Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases.
To contact Derek email him directly: email@example.com
Yesterday's post about an outsourcing business started by a couple of my former Wonder Drug Factory colleagues prompted a complaint in the comments section, which I thought I'd bring up to the front here (since I know that not everyone reads the comments). Says reader Flanders:
Yeah, Great Big D! You're plugging a chem outsourcing business? I've never seen someone so much in denial as you. You lose your job to outsourcing yet you sponsor a group looking to exacerbate the process? You'd make a great spokes-person for the American Chemical Society!
My reply was:
My site's closure had nothing to do with India or China, as far as I can see. It was a flat-out reduction in head count - and I might add the the reductions are continuing outside the US as well. The jobs didn't move - they disappeared.
My opinions on outsourcing are on the record: demand is going to push costs up in those countries, and in the long run we (and the rest of the world) are better off with the resulting educated higher-wage work forces there. After all, they have to be able to afford what we want to sell them, too.
But if you're doing a job that someone in Montana, Maine, Mexico, India or China really can do just as well for less money, then you'd better keep your CV updated. That's been true for a long time. Neither the world nor the ACS owes any of us a living.
And I'm sticking to that. Long-time readers will know that I'm one of those lunatics who believes in free trade. I deeply dislike tariffs and other protectionist barriers, and that applies to services as well as goods. As transport and communication have improved, companies have larger markets to sell to, and more places to get their work done. The industrialized nations went through this (internally) some time ago, and now it's happening between nations. I persist in thinking that it's for everyone's good.
Connecticut, where I live, used to have a reasonably thriving ironworking industry, but it didn't survive the discovery of cheaper ore deposits. These days, when a Connecticut company finds that it can do better by moving to a cheaper part of the country (and there are many), that's what they'll do unless the local environment changes. No one expects any different, and why should they? I can't see why I should tell a company to not use chemistry services in India or China, if they can really get the job done. That's equivalent to saying "No, keep that work here, even though we cost more and don't give you anything more for the money". All this means is that if we're going to cost more here, then we'd damn well better have a reason for it. Deliver something that can't be had so easily in Hyderabad, is my advice.
Besides, the expansion of such work in low-cost markets is the best way to make sure that they don't remain low-cost forever. The standard of living rises in the countries involved, and we start over again. You'll see Indian chemists complaining about being undercut by Pakistanis or Bangladeshis before all this is over, mark my words.
It's been nearly three months since my former workplace closed its laboratory doors. By now, many of my co-workers have landed positions, although certainly not all. The experiences have varied widely: some of the associates were able to move to new positions so quickly that they hardly skipped a day of commuting, while other people are still updating their CVs and hustling up every connection they can.
I wanted to put in a brief plug, then, for some former colleagues who have reacted to the closure of the Wonder Drug Factory by striking out on their own. They've started a service company called Cheminpharma, which supports all sorts of chemistry related to pre-clinical drug discovery efforts: medicinal chemistry, synthesis of intermediates, reference compounds etc. They have a site in Connecticut and synthesis capacity in India, and they'd welcome any queries:
Uday Khire (Ph.D., MBA)
25 Science Park at Yale,
150 Munson Street, New Haven, CT 06511
Phone: 203-773-1737 (O), 203-231-3060 (cell)
I hope that they can make a go of it - by publishing that e-mail address, I've at least ensured that they'll get lots of spam, anyway. Works for me! With any luck, they'll hear from some people with more need for med-chem than your average Nigerian scam artist has.
When I wrote about lousy animal models of disease a few days ago, there was a general principle at the back of my mind. (There generally is - my wife, over the years, has become accustomed to the sudden dolly-back panorama shots that appear unannounced in my conversation). It was: that a bad model system is much, much worse than no model system at all.
I've been convinced of that for a long time. When you have no model for what you're doing, you're forced to realize that you have no clear idea of what's going on. That's uncomfortable, to be sure, but you at least realize the situation. But when you have a poor model, the temptation to believe in it, at least partially, is hard to resist. Even if it's giving you the right answers at a rate worse than chance, you can still take (irrational) comfort in knowing that at least you're not flying blind - even as you do worse than the people who are.
There are many reasons to hold on to an underperforming model. Sometimes pride is the problem. I've seen groups that stuck with assays just because they'd invented them, even though the method was slowly wasting everyone's time. Never underestimate cluelessness, either. People will use worthless techniques for quite a while if they're not in the habit of checking to see if they're any good. But the biggest reason that useless procedures hang around, I'm convinced, is fear.
