About this Author
College chemistry, 1983
The 2002 Model
After 10 years of blogging. . .
Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases.
To contact Derek email him directly: email@example.com
In the Pipeline:
Don't miss Derek Lowe's excellent commentary on drug discovery and the pharma industry in general at In the Pipeline
December 19, 2014
Or as much of the inside as we're likely to have. Thanks to @AndyBiotech on Twitter, here's an SEC document detailing the negotiations between Merck and Cubist. It makes for interesting reading in general - you can see how a deal like this comes together, and all the places where it might have fallen apart - and you can also see that the Hospira patent fight was, in fact, very much on the minds of Merck's management. Emphasis added in the extracts below:
On October 16, 2014, Mr. Bonney called Mr. Frazier to discuss the Company Board’s feedback in response to Parent’s stated interest in a potential strategic transaction. . .Mr. Bonney informed Mr. Frazier that the Company would continue discussions with Parent only if Parent was prepared to move quickly, to propose consideration payable to stockholders of the Company in excess of $100.00 per Share, and to provide assurance that any definitive transaction document would not be conditioned on the outcome of, or include closing conditions based on the Company’s litigation with Hospira or regulatory decisions about ceftolozane/tazobactam. Mr. Frazier responded that he needed to discuss these terms with Parent’s senior management and consult Parent’s Board of Directors (the “Parent Board”).
. . .On October 23, 2014, Mr. Bonney and Mr. Frazier had two telephone conversations to discuss the potential business combination. . .Mr. Frazier described for Mr. Bonney certain of Parent’s assumptions for the combined businesses and identified certain key areas for further due diligence that Parent would require before signing a definitive agreement, including long-term tax planning, the Company’s pending litigation with Hospira, and the regulatory dialogue regarding ceftolozane/tazobactam. Mr. Frazier also indicated that Parent was prepared to offer between $95.00 and $100.00 per Share, with a portion of that price contingent on the outcome of the Hospira litigation. Mr. Frazier indicated that Parent was willing to accept certain regulatory risk in connection with the potential transaction, but was unwilling to assume all of the risk related to the outcome of the Hospira litigation. Mr. Bonney responded that the deal parameters laid out by Mr. Frazier did not meet each of the conditions set forth by the Company Board, but that he would review Parent’s proposal with the Company Board.
On October 25, 2014, Mr. Bonney informed Mr. Frazier that the Special Committee had discussed Parent’s most recent proposal and considered it inadequate with respect to both price and the proposed contingency associated with the outcome of the Hospira litigation. Mr. Bonney offered to facilitate a discussion between Parent and the Company’s outside patent litigation counsel regarding the status of the Hospira litigation, subject to Parent first entering into an appropriate confidentiality agreement with the Company.
. . .On November 6, 2014, representatives of the Company, external patent litigation counsel to the Company, and representatives of Parent held a telephonic diligence meeting about the Hospira litigation, including the potential outcome and timing of a district court decision. The Company also presented to Parent language for a definitive agreement between the parties excluding conditionality regarding the outcome of the Hospira litigation or regulatory action related to ceftolozane/tazobactam.
The strong impression one gets is that Merck really wanted to do this deal, and was initially trying to avoid exposure to Cubist's patent issues. But in the end, the only way to do the acquisition was to put in language that excluded this as a deal-breaker. We don't know what that November 6th meeting concluded about the timing of the District Court's action, or the likelihood that Cubist would lose - maybe the coefficients in front of those two terms were wrongly estimated? Merck certainly knew that this was an issue, but it was, in the end, not enough to make Cubist undesirable. We'll see how that works out for them.
+ TrackBacks (0) | Category: Business and Markets | Patents and IP
The clinical failure rate for disease-modifying Alzheimer's therapies remains perfect, unfortunately: a flat 100%. The latest news is from Roche. Their in-licensed amyloid-targeting antibody (gantenerumab, from MorphoSys) came up empty on an interim trial analysis. Other trials are apparently continuing, but with what hopes?
Roche's rationale seems to be that these other trials are targeting milder and/or earlier forms of Alzheimer's. And it's true that if an antibody approach is going to show something, those are probably the patients where it will. (There are a number of such trials going on now). But the odds are very long. And the situation is complicated by companies wanting to get something, anything, out of these extremely expensive drug development efforts - and by many scientists who have committed their research careers to the amyloid hypothesis. Add in the terribly slow clinical readouts in any Alzheimer's trial and the large and desperate market for anything that works, and you have a tough landscape indeed.
+ TrackBacks (0) | Category: Alzheimer's Disease | Alzheimer's Disease | Clinical Trials
December 18, 2014
Time to revisit an old favorite around here. Remember Nativis Pharmaceuticals? I do, since they provided one of my most treasured "you can expect legal action" letters. When last mentioned here, they were working on the "Voyager", a device (used in veterinary care at the time of that post) that would somehow play back some sort of radio signature of a drug solution and therefore affect the course of a disease. I have not, despite a few efforts, arrived at a better description than that of what Nativis says that they do.
Well, a correspondent alerts me to this clinical trial: Nativis apparently intends to try this out on human patients with glioblastoma. They have also published this paper a bit earlier in the fall - it describes the recording of a radio signature of a taxane in solution, and the subsequent effect of broadcasting this into a tubulin polymerization assay. I will note that the publisher of the open-access journal this this appears in is not known for their quality. To put it mildly.
My correspondent tells me (and I have no way of knowing this firsthand) that Nativis has been raising money from its private investors in advance of this clinical trial. We'll see if it gets off the ground. I await the results with more than average interest.
+ TrackBacks (0) | Category: Snake Oil
I had an interesting note this morning from a reader who's been asked about writing an introductory textbook on medicinal chemistry. He's been looking over the field, and wondering what to include (and what to leave out). Quite a few current med-chem texts have a fairly robust section on combichem, for example, but many of these seem out of proportion to the technique's current importance.
So what would you deemphasize if you were writing one of these? And what would you give more time to? (We'll take the obligatory references to finding jobs in the field as already having been made!)
+ TrackBacks (0) | Category: Pharma 101
December 17, 2014
John LaMattina has a column at Forbes about the situation with Actavis and their Alzheimer's drug, Namenda (memantine). That situation is not a pretty one: the company has an extended-release form of the drug coming on, which they believe will be more convenient to dose. And that's fine - except that part of their strategy is to discontinue the original dosage form.
This is a larger-scale version of the sort of thing that I banged on Retrophin about earlier this year. Dropping useful drugs just so that your new formulation can rule the world seems to be a particularly nasty form of portfolio management, and LaMattina is absolutely right when he says that:
Discontinuation of Namenda in order to boost sales of the XR version reinforces all of the bad views that people have of the pharmaceutical industry and provides great fodder for its critics. Actavis has joined the “Big Pharma” club. It would be nice if it became part of the solution to Big Pharma’s image woes, rather than adding to the problem.
Right now, the whole issue is in court, thanks to an injunction that prevents the company from following through on this strategy. Actavis has appealed, and a hearing took place earlier this week (more on this at Pharmalot). I would not mind seeing this tactic vanish from the earth, and if it takes the law to make it happen, then that's what we get. We'll get worse if this sort of thing continues.
+ TrackBacks (0) | Category: Business and Markets | Regulatory Affairs
A reader sent along this paper, which recently appeared in JACS. He'd read it and was puzzled - not by the content of the paper, but as to "how it got into JACS".
So I had a look. It's on the peptide hormone oxyntomodulin, a 37-residue species closely related to glucagon which stimulates insulin release as an agonist at the GLP-1 receptor. As the authors correctly note, one big problem with trying to administer naturally-occurring hormones like this as drugs is their short half-live due to proteolysis. The body already has pathways to clear these things out, and if you want a longer-lasting effect, you're going to have to get around that. The paper says that the cleavage sites of oxyntomodulin have not been well assigned, so they added some to plasma and did a mass spec assay to see what fragments were produced. A new cleavage was found, one amino acid down from one reported for the DPP-IV protease, and this one doesn't seem to involve DPP-IV at all. None of the fragments are active at the GLP-1 receptor. Mutating two arginine residues at the cleavage site to alanine gave a peptide that was still active at the receptor.
