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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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April 30, 2006

All Natural

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Posted by Derek

My thoughts the other day on the World Wildlife Fund's jungle remedies prompted me to talk about natural products chemistry a bit. It's an area that a lot of people have heard about, but not many people outside the field know what goes on there.

There aren't as many natural products research groups as there used to be, although there are enough of them to support a journal or two. That's partly because it's not considered the most cutting-edge sort of work any more, which is a bit of a shame, since there are surely still many useful compounds waiting to be discovered. But another reason not as many people work in the area is that so many compounds have already been found. If you go pick out a random organism and start searching, in most of the cases, most of the things you find are molecules that have already been characterized. The unusual compounds are down in the trace constituents, more often than not.

You have a better chance for novelty if you pick the more exotic specimens, and organisms from highly competitive ecologies are the place to look. They're the ones that find it useful to spend more metabolic energy on chemical defenses. It's no surprise that there are so many interesting compounds from marine organisms, or terrestrial tropical ones. You're less likely to find a wonder drug in an arctic lichen, partly because arctic lichens have their biochemistry pretty well spoken for just in staying alive.

All the common molecules of life, your regular lipids and amino acids and carbohydrates, are suitable food for other organisms. If a creature is devoting some of its metabolism to keep from being bothered, though, it's going to need to make something a little more interesting. This explains why the traditional strongholds of natural products as drugs are in the antibacterial/antifungal areas, and in cancer therapies. Those are the main uses that humans have for medicinal compounds that work by killing or injuring cells.

These chemical defense compounds have been under evolutionary pressure for biological activity in other living things, so drug-hunting in this area is a lot different from screening a combichem library of semi-random compounds. The famous natural product drugs - the taxanes, vinblastines, penicillins, quinines, and erythromycins of the world - hit specific biochemical targets like the ones the synthetic molecules are aimed at. They've had untold millions of years of optimization, and what we see are the variants that have been best at keeping other bacteria away, for example, or keeping insects from stripping the leaves. It's often impossible to improve on the potency of a natural product for its target. The best chances for that are when you can optimize for the human forms of the enzyme or receptor that the compounds are hitting, as opposed to the ones its been honing itself against all these years, or to improve its characteristics in the human digestive and circulatory system, which it probably also hasn't been under pressure to do anything about.

In the old days, extracting things from natural sources was a real black art, and it hasn't completely lost that aspect. There are all sorts of standard schemes that people use when they're looking at some new ground-up root or the like - extract with this solvent mixture, take what's soluble over down this pathway, take the insoluble stuff and do this other thing with it, and so on. These things used to go on for pages and pages, but modern instrumentation (HPLC-mass spec, especially) has made analysis of brutal mixtures a lot faster and more thorough.

And without modern instrumentation (NMR, especially), characterizing what you'd found could take months or years. That was one of the traditional reasons for total synthesis, since in many cases that was the only way to be really sure that a structure had been assigned properly. You'd take the real stuff and carefully break it apart, trying to work out what the fragments were and how they must have been connected, and the synthesis folks would attack the problem the other way around, building the molecule up from hand-made pieces. The heroic age of this kind of chemistry lasted up through the 1960s.

And natural products are still the target of the great majority of syntheses. They show all kinds of challenging complexities (crazy combinations of functional groups, dense and knotty stereochemistry, wild fused ring systems, and so on). Here are some marine toxins to give you an idea, and here are some plant-derived alkaloids. These are only the beginning - there are some really ridiculous structures out there.

So, what happens when you discover that some crazy compound from the Nibi-Nibi sea cucumber looks like a great lead against some dread disease? That'll be the subject of the next post in this series. For now, here are the pages for a couple of very well-known natural products chemists in academia, Jon Clardy and Jerry Meinwald. That'll give you a good take on what the field is up to these days.

Update: more worthy lab sites in the comments.

Comments (10) + TrackBacks (1) | Category: Drug Development | Drug Industry History

April 27, 2006

Golden Parachute, Still Packed and Ready

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Posted by Derek

So it looks like Pfizer's shareholder revolt didn't get much traction today. A couple of groups had urged "no" votes on issues like CEO Hank McKinnell's compensation and pension package, but all the company-endorsed positions were carried by a good margin.