Fear, that is, of being left out in the middle of the field with no models, no insights, and no path forward at all. It's a bad feeling, rather scary, and rather difficult to explain to upper management if you're a project leader. Better, then, to hold on to the assays and models you have, to defend them even if you're not sure you trust them. With any luck, the project will end (although probably not happily) before the facts have to be faced. As Belloc advised children in other situations: "Always keep ahold of Nurse / For fear of finding something worse."
Pfizer got a tiny bit of good news yesterday when an FDA panel recommended their new HIV drug, Maraviroc, for approval. There are several stories that can be told about this news, so let's try a few: The business story is that this is not going to make a lot of difference for the company, because the drug isn't going to be a first-line therapy. They have to hope that it performs well and can expand its use, because a $25 to $50 million/year drug is a roundoff error on the scale of Pfizer's financial concerns. So much for the money.
The drug development story is that this will be the first CCR5 inhibitor to reach the market. That's a useful benchmark by the standards of this blog, because back in 2002, in my second month of blogging, I wrote about this class of drugs. The first CCR5 inhibitors had already made it into human patients by that time, and here we are, five years later, and one of them is just about to make it to market. Patience is supposed to be a virtue, but in the drug business, it's a case of making that virtue out of necessity.
And the big philosophical story is how the world has changed in the last twenty years. Here's a new HIV medication, one with a new mechanism, and it makes the second business page of the paper if it makes it at all. A completely new drug for a dreaded disease is coming, and no one thinks it'll do all that well, because of all the competition, y'know. It'll be given to people who've failed courses of treatment with all the other HIV drugs out there, and unless you're paying attention it's hard to keep up with all of them.
For people who remember the 1980s, all this still feels strange - imagine a message from the future popping up in 1985, saying: "In twenty years, the viral disease with by far the most crowded market, the largest number of possible therapeutic options and the widest variety of drug mechanisms will be. . .HIV". Actually, that would have scared everyone even more than they already were, because it would sounded like the worst predictions from that era had come true. In reality, HIV isn't even in the top 15 causes of death in the US, with the most recent figures I can find putting its contribution to the death rate a bit below that of aortic aneurysm. (Some other parts of the world are a different story, of course, although the 1980s predictions for them were even more apocalyptic.) But all in all, I'm fine with living in a world where new drugs against deadly diseases aren't necessarily front-page news. . .
As everyone will have heard by now, AstraZeneca opened up the wallet but good yesterday, offering over 15 billion dollars for MedImmune. There was pressure on both sides, from what I understand. AZ has had a rough time of it the last few years, with several major clinical disappointments (one of which, Iressa, actually managed to stagger and lurch onto the market). For its part, MedImmune's big shareholders seemed to think that they weren't getting quite the value they thought the company was worth. Yesterday's offer is about a 20% premium to the previous stock price, so maybe that should cheer them up.
This is part of what seems to be a general blurring of the small-molecule and biologic worlds. One the one side, you have deals like this (and Merck's foray into RNAi, etc.), but at the same time the big biotech players are doing more small molecule work. Genentech, after some fits and starts over the last ten or fifteen years, is ramping up their traditional drug discovery (which I know since two of my former colleagues recently got hired out there). Amgen has a pretty good-sized effort, in both California and Cambridge, but (as I was talking to some people yesterday about), no one really seems to know what they're doing yet with all that money and talent.
Did AstraZeneca overpay? I'm a fine one to ask, since to me all these deals look overpriced. They have a better idea of what MedImmune's pipeline looks like than anyone on the outside (they'd better!), so I have to assume that they were able to massage the numbers into something reasonable. But the thing about these deals is that, in the end, there's really no way of knowing whether they're going to work out or not. You can get some fuzzy idea of the odds, but there are so many confounding factors that even the best thought-out move is still a leap out of an airplane. Good luck to all concerned. . .
Pretty much the only thing that an interested lay person has heard about ligand binding is the "lock and key" metaphor. I'm not saying that you could walk down the sidewalk getting nods of recognition with it, but if someone's heard anything about how enzymes or receptors work (well, anything correct), that's probably what they've heard.
And there's a lot to it. Many proteins are really, really good at picking out their ligands from crowds of similar compounds. (If they were perfect at it, on the other hand, we drug company types would be out of business). But the lock-and-key metaphor makes the listener believe that both the ligand and the protein are rigid objects, which they most definitely are not. There's no everyday analog to the way that two conformationally mobile objects fit to each other - well, OK, maybe there is, but it's not one that you can safely use for illustrative purposes. Ahem.
The other big breakdown of the lock and key is that it doesn't deal well with the numerous proteins that can recognize more than one ligand for their binding sites. Particularly impressive are the nuclear receptors and the CYP metabolizing enzymes. Both those classes bind a bewildering number of not-very-similar compounds, and they can do it impressively well. They manage the trick by having binding pockets that can drastically change their shapes and charge distributions, as parts of the proteins themselves slide, twist, and flip around. I can't come up with even a vulgar metaphor for that process.
