifacts derived from the following processes: (1) the tendency of cells with GFP reporters to go green as they are dying. (2) the ease of cross contamination of cell lines kept in the same lab. . .

. . .The DNA analysis of the chimeric mice is the only piece of data that does not fit with the contamination theory. But the DNA fragments in the chimeras don’t look the same as those in the lymphocytes. This assay is not properly explained. If it is just an agarose gel then the small bands could be anything. Moreover this figure has been reconstructed. It is normal practice to insert thin white lines between lanes taken from different gels (lanes 3 and 6 are spliced in). Also I find the leading edge of the GL band suspiciously sharp in #2-#5. . .

This report and the other two go on to raise a long list of detailed, well-informed criticisms about the experimental design of the work and the amount of information provided. Solutions and reagents are not described in enough detail, images of the cells don't quite show what they're supposed to be showing, and numerous useful controls and normalizations are missing outright. The referees in this case were clearly very familiar with stem cell protocols and behavior, and they did exactly what they were supposed to do with a paper whose claims were as extraordinary as these were.

Had any of this stuff been real, meeting the objections of the reviewers would have been possible, and would have significantly improved the resulting paper. This process, in fact, handed the authors a list of exactly the sorts of objections that the scientific community would raise once the paper did get published. And while rejections of this sort are not fun, that's just what they're supposed to provide. Your work needs to be strong enough to stand up to them.

Congratulations to the Science and Cell editorial teams (and reviewers) for not letting this get past them. I would guess that publication of these reports will occasion some very painful scenes over at Nature, though - we'll see if they have any comment.

Comments (11) + TrackBacks (0) | Category: The Dark Side | The Scientific Literature

September 9, 2014

Google's Calico Moves Into Reality

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Posted by Derek

Google's Calico venture, the company's out-there move into anti-aging therapy, has made the news by signing a deal with AbbVie (the company most of us will probably go on thinking of as Abbott). That moves them into the real world for sure, from the perspective of the rest of the drug industry, so it's worth taking another look at them. (It's also worth noting that Craig Venter is moving into this area, too, with a company called Human Longevity. Maybe as the tech zillionaires age we'll see a fair amount of this sort of thing).

On one level, I applaud Google's move. There's a lot of important work to be done in the general field of aging, and there are a lot of signs that human lifespan can be hacked, for want of a better word. The first thought some people have when they think of longer lifespan is that it could be an economic disaster. After all, a huge percentage of our healthcare money is already spent in the last years of life as it is - what if we make that period longer still? But it's not just sheer lifespan - aging is the motor behind a lot of diseases, making them more like to crop up and more severe when they do. The dream (which may be an unattainable one) is for longer human lifespans, in good health, without the years of painful decline that so many people experience. Even if we can't quite manage that, an improvement over the current state of things would be welcome. If people stay productive longer, and spend fewer resources on disabling conditions as they age, we can come out ahead on the deal rather than wondering how we could possibly afford it.

Google and AbbVie are both putting $250 million into starting a research site somewhere in the Bay area (and given the state of biotech out there, compared to a few years ago, it'll be a welcome addition). If things go well, each of them have also signed up to contribute as much as $500 million more to the joint venture, but we'll see if that ever materializes. What, though, are they going to be doing out there?

Details are still scarce, but FierceBiotechIT says that "a picture of an IT-enabled, omics-focused operation has emerged from media reports and early hiring at the startup". That sounds pretty believable, given Google's liking for (and ability to handle) huge piles of data. It also sounds like something that Larry Page and Sergey Brin would be into, given their past investments. But that still doesn't tell us much: any serious work in this area could be described in that fashion. We'll have to use up a bit more of our current lifespans before things get any clearer.

So I mentioned above that on one level I like this - what, you might be asking, is the other level on which I don't? My worry is what I like to call the Andy Grove Fallacy. I applied that term to Grove's "If we can improve microprocessors so much, what's holding you biotech people back"? line of argument. It's also a big part of the (in)famous "Can a Biologist Fix a Radio" article (PDF), which I find useful and infuriating in about equal proportions. The Andy Grove Fallacy is the confusion between man-made technology (like processor chips and radios) and biological systems. They're both complex, multifunctional, miniaturized, and made up of thousands and thousands of components, true. But the differences are more important than the similarities.

