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
October 31, 2012
Here's an interesting situation, courtesy of Retraction Watch - trying to pull back a paper because it disclosed something that was supposed to be the subject of your patent. Say the authors of the paper in the Korean Journal of Physiology and Pharmacology:
We regret to inform that the published paper included a few parts that disclosed confidential information which should have been protected under patent law. We admit that the request for retraction is due to the indiscretion of the authors, and confirmed that editorial committee of KJPP have not conducted any fault in publishing the paper.
I would think that if you've disclosed, you've disclosed, so this will all come down to timing. Shouldn't matter much whether the paper has been retracted or not. . .
+ TrackBacks (0) | Category: Patents and IP | The Scientific Literature
Solanezumab is a story that won't go away. Eli Lilly's antibody therapy for Alzheimer's is the subject of a lot of arguing among investors: some people (and I'm one of them) think that there is no strong evidence for its efficacy, not yet, and that the amount of time and effort devoted to finding that out means that there likely isn't any meaningful efficacy to be found. Others are more optimistic, which is why Lilly's stock has risen in recent months.
The latest point of contention is an independent analysis of biomarker data which came out this week at a conference in Monaco. This suggests that there was a meaningful change in the amount of circulating beta-amyloid after treatment, which could mean that the antibody was working as planned to increase clearance of soluble amyloid, thus altering the amyloid balance in the CNS. It should be noted that this line of attack depends on several factors - first among them, that amyloid is a causative factor in Alzheimer's, and secondly, that clearing it from the periphery can affect its concentration and distribution inside the brain. There's evidence for both of these, and there's evidence against both of them. Such questions can only be answered in the clinic, and I'm glad that Lilly, Roche/Genentech, and others are trying to answer them.
What I want to focus on today, though, is an issue that comes up in passing in the Fierce Biotech link above:
Biomarkers and pooled data may help support further studies of the drug, as well as other programs that rest on the beta amyloid hypothesis, but they don't prove that solanezumab works as hoped. Nevertheless, the first sign of success in this field has fueled tremendous enthusiasm that something in the pipeline could eventually work--perhaps even pushing regulators to approve new therapies with something less than clear efficacy data. And any newly approved drug would find a massive market of millions of desperate patients.
That's a big "perhaps", one that's worth tens of billions of dollars. What I worry about is pressure building for the FDA to approve an Alzheimer's therapy (solanezumab or something else) based on these hints of mechanistic efficacy. The problem is, solanezumab hasn't shown much promise of improving the lives of actual Alzheimer's patients. Lilly's own trials showed a possible improvement in a measure of cognitive decline, but this did not show up again in a second patient group, even when they specifically modified the endpoints of the trial to look for it. And neither group showed any functional effects at all, which I think are what most Alzheimer's patients (and their family members) would really want to see.
But there really is such a huge demand for something, anything, with any hint of hope. People would line up to buy anything that got FDA approval, no matter how tenuous the evidence was. And that puts the agency in a very tough position, similar to the one it was in with the Avastin breast cancer issue. Update: there was, to be sure, more of a safety question with Avastin at the same time. You can argue that one of the main purposes of the agency is to make sure that medicines that people can be prescribed in this country will actually do some good, rather than raise hopes for nothing. You could also argue that responsible adults - and their physicians, and their insurance companies - should be able to make such choices for themselves, and should be able to spend their time and money in the ways that they best see fit. You could argue that companies with marginally effective (or ineffective) therapies face a huge moral hazard, in that their incentives are to get such treatments onto the market whether they do anyone else any good or not. None of these are foolish positions, but they are also, in places, mutually incompatible. Alzheimer's disease might well turn into the next place in which we thrash them out.
+ TrackBacks (0) | Category: Alzheimer's Disease | Clinical Trials | Drug Prices | Regulatory Affairs
October 30, 2012
The Atlantic is out with a list of "Brave Thinkers", and one of them is Jay Bradner at Harvard Medical School. He's on there for JQ1, a small-molecule bromodomain ligand that was reported in 2010. (I note, in passing, that once again nomenclature has come to the opposite of our rescue, since bromodomains have absolutely nothing to do with bromine, in contrast to 98% of all the other words that begin with "bromo-")
These sorts of compounds have been very much in the news recently, as part of the whole multiyear surge in epigenetic research. Drug companies, naturally, are looking to the epigenetic targets that might be amenable to small-molecule intervention, and bromodomains seem to qualify (well, some of them do, anyway).
At any rate, JQ1 is a perfectly reasonable probe compound for bromodomain studies, but it got a lot of press a couple of months ago as a potential male contraceptive. I found all that wildly premature - a compound like this one surely sets off all kinds of effects in vivo, and disruption of spermatogenesis is only one of them. Note (PDF) that it hits a variety of bromodomain subtypes, and we only have the foggiest notion of what most of these are doing in real living systems.
The Atlantic, for its part, makes much of Bradner's publishing JQ1 instead of patenting it:
The monopoly on developing the molecule that Bradner walked away from would likely have been worth a fortune (last year, the median value for U.S.-based biotech companies was $370 million). Now four companies are building on his discovery—which delights Bradner, who this year released four new molecules. “For years, drug discovery has been a dark art performed behind closed doors with the shades pulled,” he says. “I would be greatly satisfied if the example of this research contributed to a change in the culture of drug discovery.”
But as Chemjobber rightly says, the idea that Bradner walked away from a fortune is ridiculous. JQ1 is not a drug, nor is it ever likely to become a drug. It has inspired research programs to find drugs, but they likely won't look much (or anything) like JQ1, and they'll do different things (for one, they'll almost surely be more selective). In fact, chasing after that sort of selectivity is one of the things that Bradner's own research group appears to be doing - and quite rightly - while his employer (Dana-Farber) is filing patent applications on JQ1 derivatives. Quite rightly.
Patents work differently in small-molecule drug research than most people seem to think. (You can argue, in fact, that it's one of the areas where the system works most like it was designed to, as opposed to often-abominable patent efforts in software, interface design, business methods, and the like). People who've never had to work with them have ideas about patents being dark, hidden boxes of secrets, but one of the key things about a patent is disclosure. You have to tell people what your invention is, what it's good for, and how to replicate it, or you don't have a valid patent.
Admittedly, there are patent applications that do not make all of these steps easy - a case in point would be the ones from Exelixis - I wrote here about my onetime attempts to figure out the structures of some of their lead compounds from their patent filings. Not long ago I had a chance to speak with someone who was there at the time, and he was happy to hear that I'd come up short, saying that this had been exactly the plan). But at the same time, all their molecules were in there, along with all the details of how to make them. And the claims of the patents detailed exactly why they were interested in such compounds, and what they planned to do with them as drugs. You could learn a lot about what Exelixis was up to; it was just that finding out the exact structure of the clinical candidate that was tricky. A patent application on JQ1 would have actually ended up disclosing most (or all) of what the publication did.
I'm not criticizing Prof. Bradner and his research group here. He's been doing excellent work in this area, and his papers are a pleasure to read. But the idea that Harvard Medical School and Dana-Farber would walk away from a pharma fortune is laughable.
+ TrackBacks (0) | Category: Cancer | Chemical Biology | Drug Development | Patents and IP
Over here to the west of Boston, we had a real storm - downed tree branches all around my neighborhood, power outages - but fortunately nothing like what they had further south of here, starting in Connecticut and really picking up in New York and New Jersey. So it's back to work, on the somewhat-delayed MBTA, and back to blogging on the train! I hope that readers on the East Coast made it through OK (and people on towards the Great Lakes, too, since I see that this is hitting in Cleveland and Detroit as well). What a mess.
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October 29, 2012
Well, all of us in the Northeast are battening down today for the storm, and a lot of companies and research labs either didn't open or are closing early. In that world, my sympathies go out to the people in the cell culture labs and the animal facilities, who can't just shut off the stir plates and go home immediately for the duration. Running those labs is like having a lot of very demanding pets, but ones that can cost you huge sums of money and time if they become unhappy. Good luck to everyone, and here's hoping that the maintenance on all those backup generators was actually kept up! Regular blogging will resume tomorrow. . .
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October 26, 2012
I have this from a lab-accidents-I-have-known discussion over on Reddit. It is, of course, unverified, but it's depressingly plausible. As a chemist, this one is guaranteed to make you bury your head in your hands - it's the second law of thermodynamics come to take vengeance, with the entropy increasing as you go along:
"A graduate student was constructing three solvent stills (dichloromethane, THF and toluene) inside a hood in Room XXXX. As a final step in this process, the student was cutting pieces of sodium metal to add to the stills. Once the sodium had been added, the student began to clean the knife used to cut the sodium. During the cleaning, a small particle of sodium was apparently brushed off the knife. The sodium landed in a drop of water/wet spot on the floor of the hood and reacted immediately making a popping sound. The graduate student was startled by this sound and moved away quickly.
In his haste to get away from the reacting sodium, he discarded the knife into a sink on the bench opposite the hood in which he was working.. Apparently, there was another piece of sodium still adhering to the knife since upon being tossed into the sink, a fire ignited in the sink, catching the attention of another student in the lab. As the flames erupted, the student noticed a wash bottle of acetone sitting on the sink ledge nearby. He immediately grabbed it to get it away from the flames, but in the process, squeezed the bottle, which squirted out some acetone which immediately ignited. The student immediately dropped the bottle and began to evacuate the lab. As he turned to leave, he knocked over a five gallon bucket containing an isopropanol/potassium hydroxide bath which also began to burn. This additional fire caused the sprinklers to activate and the fire alarm to sound which in turn resulted in the evacuation of the building.
When the sprinklers activated, water poured into the bulk sodium-under-mineral-oil storage bottle which had been left uncapped in the hood resulting in a violent reaction which shattered the bottle sending more sodium and mineral oil into the sprinkler water stream. This explosion also cracked the hood safety glass into numerous little pieces although it remained structurally intact. By the time the first-responders arrived on the scene, the fire had been extinguished by the sprinklers, but numerous violent popping sounds were still occurring. The first-responders unplugged the electrical cords feeding the heating mantles, shut off the electricity to the room at the breaker panel and waited until the Fire Department arrived. Eventually the popping noises stopped and sprinklers were turned off. The front part of the lab sustained a moderate amount of water damage The hood where the incident began also suffered moderate damage and two of the three still flasks were destroyed. The student, who was wearing shorts at the time of this accident, sustained second and third-degree burns on his leg as a result of the fire involving the isopropanol base bath.
There were some additional injuries incurred by the first-responders who unexpectedly slipped and fell due to the presence of KOH from the bath in the sprinkler water. These injuries were not serious but they do illustrate the need to communicate hazards to first-responders to protect them from unnecessary injury."