I'm thinking of doing several posts on the limits of metaphor and simplification in science, and if I do, this will be the first. It's a constant struggle not to mistake the picture for the real thing, particularly if the simplification is a pretty useful one. But eventually, no matter how good, the metaphor will thin out on you, and you'll be in the position of a Greek bird pecking at some painted fruit and wondering why it's still hungry.
I was talking to someone the other day about animal models, and that got me to thinking: there are several therapeutic areas with reasonably good ones, but which indication has the most useless ones?
Naturally, just getting a compound into mice or what have you is going to tell you a lot that you'd never learn otherwise. (Try predicting oral absorption and let me know how well you make out, for example). That's the rough equivalent of a Phase I for animal studies. But finding an animal model of disease (the rough equivalent of Phase II) is a lot trickier. (One of the better ones I can think of is diabetes, and even there you have to work carefully, because a mutant db/db mouse really didn't get to its condition by the same path a human type II patient did).
By "worst animal model", I mostly mean "least predictive". There are some that are a major pain to set up and run, but give you some data that you can at least believe in a bit, and I wouldn't put them in the same class. My nominee are the traditional models that have been used for Alzheimer's. No rodent (heck, no other animal at all) develops the real AD pathology, so there's one strike against you. Years of work on mutants of all stripes haven't (to my knowledge) been able to get around that problem.
And the disease is affecting higher brain functions that are very poorly modeled in any of the small animals, which is strike two. When I used to work in the field, I would occasionally wonder about the relevance of watching a rat ran into one half of his cage or another to a person forgetting an important appointment. Some of the techniques also have the lotsa-work factor going for them, too, like the infamous Morris Swim Maze, which needs its own special room, full of special equipment, and a full-time person trained in its complications to generate the data that you still don't quite trust.
So, that's my candidate. Readers are invited to submit their own - remember, arduous but trustworthy doesn't make the cut. The winner will be arduous and useless.
If you want to see a bunch of press releases from biotech companies that you've never, ever heard of in your life, just go over to Google News and type in "AACR", sorting by date. That meeting just wound up, and it was the usual fiesta of early- and late-stage oncology data.
But cancer is an odd field for drug development. There are (relatively speaking) many more targets, since the disease itself is a huge fragmented bunch of different indications. And we don't have nearly enough knowledge to have a good idea - any idea, most of the time - about which of these targets are more likely to work, and against which forms of cancer. The trials themselves tend to be smaller (thus cheaper), since the course of the disease is often so relentless, and if you get a drug to market, you don't have to take out ads on the Super Bowl to promote it to oncologists.
All that means that the entry barrier to the field is lower, and there are plenty of niches. And boy, are they filled by a lot of microscopic companies. I keep up with things fairly well, but there are outfits presenting at AACR that might as well be from the asteroid belt for all I know about 'em. . ..
Well, we're exactly on the opposite side of the year for Nobel season, but Paul over at Chembark has the latest odds on the next Chemistry prize. There are a couple of ringers in the list, but it's an excellent reference for big achievements by living chemists. It's also a useful thing for people who are immersed in synthetic organic chemistry to look over, because we sometimes have an exaggerated view of our place in the chemical world. I'll post more on this sort of thing in a few months, but clip and save Paul's post until then. . .
I have boxes and boxes of files here at home these days, the contents of my filing cabinets in my former office. Obviously, I heaved the proprietary stuff before I left, but I still have plenty of folders full of papers from the literature. Some of those went into the dumper as well, though, as I pulled them from the cabinets and realized how old they were. The biology-based folders were the main candidates - stuff on Alzheimer's from the early 1990s, for example. Old NMR manuals and such got the heave, too.
The chemistry files have held up better, although some older reviews went into the shredder. I still have the first real journal articles that I ever copied off, from my undergraduate days back in 1981. These were a series of articles from the late 1970s by two guys named Burfield and Smithers on the best ways to dry common solvents. They're looking a bit tattered these days, but the information in them is still valid.
And there's another old folder that I'll never throw out. It has my continuation exam material in it from grad school, and it looks like something made by a caveman. The bonds are drawn with pen, using a plastic template, and the atoms are the good old rub-on letters. You used to be able to buy sheets of those things from Aldrich - standard rub-on sheets didn't have the letters biased toward common atoms and tended to get used up too quickly. When you messed something up with the template, you either did the whole thing again, or used some correction fluid. When you messed up with the letters, you scraped them off with a razor blade. The whole process was much, much, closer to making gouges in a tablet of pressed buffalo dung and leaving it to dry in the sun than it is to using Chemdraw.
