About this Author
College chemistry, 1983
The 2002 Model
After 10 years of blogging. . .
Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases.
To contact Derek email him directly: firstname.lastname@example.org
In the Pipeline:
Don't miss Derek Lowe's excellent commentary on drug discovery and the pharma industry in general at In the Pipeline
May 6, 2015
Via FierceBiotech, here's an odd story about a small company you've probably never hears of, Symbiomix. They were launched just a couple of years ago, and are now heading into Phase III with an antibiotic. How, you ask, is that remotely possible?
Well, it's an antibiotic (secnidazole, a nitroimidazole) that's been sold in other countries for so many years that it's gone generic, but was never taken to the FDA over here. So that does speed things up. The company says that the compound has a real advantage in treating bacterial vaginosis (single-dose versus longer course of treatment), and plans to market it accordingly. What insurance companies will think about this as an advantage worth paying for it yet to be seen.
This looks like a one-shot regulatory arbitrage play. For some reason, this compound was never marketed here, so even though it's an older generic drug overseas, it gets to be turned into a New Drug here, with New Pricing. It's safe to say that no one is going to be holding their breath waiting to see if Symbiomix's Phase III trial goes as expected - of course it's going to go as expected. Everyone else has already done all that work. Symbiomix just gets to put together as much of a package as they need for the FDA, and then they can go try to make money with it.
It'll be worth watching to see if they do. I dislike regulatory arbitrage, as many posts around here have made clear. That's partly because, as someone who's spent all his time in new drug research, it feels to me like cheating, like pulling a fast one. Hah-hah, someone forgot to cross their fingers and stand on their right leg back in 1991, which means that I get to price my drug today as if I'd done the work of discovering it myself! Suckers! But this isn't quite as airtight a case as the odious ones of companies who pick some obscure one-supplier drug and ratchet the price up on it. There are alternatives to secnidazole out there - specifically metronidazole, one less methyl group at the cost of faster clearance and a few more pills. Symbiomix will be devoting as much time to figuring out their price point as they will to their clinical trial.
+ TrackBacks (0) | Category: Business and Markets | Infectious Diseases | Regulatory Affairs
May 5, 2015
Here you are: a public call for the head of GlaxoSmithKline's CEO, Andrew Witty:
Witty, who’s led Britain’s largest drugmaker since 2008, is facing criticism for Glaxo’s lagging share performance and a depleted pipeline of promising medicines. A bribery scandal in China that led to a $489 million fine last year and sluggish U.S. sales also eroded support.
“Mr. Witty is running out of time,” said Stephen Bailey, a fund manager at Liontrust Asset Management Plc in London, which holds Glaxo shares. “He’s either got to deliver in the next 12 months or step aside.”
It has been rough over there recently, to say the least. Here's one analyst's take on what they should do:
Hampton should reinvest in research at Glaxo, which is failing to produce drugs capable of boosting earnings, said Laura Foll, a fund manager at Henderson Global Investors Ltd. in London, which owns about 7.6 million shares in Glaxo.
Profits are still tied to the aging asthma drug, Advair, while demand for two new respiratory medicines, Breo and Anoro, remains sluggish. The company is considering a spinoff of its HIV medicines, although it has few compounds capable of replacing them. Foll recommends cutting the dividend to fund research, a move some investors might resist.
Now, I like the sound of that very much. But I'll be surprised if anything like that happens. After all, the company says itself that "We are committed to using free cash flow to support increasing dividends, share repurchases or, where returns are more attractive, bolt-on acquisitions." Do you see anything in there about using any of the free cash flow to do more research of their own? A cynical investor might say that GSK got itself into the fix it's in now by all that R&D stuff, so why would you want them to do it even harder? But more seriously, Merck also tried to tell investors to stop pestering them while they're discovering drugs, and that didn't seem to last for long, either.
My guess is that if GSK were to pop up with an announcement that they're cutting the dividend and dialing back the share buybacks in order to do more R&D, the stock would get hammered, and a lot of high-level people would end up losing their jobs for having made such unpopular decisions. It's a shame.
+ TrackBacks (0) | Category: Business and Markets
Wavefunction has a good look at Peter Thiel's Zero to One. As he puts it, "Thiel has said some odd things about chemistry and biotech before, so I was bracing myself for encountering some naiveté in his book." I don't blame him; I'd be the same way. But it wasn't quite as bad as he feared.
Nevertheless. . .there is a grain of truth in Thiel's diagnosis of many biotech and pharma companies. For some reason the pharmaceutical industry has lost the kind of frontier spirit that once infused it and which is now largely the province of swashbuckling Silicon Valley inhabitants. Whatever the hurdles and naiveté intrinsic to this spirit, it doesn't seem unreasonable to imagine that the industry could benefit from a bit more can-do, put-all-your-chips-on-the-table, entrepreneurial kind of spirit.
Still, you'll need to be ready for the phrase "high-salaried, unaligned lab drones" - just warning you. Another part of the blog post mentions a good reason for the more cautious approach that you see in biopharma as opposed to software, though: higher chances of failure via factors outside of your control. That gets back to the humans-didn't-make-this argument that I make in this situations - you really do have a better chance of bulling your way through in an IT startup by sheer skill and hard work. Whereas in drug discovery, skill and hard work are necessary, but nowhere near sufficient. We get our heads handed to us more often, and for reasons that couldn't always be anticipated by a reasonable person.
That's why the avoidable errors are so annoying in this business. Our failure rates are high enough already without own goals!
+ TrackBacks (0) | Category: Who Discovers and Why
Biocentury has a roundup of reactions to the recent human CRISPR paper:
There's no dispute that because the technology is in its infancy, much more work needs to be done to establish its safety. Stakeholders also agree that no experiments should be done, at least for now, in clinical programs that would involve modifying germline DNA and creating gene-edited embryos.
However one camp argues that research to understand the technology better and establish its safety in human cells should be permitted under appropriate regulatory controls. That means gene editing would be performed on human germline cells, but that any products would be discarded. Advocates for that position believe it's worth considering whether there are therapeutic situations where using gene editing might be beneficial.
The other school of thought is that there will never be a justifiable use related to human germline cells, and that no experiments should be done for either research or clinical applications. The argument is not just that it's a slippery slope from establishing safety and methods for well-meant therapeutic uses to providing a roadmap for eugenics.
Over the whole discussion, though, seems to be an air of "Well, someone's going to be doing it; it's just a matter of when". That's how I see it, and that makes the job how to have it happen in the least crazy way possible.
+ TrackBacks (0) | Category: Biological News
May 4, 2015
Ed Silverman at Pharmalot has a piece on a perennial source of confusion for anyone outside the drug industry (and too many inside it): the difference between Merck and Merck. One of them gets called "Merck-Darmstadt" or just "German Merck" by some people - I've never heard "Merck KGaA" used in spoken English. The other, when needed, is differentiated by saying something like "You know, Rahway".
There's history behind this, of course, dating back to World War I and before. Back when there was a Schering-Plough, and back when there was a Schering in Berlin, the same sort of confusion piled up around them, but now we're down to just the Merck case. "German Merck's" CEO, Karl-Ludwig Kley, is apparently wanting the company's name to be better known, and better differentiated from "New Jersey Merck", which could prove tricky.
So if anyone - former employees, especially - would like to suggest names for either company that might be more distinctive, memorable, or appropriate, please feel free to do so in the comments. Just don't expect to see either company take any action!
+ TrackBacks (0) | Category: Drug Industry History
in 2013 I mentioned the efforts by the Reproducibility Initiative to redo studies in the field of experimental psychology. That's a timely idea, since there have been many questions recently about the rigor of some of its results - for a fresh example, see here.