I doubt if the sodium was being added to the dichloromethane still; I've always heard that that's asking for carbene trouble. (Back in my solvent-still days, we used calcium hydride for that one). And it would take a good kick to knock over a KOH/isopropanol bath, but no doubt there was some adrenaline involved. I'm also sorry to hear about the burns sustained by the graduate student involved, but this person should really, really have not been wearing shorts, just as no one should in any sort of organic chemistry lab.
But holy cow. The mental picture I have is of Leslie Neilsen in a lab coat, rehearsing a scene for another "Naked Gun" sequel. This is what happens, though, when things go bad in the lab: we've all got enough trouble on our benches and under our fume hoods to send things down the chute very, very quickly under the wrong conditions. And were these ever the wrong conditions.
+ TrackBacks (0) | Category: Graduate School | How Not to Do It | Safety Warnings
True, but that's unfair to lemmings. This is Raghuram Selveraju of Aegis Capital, talking about deal-making executives in the big pharma companies and the string of costly blowups so far this year. That link has the list, and it's quite an impressive string of fireballs.
“What all of these deals had in common was the desperation of big pharma, because its R&D productivity has been dropping and we’ve known that for a long time,” he said.
That desperation leads to the repetition of familiar mistakes which derive from the predictable thinking of too many business development executives at big pharma, Selveraju opined. First, when looking for licensing opportunities, pharmas very often seek out their comfort zone – a potential product for which they can deploy an existing sales force or promote to doctors they already know and communicate with. Also, to be confident in an experimental drug’s preclinical and clinical data, pharmas often want to go into areas where their competitors also have a compound as well as into validated targets.
“Basically, they’re a bunch of lemmings,” Selveraju said. “As soon as a target becomes hot, they all have to have a molecule in that space, hitting that target."
But who could blame them? Going out into areas that haven't been explored, or haven't worked out for others, can get you slaughtered, too (ask Eli Lilly about Alzheimer's). And when that happens, you have nowhere to hide. If everyone else was rushing into a given therapeutic area and it turns out to be a disaster, well, you yourself might be able to get by, because that's just one of those things, and it happened to everyone at the same time. It reminds me of something I saw years ago about investment managers. If you go out and buy a bunch of (say) IBM for your clients and it drops, people might say "Man, what's wrong with IBM?" But if you go out and buy a bunch of WhoZat, Inc., and it drops, people will ask what's wrong with you.
My own biases make me think that if the chances for failure are high both ways, then maybe you should go ahead and strike out for the unknown territory, because the payoff is larger if you succeed. Selveraju himself has a much more cautious (and perhaps outright dispiriting) recommendation:
What then is Selveraju’s prescription for better business development practices? It might disappoint those who want pharma to be in the vanguard of innovation. He recommends incremental innovation – using FDA’s 505b2 pathway to develop products with already defined efficacy and safety – as well as biosimilars and re-purposing. Pharma also should focus on niche and specialty indications, and largely eliminate primary care products and the large commercial operations that come with them.
That's cranking up the dial even more on the Bernard Munos strategy. Munos also recommends getting out of the big, expensive areas and going more for niche and specialty ones, but mainly because of the cost of the clinical trials (and the validation step inherent in them). Alzheimer's, for example, scores big on innovation, but very, very poorly on the risk/cost ratio, since it's going to take you years and years in huge clinical trials to see if you've got something.
But that "develop products with already defined efficacy and safety" line is Selveraju’s own, and doesn't that sound like loads of fun? Coming up with new formulations and dosing schedules of existing drugs is what a 505(b)(2) strategy amounts to, and it brings up thoughts of alternative careers - going off to trucking school and learning to drive the big rigs, for example. Actually, as a drug-discovery chemist, that's probably what I'd end up doing if everyone switched to that plan, since you certainly don't need people like me if you're five-oh-five-bee-twoing.
+ TrackBacks (0) | Category: Business and Markets | Clinical Trials | Regulatory Affairs
October 25, 2012
I'm in Washington today for a meeting of the C&E News editorial board (which I believe is the last one I'll be attending during my term on it). I'll be able to check the blog during the day for comments, but I don't know if I'll have time to put up a post until later on this afternoon. (In theory, I should be downstairs right now, having breakfast!)
But anyone with thoughts on the magazine, its news coverage, and what you as a reader might want to see more or less of in it, please add your comments. I can assure you that the staff will see them!
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October 24, 2012
The recent discussions on awful molecules in the med-chem literature got me to thinking the other day. There are many more med-chem journals now than there used to be. Back in the day, you had the Journal of Medicinal Chemistry, and that was that. Then in the early 1990s came Bioorganic and Medicinal Chemistry and Bioorganic and Medicinal Chemistry Letters. Now we've got ACS Medicinal Chemistry Letters and MedChemComm and ChemMedChem, among others. (And as we were seeing the other day, there are levels and levels as you move down, ranging from obscure-but-respectable, to just plain obscure, all the way to disreputable crap).
This at a time when industrial medicinal chemistry has been getting cut back. Now, on the other side of the ledger, you have all the folks who are cleaning out the file cabinets for publishable material to have on their C.V.s (and don't think that's not a real force). But in general, I have to wonder if the amount of medicinal chemistry being published from industry hasn't been going down.
Here, then is the question: is there enough decent medicinal chemistry being done to usefully fill all the pages of all these journals? My answer, as you might guess, is "Probably not". But I'd welcome other opinions.
+ TrackBacks (0) | Category: The Scientific Literature
I'd say they have it pretty close to reality:
". . .a new Mayo Clinic study with widespread implications for the treatment and potential cure of the disease has found that the malignant growths have begun cruelly mocking researchers.
The findings—published this week in a rambling, expletive-laden 8,000-word article in The Journal Of The American Medical Association—provides the strongest evidence yet that abnormal cells targeted with cutting-edge cancer treatments are basically flipping off scientists left and right, and get a huge kick out of making oncologists feel like a bunch of bumbling dipshit chumps.
I feel that way about my reactions sometimes. And there were a few points during my PhD when I felt that the only explanation for the way things were going was the existence of a malignant force in the universe, one that for reasons beyond my comprehension was taking a personal interest in me.
+ TrackBacks (0) | Category: Cancer
Over at Just Like Cooking, See Arr Oh has been organizing a "Chem Coach Carnival". He's asking chemists (blogging and otherwise) some questions about their work, especially for the benefit of people who don't do it (or not yet), and I'm glad to throw an entry into the pile:
Describe your current job
My current job is titled "Research Fellow", but titles like this are notoriously slippery in biotech/pharma. What I really do is work in very early-stage research, pretty much the earliest that a medicinal chemist can get involved in. I help to think up new targets and work with the biologists to get them screened, then work to evaluate what comes out of the screening. Is it real? Is it useful? Can it be advanced? If not, what other options do we have to find chemical matter for the target?
What do you do in a standard "work day?"
My work day divides between my office and my lab. In the office, I'm digging around in the new literature for interesting things that my company might be able to use (new targets, new chemistry, new technologies). And I'm also searching for more information on the early projects that we're prosecuting now: has anyone else reported work on these, or something like them? And there are the actual compound series that we're working on - what's known about things of those types (if anything?) Have they ever been reported as hits for other targets? Any interesting reactions known for them that we could tap into? There are broad project-specific issues to research as well - let's say that we're hoping to pick up some activity or selectivity in a current series by targeting a particular region of our target protein. So, how well has that worked out for other proteins with similar binding pockets? What sorts of structures have tended to hit?
In the lab, I actually make some of the new compounds for testing on these ongoing projects. At this stage in my career (I've been in the industry since 1989), my main purpose is not cranking out compounds at the bench. But I can certainly contribute, and I've always enjoyed the physical experience of making new compounds and trying new reactions. It's a good break from the office, and the office is a good break from the lab when I have a run of discovering new ways to produce sticky maroon gunk. (Happens to everyone).
This being industry, there are also meetings. But I try to keep those down to a minimum - when my calendar shows a day full of them, I despair a bit. Most of the time, my feelings when leaving a meeting are those of Samuel Johnson on Paradise Lost: "None ever wished it longer".
Note: I've already described what happens downstream of me - here's one overview.
What kind of schooling / training / experience helped you get there?
I have a B.A. and a Ph.D., along with a post-doc. But by now, those are getting alarmingly far back in the past. What really counts these days is my industrial experience, which is now up to 23 years, at several different companies. Over that time, I don't think I've missed out on a single large therapeutic area or class of targets. And I've seen projects fail in all sorts of ways (and succeed in a few as well) - my worth largely depends on what I've learned from all of them, and applying it to the new stuff that's coming down the chute.
That can be tricky. The failings of inexperience are well known, but experience has its problems, too. There can be a tendency to assume that you really have seen everything before, and that you know how things are going to turn out. This isn't true. You can help to avoid some of the pitfalls you've tumbled into in the past, but drug research is big enough and varied enough that new ones are always out there. And things can work out, too, for reasons that are not clear and not predictable. My experience is worth a lot - it had better be - but that value has limits, and I need to be the first person to keep that in mind.
How does chemistry inform your work?
It's the absolute foundation of it. I approach biology thinking like a chemist; I approach physics thinking like a chemist. One trait that's very strong in my research personality is empiricism: I am congenitally suspicious of model systems, and I'd far rather have the data from the real experiment. And those real experiments need to be as real as possible, too. If you say enzyme assay, I'll ask for cells. If you have cell data, I'll ask about mice. Mice lead to dogs, and dogs lead to humans, and there's where we really find out if we have a drug, and not one minute before.
In general, if you say that something's not going to work, I'll ask if you've tried it. Not every experiment is feasible, or even wise, but a surprising amount of data gets left, ungathered, because someone didn't bother to check. Never talk yourself out of an easy experiment.
Finally, a unique, interesting, or funny anecdote about your career
People who know me, from my wife and kids to my labmates, will now groan and roll their eyes, because I am a walking collection of such things. Part of it's my Southern heritage; we love a good story well told. I think I'll go back to grad school for this one; I'm not sure if I've ever told it here on the blog:
When I first got to Duke, I was planning on working for Prof. Bert Fraser-Reid, who was doing chiral synthesis of natural products using carbohydrate starting materials. In most graduate departments, there's a period where the new students attend presentations by faculty members and then associate themselves with someone that they'd like to work for. During this process, I wanted to set up an interview with Fraser-Reid, so I left a note for him to that effect, with my phone number. His grad students told me, though, that he was out of town (which was not hard to believe; he traveled a great deal).
That night I was back in my ratty shared house off of Duke's East Campus, which my housemates and I were soon to find out we could not afford to actually heat for the winter (save for a coal stove in the front room). And at 9 PM, I was expecting a call from a friend of mine at Vanderbilt, a chemistry=major classmate of mine from my undergraduate school (Hendrix) who knew that I was trying to sign up with Fraser-Reid's group. So at 9 PM sharp, the phone rings, and I pick it up to hear my friend's voice, as if through a towel held over the phone, saying that he was Dr. Fraser-Reid, at Duke.