In this case, the amino acid sequences required for efficient proteolysis of OXM are not involved in OXM activation of GLP1R, which made the preparation of an active peptide-hormone analog much easier. In other situations, it is likely that additional mutants will have to be prepared to maintain activity while limiting proteolysis. . .The fact that prOXM shows similar activity to OXM in these in vitro assays demonstrates that the identification and mutation of key cleavage sites is an efficient method for designing proteolysis-resistant hormone analogs. We also appreciate that simply mutating cleavage sites to alanine will not work in every case because this may disrupt the activity of the peptide and may not inhibit cleavage.
Yes, indeed. When others have done this, and many others have, that's often just what happens. This particular mutant does show more stability in plasma, though, and this carried over to a rodent in vivo experiment. But. . .well, as has been said, it needs no ghost come from the grave to tell us this. There's absolutely nothing wrong with this work, but this summary is a bit baffling:
Since nothing in this approach is specific to OXM, we think that this approach should be applicable to the preparation of numerous peptide hormone analogs with improved pharmacological properties. Filling the pipeline with more candidates will increase the chances of identifying novel next-generation biologic therapeutics based on peptide hormones.
"Should be applicable"? Unfortunately, "has been applicable for many, many years" would be more accurate. I would find this paper much easier to take if it didn't include phrases like this. I mean, identifying a cleavage site by mass spec and mutating the adjacent residues to alanine doesn't seem like the sort of thing that needs eight co-authors from Harvard and the Salk Institute, or (to be honest) the sort of thing that I expect to see in JACS. I have to agree with my correspondent. There is, as I said above, nothing wrong with any of this, but it strikes me as utterly routine, and the suggestion that it should be a way of "filling the pipeline" is going to be greeting by actual biopharma researchers with an exasperated eye-roll.
+ TrackBacks (0) | Category: Biological News
December 16, 2014
This is a repost of a "Science Gifts" suggestion from last year - from what I can see, the field hasn't had any major additions in the past few months, and the recommendations below are all still relevant.
Interesting science-gift ideas can be found in the "home experiments" area. There's been a small boom in this sort of book in recent years, which I think is a good thing all the way around. I believe that there's a good audience out there of people who are interested in science, but have no particular training in it, either because they're young enough not to have encountered much (or much that was any good), or because they missed out on it while they were in school themselves.
Last year I mentioned Robert Bruce (and Barbara) Thompson's Illustrated Guide to Home Chemistry Experiments along with its sequels, the Illustrated Guide to Home Biology Experiments and the Illustrated Guide to Home Forensic Science Experiments. Similar books are Hands-On Chemistry Activities and its companion Hands-On Physics Activities.
Related to these are two from Theodore Gray: Theo Gray's Mad Science, and its new sequel, Mad Science 2. Both of these are subtitles "Experiments that you can do at home - but probably shouldn't", and I'd say that's pretty accurate. Many of these use equipment and materials that most people probably won't have sitting around, and some of the experiments are on the hazardous side (which, I should mention, is something that's fully noted in the book). But they're well-illustrated from Gray's own demonstration runs, so you can at least see what they look like, and learn about the concepts behind them.
And there's copious chemistry available in a series of books by Bassam Shakhashiri, whose web site is here. These are aimed at people teaching chemistry who would like clear, tested demonstrations for their students, but if you know someone who's seriously into home science experimentation, they'll find a lot here. The most recent, Chemical Demonstrations, Volume 5, concentrates on colors and light. The previous ones are also available, and cover a range of topics in each book: Volume 4, Volume 3, Volume 2, and Volume 1.
+ TrackBacks (0) | Category:
I always enjoy Adam Feuerstein's voting for Best and Worst CEO in the biotech industry. But just as number of people who've read Dante's Inferno far outnumber the ones who've read the Paradisio (I'm a halfway through the Purgatorio guy myself), I suspect that more people read and vote on the Worst CEO part. There are some truly worthy nominees in that category, and you will find it hard to choose among them.
+ TrackBacks (0) | Category: Business and Markets
Here's a good article on the illegal recreational drug trade - the boutique end of it, anyway. I've written about this sort of thing before, and this piece is squarely in the same territory (even to interviewing David Nichols).
It all comes down to this: there are quite a few people out there modifying known CNS drug structures to see what happens when people take them. There always have been such folks, some of them the pharmacological heirs of Alex Shulgin. If someone wants to fry their own synapses in the privacy of their own home, I suppose it's not much of my business. My problem, though, is that many of the people in this field would rather have someone else do the first-in-man, perhaps next Saturday night. New structures with new PK, new binding profiles, new tox, and no studies of any kind backing them up, and people just cheerfully eat the damn things hoping for a good time. I suppose it really does take all kinds, like they say, but I'm very far removed from being that kind myself. Anyone who knows enough to synthesize something like this, though, has to know that the new agent could do most anything, with "most anything" ranging all the way to seizures and death. Taking it yourself is one thing - selling it to someone else seems to me to be a criminal act.
This field has changed since that 2010 article I referenced before, which was about people making these things themselves in their own labs. Why do that, though, when you can outsource them? The author of this new article tried that process out himself, and it worked just fine:
I made an approach to the lab during Chinese business hours, and I heard back within an hour. “First, can I know the application of this compound your client use?” asked the person on the other end. “I just want to make sure it is legal application. We can do custom synthesis of this simple chemical surely. But if you can give synthesis route, it will be very good for us and we can save some time for this project.”
I replied, “We are doing basic animal research into the compound’s putative analgesic properties. Based upon its expected effect on monoamines, we believe it will have fairly potent analgesic effects, whilst causing minimal cardiovascular strain. Our intention is to use it as a proof of concept for a new type of analgesic for dogs.”
My online identity for this character and for his company are bare bones: nothing but a webmail address. My cover explanation is that I am designing a painkiller—yet phenmetrazine, the clear progenitor of this recipe, is not known to have any analgesic qualities. To anyone who cares to look, my story is blatantly false. But the lab does not seem to care.
The (unnamed) supplier late made the offer to ship the compound hidden in a book for customs, so they knew the score. But they kept up their end of the bargain - the material received, which I presume was some sort of aryl-substituted derivative of phenmetrazine, turned out to be exactly as requested - NMR and LC/MS included. (A cursory bit of Googling would suggest, though, that the simple aryl variants of that compound have already been unofficially explored). To my relief, the author (Mike Power) did not go as far as taking any himself.
What, if anything, can be done about this? As Power puts it, "We can ban drugs. But we can’t ban chemistry, and we can’t ban medical research." It is truly impossible to say what a given new compound might do and what uses it might have. legitimate or less so. I have to confess, I'm at a loss, too.
+ TrackBacks (0) | Category: Chemical News | The Central Nervous System | The Dark Side
December 15, 2014
This is a good read for anyone who's depending on cell assays to tell them something useful. Longtime cell biologists will know that there have been several upheavals over the years about misidentified or contaminated cell lines. HeLa cells have been involved in several of these, as well as mycoplasma and other unwanted guests.
In fact, you can look back to a comment made back here in the summer. An anonymous commenter noted that:
Unrelated, I've always felt a big issue with cancer research has been the cell lines. Decreased funding has labs skimping on the science without them realizing it. I invite you to talk with an academic lab (the postdocs and grad students, not the PI) about where they got their cell lines. Most are "borrowed" from neighboring labs, with contamination along the weigh (cell type and mycoplasm). Very few people are culturing them from mice, the clinic, or buying them from ATCC.