Now the results are in for the first 100 studies (here's an article at Nature News). This effort is being written up as a paper, and will probably change around a bit during that process, but the general points seem to be pretty clear. It depends on how you look at them, though, and what your priors were.
The majority of studies could not be reproduced. That's one way to interpret things. Based on the preselected criteria, the results of 61 of the 100 papers examined did not repeat. But 24 of those produced results, which while not on the mark, were "broadly similar" to what was originally reported, and here begins the arguing. How "broadly" do we mean? And is that enough? According to the Nature News piece, a number of psychology researchers have been taken aback by these figures, so the answer to the last question might well be "No, not really". Between one-third and two-thirds of the recent experimental psychology literature does not hold up to replication, and no one is very happy with either end of that range.
The very next questions that readers around here will have, then, is what would happen if we tried that out in our own fields. The famous "Amgen paper" on the irreproducibility of the oncology literature comes to mind. There have been arguments over that paper's methods and its interpretation, but we're eventually going to get a more in-depth look at things. As that last link mentions, the Reproducibility Initiative is also taking a look at the "fifty most impactful" recent papers in cancer biology. So we can have that discussion with some solid data when the time comes.
How about organic chemistry? I think that the rate of reproducibility would be solidly over fifty per cent, but beyond that, I'm not prepared to say. Depends on a lot on the journal you're getting the papers from! But if you pick the same sort of level that the two Reproducibility Initiative projects have for those fields - say, a list of papers from JACS and the like, I would like to think that we would come out better than experimental psychology, and probably better than cancer biology. This isn't some moral superiority at work - we just have fewer variables in chemistry. That's not to say that there aren't some fiendish complications hidden inside our work; there certainly can be. But overall, we have a lot better time of it proving that our reagents and products are what we think they are compared to those other areas.
But how would it go, reproducing 100 papers from Organic Letters? From Tetrahedron Letters? From Synthetic Communications? Not as well, I feel sure. I think that comparable journals in psychology or biology would fare even worse, but that thought is of limited comfort.
+ TrackBacks (0) | Category: The Scientific Literature
May 1, 2015
Here's a paper on recent clinical trials in Nature Reviews Drug Discovery that reports some changes. It's just concentrating on the trials that began in the 2005-2009 period, and in case you're wondering, over 14,000 trials started during that period. There was a steady increase in the percentage of those that were sponsored by industry (from just under 60% to over 70%). The two biggest classes, by therapeutic area, were oncology and CNS, but (to my surprise) the former decreased by small but steady amounts over this period. On the other hand, anti-infectives moved up each year, overtaking the cardiovascular category, some of which was no doubt due to all the work on Hep C. Trials in metabolic disease also increase a bit each year.
Clinical trial lengths (all three phases) also decreased during this time, for reasons that are not completely clear. Phase I trials saw the biggest decrease in length, but the change wasn't as steady as in those other factors mentioned above - 2008 and 2009 were about the same, and the authors speculate that whatever it was making trials run faster might have reached its limits by then. (The authors did all sorts of fancy regression analysis, but couldn't assign the trial length changes to any particular factors - therapeutic area, type of sponsoring organization, phase of trial, etc.) All of these had some influence, but none of them were enough of an explanation by themselves.
If that decrease is real (and it seems to be) it'll be worth knowing if it's continued. I'll bet, though, that this hasn't, for just those reaching-the-limits reasons mentioned above. There's only so much you can do to speed things up. It's also worth thinking about the effect on costs. In general, a shorter clinical trial should cost you less money, but setting one up to run that way might be more expensive. So I'm not sure how those two balance out!
+ TrackBacks (0) | Category: Clinical Trials | Drug Industry History
In the long-running saga of getting a stapled peptide to work as a drug, Aileron Therapeutics was last heard from raising money for their p53 candidate. Now comes word that the company is basically going all-in with that one, raising yet more cash and gearing up for some definitive human trials.
I wish them luck. p53 is one of those great targets that no one's ever been able to make anything out of, so a completely new approach (like a stapled peptide) is a reasonable thing to try. And the whole stabilized-helical-structure approach that the stapled compounds represent needs to be given a real-world test, too. From one perspective, you might say that such a different technique should be tried out on a well-validated target, so you at least cut the risk down that way. But that's not how things go. Exotic techniques get used on the problems that other methods have failed on. But on the other hand, p53 is (biologically) about as well-validated as you can get, total lack of clinical success aside.
This will be exciting to watch, although I can't help but wonder if it's a death-or-glory move for Aileron. They've raised a fair amount of money over the last few years, and you can't go back and fill that bucket too many times. Good luck to them!
+ TrackBacks (0) | Category: Cancer | Chemical Biology | Clinical Trials
April 30, 2015
Every company that I've ever worked for has said that they want suggestions from the employees - some of them have been serious, and others were saying it because that's the sort of thing you're supposed to say. There are, naturally, all sorts of levels to consider. Some suggestions are small and easily implemented (or not so close to the company's main purpose), while others are going to involve bigger decisions. Over at Chemistry World, Philip Broadwith has a look at how this works in the chemical industry:
Cultivating an environment in which employees feel sufficiently invested in the company’s success that they not only actively look for improvement opportunities, but also feel that such suggestions will be taken seriously, is easy to say but hard to implement. Like any behavioural change, it means overcoming psychological inertia. It’s perhaps easier to engender that motivation in small companies, whose very survival depends strongly on individual performance, than in a tucked away corner of a huge corporation.
And yet it is evidently possible. Chemicals giant BASF recently released details of its ‘idea management’ programme in 2014. The company implemented more than 23,000 employee proposals in that year alone, which saved €53 million (£38 million). BASF has been in the idea management game for 65 years, thus the culture is firmly established within the workforce. Even so, the company makes significant efforts to encourage submissions, running regular campaigns around topics like energy savings and occupational safety, says Lothar Franz, who heads up the programme.
What he doesn't have are many examples from drug research, so I thought I'd ask the question: have you worked for companies that made an honest effort in this direction? Was there a set process, or did things work more informally? At the other end of the scale, was this something that got lip service (but no real action), or did the company not even bother with this sort of thing at all?
+ TrackBacks (0) | Category: Life in the Drug Labs
As someone who does small-molecule drug discovery, I tend to value. . .small-molecule drug discovery. But today provides a good opportunity to remember that there are huge advances in public health that have nothing to do with such drugs. Rubella ("German measles") has been declared eliminated from the Americas, with no indigenous cases now for years. And this is all due to the vaccine against the virus, just like the more famous campaigns against polio and smallpox.
The amount of human suffering that has been prevented by vaccinations is beyond measuring. That's why it's so painful to see anti-vaccination activists ignore or misrepresent that fact. Somewhere, there may be such an activist who would be willing to start out by saying "OK, vaccines have prevented untold millions of agonizing deaths, permanent disablements, birth defects, and disfigurements. Diseases that we used to fear have disappeared from the world because of vaccines, but here's why they're bad. . ." Good luck finding one, though.
The anti-vaccination stuff I come across brushes lightly across these facts, just barely glancing at the idea that once upon a time, people used to get smallpox, children used to be born scarred and blinded, or end up condemned to crutches or breathing machines for the rest of their lives. These diseases weren't so bad, you hear. Exaggerated. Already disappearing, hardly noticeable, and here comes the evil medical establishment using these wisps, these figments as a pretext to pump our poor children full of poison, so who wouldn't fight back? Right?
Sure, the safety profile of any given vaccine can (and should) be examined closely. But if you're anti-vaccination in general, realize that there are millions, hundreds of millions around you, and you're not seeing them: the ones who didn't die, who weren't crippled, who didn't watch their children suffer. I salute the people who've made that happen, and the ones who are still working on it today (often at great danger to themselves). Vaccination has been one of the great triumphs of the human race. It and the provision of clean water supplies (another great public health advance that no one notices any more) have made more misery vanish than any of us could ever imagine.