Hah! Nice try. "You fool, he's out of town!" I said gleefully. There was a pause at the other end of the line. "Ah, is this Derek Lowe? This is Dr. Fraser-Reid, at Duke." And that's when it dawned on me: this was Dr. Fraser-Reid. At Duke. One of my housemates was in the room while this was going on, and he told me that he'd thought until then that watching someone go suddenly pale was just a figure of speech. The blood drained from my brain as I stammered out something to the effect that, whoops, uh, sorry, I thought that he was someone else, arrgh, expecting another call, ho-ho, and so on. We did set up an appointment, and I actually ended up in his group, although he should have known better after that auspicious start. This particular mistake I have not repeated, I should add. Ever restless and exploring, I have moved on to other mistakes since then.
+ TrackBacks (0) | Category: General Scientific News | Graduate School | Life in the Drug Labs
October 23, 2012
There was a question in the comments from a reader who's picking up med-chem, and I thought it was worth answering out here. I've been meaning to shore up the "Pharma 101" category, and this is a good opportunity. So how, in a case like that compound in the previous post, do you increase a compound's half-life?
The first thing to do is try to figure out why it's so short. That's almost certainly due to the compound being metabolized and excreted - once in a while, you'll find a compound that quietly partitions into some tissue and hides out, but for the most part, a disappearing compound is getting chewed up and spit out. For one that's being injected like this, you'd want to look in the blood for metabolites, and in the urine for those and the parent compound, and try to see how much you can account for. No point in checking feces or the bile contents - if this thing were dosed orally, though, you'd definitely not ignore those possibilities.
Looking for metabolites is something of a black art. There are plenty of standard things to check, like the addition of multiples of 16 (for oxidations). Examination of the structure can give you clues as well. I'd consider what pieces I'd see after cleavage of each of those amide bonds, for example, and look for those (and their oxidation products). The bromine and iodine will help you track things down in the mass spec, for sure. That phenol over on the right-hand side is a candidate for glucuronidation (or some other secondary metabolite), either of the parent or some piece thereof, so you'd want to look for those. Same thing could happen to some of the free acids after cleavage of the amides. And I have no idea what that difluorophosphonate does, but I'd be rooting through the PK literature to find out what such things have done in the past.
If you can establish some major metabolic routes, then you can think about hardening the structure. What if some of those amides are N-methylated, for example? Can you do that without killing the binding? Would putting another atom on the other side of the phenol affect its conjugation? There are all sorts of tricks, mostly involving steric hindrance and/or changing electron density around some hot spot.
Update: a commenter notes that I've left out prodrugs, and that's quite right. A prodrug is a sort of deliberate metabolism. You put in a group that gets slowly cleaved off, liberating the active compound - esters are a favorite strategy of this sort. Much of the time, a prodrug is put on to improve the solubility and/or absorption of a compound (that is, something polar and soluble grafted onto a brick), but they can certainly influence half-life, too.
The other major strategy is formulation. If you really can't shore up your structure, or if that isn't enough, then you can think about some formulation that'll deliver your compound differently. Would some sort of slow-release help? These things are trickier with injectables than they are with oral medications, from what experience I've had, but there are still things that can be done.
So that's a short answer - there are, of course, a lot of details involved, and a lot of tricks that have been developed over the years. But that's one way to start.
+ TrackBacks (0) | Category: Pharma 101 | Pharmacokinetics
Of the physical properties that make up the "Rule of Five" (and similar schemes), the one that I think is easiest to breach is molecular weight. I'm not saying that it's a good idea to breeze past 500 daltons with a song on your lips - you should always realize that you're probably asking for trouble up there. But trouble seems to follow a bit less often than it does with, say, a high logP. For a high-value target, I think it's certainly worth pursuing if that's really where you have to go.
Here's a whopper of a molecule, for example, an inhibitor of PTP-MEG2 (also known as PTPN9). That's an unusual phosphatase involved in hepatic insulin signaling, and it's already been shown that knocking it down seems to be beneficial in diabetic rodent models. But, like another longtime diabetes target in this space (PTP1B), it's not easy to get a decent inhibitor. Phosphatases are tricky. Their active sites are very polar (as you'd imagine, having to work with phosphate anions all day), and there aren't all that many phosphatase subtypes as you'd expect, given the amount of such work there is to do. That leads to worries about selectivity, even should you find a molecule that seems to work.
So if you can't find a decent inhibitor, how about an indecent one? That's the first reaction on seeing the structure at left. You can certainly see its resin-bound peptidomimetic library roots. I only wish the authors had found a way to incorporate a chlorine atom somewhere; it would have been one of the rare compounds that runs the table on the halogens. As it is, this floating island weighs 1084, well beyond what anyone could consider reasonable for a drug candidate.
It's selective, naturally. Something this size is making so many interactions that its chances of fitting in a lot of different places is quite small. (There's a crystal structure, which doesn't appear to be showing up in the PDB as yet). It's got a Ki of 34 nanomolar against its target, and about 600 for PTP-TC and PTP1B. All the other protein tyrosine phosphatases are dead, and I'd be very surprised if it hits something from another class. But selectivity isn't the hurdle for these leviathans - it's pharmacokinetics. And here we have a surprise.
First off, the compound shows good activity in mouse heptatocytes, and in other insulin-sensitive cell lines. That's quite interesting, since PTP-MEG2 is surely intracellular - so what part of the cell membrane is letting Godzilla through the turnstiles? The authors moved on to i.p. injection in mice, and found that at at 20 mpk level the compound hit a Cmax of 4.5 micromolar (pretty respectable, considering that molecular weight), and had a half-life of 1.8 hours. That's short, but not as short as one might have feared. Multiday treatment of mice showed just the sorts of on-target effects that one might have predicted: inhibition of hepatic gluconeogenesis, enhanced glucose clearance and insulin sensitivity. That's just the sort of profile you'd want for a Type II diabetes drug, and with a bit of work on the half-life, you might have one here as an injectable. I don't hold out much hope for oral activity with a molecule like this, but it's impressive that it gets this far, and it provides some real proof-of-concept for PTP-MEG2 as a drug target.
So in case anyone's wondering whether I can say anything kind about tool compounds, or about academic drug discovery (this paper's from Indiana U), well, here's your evidence. I don't know whether the authors were brave or just foolhardy to consider these structures, but they've latched onto something worthwhile.
+ TrackBacks (0) | Category: Diabetes and Obesity
October 22, 2012
The recent discussions here about ugly tool compounds have prompted an alert reader to send in this example, a putative agonist of the orphan receptor GPR35. Will someone rise to the defense of this one?
+ TrackBacks (0) | Category: Chemical News
Every so often, you come across scientific journals that you've absolutely, completely never heard of. Back in graduate school (mid-1980s for me), I used to keep track of the weirdest references that came up - Journal of the Siberian Oil Chemist's Society, or Bulletin of the Kentucky Academy of Sciences (1954), which I think you'd have a hard time laying your hands on even in Kentucky. Then there are all the obscure "flag carrier" journals. One that shows up fairly often in searches for odd heterocyclic systems in the Egyptian Journal of Chemistry, but there are others that I have never seen a reference to in nearly 30 years of looking at the chemical literature, such as the Revista Colombiana de Quimica. Europe used to be covered with national chemistry titles, most of which have ceased publication or were merged into Chem. Eur. J. or the like. But some of the newly independent countries were glad to start up their own literature, so you have (for example) the Journal of the Serbian Chemical Society.
Now, I have no wish to offend any Serbian readership I may have, but I will not be bringing any unexpected news if I point out that JSCS is not the most prestigious venue available. In the old days, such a title would be full of local papers, and to be sure, there are plenty of manuscripts from Belgrade. But there are also plenty from places like Brazil, Iran, Egypt, Pakistan, and (naturally) the further corners of India and China. I suspect that some authors from these countries get to count such papers as having been published in a European scientific journal, as opposed to the less-impactful venues closer to home. There is, for example, an Iranian Journal of Chemistry and Chemical Engineering, as there is a Journal of the Brazilian Chemical Society.
But these days, there's a much larger and fuzzier category of obscure journal, and we have the internet and the idea of open access to thank for them. Well, those and greed. If I had to pick, I'd say that greed is the main factor. I'm talking about scam publishing, the dozens upon dozens of "open access" journals that have sprung up that (1) accept everything, and (2) charge a significant publication fee. That money is supposed to cover the costs of editorial work and open access on publication - and such fees can be completely legitimate, of course. But in the case of these publishers, it's a scam, since there are very, very few costs involved. No one edits these papers to any significant degree, and to a good approximation, no one ever accesses the papers, either. Bandwidth charges are thus held down to manageable levels.
Here's a good resource on these outfits, Beall's List of Predatory Open-Access Publishers. Jeffrey Beall of the University of Colorado-Denver has compiled a list of shady operations, most of which are characterized by suspiciously vast lists of titles and hefty publication charges. The one publisher on the list that you might have heard of is Bentham Open, the "open-access" arm of Bentham Publishing. I've always considered their regular list of journals to be pretty borderline stuff, although they have published some useful reviews. But Beall characterizes Bentham Open as "a scholarly vanity press", and that seems pretty accurate.
Take, for example, their Open Medicinal Chemistry Journal. It appears to have published two papers so far this year. Last year, it put out a special issue on "Medicinal Chemistry of Novel Anti-Diabetic Drugs", which sounds interesting until you note that there are three papers therein: a leadoff editorial (from an author at the University of the United Arab Emirates), a paper from that editorial writer and several collaborators (four authors, four countries), and still another paper from him and one of the authors of the first paper. Hmm.
Now, the scholarly worth of such things can be debated. They're of little immediate interest, but if the results contained are real, then they are, presumably, tiny bricks in the great edifice of scientific knowledge, and might conceivably be useful to someone, someday. From that standpoint, I don't have much room to criticize them. But since I've said many unkind things about the established scientific publishing houses and their business models, it's only fair that I point out that some of the untraditional ones are just as rapacious. The sorts of "journals" on Beall's list are not even pretending to add anything to the store of human knowledge: they're publication mills, turning anything you want to pay for into a "scientific paper". Some (not all) of the authors may deserve sympathy, by virtue of their obscure, unfunded origins (although they must have enough funds to pay for these papers), but the publishers deserve none at all for taking advantage of them. And when they're not taking advantage of ignorance and/or desperation, then the transaction is a cynical one indeed, reminding me of the old joke from the Soviet Union that went "As long as they pretend to pay me, I'll pretend to work".