And that's why I'm keeping them. When I get frustrated with some device or technology, I try to remind myself of the days when a page of structure drawings involved Scotch tape, ball-point pens, and razor blades. I just barely overlapped with that era, but it was more than enough.
The doctorate-or-not discussion is roaring along in the comments to the last post, and they're well worth reading. I have a few more thoughts on the subject myself, but I'm going to turn off comments to this post and ask people to continue to add to the previous ones.
One thing that seems clear to a lot of people is that too many chemists get PhD degrees. I'm not talking about the effect of this on the job market (more on that in a bit) so much as its effect on what a PhD is supposed to represent. So, here's my take on what a PhD scientist is supposed to be, and what it actually is in the real world. I'm going to be speaking from an industrial perspective here, rather than an academic one, although many of the points are the same.
Ideally, someone with a doctorate in chemistry is supposed to be able to do competent independent research, with enough discipline, motivation, and creativity to see such projects through. In an industrial applied-research setting, a PhD may initiate fewer projects strictly from their own ideas, but they should (1) always be on the lookout for the chance to do so, (2) be willing and able to when the opportunity arises, and (3) add substantial value even to those projects that they themselves didn't start.
That value is both creative and managerial - they're supposed to provide ideas and insights, and they're supposed to be able to use and build on those of others. They should be able to converse productively with their colleagues from other disciplines, which means both understanding what they're talking about and being able to communicate their own issues to them. Many of these qualities are shared with higher-performing associate researchers, who will typically have a more limited scope of action but can (and should) be creative in their own areas. Every research program is full of problems, and every scientist involved should take on the ones appropriate to their abilities.
So much for the ideal. In reality, many PhD degrees are (as a comment to the previous post said) a reward for perseverence. If you hang around most chemistry departments long enough as a graduate student, you will eventually be given a PhD and moved out the door. I've seen this happen in front of my eyes, and I've seen (and worked with) some of the end results of the system. The quality of the people that emerge is highly variable, consistent with the variation in the quality of the departments and the professors. Unfortunately, it's also consistent with the quality of the students. But it shouldn't be. The range of that variable shouldn't be as wide as it is.
There are huge numbers of chemistry PhDs who really don't meet the qualifications of the degree. Everyone with any experience in the field knows this, from personal observation. You will, I think, find proportionally more of these people coming out of the lower-quality departments, but a degree from a big-name one is still far from a guarantee. The lesser PhD candidates should have been encouraged to go forth and get a Master's, or simply to go forth and do something else with their lives. They aren't, though. They're turned loose on the job market, where many of them gradually and painfully find that they've been swindled.
Over time, the lowest end of the PhD cohort tends to wash out of the field entirely. There are, to be sure, many holders of doctoral degrees in chemistry who go into other areas because of their own interests and abilities. But there are also many jobs that make an outside observer wonder why someone with a PhD is doing them, and that's where many people end up who shouldn't have a doctorate in the first place. Others, somewhat more competent, hold on to positions because they're able to do enough to survive in them, if no more. While there are plenty of bad or irrelevent reasons for people not to be promoted over the years, some cases aren't so hard to figure out.
Those, then, are my thoughts on the doctoral degree. What can be done about this situation, if anything, will be the subject of a future post. I have another set of opinions on the Master's degree and its holders, which I'll unburden myself of a bit later on. Comments, as mentioned, should go into the discussion here.
There's been a lively discussion in the comments thread to this post about the differences between hiring PhD and associate-level chemists. Anyone who's interested in the topic should have a look, because there are a number of issues in play: chemical knowledge, ability to manage direct reports, adaptability, and more.
There's little doubt that non-Phds have an easier time getting hired. There's almost always a ceiling over their heads, rarely one as transparent as glass, but finding a place under it isn't as hard as finding one off to its side. One question that's come up is whether chemists with doctorates could (or should) apply for associate-level positions.
This has been done - but it usually involves deception. If you have a PhD on your CV, most places just aren't going to consider you for an associate job - thinking (probably correctly) that you're going to be more trouble than you're worth. The feeling is also, even in down job markets, that you're selling yourself short by going for these jobs, and that there must be some good reason why you're doing so. . .
I have personally seen a case that bears on this. Karl (as I'll call him) was a pretty good associate. Not (I'd say) the absolute best we had at the time, but definitely above average. A vacancy appeared in the PhD ranks in the group, and Karl stunned the group leader involved by marching in to his office and revealing that he actually had his doctorate, and that he was interested in applying for the position.
What happened to him? Well, he was fired. He was fired reluctantly, and people in the organization found him a position with a small company in the area, but he was fired. He'd lied on his job application materials, and the company's legal department had only to hear that before they ruled that there was no other choice. How could we deal with people who lied about other things on their applications if we kept him on?