+ TrackBacks (0) | Category: Infectious Diseases
April 29, 2015
If you want to see the real underbelly of pharmaceutical sales and promotion, here it is. Insys Therapeutics makes a sublingual spray formulation of fentanyl called Subsys, and has been doing very well with it. But that seems to be, to a good extent, the product of, well, let's just call them extremely aggressive sales tactics. There are repeated accusations of off-label promotions and of widespread kickbacks to physicians, and various investigations are underway.
But here's a look at what makes Insys run:
Let’s start with sales. There’s no way around it: Insys’s sales force is very different from its competitors in the pharmaceutical industry. One reason is that a pharmaceutical sales background or even college science coursework isn’t required. Another is that if you appear to be driven and aggressive, the company will look past things that your local Starbucks might not. Scrolling through the LinkedIn profiles of Insys sales reps lends some credence to one of the assertions from an amended class action lawsuit filed against the company in October and which settled within the past week without disclosing terms: per three confidential witnesses, "most of Insys’s sales representatives were extremely attractive women." (To be fair, Merck and other leading pharmaceutical companies have long drawn attention for constructing sales forces with a large percentage of attractive women.)
Take the sales head of the New York region, Jeff Pearlman. Before becoming what his peers say is a highly productive salesmen of Class II opioids, he appears to have installed aquariums. Prior to that, he ran a ticket sales agency called Sitting Pretty Seating Services which, in 2004, attracted the ire of the New Jersey Division of Consumer Affairs. Shortly after, records indicate that the company's registration was revoked for not filing an annual report for two consecutive years. . .
. . .Before she joined the company in August 2012, (recently departed Western sales head Sunrise Lee) ran an adult-entertainment business of a sort called Sensuous Entertainment. Prior to that, she was a dancer at Rachel’s, a West Palm Beach strip club . . .It’s not clear what she did before adult entertainment.
I hope that this sort of thing stands out. The opioid market is a weird one, because there's a lot of legitimate unmet need for pain medication, and the only things that work as well as opioid ligands are. . .other opioid ligands. And that means that there's a lot of less legitimate prescribing going on, what with the risk of addiction and the street value of unused prescriptions. (People have tried for decades to come up with really effective pain medications that are non-addicting, with brutal lack of success). The whole area is a regulatory tangle because of this (which makes the financial results that Insys has achieved look even more strange).
So it's a strange part of the business. But what this article details only differs in degree, not in kind, from the excesses of sales forces in other parts of the industry. And every time news like this breaks out, the reputation of, and the prospects for, the drug industry as a whole decrease.
+ TrackBacks (0) | Category: The Dark Side
Yesterday's post on TC-2153 and its assay activity brought a note from Paul Lombroso at Yale, whose group is doing this work. With his permission, here's an update (slightly edited):
We have now used the drug orally in nonhuman primates with cognitive deficits: it had significant results. . .we have also given it to both schizophrenic and fragile x syndrome mouse models, with the same reversal of behavioral / cognitive deficits.
TC-2153 has proven very hard to work with in PK/ADMET studies, but hopefully this will work soon. There is no change in p-tau or beta amyloid levels [one question in the comments]: an interesting finding as it suggests that inhibiting STEP is sufficient.
GSK has selected STEP as a DPAC project with me: we will be testing lead compounds using similar in vitro and in vivo models we have in the lab. They were not interested in TC-2153, nor have I been able to get NIH funding for this compound (the structure makes medicinal chemists nauseous).
So we continue to use it in the lab as a useful tool, while searching for new STEP inhibitors.
Sounds like an interesting target, and a good field to be working in. My thoughts are that the compound itself should be run through as many assay panels as possible (commercial and in-house) to see just what other effects it may be having. If it's going to be the basis for a lot of work on STEP, it needs to be characterized as well as possible (especially with that structure and mode of action). And as mentioned yesterday, other classes of Cys-targeting covalent inhibitors might well be very useful. I'll keep an eye out for updates in this area.
+ TrackBacks (0) | Category: Drug Assays | The Central Nervous System
My Twitter feed alerted me to this press release, surely one of the sleaziest I've seen in a long time. It's not that there's no actual data in it, although that's bad enough. Nor is it that it talks about "promising results", even though the trial it touts is still underway, even though that's pretty bad, too.
No, what puts this one over the top is that it's not even from the company doing the trial (Verastem). Instead, this one is brought to you by "the mesothelioma law firm of X and Y" (damned if I'm going to give them any advertising myself). They self-identify several times with that exact phrase. And they wind up by reminding you that if you've ever seen, heard, or thought about asbestos fibers, to be sure to give them a call. Good grief.
+ TrackBacks (0) | Category: Clinical Trials | The Dark Side
April 28, 2015
A longtime reader sent in an interesting query, which I reproduce below:
We read a lot about antibiotic usage in livestock and poultry (most recently in C&E News) and how it contributes to the problem of antibiotic drug resistance in humans. In thinking about it, however, I can’t recall any case where a person has been diagnosed with a highly resistant infection that was shown to have been transmitted from farm animals. Furthermore, I don’t recall hearing of any human antibiotic that has been rendered ineffective because its use in animals (or use of a related drug) has led to drug resistance. My questions are:
· Are there any examples where a human has been diagnosed with a highly resistant infection which was shown to have been transmitted from farm animals? If so, what is the microorganism? What is the reference for the case study?
· Are there any antibiotics that are no longer effective because use of the antibiotic or a related antibiotic in animals has led to drug resistance. If so, what is the antibiotic and the drug resistant microorganism? Where is this published?
I thought it was surprising that such human cases of animal-derived resistance weren't prominent in the literature, but they don't seem to be. There have been attempts to find such crossovers, without success. I continue to think that minimizing the use of antibiotics is a good idea, as far as is practical, but I hadn't realized that there was such a shortage of cases of human disease linked to resistance that's developed in poultry and livestock. Anyone have any better examples?
+ TrackBacks (0) | Category: Infectious Diseases
Does anyone know of any phosphatase inhibitors that aren't hideous? I ask this because someone sent along a question about this paper, from last August, that I'd missed at the time (press release here, but the paper's open-access as well). Here's a commentary in the journal itself. It's work from Yale on an enzyme called STtriatal-Enriched tyrosine Phosphatase (STEP), a brain-specific enzyme which has been thought to be involved in memory and other CNS processes. The group was looking for an inhibitor, and screening for phosphatase inhibitors has been, historically, No Fun Whatsoever.
I'd say that this is still the case, given that the best molecule that turned up was TC-2153, shown at left. I've seen several molecules in this polysulfide class over the years, but I've never seen one that went very far. It's not necessarily an impossible molecule, but it's going to need some special care in development. You'd want to look out for oxidation (both on storage and metabolic), exchange reactions with other thiols, nucleophilic ring opening, and so on. The compound appears to work, in fact, by reacting with the thiol on a catalytic Cys residue in the enzyme's active site.
This structure was arrived at by an unusual route: during the initial screen, several compounds were apparent hits. Resynthesis of them, though, gave no activity (a common experience when working with difficult targets!) Checking the original samples turned up an impurity that actually showed potent activity. This was fortunate - you often go back to these things looking for such a clue, but finding something identifiable isn't easy. Often it turns out to be some sort of polar polymeric gunk (like this), colorful stuff that sticks to silica on a quick filtration, but in this case, it was a yellow crystalline substance that eluted late. X-ray crystallography of it showed it to be elemental sulfur, S8, which must have been an interesting surprise. Its IC50 was 17 nM! Potency aside, that's really going to have trouble as a CNS-targeted drug, as the team well realized, so they deliberately had a look at the benzopentathiepins as surrogates. (As a side note, the authors point out that they didn't include DTT as a reducing agent in their assay conditions - had it been there, they very likely would never have picked up on this compound class at all). It's also worth noting that when you do find the Amazing Active Impurity, the chances are increased that it's working through a covalent mechanism.