For one thing, human-designed objects are one hell of a lot easier for humans to figure out. With human-designed tech, we were around for all the early stages, and got to watch as we made all of it gradually more and more complicated. We know it inside out, because we discovered it and developed it, every bit. Living cells, well, not so much. The whole system is plunked right down in front of us, so the only thing we can do is reverse-engineer, and we most definitely don't have all the tools we need to do a good job of that. We don't even know what some of those tools might be yet. Totally unexpected things keep turning up as we look closer, and not just details that we somehow missed - I'm talking about huge important regulatory systems (like all the microRNA pathways) that we never even realized existed. No one's going to find anything like that in an Intel chip, of that we can be sure.

And that's because of the other big difference between human technology and biochemistry: evolution. We talk about human designs "evolving", but that's a very loose usage of the word. Real biological evolution is another thing entirely. It's not human, not at all, and it takes some time to get your head around that. Evolution doesn't do things the way that we would. It has no regard for our sensibilities whatsoever. It's a blind idiot tinkerer, with no shame and no sense of the bizarre, and it only asks two questions, over and over: "Did you live? Did you reproduce? Well, OK then." Living systems are full of all kinds of weird, tangled, hacked-together stuff, layer upon layer of it, doing things that we don't understand and can't do ourselves. There is no manual, no spec sheet, no diagram - unless we write it.

So people coming in from the world of things that humans built are in for a shock when they find out how little is known about biology. That's the shock that led to that Radio article, I think, and the sooner someone experiences it, the better. When Google's Larry Page is quoted saying things like this, though, I wonder if it's hit him yet:

One of the things I thought was amazing is that if you solve cancer, you’d add about three years to people’s average life expectancy. We think of solving cancer as this huge thing that’ll totally change the world. But when you really take a step back and look at it, yeah, there are many, many tragic cases of cancer, and it’s very, very sad, but in the aggregate, it’s not as big an advance as you might think."

The problem is, cancer - unrestrained cellular growth - is intimately tied up with aging. Part of that is statistical. If you live long enough, you will surely come down with some form of cancer, whether it's nasty enough to kill you or benign enough for you to die of something else. But another connection is deeper, because the sorts of processes that keep cells tied down so that they don't take off and try to conquer the world are exactly the ones, in many cases, that we're going to have to tinker with to extend our lifespans. There are a lot of tripwires out there, and many of them we don't even know about yet. I'd certainly assume that Larry Page's understanding of all this is deeper than gets conveyed in a magazine article, but he (and the other Google folks) will need to watch themselves as they go on. Hubris often gets rewarded in Silicon Valley - after all, it's made by humans, marketed to humans, and is rewarded by human investors. But in the biomedical field, hubris can sometimes attract lightning bolts like you would not believe.

Comments (24) + TrackBacks (0) | Category: Aging and Lifespan | Business and Markets

September 8, 2014

Reactive Groups: Still Not So Reactive

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Posted by Derek

Just how reactive are chemical functional groups in vivo? That question has been approached by several groups in chemical biology, notably the Cravatt group at Scripps. One particular paper from them that I've always come back to is this one, where they profiled several small electrophiles across living cells to see what they might pick up. (I blogged about more recent effort in this vein here as well).

Now there's a paper out in J. Med. Chem. that takes a similar approach. The authors, from the Klein group at Heidelberg, took six different electrophiles, attached them to a selection of nonreactive aliphatic and aromatic head groups, and profiled the resulting 72 compounds across a range of different proteins. There are some that are similar to what's been profiled in the Cravatt papers and others (alpha-chloroketones), but others I haven't seen run through this sort of experiment at all.

And what they found confirms the earlier work: these things, even fairly hot-looking ones, are not all that reactive against proteins. Acrylamides of all sorts were found to be quite clean, with no inhibition across the enzymes tested, and no particular reaction with GSH in a separate assay. Dimethylsulfonium salts didn't do much, either (although a couple of them were unstable to the assay conditions). Chloroacetamides showed the most reactivity against GSH, but still looked clean across the enzyme panel. 2-bromodihydroisoxazoles showed a bit of reactivity, especially against MurE (a member of the panel), but no covalent binding could be confirmed by MS (must be reversible). Cyanoacetamides showed no reactivity at all, and neither did acyl imidazoles.