I'm of two minds about this sort of thing, but I come down more with the revolutionaries, partly because I think that company boards should be kept on their toes a lot more than they are. And although I'm somewhat rightish in my politics, I think that CEO compensation has become out of whack over the years. Making the rewards this huge seems to me to run the risk of creating a management culture that's mostly concerned with fighting to the top of the sugar pile. I do think that higher positions should be well-paid, mind you, just perhaps not quite as asymptotically well-paid as they've become. Presumably the market will eventually correct for this, if companies become too top-heavy in their expenditures or ruin their managerial competence with perverse incentives. But it could take a while for all that to even out, and in the meantime we have some unseemly situations.

I'd rather see such rewards tied to measurable performance, insofar as it can be measured, but there's a danger in relying on any one factor. If you tie the big payoffs to the price of the company's stock, you create a moral hazard, with an incentive to do whatever it takes to elevate the stock. And that's only a rough surrogate for what's good for the company. If you use some sort of internal financial measurement, like sales growth or what have you, then the hazard is the temptation to sweeten the numbers. Examples of both of these situations abound. I think it's best to rely on a score that's made up of a number of factors, with no one of them large enough to present a target for funny business.

How does McKinnell stack up? Pfizer's stock has been no particular prize during his tenure, and I've said before that I don't see it being one for some years to come. That's one of the things that got the shareholders - some of them, anyway - wound up. Other measurements could be spun either way: if you like the bigger-bigger-bigger path the company's taken the last few years, and admire the big-decision mentality that's been needed to realize it, then you'd probably be inclined to let the man take the cash. But if you think that these moves are part of Pfizer's current problems, or at least no part of their solution, then you've got a different figure in mind for him. Pfizer seems to have more of the first type of shareholder than the second, at least for now. . .

Comments (13) + TrackBacks (0) | Category: Business and Markets

April 26, 2006

Jungle Rot

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Posted by Derek

There are all sorts of excellent reasons not to cut down the rainforests of Borneo. Biological diversity, erosion, local climate, sheer aesthetics. . .no one should have to scratch their head for very long. But this isn't one of them, at least not the way it's being sold:

"Plants thought to help treat or cure cancer, AIDS and malaria have been found in the rainforests of Borneo, a report from the Swiss-based global conservation group WWF said on Thursday. . . A promising anti-cancer substance has been found in a Borneo shrub by researchers for an Australian pharmaceutical firm, while a chemical found in latex produced by a tree appears to be effective against the replication of HIV, the report said.

In the bark of another species of tree, the researchers discovered a previously unknown substance which in laboratory tests appeared to kill the human malaria parasite, it added."

Going to the source of the story, one finds more details:

"According to the report, Cerylid Biosciences – an Australian pharmaceutical company – has identified a promising anti-cancer substance in a shrub found in Sarawak. A compound present in the plant Aglaia leptantha has been found to effectively kill 20 kinds of human cancer cells in laboratory tests, including those that cause brain and breast cancer, and melanoma.

“The fact that the compound is very effective against a number of tumour cells, presents a very good argument for preserving the plant's habitat in Borneo,” said Dr Murray Tait, Vice President of Drug Discovery at Cerylid Biosciences."

No, it doesn't. The reason I say this is that we have oh, so many compounds already that will kill off twenty different kinds of human cancer cells in the lab. I mean that - tens of thousands of the damn things. Killing cancer cells in a dish is not as hard as it sounds, unfortunately. Now, killing any of them off effectively in a mouse model, that's another story. We probably only have hundreds and hundreds of those around, maybe a few thousand. And getting these things to work in humans? Well, you already know how many of those we have. It's a rather stiff attrition rate, y'know. I note without comment that Cerylid itself doesn't seem to be doing all that well right now.

Keeping Borneo from being clear-cut is a proposition that can be sold on its real merits. It doesn't need this kind of whoop-whoop. All these arguments do, in the long run, is make the people advancing them look like fools or con artists (Rain forest medicine! Jungle cures! Real soon now!). And it makes people think that discovering cancer drugs is actually not all that hard - just look in the right plant, and there it is. We already have enough people who don't realize how long the road is between some neat result in a culture dish and a real drug, thanks very much.

Comments (16) + TrackBacks (0) | Category: Cancer | Press Coverage

April 25, 2006

A Shot Across the Bow

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Posted by Derek

The Ariad-Lilly suit that I spoke about here earlier this month is continuing along, with no news to report. But there is an interesting development: Amgen, surely one of the companies contacted by Ariad about infringement of their NF-kB patent, has decided to play offense. They've filed suit against Ariad in the US District Court in Delaware, seeking a declaratory judgement that Ariad's patent is invalid and that Amgen hasn't infringed any part of it. Interestingly, there's no press release about this to be had from Amgen. Ariad is the source of all the information on this - it's much more of a material event for them, so they're under greater regulatory pressure to disclose the news.