And that's exactly what Janet Stemwedel's getting at in that piece linked above, an issue that's even shown up on NPR. People are cutting too many corners in cell culture - whether by trying to rush results out the door, through unwillingness to spend the money, or just sheer inertia (or unwillingness to face the potential repercussions). What if, as she suggests, the NIH made it part of a grant award to get the all the relevant cell lines in the lab tested?
+ TrackBacks (0) | Category: Biological News
Here's a good look (by an all-star cast of authors) at the availability of pharmaceutical chemistry data in accessible databases. There are several points made. For one, there is far more publicly available information than ever before, and its total looks to outstrip the proprietary databases (such as CAS/SciFinder). The commercial databases, though, have the advantage of much better curation, and they remain far better for doing freedom-to-operate type searches on potential chemical matter.
But even with that advantage, searching out prior art and prior knowledge on a given structural series is not easy. The paper goes through a detailed description of the steps that might be involved if, say, one of the NIH Molecular Libraries probes turns out to be an interesting hit. Some of these have extensive annotation, and some don't. Getting a searchable string for a given compound (CAS#, SMILES, etc.) is not always straighforward, either, with issues around tautomers, double bond geometries, and salt forms. Then once you do a search, you can find some odd things:
It should be noted that if the structure search within SciFinder fails to find a CAS registry number, the search can be repeated as a similarity search to ensure that the registry number was not missed because of a salt form. Once the CAS registry number is found, the total number of literature references with biological activity captured in SciFinder can be retrieved. It is at this point that any reference to the 2009 Goldfarb U.S. patent application on life extension in eukaryotic organisms (US 20090163545) should be noted.
US20090163545 contains a data table (Figure 16 in the patent) on 499 compounds with PubChem substance IDs. However, SciFinder abstracts 6018 substances. How can this be? The patent includes the phrase, referring explicitly to (PubChem assay ID) 775, “the contents of which are herein incorporated in their entirety by reference”. This is full data disclosure taken to an extreme via subsummation of public HTS data into a patent by reference. While only 5796 substances from the HTS were referenced as “use” substances in SciFinder, 132 781 compounds were specified in the HTS (i.e., 32% of the entire Molecular Libraries screening collection, MLSMR). Thus, while this may be an exceptional patent abstraction example in SciFinder, it nonetheless illustrates how intellectual property (IP) due diligence searching can be confounded. Across the set of 322 NIH MLP probes, 72 intersect with the CIDs from AID 775, so a significant proportion will also intersect with the US20090163545 exemplifications. We were initially worried that a reference to this patent application was somehow an indicator for a flawed or promiscuous compound. We now believe the prevalence of references to this single patent application is an example of how complete data disclosure can lead to unexpected and potentially harmful consequences when performing IP due diligence.
Furthermore, not all of the structures of the NIH's MLP chemical probes are even referenced in SciFinder, weirdly (thus the "parallel worlds" of the paper's title). There are many other problems - for example, as the authors note, probably about half of the "commercially available" compounds are not actually available at all, and many have never actually been made. They're just listed because one supplier or another regards them as makeable on demand (everyone who's spent any time ordering compounds has encountered this, surely). So should such things be indexed? Have they been exemplified, in the legal sense?
And we haven't even gotten to the associated biological assay data. Comparing assays across different groups and different times is notoriously difficult - even inside single drug companies, details of the assay protocols have to be available in great detail to make sure that things are relevant. And that level of detail is often just not available in many database searches. Here's an enzyme, here's an IC50, and there you are. Good luck! The situation is a bit chaotic:
This discussion leads us to ask whether compounds in databases without any experimental data and without any link to potential utility should be considered as prior art. This class of compounds is growing dramatically, especially in the public databases, and the utility is arguably markedly less than for prophetic compounds. . .in patents, which may not be real compounds in an experimental sense but for which the relationship to experimentally tested compounds is at least clear. Such prophetic compounds have been abstracted in SciFinder since December 2007. As we have described earlier, the days when one could assume SciFinder had captured everything relevant to the entire global realm of bioactive chemistry are perhaps well passed. By definition, no quantitative assessment (such as the statistics of structure matching) across databases is possible without access to all of them, and to our knowledge this has not been undertaken to date. . .
The authors end with a call for the various database vendors and curators to hold some sort of summit meeting to keep things from diverging any more. We could end up in a situation where searching across multiple incompatible semi-redundant databases would be the only way to have any confidence that one had found what there is to find. Actually, that's the situation we're already in. We need to make that better, and the first step is to keep it from getting any worse.
+ TrackBacks (0) | Category: The Scientific Literature
December 12, 2014
There's a new and very useful paper out on the "molecular sponge" technique for crystallography (first blogged about here, with updates here and here). It's from the Clardy group at Harvard with collaboration from Argonne, in Acta Crystallographica, and you can tell by reading it that it's intended to put the whole method on a firmer footing.
That it does. Some of the data sets produced so far haven't really been up to the quality standards that most crystallographers feel comfortable standing behind, but the paper notes that synchrotron sources (as is often the case!) are a far better bet for useful structures than lab-scale equipment using Mo K-alpha X-rays. The paper also contains detailed advice on the production and handling of the MOF crystals themselves, how best to approach the structure refinement of the soaked guests, and much more. It's essential reading for anyone looking at this method. It's still not a casual stroll to high-quality structures, though:
Despite the described synthetic and crystallographic guidelines, it is imperative to note that the crystalline sponge method must be used judiciously, and that the results obtained are not always unambiguous or ‘crystal clear’, per se. Great care must be taken in interpreting the residual electron density for the guest molecules, especially in cases where the structure is not completely known, or if it exhibits conformational flexibility and thus disorder. With excessive disorder, poor data, over-modeling and/or making erroneous assumptions based upon misguided optimism, the disastrous outcome of drawing incorrect conclusions is very real. . .
Spoken like a crystallographer, for sure. These are early days for the whole MOF structure field, and it wouldn't surprise me at all to find the current "Zn-MOF" framework superseded by something with wider applicability. (Indeed, I think its inventors, the Fujita group, are busy trying to supersede it right now). One of the biggest limitations, which I've had a chance to explore personally, is the apparently complete incompatibility of the current frameworks with basic amines and/or heterocycles. But the idea has tremendous promise, and I'm happy to see this amount of work being put into it.
Update: forgot to add the link to the paper!
+ TrackBacks (0) | Category: Analytical Chemistry
December 11, 2014
Daiichi Sankyo is apparently crowdsourcing ideas for anti-obesity drug discovery. See this page at NineSigma. The requirements are that the submitted idea:
Must be a new anti-obesity drug candidate or drug target
Exhibit superior anti-obesity drug efficacy or a better safety profile than existing drugs (phentermine/topiramate, lorcaserin, orlistat).
Well, then, no problem! They'll take on small molecule or biologics, in any state of development, preferably hitting some target that known agents don't, and with at least in vitro proof of concept (preferably in vivo). How much are they paying for these? Up to $1 million, although it says that the licensing fee can be negotiated separately.
Let me give any interested applicants a hint: if you have such a compound, it is surely worth far more than one million dollars, so you'd better look into that licensing fee part before you start filling out any web forms. One million dollars is pocket lint in drug discovery and development - Daiichi Sankyo (or any large company) can part with a million dollars and never even feel it leave. I understand that all the real contract and licensing stuff will occur downstream of this NineSigma stuff, but still - is there anyone out there with a proposal that would fit this request that needs this incentive to try to get someone interested?
+ TrackBacks (0) | Category: Diabetes and Obesity | Drug Development
I have to say, I didn't even know that this could be done. This paper from Angewandte Chemie describes a mass spec/NMR combination analysis that had never occurred to me as possible. The authors (from Ohio U. and Purdue) are looking at a common peptide ion seen in proteomic mass spec studies. And what they do is collect enough of the ions to run an NMR. That just seems bizarre, somehow, because I think that most of us picture the ionic fragments in a mass spec as these ghostly, esoteric things that live only in the outer-space-like vacuum of the instrument (and are present in vanishingly small amounts, at that). The idea of piling them up and running their NMR spectrum seems like someone taking a reflectance IR spectrum of an angel's wing.