The problem was that as things stood, Karl would have moved from being one of the best associates to being one of the lesser PhDs. His strengths and weaknesses at the time fit better for an associate position than as a lab head. And that brings up another question from the comment thread: are too many people going on to get doctorates? I have no idea myself, but I have to say, it's not an unreasonable thought. . .
I've been out of the research labs for over two months now, and you know what I miss the most? No, not the safety meetings (hah!) or the smell of the solvents - what I miss is getting fresh data on experiments. Waiting for results on something crucial is hard to take, but it's also exciting, and there's nothing I've found outside of science that compares.
I've sat at my desk holding a warm printout from an LC/MS, or with a newly arrived e-mail from the biologists, and I swear, I've closed my eyes for a moment before I've looked at them. That's the last moment of not knowing; after that you're living in the new world that the experiment made. I don't know what I'd do with a job that didn't have that feeling in it, and honestly, that's one reason I'm still looking.
It occurs at all sorts of levels - checking the NMR to see if your reaction worked or not, waiting for the PK results to see if your idea raised the blood levels, holding your breath when the compound goes into two-week tox testing. And beyond that things get really terrifying, when human data start coming in from the clinic.
Ask Vertex. I wrote here about their antiviral compound (telaprevir, VX-950) for hepatitis. It's a huge market that really needs a better drug, and a lot of people have taken swings at it. Well, on Saturday night in Barcelona, the company is presenting their latest clinical data, and investors are checking their heart rates. The drug's success would be the biggest event in the history of the company (and a huge advance in hepatitis therapy), and failure (the antiviral norm, unfortunately) would be very, very hard to take.
The company's top clinicians already know the answer, of course, because a person's got to have time to make slides. They've had the experience I was talking about, on a scale that few people have ever felt. You click a button, turn a page, and the future writes itself out there in front of you. . .
I've heard from more than one source that Pfizer has laid off a large number of research staff this week in Groton. This seems to have taken people by surprise in many cases, since the expectation was just that everyone would find out where they were on the new organization charts. Well, in a way, they did.
As mentioned in a comment to this post, the company seems to want to get more people out in the lab. They're aiming for a 4:1 ratio of associates to PhDs in chemistry, where the cuts seem to have been deeper. That would (to my knowledge) probably be the highest average ratio in the industry. Pfizer seems to be approaching this through both the numerator and the denominator: I've heard of associate-level chemists who had CVs in with the company getting recent messages about some planned hiring.
But for now, there are more researchers (chemistry and biology) out of work. The Northeast, I have to say, is getting rather saturated with drug industry job-seekers. The region is still processing my own site's closure, so I have a great deal of sympathy with the Pfizer folks who are being turned out now.
Looks like my doubts about the potential of Pfizer's inhaled insulin Exubera were well-founded. Pfizer's having some trouble making headway, and have announced a re-launch of the product. Needless to say, you don't re-launch products that are performing up to expectation.
When I wrote about the product a year or so ago, various dissenting comments on that post used phrases like "grand slam", "smash hit", and the ever-popular "blockbuster". It hasn't happened, though, and odds are lengthening that it ever will.
Amgen's not getting a lot of good press these days. They're famously the House that EPO built, but (in a familiar story) they may have pressed their lead franchise too far. An excellent backgrounder can be found here at Nature Biotechnology. In short, the company was coining money in the renal market, and looked for new areas where EPO could be of use (and of profit). Chemotherapy-induced anemia looked like a winner, and Amgen aggressively promoted EPO's use in oncology. (Correction - the real extension was into cancer-associated anemia, not just that induced by chemotherapy. See the comments for more - DBL). But (as the editorial details), this whole strategy is backfiring disastrously.
First off, anemia doesn't appear to be a major cause of chemotherapy side effects. If that weren't bad enough, a series of clinical trials have shown that patients receiving standard therapy plus EPO do worse than usual. As of last month, all forms of EPO now have a new black-box label warning. Not ugly enough yet? OK, the company has admitted that it knew about some of this data but didn't talk about it for months. The SEC is investigating them for that decision, and Medicare is looking at whether the company has been overcharging. Their CFO just announced that he's "pursuing other interests".
A sample of the Nature B. editorial makes its point well:
"Amgen does not come out of this well. Although seeking new indications for existing medicines is clearly a valid strategy, the company appears to have miscalculated the balance between expansion and the risks to its existing business—and potentially opened itself to charges that it has recklessly endangered patients' lives. . .