Such rulings can be sought when one party feels what the law terms a "reasonable apprehension" of legal action by another, and I'm sure that Ariad's letter would be enough to meet that requirement.

Meanwhile, according to the U.S. Patent Office's "Official Gazette", there's been a re-examination request filed for Ariad's original patent, as of last December. The applicant is listed as Bawa Biotechnology Consulting, which would be Raj Bawa's firm. They're well-known for doing biotech freedom-to-operate and infringement work, and I would assume that they're being paid by Lilly. Or maybe Amgen. Heck, maybe even someone else - there are enough people mad at Ariad that it's hard to narrow the list down.

My opinion hasn't changed: I think that Ariad deserves to lose this case, and that they will. If their patent goes down in flames, taking all others of its sort with it, that'll be even better.

Comments (30) + TrackBacks (0) | Category: Patents and IP

April 24, 2006

Merck, So Far

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Posted by Derek

So Merck's now gone 3 and 3 in Vioxx litigation. That's a preliminary count, of course, because they're appealing all the cases they've lost. For the same reason, a total of the damages against them doesn't mean very much, either. Does that leave any way to tell how things are going?

Well, you can be sure that with ten thousand or so suits that have been filed against the company so far, that the eventual record is not going to be five thousand up and five thousand down. These things don't take place independently, and there's eventually going to be a run to one side or the other. If Merck starts knocking down some more cases, that'll gradually increase the pressure for settlements in many of the remaining cases (and many others will just evaporate). But if they hit a big losing streak, not only will the existing plaintiffs and their lawyers be more motivated to hang in there, but even more cases will condense out of the vapor phase.

This last loss wasn't a good one to take, since the late defendant was overweight, smoked, had had bypass surgery and took Vioxx (at least as far as his medical records show) for all of seven days. Merck says that this verdict was an aberration which will be reversed. They'd better hope so.

So far, unless I'm quite mistaken, they haven't settled with anyone yet, and they're vowing to take on everyone in court. For that to work, I think that they're going to have to do better than 0.500. If they don't the problem will be keeping the tide from coming in while the appeals process goes on, a process which will start to resemble the Red Queen's race from Lewis Carroll. Even people who think that Merck will come out of this (and I'm one, most days) see the cost to them being around ten billion.

Which is certainly a fine use of the money, isn't it? You could probably discover a drug or two with ten billion dollars, wouldn't you think? But why do that, when you can give it to the lawyers?

Update: a similar analysis from John Simons at Fortune, who says that Merck's only choice is to fight every case.

Comments (23) + TrackBacks (0) | Category: Cardiovascular Disease

April 23, 2006

You Can't Win If You Don't Play

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Posted by Derek

I enjoyed one of the recent comments to the "Why All the Gloom" post, where an IP lawyer mentions what people at the small startups told him: namely, that managers had figured out that by saying "No" they were right all the time, while saying "Yes" had a much lower chance of success.

I know just what he's talking about. You can have an entire career in the drug industry, just sitting around telling people that their ideas aren't going to work. And more than nine times out of ten, you'll be right. Fortunetellers and stockpickers should have such a record! So what's the problem?

Well, the problem is, the whole industry depends on those times when someone's idea actually works. For that to happen, chances have to be taken, risks run. Being in charge of reluctantly-killing-off-once-promising-projects has a lot more job security, but someone has to go and make something happen once in a while.

One problem is, I think, that some companies kill things off for a long period until the situation gets more and more desperate. Then they try to run with whatever's in the clinic at the time. Some of those projects will, no doubt, be worse bets than some of the things that were killed off through excess caution a few years before. But if you didn't let a few of those loose, you eventually get stuck with what you have.

That's what's so nerve-wracking about doing pharma research. It's like playing tournament poker: the blind bets keep going up, so if you don't get out there and play some of your hands, you'll be eaten alive. If you convince yourself that none of your cards are worth anything, you're going to have a short night of it. I say, take Francis Crick's advice: don't believe in your own negative arguments so much. Recognize that every experiment, every program, every drug has plenty of reasons why it shouldn't work. Be aware of them, sure - but be aware that everything successful once had the same questions buzzing around it, too. Something has to work - right?