Now, there are electrophiles that are hot enough to cause trouble. You shouldn't expect clean behavior from an acid chloride or something, but the limits are well above where most of us think they are. If some of these compounds (like the imidazolides) had been profiled across an entire proteome, then perhaps something would have turned up at a low level (as Cravatt and Weerapana saw in that link in the first paragraph). But these things will vary compound by compound - some of them will find a place where they can sit long enough for a reaction to happen, and some of them won't. Here's what the authors conclude:

An unexpected but significant consequence of the present study is the relatively low inhibitory potential of the reactive compounds against the analyzed enzymes. Even in cytotoxicity assays and when we looked for inhibitor enzyme adduct formation we did not find any elevated cytotoxicity or unspecific modification of proteins. Particularly in the case of chloroacetylamides/-anilides and dimethylsulfonium salts, which we consider to be among the most reactive in this series, this is a promising result. From these results the following consequences for moderately reactive groups in medicinal chemistry can be drawn. Promiscuous reactivity and off-target effects of electrophiles with moderate reactivity may often be overestimated. It also does not appear justified to generally exclude “reactive” moieties from compound libraries for screening purposes, since the nonspecific reactivity may turn out to be much inferior than anticipated.

There are a lot of potentially useful compounds that most of us have never thought of looking at, because of our own fears. We should go there.

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

September 5, 2014

A VC Firm Touts Its Successes - And Its Failures

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Posted by Derek

Here's what sounds like a good idea from VC firm Index Ventures, from the latest issue of BioCentury (same one I referenced the other day). Like many others in the biopharma venture capital world, they're trying to run the "killer experiment" as soon as possible, to see which ideas for new companies look solid. Unlike the others, though, they're planning a web site where they will detail the successes - and the failures. Here's an example:

Founded in 2013, (Purple Pharmaceuticals) was started to identify small molecule inhibitors of proprotein convertase subtilisin/kexin type 9. Two mAbs against PCSK9 are already in Phase III testing to treat hypercholesterolemia with regulatory submissions expected this year: evolocumab from Amgen Inc. and alirocumab from partners Regeneron Pharmaceuticals Inc. and Sanofi.

Grainger said the antibodies have limitations, as they require high doses to suppress PCSK9 activity and once-weekly or once-monthly infusions. Thus a pill that could match the PCSK9 inhibition of the biologics could be “the holy grail” of lowering LDL cholesterol.

Purple began by trying to identify small molecules that were highly selective for PCSK9 over other proprotein convertases because, as Grainger noted, “PCSK9 is a member of a large family of enzymes that do some pretty critical things.”

The killer experiment, he said, “was to ask could we make a small molecule that was selective over these other proprotein convertases, and could we demonstrate that it would lower LDL cholesterol?”

After a year, Purple had identified some hits selective for PCSK9, but a conversation with researchers at the Genentech Inc. unit of Roche led to the realization that the virtual company would need to run a second experiment.

“We learned from that interaction with Genentech that they had also run a PCSK9 screening program the same way we had,” Grainger said. “They discovered that their hits, while preventing PCSK9 from cleaving an external substrate, did not prevent PCSK9 from cleaving itself.”

Purple learned that in vivo, PCSK9 is auto-activated by cleaving itself — meaning the only important interaction to inhibit is PCSK9 auto- activation, not interactions with external substrates.

Purple’s second experiment showed none of its small molecule hits that inhibited PCSK9 interaction with an external substrate also inhibited auto-activation.

“Therefore we were able to kill a project which had spent at that stage only about £300,000 over a year, only to discover at the critical moment that it didn’t have the profile that we wanted,” Grainger said. “We were able to terminate that without having created any infrastructure, without having spent a painful amount of money prosecuting the project.”

That story illustrates a number of points about drug discovery. First off, congratulations to those involved for being able to definitively test a hypothesis; that's the engine at the heart of all scientific research. And as they say, it was good to be able to do that without having spent too much money and time, because both of those have a way of getting a bit out of control as complication after complication gets uncovered. Investors start getting jumpy when you keep coming back to them saying "Well, you know, it turns out that. . . ", but you know, it often turns out that way.

The next thing this story shows is that when you see an obvious gap in the landscape that there may well be a good reason for it. PCSK9 antibodies are widely thought to be potential blockbusters; a huge battle is shaping up in that area. So why no small molecules, eh? That's the question that launched Purple, it seems, and it's a valid one. But it turns out to have a valid answer, one that others in the field had already discovered. I suspect that the people behind this effort were, at the same time they were characterizing their lead molecules, also beating all the bushes for the sort of information that they obtained from Genentech. Somebody must have tried small-molecule PCSK9 inhibitors, you'd think, so what happened? Were those projects abandoned for good reasons, or was there still some opportunity there that a new company could claim for itself?