Will they really publish anything? Why, yes, they will, as a mathematician proved by submitting a paper full of incoherent gibberish and getting it accepted. He used MathGen, a modified version of the random-paper generator SciGen that I've written about here. You'd think that the institutional address of "University of Southern North Dakota at Hoople" would tip someone off, but there are no P.D.Q. Bach fans in that audience.
+ TrackBacks (0) | Category: The Dark Side | The Scientific Literature
October 19, 2012
My post the other day on a very unattractive screening hit/tool compound prompted a reader to mention this paper. It's one from industry this time (AstraZeneca), and at first it looks like similarly foul chemical matter. But I think it's worth a closer look, to see how they dealt with what they'd been given by screening.
This team was looking for hits against PIM kinases, and the compound shown was a 160nM hit from high-throughput screening. That's hard to ignore, but on the other hand, it's another one of those structures that tell you that you have work to do. It's actually quite similar to the hit from the previous post - similar heterocycle, alkylidene branching to a polyphenol.
So why am I happier reading this paper than the previous one? For one, this structure does have a small leg up, because this thiazolidinedione heterocycle doesn't have a thioamide in it, and it's actually been in drugs that have been used in humans. TZDs are certainly not my first choice, but they're not at the bottom of the list, either. On the other hand, I can't think of a situation where a thioamide shouldn't set off the warning bells, and not just for a compound's chances of becoming a drug. The chances of becoming a useful tool compound are lower, too, for the same reasons (potential reactivity / lack of selectivity). Note that these compounds are fragment-sized, unlike the diepoxide we were talking about the other day, which means that they're likely to be able to fit into more binding sites.
But there's still that aromatic ring. In this case, though, the very first thing this paper says after stating that they decided to pursue this scaffold is: "We were interested to determine whether or not we could remove the phenol from the series, as phenols often give poor pharmacokinetic and drug-like properties.". And that's what they set about doing, making a whole series of substituted aryls with less troublesome groups on them. Basic amines branching off from the ortho position led to very good potency, as it turned out, and they were able to ditch the phenol/catechol functionality completely while getting well into (or below) single-digit nanomolar potency. With these compounds, they also did something else important: they tested the lead structures against a panel of over four hundred other kinases to get an idea of their selectivity. These is just the sort of treatment that I think the Tdp-1 inhibitor from the Minnesota/NIH group needs.
To be fair, that other paper did show a number of attempts to get rid of the thioamide head group (all unsuccessful), and they did try a wide range of aryl substituents (the polyphenols were by far the most potent). And it's not like the Minnesota/NIH group was trying to produce a clinical candidate; they're not a drug company. A good tool compound to figure out what selective Tdp-1 inhibition does is what they were after, and it's a worthy goal (there's a lot of unknown biology there). If that had been a drug company effort, those two SAR trends taken together would have been enough to kill the chemical series (for any use) in most departments. But even the brave groups who might want to take it further would have immediately profiled their best chemical matter in as many assays as possible. Nasty functional groups and lack of selectivity would surely have doomed the series anywhere.
And it would doom it as a tool compound as well. Tool compounds don't have to have good whole-animal PK, and they don't have to be scalable to pilot plant equipment, and they don't have to be checked for hERG and all the other in vivo tox screens. But they do have to be selective - otherwise, how do you interpret their results in an assay? The whole-cell extract work that the group reported is an important first step to address that issue, but it's just barely the beginning. And I think that sums up my thoughts when I saw the paper: if it had been titled "A Problematic Possible Tool Compound for Tdp-1", I would have applauded it for its accuracy.
The authors say that they're working on some of these exact questions, and I look forward to seeing what comes out of that work. I'd have probably liked it better if that had been part of the original manuscript, but we'll see how it goes.
+ TrackBacks (0) | Category: Academia (vs. Industry) | Chemical News
October 18, 2012
Like night follows day: GSK completes its acquisition of HGS, and the scythe begins to come down. The company had previously notified the state of Maryland that it was cutting 114 positions, and now it's saying that 97 more are disappearing. That Fierce Biotech post says that even more are on the way after the first of the year.
GSK had offered $13 a share for the company, which the company turned down as too low. They got $14.25 in the end, which is not the sort of premium that they'd been hoping for, I'm sure. Lower-than-expected Benlysta sales are the primary cause of all this trouble. Without that approval, the company would likely have disappeared (or contracted beyond recognition). With it, the company is disappearing, and contracting anyway. . .
+ TrackBacks (0) | Category: Business and Markets
The Washington Post has published another guest blog taking the opposite side of the recent "Why Are You Forcing My Son to Take Chemistry?" article.
S. Raj Govindarajan makes his case (some of which recapitulates points made by readers here). I doubt if he's convinced anyone who holds the view of the original authors, but I think he's on target with this part:
Should your son be forced to take chemistry? Absolutely. But the curriculum needs to be rethought in a way that would instill practical knowledge, curiosity about the world, and an appetite for at least understanding scientific achievement and its necessity/implications.
People don’t have to become scientists if they don’t want to, but they should have a fundamental understanding of scientific concepts. That way, people like myself need not be terrified that an ignorant public will vote to slash funding for scientific research and understanding. . .
+ TrackBacks (0) | Category: Chemical News
One of the questions I get asked most often, by people outside of the drug industry, is whether generic medications really are the same as the original branded ones. My answer has always been the same: that yes, they are. And that's still my answer, but I'll have to modify it a bit, because we're seeing an exception right now. Update: more exceptions are showing up in the comments section.
Unfortunately, "right now" turns out, in this case, to mean "over the last five years". The problem here is bupropion (brand name Wellbutrin), the well-known antidepressant. A generic version of it came on the market in 2006, and it went through the usual FDA review. For generic drugs, the big question is bioequivalence: do they deliver the same ingredient in the same way as the originally approved drug and formulation? The agency requires generic drug applications to show proof of this for their own version.
For bupropion/Wellbutrin, the case is complicated by the two approved doses, 150mg and 300mg. The higher dose is associated with a risk of seizures, which made the FDA grant a waiver for its testing - they extrapolated from the 150mg data instead. And right about here is where the red flags began to go up. The agency began to receive reports, almost immediately, of trouble with the 300mg generic dose. In many cases, these problems (lack of efficacy and/or increased side effects) resolved when patients switched back to the original branded formulation. That link also shows the pharamacokinetic data comparing the two 150mg dosages (branded and generic), which turned out to have some differences, mostly in the time it took to reach the maximum concentration (the generic came on a bit faster).
At the time, though, as that link shows, the FDA decided that because of the complicated clinical course of depression (and antidepressant therapy) that they couldn't blame the reported problems on a difference between the two 300mg products. A large number of patients were taking each one, and the number of problems reported could have been explained by the usual variations:
The FDA considers the generic form of bupropion XL 300 mg (Teva Pharmaceuticals) bioequivalent and therapeutically equivalent to (interchangeable with) Wellbutrin XL 300 mg. Although there are small differences in the pharmacokinetic profiles of these two formulations, they are not outside the established boundaries for equivalence nor are they different from other bupropion products known to be effective. The recurrent nature of (major depression) offers a scientifically reasonable explanation for the reports of lack of efficacy following a switch to a generic product. The adverse effects (e.g., headache, GI disorder, fatigue and anxiety) reported following a switch were relatively few in number and typical of adverse drug events reported in drug and placebo groups in most clinical trials. . .
But they seem to have changed their minds about this. It appears that reports continued to come in, and were associated most frequently with the generic version marketed by Teva (and produced by Impax Pharmaceuticals). That FDA page I've quoted above is not dated, but appears to come from late 2007 or so. As it turns out, the agency was at that time asking Teva to conduct that missing bioequivalence study with their 300mg product. See Q12 on this page:
FDA continued to review postmarketing reports throughout 2007. In November 2007, taking into consideration reports of lack of efficacy, FDA requested that Impax/Teva conduct a bioequivalence study directly comparing Budeprion XL 300 mg to Wellbutrin XL 300 mg. The study protocol stipulated the enrollment of patients who reported problems after switching from Wellbutrin XL 300 mg to Budeprion XL 300 mg. Impax/Teva began the study, but terminated it in late 2011, reporting that despite efforts to enroll patients, Impax/Teva was unable to recruit a significant number of affected patients.
The agency apparently was continuing to receive reports of problems, because they ended up deciding to run their own study, which is an uncommon move. This got underway before Teva officially gave up on their study, which gives one the impression that the FDA did not expect anything useful from them by that point:
In 2010, because of the public health interest in obtaining bioequivalence data, FDA decided to sponsor a bioequivalence study comparing Budeprion XL 300 mg to Wellbutrin XL 300 mg. The FDA-sponsored study enrolled 24 healthy adult volunteers and examined the rate and extent of absorption of the two drug products under fasting conditions. In that study, the results of which became available in August 2012, Budeprion XL 300 mg failed to demonstrate bioequivalence to Wellbutrin XL 300 mg.
That FDA-sponsored study is what led to the recent decision to pull the Imapax/Teva 300mg product from the market. Their 150mg dosage is still approved, and doesn't seem to have been associated with any increased reports of trouble (despite the small-but-real PK differences noted above). And it's also worth noting that there are four other generic 300mg bupropion/Wellbutrin products out there, which do not seem to have caused problems.
How big a difference are we talking about here? There are several measurements that are used for measuring blood levels of a drug. You have Cmax, the maximum concentration that is seen at a given dosage, and there's also Tmax, the time at which that maximum concentration occurs. And if you plot blood levels versus time, you also get AUC (area under the curve), which is a measure of the total exposure that a given dose provides. There are a lot of ways these measurements can play out: a very quickly absorbed drug will have an early Tmax and a large Cmax, for example, but that concentration might come back down quickly, too, which could lead to a lower AUC than a formulation of the same drug (at the same nominal dose) that came on more slowly and spread out over a longer time period. To add to the fun, some drugs have efficacy that's more driven by how high their Cmax values can get, while others are more driven by how large the AUCs are. And in the case of bupropion/Wellbutrin, there's an additional complication: some of the drug's efficacy is due to a metabolite, a further compound produced in the liver after dosing, and such metabolites have their own PK profiles, too.
So in this case, it turns out that the AUC just missed on the low side. The FDA wants the statistical 90% confidence interval to fall between 80 and 125% compared to the original drug, and in this case the 90% CI was 77-96%. The Cmax was definitely lower, too - 90% CI was 65-87% of the branded product. And while the agency doesn't provide numbers for the metabolite, they also state that it missed meeting the standards as well. There are drugs, it should be said, that would still be effective at these levels, but Wellbutrin clearly isn't one of them.
My own take is that the FDA was willing to consider the adverse reports as just the usual noisy clinical situation with an antidepressant until the other generics were approved, at which point it became clear that the problems were clustering around the Impax/Teva product. Here's how the FDA addresses the "Why didn't we find out about this earlier?" question:
Q17. In retrospect, were FDA’s decisions regarding the approval and ongoing monitoring of Budeprion XL 300 mg appropriate?