Comments (16) + TrackBacks (0) | Category: Who Discovers and Why

April 20, 2006

Sulfurous Stenches: A Connisseur's Guide

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Posted by Derek

Inspired by Dylan Stiles' tribute to sodium ethanethiolate, I present Lowe's Guide to Sulfur Aromas:

Hydrogen sulfide: rotten eggs. No more, no less, and plenty of them. Rather more toxic than cyanide, but at least you can smell it coming more easily.

Dimethyl disulfide: not, as these things go, really all that bad. If you smelled it coming out of your refrigerator, you wouldn't be pleased. But compared to the others on the list, it's tolerable - perhaps the cleanest of the sulfur odors. And many organic chemists associate it with a successful Swern oxidation, which gives it some points.

Ethanethiol: the prototype of the class. All the basic sulfur-stink notes - skunky and intestinal. Very volatile, too, which really gives it a quick wallop, but at least it doesn't stay around forever. I had a grad school reaction that used this stuff neat as the solvent, so I know whereof I speak.

Cyclopropanethiol: not sure if you can buy this, but we made it in my lab a few years ago. Smells like a fire in a garlic warehouse - very sharp and penetrating. Notably different from its acyclic brethren.

Propanedithiol: two SH groups in one! Has the same general character as the other lower alkylthiols, but with a darker, more penetrating note. Lasts forever due to its high boiling point.

n-Butylthiol: since butyl groups reek in general, the butylthiol has a special kick all its own. Very rich and skunky indeed, and it sure does hang around.

t-Butylthiol: used as the odorant in natural gas lines, so you know it has something to recommend it. Nasty and overpowering at 100% concentration.

beta-Mercaptoethanol: rather similar to ethanethiol, but the extra OH group gives it some real staying power. Sort of the "sun and sport" version of the parent compound.

Mercaptoacetic acid: ugly, sharp, acrid reek, also with plenty of endurance. Nothing to recommend it.

Thiophenol: you've smelled it, if you've smelled burning rubber. But imagine the pure essence of burning rubber, distilled and bottle for your pleasure. Very long-lasting, too.

Mercaptopyridine: since pyridine reeks to the skies, and thiophenol is so awful, you'd expect the worst from this combination. But it has no smell whatsoever, by some trick of fate. Surely that's for the best.

Comments (41) + TrackBacks (0) | Category: Life in the Drug Labs

April 19, 2006

Why All the Gloom?

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Posted by Derek

A recent comment asks why there's all this wailing about shrinking drug-company pipelines - how did it happen? I've gone into this topic before over the years (the blog's now over 4 years old, which I can hardly believe), but it's worth a quick summary. Here are some reasons - reasonable people can and do add more, and argue about how much importance to assign to each:

1. We used up all the easy targets. That can't be completely true, but still, there's something to it. I'm fond of pointing out that there aren't many home runs like angiotensin converting enzyme out there these days. Ah, ACE - an enzyme, of a class that we know we can inhibit with small molecules, that's right in the middle of a key pathway for a condition affecting millions and millions of people. You could say similar glowing things abouit HMG CoA reductase (the target of the statins). One of the hopes of genome sequencing and mining was that there would be some more of these out there that no one had discovered. This expectation has not aged well.

2. We know too much. There are plenty of drugs on the market that looked perfectly fine back when, but wouldn't go anywhere today. You can start with aspirin. We have so many more assays and counterscreens going now that it's a wonder anything makes it through at all.

3. We're competing against ourselves. As time goes on, and we gradually discover things that work for a reasonable number of people, we have to look harder for unmet medical needs. There aren't any perfect drugs out there, of couse, but there are still some areas which are pretty well served. The bar is (or at least should be) raised higher each time a new drug comes on the market.

4. We're left with really hard diseases. This is a corollary to the previous point. The big unmet medical needs are often unmet for very good reasons. Alzheimer's is a good example - big (and growing) market, lots of human suffering, current therapies almost completely inadequate. But getting a new Alzheimer's drug off the ground is a hideously hard task, not least because we still don't understand the disease very well.

5. Financial and managerial mistakes. It's always easy to use this as an excuse, no matter what the industry. But nevertheless. . .you can argue that some of the mergers that have taken place in the drug business haven't helped anyone much, and may well have harmed things (at least in the shorter term) through disrupted productivity. And even when the dust clears, big companies have their own set of problems.