That's because NMR, for most organic chemists, is a much more home-style, hands-on technique. We take measurable amounts of compounds, stick them into glass tubes, and use pipets to dissolve them up in solvent before taking them over to the NMR instrument. You get your hands on these things - and if you need to, you can go get the tube after it comes back out of the magnet, evaporate the solvent, and get all your sample back. Mass spec, on the other hand, uses ridiculously tiny amounts of material. It's really, really hard as an organic chemist to underload an LC/MS - it seems like you'll always get something, if there's something to get. You take a spec of sample, dissolve it in solvent, and then the machine takes a sip of it that a mosquito wouldn't bother with, because it doesn't need the rest.
The structures of these "b ions", as they're known in protein mass spec, has been the subject of a lot of work. Some N-terminal sequences give you oxazolones, some give you diketopiperazines, and others are still undetermined. This study used atmospheric pressure thermal dissociation (APTD), which gets around that vacuum-chamber problem, and they were able to condense material on the inside of the thermal dissociation tube. Bradykinin's b2 ion species was isolated, and NMR showed that it was a trifluoroacetate salt of the diketopiperazine structure. A model peptide, Gly-His-Gly, gave similar results.
So how many other mass spec species can this be applied to? And here's a weird thought: could this be a small-scale preparative method for some unusual syntheses? The thermal dissociation method is similar to pyrolysis, but I wonder if there are some sorts of structures that could be made this way that would be difficult to access by other routes. . .
+ TrackBacks (0) | Category: Analytical Chemistry
Update: see also this post at Xconomy for a look at this issue.
CRISPR/Cas9 is an excellent technique for gene manipulation. Its discovery is absolutely going to be the subject of a Nobel prize; I think it's pretty much of a lock. But at the moment, there's a vicious legal fight going on over who owns the right to it. Technology Review has a good overview here.
I'm glad that they've gone to the trouble, because I wouldn't want to summarize it myself. I last wrote about this here, and things have not gotten any less tangled. There are conflicting patent claims, multiple startup companies, and all sorts of cross-licensing tangles. To add to the confusion, the technology is still evolving, and may well evolve past some of the existing claims:
Few researchers are now willing to discuss the patent fight. Lawsuits are certain and they worry anything they say will be used against them. “The technology has brought a lot of excitement, and there is a lot of pressure, too. What are we going to do? What kind of company do we want?” Charpentier says. “It all sounds very confusing for an outsider, and it’s also quite confusing as an insider.”
Academic labs aren’t waiting for the patent claims to get sorted out. Instead, they are racing to assemble very large engineering teams to perfect and improve the genome-editing technique. On the Boston campus of Harvard’s medical school, for instance, George Church, a specialist in genomics technology, says he now has 30 people in his lab working on it.
Because of all the new research, Zhang says, the importance of any patent, including his own, isn’t entirely clear. “It’s one important piece, but I don’t really pay attention to patents,” he says. “What the final form of this technology is that changes people’s lives may be very different.”
At the moment, Feng Zhang and the Broad Institute have what appears to be the first and widest patent coverage. But some key claims of the patent seem to be based on the idea that extending the technique to human cells was an inventive step, and not everyone in the field buys that at all - saying, on the contrary, that the way the technique just seems to work on everything from bacteria on up is one of its distinguishing features. So all this looks very likely to end up in court, or at least most of the way to court until the various parties can work out some sort of settlement.
I expect that to be the way this situation resolves, actually, but clarity isn't going to be available for a while yet. What will drive the whole process will be which CRISPR variants show the most medical promise, and that is yet to shake out. In the meantime, research in the area is going so quickly that it's hard to keep up - certainly on a far different time scale than the patent system.
+ TrackBacks (0) | Category: Biological News | Patents and IP
December 10, 2014
For fans of saturated nitrogen heterocycles (and there are many in med-chem), this paper is well worth a look. It's from Jeffrey Bode's group at the ETH in Zürich (authors of a recent review in this area), and it's another version of their "SnAP" chemistry, tin-mediated conditions for ring formation. Bode and coauthor Woon-Yew Siau report a variety of interesting compounds, some of which would be rather painful to make by other routes.
No one's crazy about using tin, but the transformation is too useful to pass up. It seems to work well with a variety of cyclic ketones, for one thing, and can be extended to acyclic trifluormethyl ketones as well. On the heterocycle side, there are a few limitations. Trying it on N-proteced 3-keto pyrrolidines or piperidines, for example, gives low yields (too much diversion into an enamine). I would guess that overcoming this problem is a current research focus in the group. Larger rings than the 7-membered one also don't form well - not to anyone's surprise, since those are a pain under most conditions.
But given the number of useful morpholines, piperazines, and piperidines out there, I'm very glad to have another route to crank them out, particularly with the less-studied quaternary carbons. There's probably some tin in my future, darn it all.
+ TrackBacks (0) | Category: Chemical News
Here's an interesting paper for people into metabolic disease: the authors report that JAK1/3 inhibitors (such as tofacitinib) seem to cause human adipocytes to convert from their normal phenotype into brown fat, a different beast altogether. Brown adipocytes are thermoregulators, and burn off lipids at an impressive rate. Many are the therapeutic approaches in metabolism that have targeted this pathway, but no one's every gotten into the real world.
Reading this paper, I wonder if it has something to do with irisin, a hormone that's also been reported to mediate this white-to-brown conversion. (No mention of it in the paper, though). JAK inhibition, in this case, seems to activate the Hedgehog pathway, which mediates the switchover. Of course, it mediates much more besides that, which is the problem here. As the authors themselves say:
The utility of JAK inhibition as a therapeutic strategy for obesity is complicated by the well-described role of this signalling pathway in the immune system. In fact, tofacitinib is approved in the United States to treat rheumatoid arthritis. Thus, if one were to imagine targeting adipose tissue by in vivo administration of an IFN–JAK–STAT inhibitor or similar compound it would almost certainly need to be delivered locally and prevented from spreading systemically or alternatively targeted selectively to white adipocytes. One could also conceive of a cell-based therapy wherein JAK inhibition of patient-derived adipocytes ex vivo is followed by transplantation to treat obesity, but this therapeutic modality would need to overcome numerous and significant obstacles before becoming a reality. A further limitation of the current study is the lack of evidence that JAK inhibition would promote metabolic browning in vivo, in particular in humans where evidence supporting this phenomenon is scant. Thus, additional research is required before inhibition of IFN–JAK–STAT signalling could be used therapeutically for the treatment of metabolic disorders.
There is another take-away from this work that could be of broad use, though - it relies on human adipocytes derived from a stem cell line, which seem to be, as the authors put it, "inexhaustible and rapidly expandable source of human adipocytes for screening and downstream assays". I suspect we'll see plenty of further phenotypic screening with them. Oh, and just as an aside, given my earlier post this morning: this is just the sort of thing that one might expect a discovery platform like Recursion's might pick up, if they're lucky. And it's just the sort of thing that might, in turn, keep them from discovering ten drugs a year, too.
+ TrackBacks (0) | Category: Diabetes and Obesity | Drug Assays
Here's one to put in the "hubris" file - we'll have to wait to see whether or not it's followed by the traditional divine retribution. According to Drug Discovery & Development (note: corrected source), startup Recursion Pharmaceuticals, out of the University of Utah, states that they're going to develop 100 drugs in ten years.