Furthermore, Amgen has surely miscalculated strategically. Any benefits from the commercial push to extend Aranesp into new oncology markets are likely to bring relatively modest returns—Aranesp's 2006 sales in cancer-associated anemia, for example, were approx. $500 million. But the repercussions of failure will be felt not only in cancer but also potentially across all EPO markets. A proportion of the whole $7.1 billion Epogen and Aranesp franchise—nearly 50% of Amgen's total revenue in 2006—is thus under threat."
Amgen isn't the first drug company to have over-reached. Everyone's going to try to make the most of their existing drugs, especially when there aren't all that many things coming along to replace them. But readers with some classical background may well think of Croesus crossing the Halys every time they hear about this kind of thing. . .
I had a question the other day in my e-mail about various sulfur-containing functional groups in drugs. My answers, condensed, were as follows:
Sulfides: will always be under suspicion for oxidation in vivo. If that's your main mode of metabolism and clearance, though, then the problem can be manageable. Still, many people avoid them to not have to deal with the whole issue, and I can't blame them. I do the same. Since the reagents needed to prepare them tend to reek, it's a handy bias to have.
Sulfoxides: I spent quite a while on an old project turning out a whole line of these. I'm not sure if I'd do that again, though. Sulfoxides are interestingly polar, but they're also frustratingly chiral. If you need a specific right-hand or left-hand sulfoxide (and I did!), there are numerous not-always-appealing ways to get them. The other worry about them is that they can get either oxidized (up to the sulfone) or reduced back down to the sulfide. A good example of this problem is in the -prazole proton pump inhibitor drugs, which are probably the most prominent sulfoxides on the market. Some of them (like omeprazole) get oxidized, and others (like rabeprazole) get reduced. I've even heard of a chiral sulfoxide going in vivo and coming back out in the urine as the other enantiomer, via reduction and chiral oxidation. Many people prefer to avoid the whole issue - and after my experiences, I can't say I blame them here, either.
Sulfone: finally, a metabolically stable one. Sulfones have a reputation as rock-solid functional groups, at least when there aren't active hydrogens next to them. Of course, sometimes the compounds are also stable rocks that don't like to dissolve, but we have that problem with everything. I haven't come across anyone with an unkind word for sulfones.
Sulfonamides: If you're an experienced medicinal chemist, boy, have you cranked out some sulfonamides in your time. They're just so easy to make, and you can get so much structural variation out of them. But secondary ones (with a free NH) can get you into trouble in vivo, since they're so acidic. Acidic compounds can behave weirdly when they try to cross out of the gut or into cells, and have a reputation for hanging around in the blood forever. My bias has always been to go with sulfonamides that have fully substituted nitrogens, and I say let 'em rip.
So, those are my biases. Readers are invited to unload their buried feelings about sulfur functionality in the comments.
Some readers will remember a 2005 run-in that I had with stock pundit Jim Cramer over Biocryst Pharmaceuticals. I disagreed with his recommendation to buy the stock, since I didn't think much of their drug for avian influenza, and (rather to my surprise) he e-mailed me, saying that hey, the call was correct because it made money. The best response to this line of thought was the one I saw over at The Stalwart, namely: "Jim Cramer likes to say "There's always a bull-market somewhere" and in the short-term he's right; it's wherever he says it is." When you're the host of a hugely popular stock-picking show, it's a little precious to defend your picks because they went up after you picked them.
But what if they go up after you tell people to sell them? I wrote last week about the cancer vaccine companies. Well, as it happens, Cramer told people to bail out of Dendreon the day before the FDA advisory panel gave them a good review. As you'd imagine, some of his listeners are rather peeved about that, looking at the stock move they missed out on.
But I actually have a bit more sympathy for Cramer this time. Predicting which way some of the FDA hearings will go is a fool's game, and you're as likely to be wrong as right. Picking against Dendreon made as much sense as coming out for them; it wasn't a stupid call, except in the sense that any call was a stupid one. The reaction of his audience leads to a larger conclusion, though, which is that picking stocks based on listening to Jim Cramer yell about them is a fool's game, too.
For example, if you'd bought Biocryst right after Cramer told you to in October of 2005, you'd have gotten in at about 13 at the open. It went right up past 17, at which point he told his audience that the trade was over, and it was time to get out. Once his listeners did that, the stock went back to 11 and change in November - but by the next spring, it was over 20. You'd have done better buying right after Cramer told you to sell, in other words - but only if you knew when to sell, yourself, which is the fine-print clause that sinks most of these wonderful stock stories. BCRX is now below 9, by the way. I have no clue whether you should buy it or not.
All of its price changes were driven by all kinds of news - alliances with other companies, development news on both the bird-flu stuff and on completely unrelated drugs, the usual range of things. None of them had anything to do with some guy shouting on a TV show. They were all about things out in that other place - the real world, which (as has been demonstrated many times) isn't as well-scripted as television.