Another mistake in this category: companies have in some cases also spent too much time searching for great big blockbusters, at the expense of potentially putting several smaller drugs onto the market. If you live by huge whopper home runs, you often die by them too, when the patent runs out.

There - those are a few I can think of immediately. What have I left out?

Comments (30) + TrackBacks (0) | Category: Drug Industry History

April 18, 2006

There Is a Tide. . .

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Posted by Derek

Looking back through the archives, I see that two or three years ago I spent a lot more time than I do now on the issues of drug reimportation and the industry's ability (or lack of it) to deal with Congress. I haven't written about these topics for a while, and by golly, there's a reason:

"After years of pumping millions of dollars into election campaigns, the pharmaceutical industry is reaping the benefits of a vastly improved political climate on Capitol Hill.

The increases in donations have moderated since the last decade as the industry has won passage of long-cherished legislative objectives or fended off challenges that it deemed a threat to its way of doing business.

In the last year, drug companies have won protection from lawsuits involving production of a pandemic flu vaccine. They have been invited to join President Bush in mapping a government strategy to fight a pandemic and have been sought out to assist in producing vaccines against flu and bioterrorism.

At the same time, legislative measures aimed at the industry - notably, bills that would permit importing cheaper prescription drugs from abroad - appear stalled, with little likelihood they will come up soon. . ."

The article goes on to say that the 2004 increases in drug prices (8.4%) were the lowest since 1982, a fact that seems to have been very slightly underreported. It also makes much of the passage of the Medicare drug benefit, which is something that I'm still quite ambivalent on. The provision which prohibits selection based on price worries me, since I'd rather have pricing signals than not. Of course, the flip side of that is that negotiating with Medicare would be a real Godzilla-versus-Megalon situation, and I worry that allowing the program to negotiate prices on individual drugs would be a backdoor route to general price controls. A middle ground would be allowing price discrimination between drugs in the same therapeutic category - just like private insurance does.

On the larger scale, part of this easing of the pressure on the drug industry is probably just other issues (Iraq, energy prices) coming along to take up the slack. Political outrage obeys conservation laws just like anything else. Somehow, I don't think it's safe to put the clip-on horns back in the costume box just yet.

Comments (6) + TrackBacks (0) | Category: Why Everyone Loves Us

April 17, 2006

Reading Our Own Press Releases

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Posted by Derek

So, what's the problem if some of the yields in total synthesis papers are a bit. . .enhanced? If the reactions worked, why get worked up about it?

Well, aside from nagging thoughts of intellectual honesty, there's a practical implication. Even if no one ever tries most of these reactions again - and believe me, no one will - the problem with advertising our mighty chemical powers is that people who don't know any better will believe us.

You can start with other chemists. We've all heard stories about people who've tried to repeat reactions from the Famous Labs of one or another Famous Professors and been unable to get them to work. It's to the point that synthetic chemists with some experience automatically discount the yields that they see from some groups, because they know that they can't reproduce them. (See the comments to yesterday's post if you want some concrete examples). The ones who haven't heard, though, will continue to discover the nasty reality on their own, often wasting their time and effort in doing so.

But I think the serious trouble starts when we get outside of the field. I've worried for some time that synthetic organic chemistry has been in danger of making itself seem more powerful and efficient than it really is. This can be a noticeable problem in industry, where you deal with molecular biologists, toxicologists, and other people who have to take our word for things. And if what they hear about are mighty synthetic chemists banging out mighty molecules in mighty impressive yields, what kind of reception do we mortals get when we tell them that we're having trouble making their lead compounds in enough quantity?

We really don't want to make people think that we can make everything, you know, because we can't. Not in any real-world sense, we can't. Experienced synthetic chemists all know this, because we've all been humbled by comparatively simple molecules and supposedly easy reactions. These things are smarter and trickier than we are, and they'll remain so for a long time to come. It would go easier on us if people outside the field knew that we can't just magically deliver on whatever they'd like us to make. And who knows, perhaps if word got out that organic chemistry isn't a tapped-out all-tied-up field, we'd get some more good people to come help with it.

Comments (26) + TrackBacks (0) | Category: The Scientific Literature

April 16, 2006

Don't Know. Don't Care?