A17. A less cautious approach in studying the bioequivalence of Budeprion XL 300 mg could have brought the data to light earlier. The FDA-sponsored study was completed only weeks ago, which is a very short time for data from a clinical experiment to be announced to the public.
Bupropion is associated with a risk for seizures, which was the basis of the Agency's cautious approach with regard to the early Budeprion XL bioequivalence studies, in which data were extrapolated from Budeprion XL 150 mg in patients to the projected consequences of exposure to Budeprion 300 mg. In retrospect, it is clear that this extrapolation did not provide the right conclusion regarding bioequivalence of Budeprion XL 300 mg. FDA also has much more knowledge today of the seizure-associated risk of bupropion-containing drugs. The trial design of the sponsor-initiated study of 2007 could have been successful, had it been replaced by the trial design employed in the recent FDA-sponsored study.
Of course, the trial design in the sponsor-initiated study of 2007 was that requested by the FDA. But Teva, for their part, does not appear to have been a ball of fire in getting that study recruited and completed, either. It's quite possible, though, that they couldn't round up enough patients who'd had trouble with the generic switch and were also willing to go back and experience that again in the cause of science. Overall, I think that the FDA is more on the hook here for letting things go on as long as they did, but there's plenty of blame to go around.
Still, I find this post at Forbes to be full of unnecessary hyperventilation. You wouldn't know, from reading it, that the FDA initially waived the requirement for 300mg testing in this case because of the risk of seizures. There's a line in there about how the agency is making patients their guinea pigs by not testing at the higher dose, but you could have scored the same debating points after a 300mg study that harmed its patients, which is what it looked at the time would happen. You also wouldn't know that the other generic 300mg formulations don't seem to have been associated with increased adverse-event reports, either.
And that post makes much of the way that these bioequivalence tests are left up the manufacturers. That they are: but if you want to change that, you're going to have to (1) fund the FDA at a much higher level, and (2) wait longer for generic switches to occur. The generic manufacturers will run these tests at the absolute first possible moment, since they want to get onto the market. The FDA will run them when they get around to it; they don't have the same incentives at all. Their incentives, in fact, oscillate between "Don't approve - there might be trouble" and "Definitely approve - we might be missing out on benefit". The winds of fortune blow the line between those two around all the time.
In this case, I think the FDA should have exercised its court-of-last-resort function earlier and more forcefully. But that's easy for me to say, sitting where I am. I don't have to see the mass of noisy adverse event reports coming in over the transom day after day. If the agency acted immediately and forcefully on every one, we'd have no drugs on the market at all. There's a middle ground, but boy, is it hard to find.
+ TrackBacks (0) | Category: Clinical Trials | Regulatory Affairs | The Central Nervous System
October 17, 2012
Zafgen is a startup in the Boston area that's working on a novel weight-loss drug called beloranib. Their initial idea was that they were inhibiting angiogenesis in adipose tissue, through inhibition of methionine aminopeptidase-2. But closer study showed that while the compound was indeed causing significant weight loss in animal models, it wasn't through that mechanism. Blood vessel formation wasn't affected, but the current thinking is that Met-AP2 inhibition is affecting fatty acid synthesis and causing more usage of lipid stores.
But when they say "novel", they do mean it. Behold one of the more unlikely-looking drugs to make it through Phase I:
Natural-product experts in the audience might experience a flash of recognition. That's a derivative of fumagillin, a compound from Aspergillus that's been kicking around for many years now. And its structure brings up a larger point about reactive groups in drug molecules, the kind that form covalent bonds with their targets.
I wrote about covalent drugs here a few years ago, and the entire concept has been making a comeback. (If anyone was unsure about that, Celgene's purchase of Avila was the convincer). Those links address the usual pros and cons of the idea: on the plus side, slow off rates are often beneficial in drug mechanisms, and you don't get much slower than covalency. On the minus side, you have to worry about selectivity even more, since you really don't want to go labeling across the living proteome. You have the mechanisms of the off-target proteins to worry about once you shut them down, and you also have the ever-present fear of setting off an immune response if the tagged protein ends up looking sufficiently alien.
I'm not aware of any published mechanistic studies of beloranib, but it is surely another one of this class, with those epoxides. (Looks like it's thought to go after a histidine residue, by analogy to fumagillin's activity against the same enzyme). But here's another thing to take in: epoxides are not as bad as most people think they are. We organic chemists see them and think that they're just vibrating with reactivity, but as electrophiles, they're not as hot as they look.
That's been demonstrated by several papers from the Cravatt labs at Scripps. (He still is at Scripps, right? You need a scorecard these days). In this work, they showed that some simple epoxides, when exposed to entire proteomes, really didn't label many targets at all compared to the other electrophiles on their list. And here, in an earlier paper, they looked at fumagillin-inspired spiroexpoxide probes specifically, and found an inhibitor of phosphoglycerate mutase 1. But a follow-up SAR study of that structure showed that it was very picky indeed - you had to have everything lined up right for the epoxide to react, and very close analogs had no effect. Taken together, the strong implication is that epoxides can be quite selective, and thus can be drugs. You still want to be careful, because the toxicology literature is still rather vocal on the subject, but if you're in the less reactive/more structurally complex/more selective part of that compound space, you might be OK. We'll see if Zafgen is.
+ TrackBacks (0) | Category: Chemical Biology | Diabetes and Obesity | Drug Development
October 16, 2012
Here's a blog post at The Washington Post in which a parent asks the musical question: "Why Are You Forcing My Son to Take Chemistry?"
It's short, but it can be summarized as My son will not be a chemist. He will not be a scientist. A year of chemistry class will do nothing for him but make him miserable. He could be taking something else that would be doing him more good. And this father is probably right about his son, who's 15, not becoming any sort of scientist. But his argument breaks down a bit after that.
That's because the same objections could apply to most other things that his son could be taking. He says that his son "could be really good at" public speaking, or music, or creative writing, for example. Or not. Perhaps one of them would make him miserable, or simply do nothing for him, and be an opportunity cost as well. The difference is that the boy (and/or his father) are already pretty sure that chemistry will be a waste, and they haven't had the chance to find that out about the others yet.
But again, I take him at his word when he says that his son will be lousy at chemistry (leaving aside the self-fulfilling prophecy aspect, although that's definitely something to consider). This gets back to questions that I wrote about here, namely: how much science should people know? How much should they get in school? How much will do them some good? I think, in this case, that everyone should know that there are such things as chemical elements, and that they combine to form compounds. They should know about reactions like combustion, and a bit about energy and thermodynamics. Knowing an acid from a base would be nice, but the list just keeps on going from there, and where does one draw the line?
I think, after a basic list of facts and concepts, that what I'd like for kids to get out of a science class is the broader idea of experimentation - that the world runs by physical laws which can be interrogated. Isolating variables, varying conditions, generating new hypotheses: these are habits of mind that actually do come in handy in the real world, whether you remember what an s orbital is or not. I'm not sure how well these concepts get across, though.
Do you need a year of high school chemistry to learn these things? I doubt it. A lot of it will be balancing acid-base equations, learning about the columns and rows of the periodic table, oxidations states, Lewis structures, and so on. And the son probably will have no use for any of that - the father has no memory of any of it himself, and although I'd like people to know some of these things, I wonder if not knowing them has harmed him too much. What might have harmed him, though, is a lack of knowledge of those broader points. Or a general attitude that science is That Stuff Those Other People Understand. You make yourself vulnerable to being taken in if you carry that worldview around with you, because claiming scientific backing is a well-used ploy. You should know enough to at least not be taken in easily.
Update: See Arr Oh's thoughts here.
+ TrackBacks (0) | Category: Chemical News
Texas put up a lot of money a few years ago for cancer research. "A lot", in this case, means three billion, to be awarded by the Cancer Prevention Research Institute of Texas (CPRIT). This is where the money came to get K. C. Nicolaou for Rice University, for example, and much other research spending besides.
But - and I know that you'll be shocked to hear this - it turns out that the distribution of such funds can end up being tainted by politics. A number of high-profile resignations have shaken up the effort - here's an editorial by two of the most prominent (Nobel prominent, and now former) members who talk about what's gone wrong:
The past eight months were difficult. Controversy flared when several well-regarded, multi-investigator, multi-institutional collaborative research projects were put in the freezer for months - not brought to the Oversight Committee for funding after strong recommendation by the Scientific Review Council.
This delay was at least partially based on the concern that several of these projects came from one institution. CPRIT's executive director has offered different and conflicting explanations for this action.
Simultaneously, an expensive "commercialization" proposal, constructed and submitted in unorthodox ways that circumvented CPRIT's rules, was rushed to the Oversight Committee and approved for $20 million for its initial year of operations, despite the absence of description or scientific review of its drug development program. This was ultimately corrected, albeit with great effort. . .
Texans deserve to hear the truth about cancer. They must understand that miracles will not happen in a short time. Progress will not be made by those who simply proclaim without explanation that they can do better than hundreds of skillfully staffed and well-financed pharmaceutical and biotechnology companies. Real progress requires the concerted high-quality efforts of basic, translational and clinical investigators from the academic community collaborating with counterparts from the private sector when appropriate.
Here an example what they're talking about. It looks like the sort of stuff you'd expect - backdoor maneuvering to bypass peer review and speed up funding. Texas should have expecting trouble like this; there's no way that a pot of money this size could be distributed without grief. That would be true even if everything had gone smoothly - people outside research are often amazed when they realize the sums of money that can be thrown at these problems, sometimes to little visible effect. The history of the California Institute for Regenerative Medicine (CIRM), a state-funded stem cell research effort, is instructive here - they haven't quite had the controversies that Texas has, but the voters of California may well have expected more by now than they've feel they've received, which is a side effect of stem-cell hype. Add in some favoritism and fast dealing, and you have a real recipe for trouble.
+ TrackBacks (0) | Category: Cancer
October 15, 2012
There may be no more R. B. Woodwards, but never let it be said that there's nothing more to be found in organic synthesis. Until we can make natural products the way that they're made in nature, at room temperature, atom by atom, our skills don't stand comparison with what we know is possible. But that's not going to be the work of a single genius, for sure, although applications are always being accepted.
New reactions, though, are always out there. Here's an example of one, in a field (the Diels-Alder reaction) that you'd think would have been pretty well worked over. This will win no Nobels, and only synthetic organic chemists will pay attention. But I'm always glad to see discoveries like this, and to know that they're still out there.
+ TrackBacks (0) | Category: Chemical News
Explaining R. B. Woodward to a non-chemist, via jazz. And they were probably right, too. But that brings up an interesting question, one that applies to organic synthesis as well as every other human activity. At what point does a field become incapable of supporting Titans?