That paragraph break was deliberate, to allow the biopharma industry readers a chance to catch their breath, and perhaps find some paper towels for their keyboards. How, exactly, are these folks going to do this, you ask? The idea is not crazy, nor is it stupid - they're going to repurpose known drugs through phenotypic screening. Not a bad plan at all. In fact, it's so reasonable that a lot of other people have had it. (It's not clear from the article whether or not Recursion's people are completely aware of this - there's quite a bit of stuff contrasting their approach to traditional target-based drug discovery). Where they feel they have an edge is in their computational approach to high-content screening:
". . .most drug-repurposing successes happen serendipitously, or with an educated guess based on deep biological understanding of a given disease. And while that may work for well-studied diseases, we don’t have that same level of understanding with rare disorders,” said Li, Recursion’s co-founder. “With disease modeling and computational algorithms we developed, we’re able to make drug repurposing scalable for use with rare diseases.”
They actually do have a couple of leads for cerebral cavernous malformation, but the article mentions in passing that the Utah lab has been studying that particular condition for about ten years now. They seem to feel, though, that this experience should carry over to thousands of other rare-disease targets pretty easily, though. Recursion's co-founder and CEO Christopher Gibson, who has just finished his PhD, has anticipated my objections:
The idea of a pharmaceutical company tackling hundreds of diseases in a year is unthinkable for even the largest drug makers, which may be working on a dozen diseases at a time. “There will be doubters, those who say we’re naïve to think we can accomplish that. But that’s where science is taking is us,” Gibson said.
I actually appreciate the amount of nerve being shown here. True, I'd appreciate it more in someone who's actually had some more experience, because then it would really stand out. Drug discovery is a pretty humbling experience - at least in my experience, and I don't think it's just me. I think that "naïve" is a completely accurate description of Recursion's plan, to be honest. I believe that they truly don't know what they're in for, and that there may well be many things that they don't even know yet that they should know. That's naïveté, and no mistake.
But on the other hand, everyone starts out like this, more or less. I can't fault people who've never done this sort of thing just for having no experience. I suppose the difference is that we don't all start companies and tell everyone that we're going to discover one new drug every four weeks for the next ten years in a row, or make sure that we're quoted saying things like “These drugs are just sitting in freezers. We’re saying, ‘Give us your drugs and we’ll monetize them". Still, I think that Recursion should come on down and give it a try. Anyone with ideas about how to improve drug discovery should come on down and give it a try. Reality will sort us all out soon enough. Won't it just?
+ TrackBacks (0) | Category: Academia (vs. Industry) | Drug Assays | Drug Development
December 9, 2014
Back to the Bielawski lab's "unclick" trouble. Back in June, Science had published an "Expression of Concern" about the group's original paper. Two more journal articles have had similar notes added to them since then. And now C&E News reports that UT-Austin has concluded an investigation into the problem and has stated that a common author of all three papers has confessed to fabricating data.
As the article notes, there's only one common author other than Bielawski himself, so that sort of narrows things down. And that author (Kelly Wiggins) appears on several other papers from the group, which are now being re-examined in turn. Her whereabouts seem to be unknown, after leaving a postdoctoral position at Illinois. Bielawski himself is no longer at UT either, having taken a position at an institute in South Korea (on the face of it, an unusual choice). Nothing good has come out of this, as far as I can see, and nothing looks likely to, either.
+ TrackBacks (0) | Category: The Scientific Literature
For many years, enzymes were thought to be basically the only biological catalyst molecules out there. Then things like ribozymes were discovered, and it was appreciated that the nucleic acid polymers could also bind substrates and catalyze their reactions. That brought up a natural question: what other sorts of complex polymers might be able to do the same thing? Proteins can clearly do a terrific job, but is that because they're clearly the best choice, or just the one that evolutionary biochemistry landed on?
That's a hard question to answer, but it covers a lot of important ground. Can enzyme-like catalysts be made from chemically more robust scaffolds? These could be of great industrial use - proteins don't stand up to very much rough handling. And since catalysis would seem essential for living systems, how many alternatives are there for extraterrestrial chemical-based life? Those may not be too far off of what we know, but still be strange to us: we find amino acids, nucleotides, and simple carbohydrates in carbonaceous solar system debris, so they would appear to be produced by the sorts of processes (heat, pressure, irradiation) involved in the formation of planetary systems. And they may well form the most likely building blocks for life in general, assuming that we're not particularly special. But did we have to end up with ribose, 2-deoxyribose and the four nucleotides we have (or our twenty-ish amino acids?)
Maybe not, according to this new paper. The authors describe several new "synthetic generic polymers", with new and completely unnatural carbohydrate backbones, and show that these, too, can fold into catalytic species. Random pools of these polymers were selected out to find ligase and endonuclease activity:
We have shown the discovery of catalysts (RNA endonucleases) in four such XNA sequence spaces (ANA, FANA, HNA, CeNA) and the elaboration of three different catalytic activities (RNA endonuclease, RNA ligase and XNA ligase) in one (FANA). These results indicate that properties such as catalysis (as well as heredity and evolution) are generalizable to a range of nucleic acid scaffolds and are likely to be emergent properties of many synthetic genetic polymers. This argues against a strong functional imperative for the chemistry of life’s genetic systems.
Indeed it does. A few billion years of selection pressure on any of these, one imagines, might well produce biochemistries just as robust as ours. And how many more are possible? We might eventually find that life in the universe might be, in general, sort of like us (DNA-ish genetics to make protein-ish molecules, decorated with carbohydrate-y surfaces), but very different in the particulars. I hope we get a chance to find out.
As an aside, this sort of thing brings up a thought that has occurred to me many times about extraterrestrial life: if it does tend to be broadly similar to us, biochemically, might it not also be the source of wildly potent
allergans allergens? A few science-fiction writers have speculated about this, but most popular treatments tend to ignore this possibility, for obvious dramatic reasons: imagine Kirk and Spock beaming down to the surface of a new planet, greeting the natives, and then swelling up while collapsing in sneezing fits. . .
+ TrackBacks (0) | Category: Life As We (Don't) Know It
This probably isn't quite as embarrassing as it looks: the very day of Merck's bid for Cubist Pharmaceuticals, the company loses a patent case for protection of its flagship drug. Cubicin (daptomycin) is by far the main source of revenue at the company right now ($800 million last year, and continuing to climb), and as one might imagine, the generic companies would like some of that action as soon as possible. That's what the present case is about: four patents that take the drug's protection out to 2019 or 2020.
These were invalidated by a district court in Delaware, on the grounds that they do not actually represent new inventions. So as it stands, Hospira could take Cubicin generic in 2016. This can't be welcome news to Merck, since those extra years of revenue would go a long way towards paying off the entire cost of the acquisition. But the risk was known - in fact, the offer specifically states that an unfavorable decision in the case would not be a material event and would not derail things. It'll be appealed, for one thing, and enough legal skill will surely be applied to grind the gears past that 2016 date, no matter what the final decision is. You can't always count on a big drug company to be able to discover the drugs it needs (nor a small one, for that matter), but big companies tend to be pretty good at maximizing the revenues that they already have.
The other part of the deal is that Cubist has other antibiotics in development, which you can count on Merck also making the most out of. The main way that things can fall apart is if there's a combination of lost Cubicin revenue and some clinical failures among these new drugs. Embarrassment still awaits, as it does, potentially, for all of us in the business.
Update: not everyone agrees with this take, with some in the comments section citing this as a major Merck mistake.
+ TrackBacks (0) | Category: Business and Markets | Infectious Diseases | Patents and IP
December 8, 2014
A friend of mine in the drug discovery business asked me this morning on the train if I'd seen "60 Minutes" last night. I hadn't, but he went on to tell me about a report they'd done on Patrick Soon-Shiong, an entrepreneur who's trying to change cancer diagnosis and therapy. What struck my colleague was that pretty much all the points made during the piece seemed to him, as an experienced drug discovery scientist, to be pretty common knowledge, but that the program treated them as a series of amazing breakthroughs.
Matthew Herper has more here, based on a longer report he wrote back in September. Overall, he has a favorable impression of Soon-Shiong, but not a universally favorable one. Well worth a read.