TC-1253 itself showed good activity in cells and in mice. But it also shows evidence of off-target effects at higher doses, as well it might, and shows some activity against related protein tyrosine phosphatases in vitro. (It looks better in cells and in the mice than it does against the straight enzymes, which might be the same sort of effect that the Cravatt group saw with covalent inhibitors as well, moving from proteins to cells).
Given these results, I'd suggest going full-on covalent for the discovery of further STEP inhibitors. Since that catalytic Cys is important, and indeed seems to be more nucleophilic than usual, why not go after it with a big array of acrylates, weak leaving groups, and so on? The tolerance for such mechanisms has increased over the years in med-chem. There are a lot of interesting Cys groups out there, and sufficiently diverse compounds should be able to target them selectively. It's tricky work - the line between a lead compound and an assay-interfering compound is not a clean one - but what other success has anyone had against phosphatases, anyway?
Update: more on this compound here.
+ TrackBacks (0) | Category: Alzheimer's Disease | Drug Assays | The Central Nervous System
April 27, 2015
Here's a report from a team at the University of Toronto of a new way to get protein structures - always a welcome development. (There a summary at Technology Review here). It's another application of electron cryomicroscopy, which was the subject of a blog post here about a year and half back.
As with many cryo-EM applications, this one is done on a thin film. What you get when you hit individual molecules/particles in this film with a beam of electrons is a series of pictures formed by the electron density of the target - but you don't know how all those target molecules are oriented. So if you want to assemble the three-dimensional structure that gave you all these snapshots, you're faced with a massive computational problem, one that's full of unproductive local minima ready to lead you astray, and one that requires some pretty big assumptions just to get started.
What this new paper offers is what looks like a far more efficient way to get a handle on that problem. They have a new way to increase the signal/noise of the data, which is welcome, because you tend to have to use low-intensity electron beams for fear of demolishing your samples. But the biggest innovation seems to be the realization that protein molecules tend, when frozen into thin films, to lie on along their long axis. Getting rid of the other possible looking-down-the-long-axis poses speeds things up considerably, and avoids some potholes as well. Another key advantage to their method is that it doesn't require you (by luck or talent) to have picked a good initialization.
My own take on this is that it's going to be most useful when combined with some modeling (and whatever X-ray data might exist, of course). The hope would be that you can fit the protein sequence to the three-dimensional shape that you obtain from the cryo-EM technique. The shapes that they're pulling out look like they'll be pretty useful for this purpose, and I look forward to seeing how general the technique turns out to be.
+ TrackBacks (0) | Category: Analytical Chemistry
Readers might remember a small company called Catalyst Pharmaceuticals, who have had a business plan that goes something like this: take the known small molecule that's used for the rare disease Lambert-Eaton Myasthenic Syndrome LEMS, 3,4-diaminopyridine. Rebrand it as "Firdapse", and do the clinical work needed to get it officially recognized by the FDA (it's one of those therapies that's been grandfather in for many years). Oh, and charge a lot more than the current supplier, Jacobus Pharmaceuticals, who provide it for free. (It truly is a small market).
Well, that plan has been diverted somewhat. As mentioned in that 2013 post, Jacobus was planning a clinical trial of their own, and Catalyst was apparently taken by surprise when those results showed up last week in a poster presentation. Now no one's sure who will file with (or get approval from) the FDA first.
Jacobus Pharma decided to conduct a clinical trial of 3,4 Dap in LEMS and seek FDA approval as a way to stop Catalyst from profiting off LEMS patients with Firdapse, Laura Jacobus said in a 2013 interview. Laura runs the eponymously named drug company with her father David.
"Firdapse is not a new compound. It's the same drug we make. What Catalyst is doing is not the same as a company profiting from a new invention. What Catalyst is doing is making money off LEMS patients. They don't want to help LEMS patients, they just want to make money. If I worked for Catalyst, I wouldn't be able to sleep at night," said Laura Jacobus.
She has a point there about new inventions. As mentioned in those posts I linked to in the first paragraph, and in several others here over the years, many of these cases are unintended consequences that the FDA unleashed when it asked for older drugs to be put through the regulatory system. But that doesn't always have to be the case. Companies can buy up older approved drugs and just ram a new price home, because why not? That's what's been going on with Thiola, and this new piece at Pharmalot details a number of other recent cases.
Valeant, for example, seems to have a very predictable strategy: the day that they get the rights to an old drug, its price at least doubles, and can go up fivefold or more, depending on what they think the market will put up with. You sometimes hear companies like Catalyst talking about how now that the old drug under study has been taken under their regulatory and manufacturing wing, that it'll be so much better quality, and be so much better for the patient community. Valeant doesn't bother with any of that crap:
On Feb. 10, Valeant Pharmaceuticals International Inc. bought the rights to a pair of life-saving heart drugs. The same day, their list prices rose by 525% and 212%.
Neither of the drugs, Nitropress or Isuprel, was improved as a result of costly investment in lab work and human testing, Valeant said. Nor was manufacture of the medicines shifted to an expensive new plant. The big change: the drugs’ ownership.
“Our duty is to our shareholders and to maximize the value” of the products that Valeant sells, said Laurie Little, a company spokeswoman. “Sometimes pricing comes into it, sometimes volume comes into it.”
Pricing power should come to those who have earned it, as far as I'm concerned. Do the work, conduct the research, take the risk, and you should be able to reap the rewards. Take over a smaller company that (from your standpoint) is just too dumb to realize that they could have put the squeeze on by cranking the price up by a factor of five? That doesn't deserve so much of a reward. What I'd like to see is an easier path for generic competition in such cases. Let someone come in and compete on price, because there's clearly room for it.
Whenever I write about these cases, there are always a couple of comments to the effect that hey, that's the free market, dude - that's what you like, isn't it? But drugs are not generally sold under a free market system. No market in which a single supplier can raise the price by 525% overnight for no reason other than "Because we can" can be all that free, or all that much of a market, if by "market" we mean "competition between various firms for a share of the customers". The market-exclusivity incentives provided by the FDA (through deliberate action or through regulatory barriers) are strong ones, but they should be handed out with care. As it stands, I think it's too much of a reward, in these cases, for too little work.
+ TrackBacks (0) | Category: Business and Markets | Drug Prices
April 24, 2015
As you'll have heard, the rumors that CRISPR/Cas9 experiments had been performed on human embryonic tissue have turned out to be true. The recent calls for a temporary moratorium on such work were said to have been prompted by word that such a paper was being reviewed, and indeed, the paper that has appeared was apparently reviewed and rejected by both Nature and Science.
And what's interesting is that this paper's results are going to actually strengthen the case for such a moratorium. The team from Sun Yat-Sen University in Guangzhou tried to edit the gene involved in beta-thalassemia in human zygotes, but things went awry in several ways:
We found that CRISPR/Cas9 could effectively cleave the endogenous β-globin gene (HBB). However, the efficiency of homologous recombination directed repair (HDR) of HBB was low and the edited embryos were mosaic. Off-target cleavage was also apparent in these 3PN zygotes as revealed by the T7E1 assay and whole-exome sequencing. Furthermore, the endogenous delta-globin gene (HBD), which is homologous to HBB, competed with exogenous donor oligos to act as the repair template, leading to untoward mutations. Our data also indicated that repair of the HBB locus in these embryos occurred preferentially through the non-crossover HDR pathway.
So in short, this process appears to be much harder to realize in human embryos than it is in other cell lines, or even in mouse embryos, and the era of human germ-line manipulation looks like it's going to have to wait a bit. But I would have to think that it's still on the way. Like almost every other big medical advance, though, it's going to be more complicated than it might have looked.