Consider organic chemistry. There were many major discoveries that had to be made before we (as a civilization) even understood what was going on. Atomic theory itself, valences, tetrahedral carbons, spectroscopy: without these and similar foundational work, you're not going to get very far. But at some point you've got enough material for the next genius to come along and make the most out of it, and I'd put Woodward in that category. He had just enough tools to make his work barely possible, and he had to invent quite a few more along the way. This gave him plenty of room to demonstrate just how good he was at organic synthesis. Complex molecules that would have been beyond structural determination in years past were now there (in theory) for the taking, but these were still well out of reach for all but the most inspired.
To switch fields of achievement, I recall reading someone's opinion once that Bach wasn't all that good, all things considered. I didn't care for that when I saw it (I like Bach very much), but the argument was that he got there "firstest with the mostest", as they said in the Gold Rush, and did such a thorough job on the musical styles of his day (counterpoint, the fugue form, etc.) that no one could ever stand on his level again. You couldn't, because Bach had already Been There and Composed That. Now, that undermines the author's original point, I think, because only a musical genius could have covered so much ground so well, but his second point stands: once Bach had done it, it was done. Anyone who composes a theme-and-variations in contrapuntal style will be compared to him, and probably unfavorably.
Similar arguments can be made across the arts and sciences. But the sciences have the advantage of not being subject so much to the whims of fashion. Picasso, I've long thought, helped create the art world in which he would be considered a great painter. (It reminds me of the way that successful organisms set up a positive feedback loop with their environment, helping to induce the conditions in which they can thrive). There are catastrophic events in both ecologies, of course, that change the requirements of fitness - Burne-Jones (to pick one example) went so far out of fashion by the 1950s and 60s that people were throwing his paintings away with the trash. But the art world has set itself up with fashion as part of its motor. Styles of painting come and go, because styles of painting have to come and go. But Newton's discoveries stand right where they were when he made them - si monumentum requiris, circumspice. Newtonian mechanics do not go out of fashion.
The only thing that can be done to alter great scientific discoveries of the past is to show how they fit into previously-unrealized larger contexts (as Einstein did with Newton). That, naturally, tends to get harder and harder as time goes on. Once the brush is cleared in science, it tends to stay cleared. That process can uncover new problems, but those are the tougher ones. This line of thought brings on talk of the End Of Science, as John Horgan put it, with which you may contrast Vannevar Bush's "Endless Frontier" (which helped establish the modern funding system for academic science in the US. My own take is that the frontier is endless for practical purposes for the foreseeable future, but not similarly endless in every direction at once.
There will, I'd say, never be another R.B. Woodward. Heraclitus aside, we have stepped into that river already, and crossed it. That's not to say that there are not great challenges in synthetic organic chemistry - there are - but it means that there is much less scope for a sky-filling fireworks display like Woodward's career. Anyone trying to recapitulate it is wasting time and effort that could be better applied.
Update: Wavefunction has thoughts on the issue here.
+ TrackBacks (0) | Category: Chemical News
October 12, 2012
Let's talk tool compounds. This topic has come up around here before, generally when some paper gets published from an academic group featuring a hideous molecule. Today, alas, is no exception. Feast your eyes on this one, an inhibitor of tyrosyl-DNA phosphodiesterase I.
Now, on one level, I'm sympathetic. That's an unusual enzyme, and there really aren't any decent inhibitors known for it. It's pretty hard to work out the function of an enzyme without a good inhibitor to watch the effects in living cells, and in that sense, it's good to have found something. But here comes the other hand: your compound for such a purpose needs to be a good one, or the studies you run with it risk being meaningless. "Good" is a relative term, I realize, depending on how much you're expecting the compound to do for you: enzyme assay only? Cells? Mice? But at a minimum, it should be selective for the target you're trying to figure out.
And that's where my eyebrows go up with this little beast. It's not quite a rhodanine (switch the carbonyl and thiocarbonyl if you want that), but it's not a particularly pretty heterocycle, either. This paper, which I wrote about here, looked at the promiscuity of several related heterocycles, but not this one in particular. Any time I see a thioamide group, I get worried. This very system, in fact, shows up in the PAINS paper (open access copy), which I blogged about here, warns against this whole class (see page S45 of the supplementary material).
It also warns, with good reason, against the alkylidene branching off of such rings. I know that there are drugs with such features (epalrestat, Sutent), but your chances of such compounds being real and going all the way are surely lower. Finally, we come to the triphenol. Polyphenol compounds are notorious in medicinal chemistry. They're reactive, they're unstable, they show up in all kinds of assays, and their SAR almost never makes any sense. So this compound has lots going for it.
The authors realize this, and checked the compounds against bovine serum albumin as a way to assay nonspecific protein binding. They also did some work with whole-cell extracts, and continue to feel that these "controversial scaffolds" (their words) can still be useful. (And to be fair, they're also looking at replacing the phenolic section with less nasty polar groups). But while their hearts (and their heads) are in the right place, I still worry very much about these compounds. I'd be quite interested in seeing them run across a broad panel of assays, just to see how promiscuous they really are, and I would be very careful about trusting cellular data (or anything close to it) until that's done.
+ TrackBacks (0) | Category: Drug Assays
I wrote here about a prospective Alzheimer's trial that's starting soon among a population in Colombia, and now comes word of another large effort along the same lines. DIAN, the Dominantly Inherited Alzheimer's Network, will test several current Alzheimer's candidates in groups of people around the world with genetic mutations that make them susceptible to the disease. The hope is that these different mutations will provide a fast-forward-button look at the progress of Alzheimer's in the general population, and help to settle the question of which mechanisms (if any) are appropriate to fight it. They'll go two years of clinical observation (memory tests and brain imaging), and then the plan is to switch everyone to the most efficacious therapy and continue monitoring for real-world benefits.
Currently, it looks like there will be three candidates, with two from Eli Lilly: their beta-secretase inhibitor LY2886721, and their circulating-amyloid antibody Solanezumab, currently the subject of controversy about its efficacy or lack of same. The Roche antibody gantenerumab, which appears to bind more to amyloid that's already precipitated, completes the trio.
This is an excellent idea, and I'm very glad to see so much work being done on prospective trials like these. There's always the danger that working in genetic-mutation populations will give you an answer that's not generally applicable, but I think that we know enough about the specific mutations to make a call on that, should anything stand out. The worry, naturally, is that nothing will stand out. The DIAN trial and the Roche crenezumab trial in Colombia are all aimed at various parts of the amyloid hypothesis, which has been the dominant strain of thought in Alzheimer's etiology for decades. If nothing distinctive comes out of these efforts, that hypothesis will have taken some major hits - but they'll have to be major hits to damage it in the first place.
The best result will be if something looks useful in preventative or early-stage Alzheimer's. Second best would be a painful realization that the amyloid hypothesis is insufficient. And way down at the bottom would be a bunch of "Well, maybe. . ." clinical data showing that some of the agents seemed to help some of the patients, some of the time, to an extent, but maybe not enough to be effective by real-world standards. Anything but that, please.
+ TrackBacks (0) | Category: Alzheimer's Disease | Clinical Trials
October 11, 2012
GlaxoSmithKline took an unusual step today: they announced that they're opening up clinical trial data:
"GSK is fully committed to sharing information about its clinical trials. It posts summary information about each trial it begins and shares the summary results of all of its clinical trials – whether positive or negative – on a website accessible to all. Today this website includes almost 4,500 clinical trial result summaries and receives an average of almost 10,000 visitors each month. The company has also committed to seek publication of the results of all of its clinical trials that evaluate its medicines – regardless of what the results say – to peer-reviewed scientific journals.
Expanding further on its commitments to openness and transparency, GSK also announced today that the company will create a system that will enable researchers to access the detailed anonymised patient-level data that sit behind the results of clinical trials of its approved medicines and discontinued investigational medicines. To ensure that this information will be used for valid scientific endeavour, researchers will submit requests which will be reviewed for scientific merit by an independent panel of experts and, where approved, access will be granted via a secure web site. This will enable researchers to examine the data more closely or to combine data from different studies in order to conduct further research, to learn more about how medicines work in different patient populations and to help optimise the use of medicines with the aim of improving patient care."
I very much applaud this step, and I very much hope that the rest of the industry follows suit. We're getting a lot of flack - and we deserve it - for the way that we handle clinical trial data, with accusations of cherry-picking, data-burying, and all the associated sins. (Ben Goldacre has a book out on the drug industry, which I'm going to read more of before posting on, and he's taken the industry to task on this very point in it). The only cure for this will be to open the books as much as possible - saying "Trust us" will not cut it, and (unfortunately), neither will trying to say "None of your business".
Here's a look at this idea from John Carroll at FierceBiotech. So, Pfizer, Novartis, Merck, all the rest of you? What's the response?
+ TrackBacks (0) | Category: Clinical Trials | Why Everyone Loves Us
Here's a look at something that doesn't make many headlines: the apparent failure of an entire class of potential drugs. The insulin-like growth factor 1 receptor (IGF-1R) has been targeted for years now, from a number of different angles. There have been several antibodies tried against it, and companies have also tried small molecule approaches such as inhibiting the associated receptor kinase. (I was on such a project myself a few years back). So far, nothing has worked out.
And as that review shows, this was a very reasonable-sounding idea. Other growth factor receptors have been successful cancer targets (notably EGFR), and there was evidence of IGFR over-expression in several widespread cancer types (and evidence from mouse models that inhibiting it would have the desired effect). The rationale here was as solid as anything we have, but reality has had other ideas:
It is hardly surprising that even some of the field's pioneers are now pessimistic. “In the case of IGF-1R, one can protest that proper studies have not yet been carried out,” writes Renato Baserga, from the department of Cancer Biology, Thomas Jefferson University in Philadelphia. (J. Cell. Physiol., doi:10.1002/jcp.24217). A pioneer in IGF-1 research, Baserga goes on to list some avenues that may still be promising, such as targeting the receptor to prevent metastases in colorectal cancer patients. But in the end, he surmises: “These excuses are poor excuses, [they are] an attempt to reinvigorate a procedure that has failed.” Saltz agrees. “This may be the end of the story,” he says. “At one point, there were more than ten companies developing these drugs; now this may be the last one that gets put on the shelf.”
But, except for articles like these in journals like Nature Biotechnology, or mentions on web sites like this one, no one really hears about this sort of thing. We've talked about this phenomenon before; there's a substantial list of drug targets that looked very promising, got a lot of attention for years, but never delivered any sort of drug at all. Negative results don't make for much of a headline in the popular press, especially when the story develops over a multi-year period.