Cancer drugs have a terrible history in clinical trials. The most definitive figure, from development candidates of the 1980s and up to the mid-1990s or so, was a cold, hard, 95% failure rate. That beat even the central nervous system (CNS) drug category, which is a spacious haunted mansion all its own. One reason for this is that all kinds of things get thrown at oncology targets, because there's so much unmet need in the category. Whenever someone comes up with a new technology - monoclonal antibodies, antisense DNA (or RNA interference), disease-altering vaccines, etc. - you can bet that someone's going to try it out on a cancer target. Not all this stuff is going to work, needless to say.
But I wonder if that figure still holds. Starting later on in the 1990s, and gathering speed ever since, a lot of the small-molecule drug candidates in the cancer area have been kinase inhibitors. Now, back when I took my first pharma job, those compounds weren't in very good favor, partly because the key structural motifs that everyone uses today hadn't been worked out yet. If you mentioned kinase inhibitors in the labs, likely as not someone would spit in the sink and say something rude about staurosporine.
That was one of the early potent kinase inhibitors, a fairly nasty natural product. (Note: outdated web page in that link, which fits the subject). All sorts of people worked on staurosporine-like compounds during the 1980s and beyond, and most all those projects came to grief of one sort or another. It gave the whole field an unhealthy look.
There were also good reasons to think that no really selective kinase inhibitors could be discovered (since the enzymes have many structural similarities), and that the resulting broad-spectrum compounds would have just too many side effects to be useful. But molecular biology was uncovering a role for many kinase enzymes in cancer and other disease states, so people kept taking a crack at the area, and finally some far less ugly compound classes were discovered that broke the field open. Once decent compounds were in hand, it was found that they weren't as toxic as everyone had feared. Selectivity was still an issue, but you could sort of tune the structures to inhibit various groups of kinases over others.
I would not want to hazard a guess as to how many kinase inhibitors have gone into development over the past ten or twelve years. It's a pile, for sure - just look at KinasePro and Xcovery to get the idea. I will guess, though, that they haven't failed at quite that horrific 95% rate, and that a 1995-2010 survey of the field will show an improvement. Mind you, the record-holder in the earlier survey was, cardiovascular area, where only about 85% of the compounds collapsed, so don't think I'm talking about a huge increase. But when only one out of twenty of your drugs makes it, getting up to two in twenty means that you have twice as many drugs.
I'll be posting later on today as well, but I wanted to mention another crop of science blogs that have been added to the blogroll.
First off, I'm glad to report that there's another pharma drug discovery blogger at One in Ten Thousand. And there's The Futile Cycle, on the biology side, which includes the only poem I've ever seen written about ion channels. I've also added a new blog called Science, Theory, and Liberty, which I hope keeps going. Those air-sensitive organometallic folks now have representation of their own with Organometallic Current. And finally, there's Med Tech Sentinel, with news from the whole medical-device world, which is an area that I don't manage to cover very much. Enjoy!
You know, small-molecule folks like me are going to have to learn to deal with immunology. I don't mind saying that it's not my field - yet - but who knows, perhaps it will be. The recent successes of Dendreon and (today) Cell Genesys prompt these thoughts. Both companies have shown useful efficacy with immune-based prostate cancer therapies, good enough to make you wonder how effective these things will eventually be when we understand more about what's going on.
As things stand, there are a bewildering number of possibilities. Both of these vaccines depend on production of GM-CSF secreting cells (a powerful cytokine which stimulates white blood cell production and activity), but they're rather different otherwise. Dendreon's Provenge is autologous, that is, derived from each patient's own cells, for one thing, while the Cell Genesys GVAX vaccine isn't individualized at all (that is, allogeneic). That's just the first choice to make. There are all sorts of options about what kinds of cells to use, which antigens to decorate them with and what proteins to have them secrete, how to administer them to patients singly and in combination with other conventional chemotherapies, and so on. This work has been going on for years now, and I've no doubt that a lot of blind alleys have been followed. And a lot more will get followed, too, but the results so far are pretty impressive. They're beating the small-molecule conventional therapies in the difficult cases, that much is clear. It's important to remember that the patients are still dying of cancer, but they're taking noticeably longer to do it, which is success in our era.
We'll probably see a rush into the stocks of every company that has both "cancer" and "vaccine" in its 10-K filings, but I'd say be careful. For example, if you bought Cell Genesys last week, you're quite happy. But if you bought it this time last year, you're still in the red. Although I find these current results quite interesting, the field is still very young indeed. Companies are targeting prostate cancer because it's a non-essential organ (so it doesn't matter if the immune system trashes it), but they're also going to be going after tumors in rather more vital organs like the lung and pancreas. Development of immune therapies in those areas is going to be full of more excitement than some of the stockholders will be ready for.