+ TrackBacks (0) | Category: Biological News
Lisa Jarvis of C&E News asked a question on Twitter that's worth some back-of-the-envelope calculation: what are the odds of a medicinal chemist discovering a drug during his or her career? And (I checked) she means "personally synthesizing the compound that makes it to market". My own hand-waving guesstimate of an upper bound starts with an assumption of around 10,000 people trying to do this, worldwide (which is surely on the high side - see below).
Now, if you start work at 25 (I'm counting master's degrees in there) and go to 65, you've got 40 years of career, but (1) not all of that, as time goes on, is going to be spent full-time cranking away in the lab, in most cases, and (2) God knows that there aren't nearly as many solid 40-year careers in this gig as there used to be. A more realistic count, and still on the high side, might be 25 years. Now, over that 25-year span, how many small molecule drugs are there for a medicinal chemist to score with? A generous count of 20 per year (see here, and note that in the last 20 years you'll need to subtract antibodies/biologics) would give 500 drugs discovered and sent to market during that time, so with the same 10,000 people working over that span, that would give you rough odds of 5%, one in twenty. That is surely an upper bound, by a very substantial amount.
That's because it's not the same cohort of people during that time, of course, so the odds are going to lengthen because of that. The real number of people will be smaller than 10,000, on the average, and the years of lab career will be shorter than 25. It's harder to assign solid numbers at this point, but my own impression is that the real odds are 1% or less. When I think back over my own career, the number of new small-molecule drugs that have come out of the shops I've worked in can be counted easily on my fingers, and I've worked around a lot of medicinal chemists during that span.
Now, this brings up another familiar subject, which comes up whenever I discuss the above topic with anyone outside the whole field of scientific research. "How can you stand that" is not an unusual question. If 99% of the patients a doctor saw were not helped by their medical care, that would be a discouraging way to make a living, for sure. But there are differences, important ones. For one thing, this is science, after all. Even when we find out that something doesn't work, we've found something. I'd rather make a drug that works, but many of the projects I've worked on have added to medical knowledge even when they didn't put a drug on the market. I can tell you, most definitely, that a selective m2 muscarinic antagonist is not going to help Alzheimer's much, nor will a D1 antagonist do much for schizophrenia. Similarly, an inhibitor of hormone-sensitive lipase is not an appropriate therapy for type II diabetes, and you will want to be very careful if you want to take a mixed PPAR ligand on for patients with metabolic syndrome, because they don't all do what you'd expect. And so on. A lot of people got to find out that last one, across several companies and in all sorts of interesting and unusual ways, but I have to say, in those other three examples, my colleagues and I were pretty much up at the front lines, and came up with some of the best compounds you could want (and some of the best ever seen for those targets). And they didn't work, for the usual reasons: failure to understand the disease well enough, failure when hit by toxicity through other mechanisms.
But the only way to find those things out was to make such compounds. So yeah, to invoke the cliché, I've pushed back human knowledge in those areas (and a number of others besides). The projects I'm working on right now are long odds, too, but I have reason to believe that my colleagues and I are again at the very edge of what's known in these areas, right up on the foaming front of the breaking wave. That's where I've always wanted to be. These are important problems, extremely relevant to human disease (as you'd imagine, since a drug company is willing to spend its money on them even though they're very hard indeed). Just getting the chance to work up at that level, to know that no one's ever put a foot down where the next step is going to go, is what does it for me.
Wavefunction has some good thoughts on this question here.
+ TrackBacks (0) | Category: Drug Development | Drug Industry History | Life in the Drug Labs | Who Discovers and Why
April 23, 2015
Ever hear of Genervon, and their ALS therapy, GM604? There's not too much to hear about, unless of course you're a desperate patient or relative, looking for something, anything that might help. Genervon is certainly trying to reach those people, with press releases that include phrases such as "dramatic" and "very robust". And they've been giving everyone the impression that this dramatic, robust therapy was already being evaluated by the FDA. But not so fast. As Pharmalot reports, the company is now acting as if it's never said anything of the kind:
. . .Genervon said in an email that it is “at the point of communicating with FDA about whether [the agency] would accept our formal application” for accelerated approval. In other words, the company has not yet submitted a New Drug Application, a step needed to officially set the FDA approval process in motion.
The company's acknowledgement that it has not filed an NDA appears to contradict earlier press releases and statements made by the firm's owners, Winston and Dorothy Ko -- or at least to have sown confusion about the actual status of GM604. In one February press release, for example, the company said that in a meeting with the FDA, "three times during the one-hour meeting we requested that the FDA grant GM604 accelerated approval."
The drug's effects had better have been dramatic: the trial that's causing all this controversy was twelve patients for twelve weeks. That's not a very long time to evaluate a disease like ALS, and you have to wonder just how impressive these numbers are with such a small sample size, and what the FDA is going to think about them. (There's a lot of room to wonder). Genervon isn't doing itself any favors, either, by its response to questions about all this, saying that "Some are crating [sic] an issue out of nothing hoping to discredit Genervon and causing delay to make treatment available to ALS sufferers".
Big red flag there. When you start accusing people of plotting against your company and trying to harm patients, you sound like a crank. Or a fraud. Or a fool, or maybe some of each of those - they're not mutually exclusive. I certainly hope that Genervon's owners are none of the above, and that GM604 will prove to be a useful therapy. But they should realize that they're not making a good case for that so far.
This sort of situation is the beginning of what I fear could develop from "right to try" laws, if they're not carefully written. I certainly understand people wanting access to experimental therapies, especially for a terrible condition like ALS, where there's basically nothing that anyone can do. But figuring out whether a new drug works is really a lot harder than it looks. For the most part, it takes more than twelve people, and it takes more than twelve weeks. We may decide that patients have the right to waste their money and to waste their time chasing such things, but letting them do that without also hurting the chances of finding something real, that's the hard part. A rare disease may wind up with not enough patients around to participate in controlled trials. A small company might end up spending too much of its resources providing its unproven therapy to people who want it now, proof or not. And worst of all, you might end up enabling unscrupulous operators to keep providing "drugs" at "cost" for as long as people are willing to pony up, and the heck with clinical trials.
These aren't the issues with Genervon. But this story shows, I think, how such things could happen. What the issues are with Genervon, though, are hard to say. The FDA has called on the company to release all its data, and the company says it's already sent everything they have (although for the purposes of applying for accelerated approval, not for an NDA package). Someone's confused. Or confusing. Or both - those aren't mutually exclusive, either.
+ TrackBacks (0) | Category: Clinical Trials | Regulatory Affairs | The Central Nervous System
April 22, 2015
I've written here a few times about the vibrational theory of olfaction (and Luca Turin's efforts to revive and prove it). This is an attempt to add a new mode to the existing shape/size/polarity ones known to affect the olfactory receptors - the idea is that some of them may actually sense molecular vibrational modes through electron transfer. When I last mentioned this, the theory seemed to have returned serve, with results on human subjects being able to distinguish deuterated forms of musk compounds. Now comes a very strongly worded response in PNAS from a multi-center team. (Here's a good summary in C&E News from Sarah Everts).
This group, led by Eric Block at Albany, has several points to make. They've cloned and expressed what is believed to be the human musk receptor, and find that it responds (in vitro, at any rate) no differently to the deuterated and nondeuterated forms of several prototype musks. This looks like careful work - preparing the deuterated compounds and making sure that they're clean enough for such studies is not easy (past reports, positive and negative, have been confounded by small levels of odorous impurities). And there really does seem to be no difference in receptor response.