I think it would be worthwhile for people to hear about this, though. I once talked with someone who was quite anxious about an upcoming plane trip; they were worried on safety grounds. It occurred to me that if there were a small speaker on this person's desk announcing all the flights that had landed safely around the country (or around the world), that a few days of that might actually have an effect. Hundreds, thousands of announcements, over and over: "Flight XXX has landed safely in Omaha. Flight YYY has landed safely in Seoul. Flight ZZZ has landed safely in Amsterdam. . ." Such a speaker system wouldn't shut up for long suring any given day, that's for sure, and it would emphasize the sheer volume of successful air travel that takes place each day, over and over.
On the other hand, almost all drug research programs, or never even make it off the ground in the first place. In this field, actually getting a plane together, getting it into the air, and guiding it to a landing at the FDA only happens once in a rather long while, which is why there are plenty of people out there in early research who've never worked on anything that's made it to market. A list of all the programs that failed would be instructive, and might get across how difficult finding a drug really is, but no one's going to be able to put one of those together. Companies don't even announce the vast majority of their preclinical failures; they're below everyone else's limit of detection. I can tell you for sure that most of the non-delivering programs I've worked on have never seen daylight of any sort. They just quietly disappeared.
+ TrackBacks (0) | Category: Cancer | Drug Development | Drug Industry History
October 10, 2012
A deserved Nobel? Absolutely. But the grousing has already started. The 2012 Nobel Prize for Chemistry has gone to Bob Lefkowitz (Duke) and Brian Kobilka (Stanford) for GPCRs, G-protein coupled receptors.
Update: here's an excellent overview of Kobilka's career and research.
Everyone who's done drug discovery knows what GPCRs are, and most of us have worked on molecules to target them at one point or another. At least a third of marketed drugs, after all, are GPCR ligands, so their importance is hard to overstate. That's why I say that this Nobel is completely deserved (and has been anticipated for some time now). I've written about them numerous times here over the years, and I'm going to forgo the chance to explain them in detail again. For more information I can recommend the Nobel site's popular background and their more detailed scientific background - they've already done the explanatory work.
I will say a bit about where GPCRs fit into the world of drug targets, though, since they've been so important to pharma R&D. Everyone had realized, for decades (more like centuries), that cells had to be able to send signal to each other somehow. But how was this done? No matter what, there had to be some sort of transducer mechanism, because any signal would arrive on the outside of the cell membrane and then (somehow) be carried across and set off activity inside the cell. As it became clear that small molecules (both the body's own and artificial ones from outside) could have signaling effects, the idea of a "receptor" became inescapable. But it's worth remembering that up until the mid-1970s you could find people - in print, no less - warning readers that the idea of a receptor as a distinct physical object was unproven and could be an unwarranted assumption. Everyone knew that molecular signals were being handled somehow, but it was very unclear what (or how many) pieces there were to the process. This year's award recognizes the lifting of that fog.
It also recognizes something else very important, and here I want to rally my fellow chemists. As I mentioned above, the complaints are already starting that this is yet another chemistry prize that's been given to the biologists. But this is looking at things the wrong way around. Biology isn't invading chemistry - biology is turning into chemistry. Giving the prize this year to Lefkowitz and Kobilka takes us from the first cloning of a GPCR (biology, biology all the way) to a detailed understanding of their molecular structure (chemistry!) And that's the story of molecular biology for you, right there. As it lives up to its name, its practitioners have had to start thinking of their tools and targets as real, distinct molecules. They have shapes, they have functional groups, they have stereochemistry and localized charges and conformations. They're chemicals. That's what kept occurring to me at the recent chemical biology conference I attended: anyone who's serious about understanding this stuff has to understand it in terms of chemistry, not in terms of "this square interacts with this circle, which has an arrow to this box over here, which cycles to this oval over here with a name in the middle of it. . ." Those old schematics will only take you so far.
So, my fellow chemists, cheer the hell up already. Vast new territories are opening up to our expertise and our ways of looking at the world, and we're going to be needed to understand what to do next. Too many people are making me think of those who objected to the Louisiana Purchase or the annexation of California, who wondered what we could possibly ever want with those trackless wastelands to the West and how they could ever be part of the country. Looking at molecular biology and sighing "But it's not chemistry. . ." misses the point. I've had to come around to this view myself, but more and more I'm thinking it's the right one.
+ TrackBacks (0) | Category: Biological News | Chemical News
October 9, 2012
In anticipation of tomorrow's Nobel Prize, here's a graph of the average age of Nobel chemistry laureates. (Link via Stuart Cantrill). It runs about like you'd figure - lots of people in their 50s, which should make some of us feel good, I suppose (!)
I'd like to see this charted over time to see if there are any trends that way. Update - I should scroll down more! They have that data at the link above. Note also that chemistry is still one of the "younger" disciplines by average age. . . We already know a bit about changes in the ages of grantees and highly-cited papers; it would be interesting to see if that shows up in the Nobel data as well. . .
+ TrackBacks (0) | Category: Who Discovers and Why
Eight tons of hydrofluoric acid released? This industrial accident in South Korea sounds horrific. I'm surprised that only 3,000 people were injured, given the population density there. And declaring it a "special disaster zone" seems appropriate, because believe me, that's a special disaster.
+ TrackBacks (0) | Category: Current Events
"Hope Rises For Alzheimer's Treatment, Scientists Say". Not this scientist. That's a composite of headlines, but it captures the unfortunate tone.
We're talking about solanezumab, Eli Lilly's antibody therapy. The company presented analysis of their trial data yesterday, and put a very optimistic face on things. But wait, you say, didn't Lilly already report on this? And didn't the drug miss all its endpoints? Yes, indeed it did. But this is a secondary analysis by the Alzheimer's Disease Cooperative Study, a third-party look at the data. It's hard for me to imagine an optimistic take on the numbers that Lilly itself didn't find, to be honest, but here we have it:
But after a secondary analysis of the first study showed that there was a 42% reduction in the rate of cognitive decline among a subpopulation of patients in the solanezumab arm with only a mild form of the disease, investigators decided to hunt for confirmation of that endpoint in a second Phase III. They didn't find it, seeing the numbers fall short of statistical significance after switching from one measure (ADAS- Cog11) to another (ADAS-Cog14). But by "pooling" the data they came up with a 34% reduction in cognitive decline in that particular group. None of the data indicated a significant reduction in the rate of functional decline.
This looks to me like grasping at straws. I understand that people want to see any tiny edge of possible efficacy as an avenue for further research, but I can't help but think that the path to an effective Alzheimer's therapy would announce itself a bit more clearly than this. Anything should. Chasing after these sorts of results looks like the path to another Phase III trial that might just manage to miss its endpoints by an even narrower margin. The best one could hope for would be a therapy that might, possibly, help a few patients in the early stage of the disease a bit, for a while. Maybe.
The problem is that the pent-up need for anything effective in Alzheimer's is so great that vast hordes of people will likely rush to take anything - or put their aging relatives on anything - that might offer any shred of hope. And I know just where those people are coming from, and I sympathize greatly. Eli Lilly, for its part, is strongly motivated to have something in its large and expensive Alzheimer's portfolio actually work - the company is facing a very, very rough time with its patent expirations, and something like this is about the only thing that could pull them back from the cliff. On all sides, this is not a situation that encourages sound decision-making.
+ TrackBacks (0) | Category: Alzheimer's Disease | Clinical Trials
October 8, 2012
It hasn't been good over at Targacept. They had a big antidepressant failure a while back, and last month ended development of an ADHD drug, the nicotinic acetylcholine receptor ligand TC-5619.
They cut back staff back in the spring, and the CEO departed. Now the expected has happened: the company has apparently laid off everyone in research, and is conserving what cash it has to try to get something to the deal-making point. A sad, but familiar story in this business. . .sometimes companies come back after this point, and sometimes the event horizon turns out to have been passed.
+ TrackBacks (0) | Category: Business and Markets | The Central Nervous System
You've probably seen the headlines about fungal meningitis showing up, caused (it appears) by contaminated injectable steroid supplies. As soon as I heard these stories, I wondered what you treat this condition with, and my first thought was "Amphotericin B, most likely". And so it appears.
That compound still seems to be the usual answer for the nastiest fungal infections, a role it's occupied for decades. That's not by choice. It's an awful compound in many ways, as illustrated by that Wikipedia article linked above:
Amphotericin B is well known for its severe and potentially lethal side-effects. Very often, a serious acute reaction after the infusion (1 to 3 hours later) is noted, consisting of high fever, shaking chills, hypotension, anorexia, nausea, vomiting, headache, dyspnea and tachypnea, drowsiness, and generalized weakness. This reaction sometimes subsides with later applications of the drug, and may in part be due to histamine liberation. An increase in prostaglandin synthesis may also play a role. This nearly universal febrile response necessitates a critical (and diagnostically difficult) professional determination as to whether the onset of high fever is a novel symptom of a fast-progressing disease, or merely the induced effect of the drug.
Organ damage is also distressingly common, and patients who are dying of a systemic fungal infection can suddenly find themselves dying instead of kidney or liver failure. As you'd imagine from that structure, it has to be given intravenously, unless you're treating an oral infection. (Note that it's quite similar to the common topic medicine nystatin). The drug works, as far as anyone can tell, by opening pores in cell membranes, particularly associating with sterols. It seems to have a greater affinity for ergosterol (found in fungi) over cholesterol, which gives it whatever therapeutic window it has.
People have tried for years to replace Amphotericin B, but it remains with us. If you're taking it, you are probably in a bad way.
+ TrackBacks (0) | Category: Infectious Diseases
The "arsenic life" bacterium has taken a number of blows in the scientific literature, and now it's taken another. A close look at its phosphate uptake system shows that these proteins in the GFAJ-1 bacteria not selective for arsenate (or at least tolerant of it, compared to normal lines). They are, in fact, extremely selective for phosphate.
All of the proteins can discriminate at least 500-fold over arsenate, but one of them from GFAJ-1 (highly expressed under the arsenate conditions) is 4,500-fold selective. The authors show, via X-ray crystallography, what sort of mutations hae occurred to give the binding site such high selectivity, which lead to the (slightly larger) arsenate disturbing a key hydrogen bond. This is what you'd expect if these bacteria were, in fact, still phosphate-dependent and needed to extract every bit of it they could from their arsenate-rich environment.
Here's a summary at Nature News. I believe that we can now declare this particular idea dead - everything is pointing the other way.
+ TrackBacks (0) | Category: Life As We (Don't) Know It
October 5, 2012
Ethan Perlstein at Princeton is the main author of this research on sertraline that I blogged about earlier this year. Now he's looking to crowdfund his next research project, on the neuronal effects of amphetamines. He's trying to raise $25,000 to do radiolabeling and electron microscopy studies, which would make this the largest crowdfunding experiment in the sciences so far (but still, I might add, small change compared to the sorts of grants that much of academia spends its time trying to line up).