+ TrackBacks (0) | Category: Cancer
So Merck is buying Cubist, the specialty antibiotic company. There's been a lot of talk in the press over the years about how big drug companies have bailed out of antibiotic research because no money could be made in it, and this deal will probably set off more stories about how all that's changing, but that's really not the main part of the story. Cubist has been doing fine, with revenues of over $800 million, mostly from Cubicin (daptomycin), a ferocious-looking natural product that has one of the very new antibiotic mechanisms of recent years.
Here are a couple of posts on the problems of antibiotic drug discovery. It's no stroll through the garden, I can tell you from personal experience, and it's gotten harder and harder over the years. If you find something, you can do well with it, as Cubist has shown, but first find something that hasn't been found before, and we'll talk. That hasn't changed; nothing about antibiotic drug discovery has changed. It's just that Cubist has had some success, and Merck would like to appropriate that for its own pipeline.
+ TrackBacks (0) | Category: Business and Markets | Infectious Diseases
I was reading this interesting commentary on the bizarre meltdown of The New Republic, when something struck me. Megan McArdle is talking here about how hard it can be to manage journalists:
Both journalists and non-journalists usually fail to understand just how weirdly different media companies are from other sorts of firms, which means they don't understand that experience with one side gives you virtually zero insight into how the other kind works. . .
. . .Prominent among the unique challenges of the media manager: the frequent tension between the actions that build your reputation and audience, and those that monetize it; the difficulty of getting creative types to produce great stuff on demand; the astonishing amount of autonomy that journalists need, because it's impossible to write hard guidelines, and too expensive to supervise long hours of reporting and typing; the fact that great writers are frequently terrible managers and editors, which screws up the normal management pyramid; the simultaneous need for speed and accuracy; the fact that media employment selects for a cluster of personality traits that resists closer management;. . .
All you have to do is substitute "scientist" or "researcher" for every mention of "journalist" or "writer" in there. Sounds pretty familiar, doesn't it?
+ TrackBacks (0) | Category: Business and Markets | Life in the Drug Labs | Life in the Drug Labs
December 5, 2014
. . .is not very pleasant, according to this report. It never has been, but it's not getting any better. This should sound familiar to many people:
it is notoriously difficult to determine how many postdoctoral scholars there are, let alone what kind of training they are or should be receiving. The National Institutes of Health (NIH) and the National Science Foundation (NSF) define a postdoctoral scholar as “an individual who has received a doctoral degree (or equivalent) and is engaged in a temporary and defined period of mentored advanced training to enhance the professional skills and research independence needed to pursue his or her chosen career path” (Bravo & Olsen, 2007). Most postdoctoral “trainees” conduct research under the supervision of a single Principal Investigator (PI), and there are no explicit guidelines to determine what training a postdoc should receive or when this training is complete. In reality, postdoctoral research is often not a training period at all, but a time when experienced junior researchers contribute significantly to the goals of a PI’s grant. There is no expectation of specific training, and no defined period in which the training takes place: “training” ends only when the postdoc takes another job.
To be fair, I don't see how any meaningful guidelines could be drawn up for what kinds of specific training would be needed. That's the problem with the postdoctoral world: you're a bäckfisch, more than a grad student who hasn't defended a dissertation, but less than someone with experience in an academic or industrial job. The situations postdocs find themselves in vary wildly; they almost have to vary wildly. You're also supposed to, as much as possible, be starting to make your own way, and that means very different things in different labs.
One disturbing point raised in this article is the possible rise in fraud and dishonest behavior in research labs as a result of the postdoctoral glut. The competition has gotten nasty, and desperate people will do desperate things. As the Nature News commentary puts it:
. . .a whopping 58% of scientists in the UK report said that they were aware of colleagues feeling tempted or under pressure to compromise on research integrity or standards. Asked whether they felt this way themselves, just 21% of scientists aged 35 or over said yes; strikingly, that figure shot up to one-third of those aged under 35.
Worth noting. And as Nature goes on to say, correctly, even though postdocs have complained about their situation forever, under the current conditions senior scientists really can't go on ignoring them. And they can't go on ignoring the fact that only a small number of their students and postdocs will, or can, go on to a similar academic career to their own. The lack of those prospects, and the denial of that lack in some quarters, is probably the root of the problem.
A related article is found here at Bloomberg - another worthy attempt to get across to people that there is no across-the-board shortage of qualified scientists and engineers. Good luck! Many have tried. Here's a particularly appropriate quote, in reference to the IT field:
“There’s no evidence of any way, shape, or form that there’s a shortage in the conventional sense,” says Hal Salzman, a professor of planning and public policy at Rutgers University. “They may not be able to find them at the price they want. But I’m not sure that qualifies as a shortage, any more than my not being able to find a half-priced TV.”
Oh yes indeed. But next week, and the week after, and the week after that we'll see more people talking about the terrible shortage of tech and science people. Bet on it.
+ TrackBacks (0) | Category: Academia (vs. Industry) | Business and Markets
For you flow chemistry fans, here's a paper on the flow equivalent of speed chess: a three-minute synthesis and purification of ibuprofen. Three bond-forming steps, one work-up, and one purification all take place in that time, producing about 8g/hour of final product. Notable features include the use of aluminum chloride, which is the sort of reagent that most flow syntheses try to avoid, aluminum workups being widely known for their gunky, sticky, frozen-yogurt-like properties.
This work, from the Jamison lab at MIT, was funded by DARPA, and it's far from the only "on-demand drug synthesis" project I've seen them fund. A lot of interesting flow chemistry and in-line processing has come out of this stuff, but I have to admit, I'm still a bit puzzled about DARPA's rationale for the whole thing. I gather that the eventual futuristic goal would be some sort of gizmo that can be taken into the field and which will crank out fresh pharmaceutical supplies on demand. But that means carrying along a lot of extra mass for reagents whose components have to be thrown away (like, say, the oxide gunk left from an aluminum chloride workup). And it also means carrying along a lot of ingredients that are more storage-sensitive than the final products as well, like aluminum chloride, or (also in the current paper) iodine monochloride.
So all in all, it would seem easier to ship or carry some ibuprofen rather than an ibuprofen-making machine. A machine of the same size that could synthesize a wide range of useful drugs would be easier to make the case for, naturally, but organic synthesis may not allow you to do that, or not yet. It starts to get into the territory of the old Star Trek method of feeding the crew: tell the wall what you want, and then reach in and take it out of the slot. I have no problem with DARPA trying to push into unknown territory - that's their job - but there's a lot of territory here to cover.
+ TrackBacks (0) | Category: Chemical News
December 4, 2014
Today I wanted to highlight books specifically on medicinal chemistry and drug discovery. Those are always festive additions to the holiday season, right? This list builds on last year's recommendations, with updated editions of some titles, and adds a number of suggestions from readers.
I'll start out with a recent history of our whole field: The Evolution of Drug Discovery. There are a lot of good books written at various levels about the discovery of particular drugs or therapies, but it's rare to see the entire business of drug discovery looked at in this way.
For general medicinal chemistry, you have Bob Rydzewski's Real World Drug Discovery: A Chemist's Guide to Biotech and Pharmaceutical Research. A recent addition to this area is Drug Discovery: Practices, Processes, and Perspectives, by Jack Li and E. J. Corey. Another recommendation is Textbook of Drug Design and Discovery by Krogsgaard-Larsen et al. Several readers here have recommended earlier verions of Silverman's medicinal chemistry book, and there's now a third edition: The Organic Chemistry of Drug Design and Drug Action. Readers have also recommended Camille Wermuth's The Practice of Medicinal Chemistry. For getting up to speed, several readers recommend Graham Patrick's An Introduction to Medicinal Chemistry. Similarly, Medicinal Chemistry: The Modern Drug Discovery Process is a recent introductory textbook that I thought was well done.