The authors also have a lot of objections to the vibrational hypothesis in general, and they're not shy about stating them, saying that"While Brookes et al. bring the vibration theory to a more concrete theoretical level, none of the key assumptions has supporting experimental evidence." They go into a detailed list of problems with the idea, which they say have really not been addressed (the amounts of energy needed, the complications of quantum effects swamping the proposed couplings, the effects of dynamical fluctuations on them, and their sensitivity to bonding character in the odorant molecules. There are, they conclude, just too many complication that have to be dealt with, and for a theory that has little empirical support (given their own results), it's just not plausible.
I have to say (as I'm quoted saying in the C&E News piece) that this is the most thorough challenge to the vibrational hypothesis yet. Block et al. have paid Turin and co-workers the compliment of taking them seriously, and this is a serious response. I'll be quite interested in seeing the response to it, and I hope that it's an equally serious one. If there are problems with this new paper's approach (and there could be), then the only thing to do is challenge them head-on, with testable hypotheses and new data. If, on the other hand, the response is vague, ad hominem, or relies too much on special pleading, that's not a good sign.
For example, Turin is reported as expressing doubt that the cloned receptor in this study is the relevant human one. That's the sort of thing, then, that he should press: is it? Can it be shown that Block and co-workers did all the work on the wrong receptor? That would help Turin's case, but what would help it even more is if he (or someone) could show a deuterated-compound effect on any cloned olfactory receptor at all. I realize that in vitro isn't in vivo, but the number of variable that might help the vibrational theory in the latter situation are matched (probably more than matched) by the number of new explanations that become possible for it not to be true at all. You'd think, that if olfactory receptors really can respond in this fashion, that they'd be able to do it in an assay like this. If not, well, there's another strong case to be made, if that one is indeed makeable. Just saying "Well, there has to be such a factor" is not enough. So let's see how things play from here. . .
Update: more from Wavefunction.
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April 21, 2015
I'm traveling today, with no time to do a full blog post. So I'm going to toss out a couple of questions for everyone:
What diseases or therapeutic areas do you think have the best opportunities now for "traditional" small-molecule drug discovery? And which ones do you think have the worst or fewest? All factors are in play - number and quality of targets, suitability for small molecules to work, market size, etc.
+ TrackBacks (0) | Category: Drug Development | Drug Industry History
April 20, 2015
Via AndyBiotech on Twitter, here's a chart from the ongoing AACR meeting on what sorts of tumors are responding best to the PD-1 antibodies that are creating such excitement. You can look at this two ways - what parts of oncology practice are on their way to being transformed, and/or what parts still have a big need for small molecules (!) Here's more from Matthew Herper.
+ TrackBacks (0) | Category: Cancer | Clinical Trials
You'll have heard that a group of physicians has written a public letter to Columbia University asking why Dr. Oz is still on the faculty there. Here's the text, and it includes some heartwarming stuff:
. . .We are surprised and dismayed that Columbia University's College of Physicians and Surgeons would permit Dr. Mehmet Oz to occupy a faculty appointment, let alone a senior administrative position in the Department of Surgery. . .
. . .Dr. Oz has repeatedly shown disdain for science and for evidence-based medicine, as well as baseless and relentless opposition to the genetic engineering of food crops. Worst of all, he has manifested an egregious lack of integrity by promoting quack treatments and cures in the interest of personal financial gain.
Thus, Dr. Oz is guilty of either outrageous conflicts of interest or flawed judgements about what constitutes appropriate medical treatments, or both. . .
It goes on in that vein, and I have to say, I basically agree with every bit of it. I have a good amount of contempt for Oz himself, and that has only increased with time. Columbia, or parts of it, may well be fine with having such a famous, high-profile person associated with the school, but Dr. Oz's fame rests on such a shabby foundation. He spouts nonsense to people who don't know any better - is that such a thing to be proud of?
Columbia is taking an academic-freedom, freedom of speech approach to this request, and Oz himself has said that he'll respond on his show. And I'm sure that we're going to hear oh, so much about bringing in all points of view, and being inclusive, and having an open mind, and providing information to the public (and don't they have a right to that?), and much more in that style. There will probably also be a tone of martyrdom - they're out to get him! - and perhaps a few hints about various "interests" with "agendas" that are behind these baseless attacks.
But I would happily sign a statement requesting that Dr. Oz be shown the door - several doors, at speed - and my only agenda is that I think he peddles sensationalist crap for fame and money. Listening to Dr. Oz is all too often a way to end up less informed than when you started, and full of ideas that have no real basis in fact. Remember, this is the man who told a reporter for the New Yorker that "Cancer is our Angelina Jolie. . .we could sell that show every day". Spoken like a man of medical science!
I'm under no illusions that they're going to get rid of him, though. Hey, Columbia sailed right past that green coffee bean nonsense and the Congressional committee grilling. They're not going to worry about some doctors writing a letter. What would get their attention, though, is if some wealthy donors were to start making some noise. Is that going to happen.
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April 17, 2015
Well, just weeks after Merck halted a trial of their anti PD-1 antibody Keytruda (pembrolizumab) due to efficacy, Bristol-Myers Squibb has announced that a trial of their own PD-1 antibody, Opdivo (nivolumab) against non-squamous non-small-cell lung cancer has been halted for the same reason: it's working so well that it's unethical to continue. Nivolumab has already shown activity like this before in another lung cancer trial, so there's no doubt that the PD-1 excitement is justified. Oncology is really going through a big change, and we can hope that this is just the start.
+ TrackBacks (0) | Category: Cancer | Clinical Trials
The European Federation for Medicinal Chemistry has a competition open, for the best one-minute video explaining what medicinal chemistry is and why it's important. Here's the link - the prize is 500 euros, and fame/fortune/etc.
"Why Medicinal Chemistry" is a competition that invites medicinal chemists to make an original video highlighting what medicinal chemists do and why it is important. We want medicinal chemists from any level (eg. students to expert professionals) and affiliation (eg. academia and industry), as individuals or as groups of up to 4 medicinal chemists, to produce an original 1 minute video demonstrating the importance of Medicinal Chemistry to society. The video should be targeted at a non-specialist audience, but otherwise can use any style you like and should be as imaginative as possible.
That's a challenge, but you'd be surprised what you can get across in that length of time with well-chosen words. It's going to be interesting to see what comes out of this one; I hope that they get some good entries.
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Update: there's more going on here than meets the eye - see the end of the post.
Crazy structure alert! See Arr Oh has pointed out a paper that appeared a few months ago in PLoS ONE, describing a new antibiotic.
Yep, that's it at left. Note that it's a symmetric sulfoxide, with those. . .unusual groups on each side. An acenapthalene in a natural product? Substituted at those positions to make a macrocycle? A macrocycle with that tetracyclic group as part of it, one with two four-membered rings buried in it? Now, there are some truly crazy-looking natural products out there, but this one, were it to be real, would be a strong contender for the craziest.
I don't think it's real. Like See Arr Oh and the folks commenting on his post, I don't see how you can wrench carbon-carbon bonds into those positions. If you tried to make that structure out of one of those nice old metal Dreiding model sets, you'd need a pair of pliers, or perhaps a welding torch. The spectral data in the supporting information, while not at all silly, are nowhere near as extensive as they'd need to be to support such a proposal. This, to me, looks like another case of a structure put out by people who don't realize just how wild it really is. There are quite a few of these in the literature already. And natural product structure assignments do indeed get hosed up at times.
When you read the paper, you see that the authors make a big deal out of how extremely unusual it is to find a sulfoxide natural product, but present the rest of the structure as if they're reading the label off of a can of soup. This compound is worth being on the cover of Angewandte Chemie if it's really as drawn - that sulfoxide, while quite weird, is just a decorative ribbon on top of that wild ring system. I'll go ahead and put my marker down: whatever xinghaiamine A is, it isn't that.