Here's something that you don't see discussed very often, but it's worth some thought: what kind of personality do you need to have to do drug discovery research? Clearly, any conclusions are going to carry over well to other fields, but drug work has some peculiarities that can't be ignored.
The most obvious one is that the huge, horrible, overwhelming majority of projects never lead to a marketed drug. Many readers will have seen the sobering statistics of 85 to 95% failure rates in the clinic, but (bad as that is) it doesn't get across the number of times that projects get nowhere near the clinic at all. Take it from the top: the majority of targets that are screened for chemical matter don't turn up anything useful (it's not even close). The majority of the ones that do still die on their way to clinical trials. And then a solid 90% of those don't make it to market.
So, if you define yourself as a success by whether or not you've put something on a pharmacy shelf, you've set a very high bar, one that many people in basic research don't reach. It's different for people further down the line, where the field has already narrowed. But if you're working on early med-chem, for example, you're likely to go years between realistic shots at a drug you can claim part of the credit for.
That'll vary by your company's culture, too. Some companies bang out projects like a sawmill spitting out boards - or try to, anyway - while others carefully take their time for years and years. There's no certain advantage to either method, as far as I can see (else the companies doing the best one would have taken over by now and driven other modes out of existence). But you'll certainly have more shots on goal at the first type of company, which might keep your spirits up. Of course, the fact that you're largely going to be getting more chances to fail in the clinic might just depress them again, so you have to take that into account.
It'll also vary by therapeutic area. Central nervous system projects are going to run slower than oncology ones, by and large. In cancer, the clinical goals are comparatively clear, and where the disease is often (and most terribly) progressing at such a pace to give you solid numbers in a reasonably short period. Contrast that to Alzheimer's disease, for example, whose ruinous clinical trials could take years to tell you anything useful. Cancer will also give you more shots per compound, since a drug that does zilch for pancreatic cancer (and most do just that) might be useful in the lung or liver. While what we call cancer is several hundred diseases, what we call Alzheimer's might only be one. Depression and schizophrenia are clearly more complicated and split up, but (as opposed to cancer), there's no easy way to tell how many types there are or what particular one a patient might be presenting with, so the clinical work is correspondingly more difficult.
So, this is the pharmaceutical world you're going to have to live in. If you take each drug project personally, as an indicator of your own worth, you're probably not going to make it. You'll be beaten down by the numbers. As an antidote, a bit of realistic fatalism is helpful, although too much of it will shade into ah-that'll-never-work cynicism, which is the ditch on the other side of the road from prideful optimism. I'd recommend learning to enjoy the upside surprises, and to not be surprised by the failures (while still looking them over to see if there's something you can avoid next time around). You really have to draw a line between the things you can affect through your own talent and hard work, and the things you can't. Most of the crucial stuff is in the second category. A sense of humor about your own abilities and limitations will serve you well. But that goes for a lot of other jobs besides the drug business, doesn't it?
There's a good article at Forbeson the various attempts to improve cardiac outcomes by raising HDL levels. Matthew Herper and Robert Langreth round up the latest disappointing results, starting with Pfizer's torcetrapib and going on from there. It isn't an appealing sight.
You'd have thought that raising HDL would be a lot more effective than this, wouldn't you? Think of all the associated evidence that's piled up over the years saying that high HDL levels are cardioprotective. We in the industry have been betting hundreds and hundreds of millions of dollars on the hope that we knew enough to make useful drugs out of this information, and by golly, we appear to have been wrong.
This is just one more example, in what appears to be a literally endless series, of how scientific issues get more complicated the more you learn about them. There is clearly an awful lot that we just don't understand about HDL and cardiac risk, for example. Trying to treat the varying distributions of the many different sorts of HDL particles as if they were all one unit has not been fruitful, to put it mildly, so right in front of us the field divides, branches, and fans out into fuzziness: How many different sorts of HDL are there, and how do we tell them apart? What causes different types to be produced or eliminated? What time scale does this happen on, and how do all these things vary between individuals and populations? What do the various HDL species do, individually and in concert, to affect atherosclerosis and other cardiovascular conditions? How on earth can we come up with drugs to differentiate among them, assuming we ever figure out which ones to go after? We are remarkably far away from answers to any of these questions.
Our business is already dependent to an unnerving degree on rolls of invisible dice. If anyone gets an HDL-directed therapy to work in the next few years, their success will surely have an even greater share of plain good luck in it than usual. We're all going to have to know a lot more about lipoproteins before we can safely reach for our wallets in this area. For now, an awful lot of development money has been irrevocably shredded, and earning it back will be quite the job.