What he's looking at is 2 to 3 months of work for one MS-level scientist. In this post he describes some of the reactions he's had to the idea so far, and lists the benefits that donors will receive, according to the amounts they contribute. That list is a real eye-opener, let me tell you - it's a different world we're entering, or trying to enter, at any rate. For example: "$100 or higher – You’ll get a hearty thanks in person, and the opportunity to talk science over a round of beer or glass of wine at a NYC watering hole one night after work, or when you visit NYC within the next 6 months." Or how about this one: "$1,000 or higher – Attend up to 2 lab meetings during the project and 1 publication brainstorming session at the end of the project. You will also receive access to a Google Doc during the manuscript writing stage. Supporters who contribute substantially to the final manuscript may receive co-authorship."
Needless to say, I'm going to watch this with great interest. The projects that can be funded at this level (with some expectation of producing something useful) are, perhaps, special cases, but it's the principle of the thing that intrigues me the most. That's why I'm also putting this one in the "Business and Markets" category, because asking for donations like this is a pure market activity. As a person with a pronounced free-market bias, I'm very much wondering how this will all play out. Thoughts?
Update: Wavefunction has a post on this here.
+ TrackBacks (0) | Category: Business and Markets | The Central Nervous System
CB1 ligands were all the rage a few years ago, headlined by Sanofi's rimonabant. These looked like the best shot at the obesity market in a long time, if you were of an optimistic frame of mind. But the entire class came crashing down with the regulatory rejection of rimonabant itself, followed by the failure of Merck's taranabant in the same area. (Pfizer publicly dropped out of the area, and number of other CB1 programs never even upped periscope, after watching the chaos up there on the surface).
Now there might be another shot. CNS side effects doomed the original ligands, but many people thought that the brain was the site of action. How about a compound that's selective for the periphery? Work has been going on over the last few years to just that end, It turns out that these actually do seem to show effects in rodent models, so the chase might be on again. You'd think that anything that avoids the brain, with its ever-present potential for "Wow, who knew that would happen?" effects, would have a better shot. Given the size of the obesity market, I think we'll be given the chance to find out. . .
+ TrackBacks (0) | Category: Diabetes and Obesity
October 3, 2012
I wanted to take a moment to mention this conference, coming up on November 6 at Northeastern in Boston. They have a wide-ranging program on drug discovery scheduled, with some people that I know from experience to be good speakers. Worth a look if you're in the area.
+ TrackBacks (0) | Category: Chemical News
So after all the talking we've done around here about stock buybacks in the pharma world, it's worth noting that the new CEO of AstraZeneca has halted their program. Naturally, that has people talking about what they're going to use the money for otherwise - that is, what company they're going to buy. But it's interesting to see a public mention of the buyback program hitting the brakes like this. . .
+ TrackBacks (0) | Category: Business and Markets
I can't resist pointing out this compound, which recently showed up in J. Med. Chem.. Now, that's a Bcl-2/Bcl-xl inhibitor, the star of the protein-protein interaction world, and there's probably never going to be a nice-looking compound that does the job in that system. The interacting surfaces are too wide and too shallow; it's a real triumph that people have compounds for this system at all. But people have, and there are compounds in the clinic.
But man, will you look at the things. This is one from
Bristol-Myers Squibb the University of Michigan, and it is a beast in all directions. It weighs a mere 811 daltons, and is actually one of the more svelte compounds in the paper. Solubility, formulation, absorption, clearance. . .it all looks like fun. But we may well have to start learning how to deal with compounds like these, so we'd better steel ourselves.
+ TrackBacks (0) | Category: Cancer | Chemical News
October 2, 2012
Now, here's a big idea. Thirty billion dollars worth of big idea. Andrew Lo, professor of finance at MIT (Sloan) and hedge fund manager, along with Jose-Maria Fernandez (Sloan) and Roget Stein (Sloan and Moody's) propose raising that much money for discovery-stage oncology research. But he's not running a fund-raising appeal for a charity; he wants to raise that money as an investment:
Here we propose a financial structure in which a large number of biomedical programs at various stages of development are funded by a single entity to substantially reduce the portfolio's risk. The portfolio entity can finance its activities by issuing debt, a critical advantage because a much larger pool of capital is available for investment in debt versus equity. By employing financial engineering techniques such as securitization, it can raise even greater amounts of more-patient capital. In a simulation using historical data for new molecular entities in oncology from 1990 to 2011, we find that megafunds of $5–15 billion may yield average investment returns of 8.9–11.4% for equity holders and 5–8% for 'research-backed obligation' holders, which are lower than typical venture-capital hurdle rates but attractive to pension funds, insurance companies and other large institutional investors.
Here's a Boston Globe story on the idea. Lo and his co-authors note the low productivity of drug research in recent years (which he doesn't seem to think is a scam!), and its increasing costs. At the same time, there have been many scientific advances in areas that you might have thought would have helped, but here's how he reconciles these trends:
Here we propose one explanation for this apparent inconsistency and a possible solution. Our proposed explanation is the trend of increasing risk and complexity in the biopharma industry. This trend can be attributed to at least two distinct sources: scientific advances and economic circumstances. That biomedicine is far more advanced today than even a decade ago is indisputable, but breakthroughs such as molecular biomarkers for certain diseases generate many new potential therapies to be investigated, each of which requires years of translational research at a cost of hundreds of millions of dollars and has a substantial likelihood of failure. Although such complexity offers new hope to the afflicted, it also presents an enormous number of uncertain prospects that must be triaged by researchers, biopharma business executives, investors, policymakers and regulators. . .the lengthy process of biomedical innovation is becoming increasingly complex, expensive, uncertain and fraught with conflicting profit-driven and nonpecuniary motivations and public-policy implications. Although other industries may share some of these characteristics, it is difficult to find another so heavily burdened by all of them.
Hard to argue with that. He then goes on to one of the same questions that's been discussed around here - the effect of the stock market on a drug company's behavior. If the quarter-by-quarter focus of most investors is inappropriate (or downright harmful) when applied to an R&D-driven company with timelines like the drug industry's, and if private equity doesn't have the cash to invest on that scale (or the willingness to take the expected returns even if things work out), what's left?
That's the idea here, to provide something that currently doesn't exist. The idea is to finance things via securitization:
Our approach involves two components: (i) creating large diversified portfolios—'megafunds' on the order of $5–30 billion—of biomedical projects at all stages of development; and (ii) structuring the financing for these portfolios as combinations of equity and securitized debt so as to access much larger sources of investment capital. These two components are inextricably intertwined: diversification within a single entity reduces risk to such an extent that the entity can raise assets by issuing both debt and equity, and the much larger capacity of debt markets makes this diversification possible for multi-billion-dollar portfolios of many expensive and highly risky projects.
These debt instruments will have longer time horizons, which can be tailored a number of different ways. Securitization can provide a whole range of different bonds to be issued, with different maturities and different levels of risk. The fund itself would earn its returns from the sale of whatever assets its funded projects generate - outright purchases by larger companies, milestone payments, royalties, whatever. With enough diversification, Lo et al. think that this could work, if some cost savings kick in as well:
Compared with the plethora of small pharmaceutical companies currently pursuing just one or two projects, these savings are especially important for a megafund. It is considerably harder to cull compounds efficiently in a small company because the livelihoods of the employees and management depend on the continued development of the company's few compounds—in these cases, development tends to continue until the money runs out. With a megafund, this conflict is greatly reduced—capital can be more efficiently allocated to projects that are likely to succeed, and failing projects and compounds can be abandoned rapidly. In fact, for megafunds that have invested in a sufficient number of early-stage projects, it may be worthwhile to build and operate shared facilities for conducting preclinical studies motivated by the megafund's projects. Such a 'preclinical incubator' could provide the megafund with valuable economies of scale as well as reduce duplicative costs in the industry.
Now, this idea is fascinating, but it raises several big questions. Readers with some knowledge of the financial markets will have noted that this whole securitization-and-repackaging process was one of the main engines of destruction during the recent financial crisis. (I continue to recommend Michael Lewis's The Big Short for details on this). Vast amounts of mortgage-backed securities were generated, and their risks were, it is fair to say, poorly evaluated. The paper explicitly addresses this problem, with suggestions on how to keep things from getting out of hand, but this is something that will have to be watched carefully. Securitization, the authors note, can almost be too efficient a way to raise capital.
The rest of the article is a detailed look at the idea through the lens of portfolio theory, along with some simulations of how it might have worked in the past. I strongly recommend that anyone who finds this idea interesting check out these details, but they're beyond the scope of an already-lengthy blog post. I note that Felix Salmon has looked at this from a financial writer's point of view. His take is that this is quite possibly a worthy idea, but he has doubts. For one thing, the proposed "megafund" might find it difficult to pay investors in its early years, and might be forced to make some bad decisions in order to do so. He's also skeptical that the training-set period used for Lo's simulations is representative of what we might expect in the future.
But Salmon's biggest objection is that the idea might well prove unworkable even to test. A smaller version of such a fund would lose many of its advantages; it has to start off large or not start at all. And he's not so sure that anyone can raise that kind of money for something that's as big a change as this would be. There is, in chemical terms, too high an activation barrier.
I'm still thinking about all this myself; there's a lot to think about. Take a look and see what occurs to you - I think that I can guarantee that you'll have some strong opinions, because this is one of those proposals that it's hard to be neutral about.
Update: Nature Reviews Drug Discovery weighs in with a detailed assessment. The article is cautiously optimistic, but wonders if more money will really do the trick.
+ TrackBacks (0) | Category: Business and Markets
October 1, 2012
Bruce Booth has a look at some rules suggested by Glenn Begley of Amgen, who's been involved in trying to reproduce published data. He's had enough bad experiences in that line (and he's not alone) that he's advocating these standards for evaluating something new and exciting:
1) Were studies blinded?
2) Were all results shown?
3) Were experiments repeated?
4) Were positive and negative controls shown?
5) Were reagents validated?
6) Were the statistical tests appropriate?
Applying these tests would surely scythe down an awful lot of the literature - but a lot of the stuff that would be weeded out would deserve it. I really wonder, for example, how many n=1 experiments make it into print; I'm sure it's far more than anyone would be comfortable with if we knew the truth. As I've mentioned here before, different fields have different comfort levels with what needs to be done to assure reproducibility, but I think that everyone would agree that complex biology experiments need all the backing up that they can get. The systems are just too complex, and there are too many places were things can go silently wrong.
That "Were all results shown" test is a tough one, too. Imagine a synthetic paper where each reaction has a note next to it, like "4/5", to show the number of times the reaction worked out of the total number of times it was tried. There would be a lot of "2/2", which would be fine, and (in total synthesis papers) some "1/1" stuff in the later stages, which readers could take or leave. But wouldn't it be instructive to see the "1/14"s in print? We never will, though. . .
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