Update: several sharp-eyed readers have been looking at the spectral data in the supplementary material of this paper (see the comments section). And there's some troubling stuff. Just to pick one example, the graphic below is a zoom in on one region of the authors' Figure S9, contrast and tints altered from the original. This is supposed to be the HMBC spectrum of the compound, but there are artifacts all over it. You'll note that some of the peaks appear, digitally, to be very different from the others (insharpness, color, and contrast), and there are rectangular bits of noise that may be cutouts as well. I hope that there's a good explanation for this, but it's worrisome, at first glance.
Update 2: Note that the two tan-colored spots at the top of the figure appear to be the same spot (as spotted by another commenter), noise and all, except the left-hand one has a straight clipped edge at the very bottom. And the spot two down from it, in the lower left corner, has what appears to be another clipping artifact on its left side. All of the "tan" spots in this figure appear to have squared-off areas of noise around them, as if they have been cut and pasted into position, and/or the background around them has been cleaned up. Also note that the second spot down on the right-hand side of the figure has stair-step pixel artifacts around its edge, which suggests that it could have originally been much smaller and blown up to this size.
Third update: I've contacted the editorial staff at PLoS ONE about this article. The closer you look at it, the worse it gets.
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April 16, 2015
I'm traveling today to give a talk (at this regional meeting of the AAPS), so I don't have my usual train commute wherein to do the morning blog post. So I wanted to set off a bit of discussion instead. I had an email from someone whose boss was at Merck during the Ed Skolnik R&D era, and he had referred to one "Skolnik Unit" as being approximately 20 medicinal chemists. I found that interesting, because I myself have rarely (if ever) been on a project that had that many med-chem participants. Looking back, I think the maximum I can recall is about 16, and that's been a while. I've seen a couple of projects that I'd say reached the 20 head count in chemistry, but that was a peak that didn't sustain.
So here are a couple of questions: what's the largest number of medicinal chemists (discovery, not process) you've ever seen on one project? (I assume that the people from the large organizations will hold the records here). How long did peak number that go on? My correspondent mentioned a project that was said to have two "Skolnik units" worth of chemists. Has anyone been on one that large? If so, how was it organized - the traditional "this team on the eastern amine part, that team on the central ring, that team on the western heterocycles" way, or something different?
And finally, if there was an era where scores (literally) of medicinal chemists were deployed against a given target, is it over?
+ TrackBacks (0) | Category: Drug Industry History | Life in the Drug Labs
April 15, 2015
With free energy perturbation having its time in the calculational spotlight, thanks to Schrödinger and others, it seems worthwhile to link to this new paper. It's a proposal for a common framework to analyze the results of such work. That's needed, because (as far as I can tell, as a definite outsider) every group seems to have its own idea of how to do that. This situation makes it difficult-to-impossible to compare various approaches, so even if this isn't the best possible set of benchmarking tools (I'm not qualified to say), just getting everyone to use the same ones would be a step up. (Thanks to Ash/Wavefunction on Twitter for pointing this one out).
+ TrackBacks (0) | Category: In Silico
Here's a good article at Vox about what to do with idiots like the Food Babe and Dr. Oz. (OK, perhaps he just plays an idiot on TV, but by this point you have to wonder). Like any scientist with any sort of public platform, I've wondered about this, too. Bash them over the head at every opportunity? Doesn't seem to do any good, and it gets tiresome, both to write and to read. Totally ignore them? Can't stand it. These people are getting so much attention that they have potential to cause a lot of harm, and besides, the sheer level of self-confident ignorance and misinformation is too much to put with sometimes.
So where do you land in between those two extremes? Julia Belluz's suggestion are to not just go after the cranks, but the people who make their career possible. The TV shows that have them, the advertisers that fund them, the publishers that bring out their awful books. You have to make sure that you get the weight of the scientific evidence right (or risk becoming what you behold). And you also have to, as she says, "beware of turning cranks into martyrs", while also not overstating their influence. That's a narrow road, in some cases, but those are indeed the ditches on both sides of it that you have keep from driving into.
The trickiest part is that you don't want to become part of the show yourself:
I've been covering Dr. Oz's promotion of pseudoscience for several years. Recently, my dad made an astute observation about that work. He suggested I was somehow dependent on Oz's shenanigans, benefiting from his erroneous medical infotainment to build an audience. I couldn't deny the charge, and his words made me think of the central conflict in Janet Malcolm's ethics tome, The Journalist and the Murderer, summed up on its first page: "Every journalist who is not too stupid or too full of himself to notice what is going on knows that what he does is morally indefensible."
But given that Oz is, depressingly, the most influential public figure in health in America, I would argue that the coverage is warranted and necessary.
Brendan Nyhan raised this conundrum, calling it a "synergy between people who are pushing these theories and people who are covering them in a kind of freakshow style."
I really think that Dr. Oz is where he finds himself because he really likes to be on television, enjoys being a wealthy public figure, and has convinced himself, as much as he needs to, that he's doing some sort of good along the way. But I also think that if you'd shown him (as a young medical student) where he is today, he'd probably approve of the lifestyle and the fame, but (I hope) be taken aback by what he does to keep it going. He's a performing clown, presiding over a medical and nutritional freak show.
Going after the fools while not being taken for one of them - that's quite a trick to pull off. As I heard growing up in Arkansas, "Never wrestle with a pig - you both get filthy, but the pig enjoys it". That's one reason why I don't spend more time hammering on these people, even though it is sort of fun. Maybe especially because it's sort of fun.
Update: thoughts on the same article from Orac at Respectful Insolence.
+ TrackBacks (0) | Category: Snake Oil
We all know about the placebo effect - in some therapeutic areas (depression being a classic case), it's so strong that finding a drug that works better is no small feat. And it's been thought for some time that the strength of the placebo response varies from patient to patient, in ways that aren't really understood. But what if there were a genetic component? What if you could tell, beforehand, which people were most likely to respond to just the thought of a drug?
This idea is getting closer to reality. Here's a review in Trends in Molecular Medicine - as the authors show, it's thought that variations in the serotinergic and dopaminergic systems, among others, are likely to be the fundamental differences in varied placebo response. If there are really trends to be discovered, and these can be tracked down all the way to the genetic level, then that will change the way that we conduct clinical trials, for sure. It also has the potential to change medical practice, at least in some areas.
What's more, it opens up a lot of questions that we certainly don't know the answer to. If someone knows that they're a "strong placebo responder", do they continue to be one? Does it wear off over time after repeated applications of self-knowledge, or are the neural pathways involved unconcerned with that sort of high-level activity? When would it be ethical to give one person a placebo and another person a drug substance, just based on their "placebogenic profile"? How do we compensate for these patients in drug clinical trials - leave them out of Phase II, so as to get a clear look at the mechanism, and bring them back in for Phase III as a more real-world test? Do we take more care to remove them from (say) an antidepressant trial, where responses have historically been high, and if so, to what extent is that justified?
And unraveling the mechanisms behind the placebo response itself is bound to produce some interesting information, in an area where we have very little to go on. The slow and gradual clearing of the fog that's covered neuroscience for so long is a very big story that's going to take a long time to completely develop, but in the end, there may not be many bigger ones.
+ TrackBacks (0) | Category: Clinical Trials | The Central Nervous System
April 14, 2015
Here's a comprehensive and very timely review on monofluorination methods. 84 pages, before you get to the references, and there are 562 of those! It covers the last ten years of the literature, a busy time indeed in the organofluorine field, and no one should be without it who's interested in fluorination. That means pretty much all medicinal chemists - enjoy!
+ TrackBacks (0) | Category: Chemical News
A colleague tells me that he just got a come-on from yet another unknown open-source journal, "Pharmaceutical Chemistry Review". Reproduced below, word-for-word, is the pitch. And it's hard to resist when they butter you up like this:
One of your papers has drawn our attention:
Published in: *source*.