Process chemistry is its own world with its own issues. Recommended texts here are Practical Process Research & Development by Neal Anderson, Repic's Principles of Process Research and Chemical Development in the Pharmaceutical Industry, and Process Development: Fine Chemicals from Grams to Kilograms by Stan Lee (no, not that Stan Lee) and Graham Robinson. On an even larger scale, McConville's The Pilot Plant Real Book comes recommended by readers here, too.
Case histories of successful past projects can be found in Drugs: From Discovery to Approval by Rick Ng and also in Walter Sneader's Drug Discovery: A History.
Another book that focuses on a particular (important) area of drug discovery is Robert Copeland's Evaluation of Enzyme Inhibitors in Drug Discovery. Other recent books on particular areas of med-chem are Bioisosteres in Medicinal Chemistry by Brown et al., recommended by several readers, Scaffold Hopping in Medicinal Chemistry, and Protein-Protein Interactions in Drug Discovery, Volume 56
For chemists who want to brush up on their biology, readers recommended an earlier edition of this now updated Terrence Kenakin book: A Pharmacology Primer: Techniques for More Effective and Strategic Drug Discovery , as well as Pharmacology in Drug Discovery: Understanding Drug Response. Cannon's Pharmacology for Chemists, and Molecular Biology in Medicinal Chemistry by Nogrady and Weaver have also been recommended.
Overall, one of the most highly recommended books across the board comes from the PK end of things: Drug-like Properties: Concepts, Structure Design and Methods: from ADME to Toxicity Optimization by Kerns and Di. This one is from 2008, but the same authors have another book coming out in February: Blood-Brain Barrier in Drug Discovery: Optimizing Brain Exposure of CNS Drugs and Minimizing Brain Side Effects for Peripheral Drugs. Another recent PK-centric book is Lead Optimization for Medicinal Chemists. For getting up to speed in this area, there's Pharmacokinetics Made Easy by Donald Birkett, and the Drug Metabolism and Pharmacokinetics Quick Guide has also been recommended.
In a related field, standard desk references for toxicology seems to be Casarett & Doull's Toxicology: The Basic Science of Poisons and Hayes' Principles and Methods of Toxicology Every medicinal chemist will end up learning a good amount toxicology, too often the hard way.
And a recently mentioned book here might prove useful as well: Navigating the Path to Industry, aimed at academic scientists (not just entry-level ones, either) who are looking at industrial research positions and wondering how to get from here to there.
As always, suggestions for more titles to add to the list are welcome.
+ TrackBacks (0) | Category: Science Gifts
Eight or ten years ago, there was a good deal of excitement about non-mammalian small animal model systems for compound screening - specifically fish and frogs. More specifically, zebrafish and Xenopus. A number of small companies started up to do this sort of thing, and large companies paid attention as well. A correspondent, though, wrote me the other day noting that few (if any) of these companies seem to have made it. Phylonix and Znomics seem to be inactive, and InDanio, while apparently still with us, has a low profile. (Are there others?)
More generally, it's worth asking what's become of the whole idea. I've read some interesting papers over the years using these systems in compound screening, mostly uncovering effects developmental pathways. But how has it worked out overall? There are still people working in the field, of course, but have they been able to get any traction in drug discovery? From my perspective, I just know that I seem to hear a lot less about this than I did a few years back.
Is there still a zebrafish case to be made, or one for the (evolutionarily closer) Xenopus? If so, is that case best made for developmental biology/embryology, or for more open-ended high-content phenotypic screening, or for toxicology? Thoughts welcome.
+ TrackBacks (0) | Category: Animal Testing | Drug Assays | Toxicology
Whistleblower lawsuits are hard to interpret. Sometimes massive problems are uncovered, by the only people (insiders) who could uncover them. And sometimes it's a disgruntled employee looking for revenge, a payout, or both. So I don't know what to make of this one, but it's certainly worth keeping an eye on:
A new lawsuit claims the recently ousted CEO of Sanofi and other executives at the huge drugmaker conducted a scheme in violation of federal law to funnel tens of millions of dollars in kickbacks and other incentives to get the company's diabetes drugs prescribed and sold.
The whistleblower lawsuit also claims Sanofi CEO Christopher Viehbacher was fired by the company's board in October "in part, because Defendant Viehbacher was involved in the aforesaid illegal and/or fraudulent activity," which allegedly went on "over the course of many years."
Well, then. The sort of proof the plaintiff (a 13-year paralegal with the company) offers for these allegations will be very interesting to see. She claims that her review of several contracts (with Accenture and Deloitte) made it clear that they were part of a kickback scheme. Worryingly, Sanofi had already settled with the Justice Department two years ago over, well, another kickback scheme. So this is worth watching. At the very least, it has just complicated Chris Viehbacher's near-term employment prospects, I should think.
+ TrackBacks (0) | Category: Business and Markets | Business and Markets | The Dark Side
December 3, 2014
Given today's bad news from GlaxoSmithKline, what an excellent time it is to revisit this infuriating McKinsey Consulting report on "Why pharma megamergers work", published earlier this year.
Uh-huh. That's the title. You thought that they disrupted the entire company, from top to bottom? Sowed fear and uncertainty? Hurt productivity? Au contraire. As the authors say, "These critiques have some merit but ignore larger points: megamergers have created significant value for shareholders, and some of these deals have been critical for the longer-term sustainability of acquirers." How do we know this? Why, by analyzing the returns for two to five years post-deal, that's how. This in an industry with ten-to-fifteen year timelines for new drugs to make it to market. That's McKinsey's idea of long-term value creation, apparently.
+ TrackBacks (0) | Category: Business and Markets | Drug Industry History
Word is so far that about 900 R&D jobs are leaving GlaxoSmithKline's site in the Research Triangle Park. An "undisclosed number" will be offered positions back at the Philadelphia site, but no one seems to have any estimates on how many that will be. There's also word that one of the company's CRO partners, Parexel, will be running a unit at RTP and will hire "some" of the people who have been let go, but I have no more details on that yet, either.
But GlaxoSmithKline itself seems to have basically exited North Carolina, which is a damned shame. That site has a long history, and a lot of good work has been done there.
Update: Looks like there will be some cuts in Philadelphia, too, as well as at some other GSK locations outside the US. I'm hearing complaints that the information being presented is so vague as to make it hard to figure out what's going on (other than the broad take-home, which is that the company is getting significantly smaller).
Update: Here's as much as FierceBiotech has been able to get out of the company on the situation.
Update: More from WRAL. The company has filed a notice with the state that they are eliminating approximately 900 jobs (confirming the figure given here this morning). The letter also notes that up to 450 people could end up being employed by Paraxel, but no timetable is given on when that might ramp up, or under what conditions.
Update People in the comments section doubt the figures in the company's WARN letter to the state. Claims are being made that the numbers are actually going to have to be far higher, given the cuts that people in different areas are seeing with their own eyes. And internationally, the Singapore site is said to be gone, with others uncertain.
Update: Lisa Jarvis' piece at C&E News is here.
+ TrackBacks (0) | Category: Business and Markets
When I last wrote about Puma Biotechnology and their irreversible kinase inhibitor neratinib, things were going great. The company had reported good Phase III data, taking investors by surprise, and the stock had shot up. An FDA filing was planned for just after the first of the year, and the future was bright.
The story has become complicated since then, as a lot of stories in our line of work have a tendency to do. Neratinib recently failed to beat Herceptin in a head-to-head trial (one Puma had downplayed, at least for that primary endpoint). And now comes more bad news: the company has been talking about changing its target patient population, and a recent meeting with the FDA looks to delay their regulatory filing for at least a year. (They need to address some preclinical carcinogenicity data).
So this is not exactly a home run just yet. Neratinib may well make it through fine after the delay. But if you bought the stock when it jumped back in the summer, you're flat now, and probably wondering if you're ready to be a long-term investor or not. . .