There may well be more to this story, though, than the Index Ventures people are saying. Update: there is - see the end of this post. The autocatalytic cleavage of PCSK9 was already well-known - pretty much everything in the that protease family works that way. (The difference is that with PCSK9, the prodomain part of the protein stays on longer - details of its cleavage were worked out in 2006). And in this 2008 paper from Journal of Lipid Research, we find this:

Several approaches for inhibiting PCSK9 function are theoretically feasible. Because autocatalytic cleavage is required for the maturation of PCSK9, a small-molecule inhibitor of autocatalysis might be useful, provided that it was specific for PCSK9 processing and did not lead to a toxic accumulation of misfolded PCSK9. Small molecules that block the PCSK9-LDL receptor interactions would likely be efficacious, although designing inhibitors of protein-protein interactions is a tall order. Antisense approaches pioneered by Isis Pharmaceuticals (Carlsbad, CA) are well suited for liver targets, and studies in mice suggest that this approach is efficacious for PCSK9. Finally, there is considerable interest in developing antibody therapeutics to inhibit PCSK9-LDL receptor interactions.

Even more to the point is the paper that that JLR piece is commenting on. That one demonstrates, through studies of mutated PCSK9 proteins, that its catalytic activity does not seem to be necessary at all for its effects on LDL receptors (a result that had already been suggested in cell assays). Taken together, you'd come away with the strong impression that inhibiting PCSK9's catalytic activity, other than stopping it from turning itself into its active form, had a low probability of doing anything to cholesterol levels. And you'd come away with that impression in 2008, at the latest.

So Purple's idea was a longer shot than it appeared on the surface, not that the real information was exactly buried deep in the literature. They shouldn't have needed someone at Genentech to tell them that PCSK9's autocatalysis was the real target - I've never worked in the area at all, and I found this out in fifteen minutes on PubMed while riding in to work. They must have had more reason to think that an assay for PCSK9's exogenous activity would be worth running - either that, or this story has gotten garbled along the way.

But this example aside, I applaud the idea of making these early-stage calls public. And I agree with the Index Ventures folks that this should actually help academics and others unused to drug discovery to see what needs to be done to actually launch an idea out into the world. I look forward to seeing the web site - and perhaps to hearing a bit more about what really happened at Purple.

Update: David Grainger of Index Ventures has more in the comments, and says that there is indeed more to the story. He points out that mutations of PCSK9 were found that inhibited its autocatalytic activity (such as this one), and that work had appeared that suggested that molecules that inhibited only the autocatalytic activity could be useful. This is what Purple was seeking - the BioCentury piece makes things sound a bit different (see above), but the problem seems to have been that molecules that inhibited PCSK9's activity against other substrates turned out not to inhibit its activity against itself. If I'm interpreting this right, then, Genentech's contribution was to point out that the autocatalytic activity couldn't be modeled by looking at another substrate.

Comments (5) + TrackBacks (0) | Category: Business and Markets | Cardiovascular Disease | Drug Assays

September 4, 2014

Are Your Compounds Ugly? Do You Know?

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Posted by Derek

A reader sends along this paper, on some small molecules targeting the C2 domain of coagulation factor VIII. It illustrates some points that have come up around here over the years, that's for sure. The target is not a particularly easy one: a hit would have to block the interaction of that protein domain with a membrane surface. There is something of a binding pocket down in that region, though, and there were some hits reported from a screen back in 2004. Overall, it looks like a lot of targets that show up, especially these days - you're trying to affect protein conformation by going after a not-necessarily-made-for-small-molecules cavity. Possible, but not something that's going to light up a screening deck, either.

And many of the things that do show up are going to be false positives of one sort or another. That's always the tricky part of doing low-hit-rate screening. The odds are excellent that any given "hit" will turn out not to be real, since the odds are against having any hits at all. This is especially a red flag when you screen something like this and you get a surprisingly decent hit rate. You should suspect fluorescence interference, aggregation, impurities, any of the other myriad ways that things can be troublesome rather than assume that gosh, this target is easier than we thought.