Yep, personal attention will do the trick every time. The journal says that it publishes papers in (among other subject areas), "Lead Compounds and Enhance the New Drug Research", "Based on Potential Drug Targets for Life Science Research Reveals" (that's what it says, honest), and "The Penetration of Molecular Mechanics and Quantum Chemistry and Pharmaceutical Science". You will not be surprised to find that the go-getters behind this "journal", Biological and Chemical Publishing, are on the list of predatory publishers. And man, with bait like this, they must be reeling them in. . .
+ TrackBacks (0) | Category: The Scientific Literature
Ed Silverman Peter Loftus at Pharmalot, looking back at the Merck/Schering-Plough merger. It has not gone quite like the initial plan:
First, a little history. In November 2008, Schering-Plough Chief Executive Fred Hassan told analysts and investors gathered at the company’s Kenilworth, N.J., headquarters it was developing “five stars” with big sales potential. They were: 1) rheumatoid-arthritis treatment golimumab (with Johnson & Johnson JNJ -1.50%), 2) the antipsychotic Saphris 3) Bridion 4) the anticlotting drug vorapaxar and 5) a hepatitis C treatment called boceprevir.
It was within weeks of Hassan’s stargazing that Merck began courting Schering-Plough, leading to the Merck takeover in 2009. Merck touted the five stars among other Schering drugs, as well as the deal’s potential for big cost cuts.
The five stars did make it to market (in the case of Bridion outside the U.S.). But none has significantly moved the needle for Merck, whose annual sales have fallen each year since 2011—to $42.2 billion last year—hurt by patent expirations for older drugs. . .
Well, a lot of people will tell you that this sort of salesmanship was Hassan's strong point. And drug development is, as we all have had chances to notice, unpredictable. But doesn't everyone sound so confident when they announce these mergers? Isn't the future just laid out there to be marched into and conquered? You don't hear anyone going on about how gosh, you just never know in this business, it might work out and it might not. No, the bold leadership of Company A has stepped up and seized the opportunities provided by Company B, and all manner of things will be well in consequence.
Silverman Loftus shows, in the Merck/SP case, the bright spot has been Keytruda (pembrolizumab), which was considered to be a roundoff error in the deal compared to all those other big, promising compounds. It's not like Schering-Plough thought a lot of it, either (if they had, you can bet that Hassan would have put a sixth star up there immediately). Keytruda was originally from Organon, and when S-P bought them in 2007, it wasn't even mentioned in the press release or the articles written at the time.
So it's a pretty safe bet that Merck's management would have been nonplussed to hear that Keytruda would turn out to be the best thing that they got out of the deal. And they would probably have had to hold on to the back of a chair or something if you'd shown them what was in store for Fred Hassan's "five stars". As The Clash used to put it, the future is unwritten.
+ TrackBacks (0) | Category: Business and Markets | Drug Industry History
April 13, 2015
This is a fascinating article about a guy who's looking into the chemistry of aged spirits - rum, whiskey, cognac, and so on - and trying to find ways, as he puts it, to hack the process. I'm not a drinker myself, but I've watched with interest as the craft spirits movement has become popular. How, I wondered, could anyone start up a business in this area, when you need years in wooden barrels to make the stuff high-quality? Did someone have the idea back when Bill Clinton was running for office that there would be a market for small-volume distilled spirits, and plan accordingly?
Not at all. What happens is that the many of these tiny-label outfits buy their stuff from large-volume distilleries, sometimes doing the minimum possible to get their own brand on it. That might involve running some neutral spirits through another layer of charcoal to make your own "proprietary" vodka, or in the case of the aged liquors, it might just involve slapping a label on whatever showed up on the truck from Lawrenceburg, Indiana, which is where a lot of this stuff really comes from.
But that's not the business model that this new piece is talking about. It's been known for a long time that many of the flavor notes that come into aged spirits are products of extraction from the wood and often subsequent esterification. So do you have to wait twenty years for this to happen, or not?
The trick then is to encourage esterification in a short time period, and that’s the core science behind Davis’s Model 1 reactor. The reactor accomplishes this in three stages, taking white distillate and chunks of oak as inputs. The first stage forces the esterification of short-chained fatty acids in the white spirit, turning them into fruity, short-chained esters. Phase two literally splits apart big polymer molecules in the oak, extracting the compounds needed to complete the esterification process. This pulls out the aldehydes needed for the final step, but also some unpleasant medium-chained acids. In the final stage, those acids and phenolic compounds are forced to esterify, with simple esters being made to bind and combine into longer-chained esters that would normally be associated with a very mature spirit.
What comes out the other side is not necessarily an aged spirit, but rather one that bears the same chemical signature of an aged spirit. Davis uses mass spectrometry to compare old spirits with products put through his process. Spikes on the chromatogram correspond to compounds that appear in the highest concentrations in the spirits.
He's planning to be completely up front about the process, not trying to sell the products as if they've been sitting around for decades, but just tasting as if they do. And it sounds like it could be a successful business, at the right price point. It also sounds like the sort of thing that could bring on a lot of irritated commentary from fans of the traditional methods, naturally. I would doubt that the two techniques produce identical results (and they're not claimed to), but what if they produce equally desirable ones? Blind-taste-test style results? The traditional distillers will always have a market, because some customers will surely always want to pay for the time and effort that goes into making that product (or be seen paying for it, which amounts to the same thing, economically). But if this new technique catches on, they may well not have as large a market as they do now.
It'll be interesting to watch this play out. The same points that get debated around industrially produced foods will surely be argued in this area, too, but the line between nasty, lowbrow "processed food" and high-end "molecular gastronomy" can get pretty blurry, especially if you need an LC/MS to distinguish them from each other, or from a classic preparation. And we're going to see that debate played out in many other food and drink areas in the coming years, too. . .
+ TrackBacks (0) | Category: Analytical Chemistry | Chemical News
Flow chemistry has a lot of potential for catalyzed reactions - just keep flowing your starting materials across the catalyst, and product comes hosing out the other end. Well, in theory. In practice, although this sort of thing is done on gigantic scale in the chemical industry, it can take a fair amount of engineering. You want to have your catalyst firmly immobilized, but still active, and you don't want your reaction gradually fouling it and killing it off, either. That fouling process can lead to clogging, the bane of every flow chemist's life. Just as annoyingly, you don't want the catalyst gradually washing away from the support, contaminating your product stream and deactivating your whole system.
Realizing all of these at the same time is not the work of a moment. For a dedicated plant, it can definitely be worth the time and effort to tweak everything up to concert pitch, but one of the things that holds back benchtop flow experimentation is that most people don't want to face that every time they run a reaction. There are all sorts of solid-supported catalyst products and ideas out there, but here's another one that might have some promise: a joint Emory/Georgia Tech team reports a scheme to use hollow-fiber reactors with imbedded catalysts.
The fibers themselves are made out of cellulose acetate and inorganic oxide particle, a combination that's already well established in industrial gas separation techniques, desalination, water treatment and so on. You pump your reaction stream into the middle of this tube, and the solvent flows radially out through the walls, with the reaction taking place in that transit. A separate flow outside the walls can sweep the product along from there. Acid- and base-catalyzed conditions with two different kinds of hollow fiber worked fine, so they tried tethering a rhodium catalyst for some diazo cyclopropanation and the like. (They'd already worked out how to get the catalyst onto functionalized silica particles). That's a bit more demanding, but it seems to have worked well.
From the data they present, it looks like the rhodium fibers hold up reasonably well, but there is a very small deterioration with time. Hard to say if that's going to keep going, or if it just sort of levels off. The team promises that more work on various metal-catalysed reactions is on the way, so it'll be worth keeping an eye on this stuff as it develops.
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