+ TrackBacks (0) | Category: Business and Markets | Cancer | Regulatory Affairs
December 2, 2014
It's that time of year again! I wanted to go ahead and put up a few posts over the next few days with science- and chemistry-themed gift recommendations. Today will be books in the general chemistry category.
I've mentioned Theodore Gray's book The Elements before as an fine gift for anyone's who's interested in science or chemistry. I have a copy at home, although I still don't have the follow-up, the Elements Vault, which has some chemical samples in it (doubtless some of the more obtainable and less offensive elements!)
This year, Gray has a second volume out in what he says will be a trilogy: Molecules. I haven't seen this one yet in person, but it looks like it has high production values, and Chemjobber enjoyed the accompanying iPad and iPhone app.
Two years ago I ordered the companion Elements Jigsaw Puzzle, which I did with the kids during January and February, to produce a three-foot-wide periodic table with information and photographs of each element. Being the sort of person I am, I didn't miss the chance to teach a bit of chemistry along the way, based on personal experiences with quite a few of the elements themselves. Gray also has a deck of element cards and a calendar, for your decorating needs.
There are other good entries in this area. The Disappearing Spoon is an entertaining book on various odd properties of the elements (chemists will have said "Gallium!" by now just after having seen the title). I haven't seen Periodic Tales myself, but it comes well recommended. Readers here have also recommended Napoleon's Buttons: How 17 Molecules Changed History and the (out of print) 1959 The Romance of Chemistry by Keith Irwin.
Update: Stuart Cantrill has a very good list of popular-level science books here, and from that I'd like to add two by Thomas Hager that I've also heard good things about: The Alchemy of Air, on the Haber-Bosch process and its effects on everything from feeding the world to the rise of Hitler, and The Demon Under the Microscope, on the discovery of sulfanilamide. And fellow chem-blogger Wavefunction recommends Stuff Matters, a new book on materials science.
An inevitable subset of books on chemistry concentrates on the poisons. Readers here have recommended books by John Emsley, Molecules of Murder and The Elements of Murder. Deborah Blum's The Poisoner's Handbook has done very well since its publication. It originally had a number of errors in its chemistry, but looking at the current paperback, I see that things have been fixed in many cases.
A slightly different note is struck by another book I've long recommended, Oliver Sacks' Uncle Tungsten, which is a memoir as well as a meditation on chemistry (and the love of chemistry). Another memoir, an episodic one, is of course the late Primo Levi's The Periodic Table. It's somber at times, but also amusing, and when I read in it the phrase "Chlorides are rabble", I knew I was in the presence of a good writer, a good chemist, and a good translator. (As Wavefunction noted last year when I mentioned this book, Levi's text is not without mistakes, either, such as stating that Neil Bartlett won the Nobel for his noble gas fluoride discovery. He should have, and I'd bet that most people who know about it think that he did, but. . .)
I should note here that the links above are affiliate links to Amazon and iTunes, meaning that although your price per item will be the same, I'll receive a percentage of the sales through them. I promise to use it wisely. Mostly.
+ TrackBacks (0) | Category: Science Gifts
It's generally painful to go back a few years and look at the large-scale pronouncements of a drug company's upper management. Thanks to commenter Metamonad, we can, in light of tomorrow's GlaxoSmithKline re-org, step back to 2006:
At the time of the £107bn merger of Glaxo Wellcome and SmithKline Beecham in 2000, the architect of the deal, Glaxo's chief executive Sir Richard Sykes, spoke of creating the "Microsoft of the pharmaceuticals industry". Now Mr Garnier, previously the head of SmithKline and the man who became the chief executive of the merged company, believes ramping up investment in the research and development of new drugs is crucial to making this vision come true.
Mr Garnier said: "In terms of creating the Microsoft, this is a vision of the most R&D intensive company which I completely agree with. We have a chance to step away from the rest of our competition if we execute our plan well and we're now in a position to do so."
GSK is the second-largest drug company in the world, with a 7 per cent market share behind America's Pfizer at 11 per cent. Last week Mr Garnier's contract was extended by seven months to May 2008 so he could steer the group through a crucial year that will see the launch of several key medicines. They include Cervarix, a vaccine for cervical cancer, Tykerb, an oral treatment for breast cancer, and Eltrombopag, a blood clotting agent in the treatment of breast cancer.
These blockbuster drugs are set to bring in billions of dollars of extra revenue, enabling the company to pour large chunks into drug discovery from 2008, Mr Garnier said. This year the group is spending $4.4bn on developing new medicines, around 16 per cent of overall revenues, but the goal is to get that figure to the 20-25 per cent range over the next 10 years.
So how'd that work out? Tykerb has had a rough time of it in some clinical trials, and its revenues last year were about $340 million and falling. Ceravix brought in $270 million, down 37 per cent (although that drop was mostly due to trouble in the Japanese market). And eltrombopag, known as Promacta, was a brighter spot, with $307 million in revenues, up 46%. But you'll note that all three of these put together did not bring in a billion dollars of revenue in 2013, which would surely not have made anyone happy if you'd told them that in 2006.
And the R&D spend last year was 15% of overall revenues - less than the starting point in the above article, and nowhere in sight of that 20 to 25%. And with the company set to cut even more tomorrow, I think we can rule that out for the near future, too.
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This will be interesting to watch: Nature (and 48 other journals of the Nature Publishing Group) are experimenting with making their current paper and archives open to view, but not to save or print.
ReadCube, a software platform similar to Apple’s iTunes, will be used to host and display read-only versions of the articles' PDFs. If the initiative becomes popular, it may also boost the prospects of the ReadCube platform, in which Macmillan has a majority investment.
Annette Thomas, chief executive of Macmillan’s Science and Education division, says that under the policy, subscribers can share any paper they have access to through a link to a read-only version of the paper’s PDF that can be viewed through a web browser. For institutional subscribers, that means every paper dating back to the journal's foundation in 1869, while personal subscribers get access from 1997 on.
Anyone can subsequently repost and share this link. Around 100 media outlets and blogs will also be able to share links to read-only PDFs. Although the screen-view PDF cannot be printed, it can be annotated — which the publisher says will provide a way for scientists to collaborate by sharing their comments on manuscripts. PDF articles can also be saved to a free desktop version of ReadCube, similarly to how music files can be saved in iTunes.
I don't seem to be in the top 100 media outlets, or if I am, I haven't heard about it yet. But I'm looking forward to trying this out. My company will pay for whatever papers we need, but this will be a way to get lots of good information without having to go through that process, or that expense. This policy seems to split the difference in the great open-access war, and may make strong advocates of either side less than happy. More thoughts as the advantages (and disadvantages) of all this become clearer. . .
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December 1, 2014
I'd like to echo this question over at Chemjobber's blog. What is Cambrian Genomics talking about? For example, see this Q&A:
How do you plan to stop people from using your technology to create very dangerous microorganisms?
Virtualization. Instead of mailing out DNA we will send the DNA to a virtualization center like Transcriptic, Synthego, or Emerald Cloud Lab. From there they can put thousands of different DNA strands into thousands of cells then make thousands of video files of what those cells are doing and then do image process and machine learning on those videos and send that data back to the user to do the next design.
That's by no means the weirdest thing in it - go have a look and you'll see. Chemjobber has had a go at deciphering these people before, and I can see why he's puzzled. With all the talk about "3-D laser printing of DNA", it's easy to get confused. But while one could blame confused PR people for that sort of thing, when the CEO of the company (Austen Heinz) is out there saying stuff like:
"Everything that's alive we want to rewrite," Heinz said. "Everything that's alive can be made better and more useful to humankind, including human cells. Plants can be made to take out much more carbon out of the atmosphere. We can make humans that are born without disease that can live much longer. We can make humans that can interface directly with computers by growing interfaces into the brain."
. . .well, you have to wonder. Do people realize that providing DNA sequences might not be the rate-limiting step in these worthy goals?
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