It's often a chemist who's in charge of dumping these buckets of cold water (if you have the help of the people who set up the assay, so much the better). Traditionally, it's one of the biology project champions who gets enthusiastic about the great list of compounds, but if you have someone who's been burned by false positives a few times, then so much the better, too. It's not fun to knock down all these "hits" and "leads", but someone's got to do it, otherwise everyone's time will be wasted to an even more painful extent.

And you should be especially worried when your screen turns up compounds like some of the ones in this paper. Yep, it's our old friends the rhodanines, everybody's cheap date of the screening deck. These compounds have come up around here many times, because they keep on showing up in the flippin' literature. In this case, the authors did some virtual screening over the ChemBridge collection and then moved on to assays against the protein itself, eventually finding a number of active compounds in the micromolar range. The compounds look a lot like the ones from 2004, since those were used as the template for screening, and that was a pretty ugly rhodanine-infested set, too.

Indeed most of the compounds they found are pretty unattractive - the aforementioned rhodanines, lots of nitroaromatics, some other heterocycles that also hit more often than one would like. I would feel better about these sorts of papers if the authors acknowledged somewhere that some of their structures are frequent hitters and might be problematic, but you don't often see that: a hit is a hit, and everything's equally valid, apparently. I would also feel better if there were something in the experimental section about how all the compounds were assayed by LC/MS and NMR, but you don't often see that, either, and I don't see it here. Implicitly trusting the label is not a good policy. Even if the particular compounds are the right ones in this case, not checking them shows a lack of experience (and perhaps too trusting a nature where organic chemistry is concerned).

But let's cross our fingers and assume that these are indeed the right compounds. What does it mean when your screening provides you with a bunch of structures like this? The first thing you can say is that your target is indeed a low-probability one for small molecules to bind to - if most everything you get is a promiscuous-looking ugly, then the suspicion is that only the most obliging compounds in a typical screening collection will bother looking at your binding site at all. And that means that if you want something better, you're really going to have to dig for it (and dig through a mound of false positives and still more frequent hitters to find it).

Why would you want to do that? Aren't these tool compounds, useful to find out more about the biology and behavior of the target? Well, that's the problem. If your compounds are rhodanines, or from other such badly-behaved classes, then they are almost completely unsuitable as tool compounds. You especially don't want to trust anything they're telling you in a cellular (or worse, whole-animal) assay, because there is just no telling what else they're binding to. Any readout from such an assay has to be viewed with great suspicion, and what kind of a tool is that?

Well then, aren't these starting points for further optimization? It's tempting to think so, and you can give it a try. But likely as not, the objectionable features are the ones that you can't get rid of very easily. If you could ditch those without paying too much of a penalty, you would have presumably found more appealing molecules in your original screen and skipped this stage altogether. You might be better off running a different sort of screen and trying for something outside of these classes, rather than trying to synthesize a silk purse out of said sow's ear. If you do start from such a structure, prepare for a lot of work.

As mentioned, the problem with a lot of papers that advance such structures is that they don't seem to be aware of these issues at all. If they are, they certainly don't being them up (which is arguably even worse). Then someone else comes along, who hasn't had a chance to learn any of this yet, either, and reads the paper without coming out any smarter. They may, in fact, have been made slightly less competent by reading it, because now they think that there are these good hits for Target Z, for one thing, and that the structures shown in the paper must be OK, because here they are in this paper, with no mention of any potential problems.

The problem is, there are a lot of interesting targets out there that tend to yield just these sorts of hits. My own opinion is that you can then say that yes, this target can (possibly) bind a small molecule, if those hits are in fact real, but just barely. If you don't even pick up any frequent hitters, you're in an even tougher bind, but if all you pick up are frequent hitters, it doesn't mean that things are that much easier.

Comments (21) + TrackBacks (0) | Category: Academia (vs. Industry) | Drug Assays | The Scientific Literature

September 3, 2014

A Question: Monoclonal Antibodies in the Clinic

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Posted by Derek

A reader sends along this query, and since I've never worked around monoclonal antibodies, I thought I'd ask the crowd: how much of a read on safety do you get with a mAb in Phase I? How much Phase I work would one feel necessary to feel safe going on to Phase II, from a tox/safety standpoint? Any thoughts are welcome. I suspect the answer is greatly going to depend on what said antibody is being raised to target.

Comments (16) + TrackBacks (0) | Category: Drug Development | Toxicology