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Posted by Derek

Thinking about the scientific literature, I got to wondering: which part of the chemistry literature is the most unreliable? (That is, fitting that "pessimist universe" model from my post the other day). There's been a recent bit of trouble in the organic chemistry world that I've been meaning to talk about, so I thought I'd lead up to it this way.

If you look at what organic chemistry papers have been retracted over the years, my strong impression is that most of them have been papers on new synthetic methods. That might make you think that this is the weak spot, but I'd disagree - I think that these stand out because people actually read them and try to reproduce them. An interesting new method is going to be tried out by others, and it'll be clear very quickly if there's a problem. I wrote about such a case on my old site, back in 2002:

". . .There's a paper out now (which for those of you in the field is Synthesis, 29, 2002), that belongs to the select group of articles whose sole purpose is to demolish another one. The now-discredited article was in the same journal over a year ago, presenting an interesting reaction that I thought we could make use of in my lab. (Keep in mind that the classic definition of "interesting" in the scientific literature is "interesting to me!") We actually tried the chemistry out. It flopped cleanly and completely, giving exactly the wrong product. I chalked it up to the weirdness of our current compounds, which is not to be underestimated. Some things work on them; some don't. We poured the reaction into the red waste can and did something else, which is one of the things I like most about medicinal chemistry.

The author of the latest article, though, had the same thing happen to him, and he didn't take it as quietly. Going back over the original examples, he shows that the published work won't, didn't, and can't go the way it was reported to. Some of this can be put in the "honest mistake" category, subheading "really sloppy honest mistakes," but I'm afraid, in the end, that some of it can't. . ."

Even things that don't look all that useful at the time will often get dragged out into the light by somebody eventually. No, my vote for unreliability is the papers on total synthesis of natural products. In almost all cases, no one will ever do those reactions again. The exceptions are the rare examples where the product is itself useful and the synthesis has industrial relevance (taxol!), or the times when more than one group is working on the molecule simultaneously and using similar approaches.

But how often do such things happen? Mostly, it's "Total Synthesis of Timewastotoxin", which either no one will ever see fit to make again, or if they do will have to use a completely different synthesis (because otherwise, what's the point?) The yield in step 48 could be inflated like a beach ball - who will ever know? Step 33 might be the only run that worked out of 64 tries. In fact, the pressures of such work make it rather likely that these very things have taken place.

I'm not saying that the majority of total syntheses in the literature are incorrect - since (in the end) the synthetic product can be compared against the natural one. Only outright fraud could explain papering over a problem that goes all the way to the last step. I don't think that that's very common at all, although I sure wouldn't bet on it never having happened. (When it has, it's most likely been due to a desperate grad student spiking a sample with the real product).

I supposed a better word than "unreliable" would be "indeterminate". Even though they're probably fine, no one knows if the advanced steps in a long synthesis are real or not. It's just not worth the trouble to find out. It's as if Schrodinger's cat stayed in a superposition of states because it was so hard to open the box, and because no one cared very much whether he was alive or dead anyway.

Comments (50) + TrackBacks (0) | Category: The Scientific Literature

April 12, 2006

The Process of Process

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Posted by Derek

Mentioning HMPA the other day prompts me to talk a bit about the relationship between the two branches of drug-company chemistry: discovery and process. I'm in the first camp - I've done a little of the second, but nothing hard-core. At most companys, there isn't too much crossover, because the two kinds of work are quite different.

Discovery, as you'd figure, involves a lot of different reactions, on different substrates, all to the end of making a lot of different products. Our targets are constantly changing, particularly in the first stages of a new program. If the synthesis of some analog doesn't work out well for us, often the best solution is to drop it and make something else. There's generally something just as good on the list that hasn't been done yet. We like easy, reliable reactions, because those help us generate the widest variety of compounds in the shortest amount of time (and with the least amount of work, come to think of it).

Process chemistry comes into the picture when something has been seriously considered as a clinical candidate, and there's a need to make large, reproducible batches of it. They work on one molecule, and they beat the stuffing out of it. The route that the medicinal chemists used to make the candidate is almost never the best that can be found - at least I've never heard of a case yet where it was. There's always room to use cheaper reagents, higher-yielding reactions (and fewer of them), and solvents that can be dealt with on large scale. And there's the reproducibility issue, too. A synthesis that gives you 90% yields four times out of five and 40% the other time is a disaster. That's an average of 80% yield, but the process chemists would be much, much happier with a lower-yielding route that gives exactly the same yield (with the same degree of purity) every single time.

The process gang will ditch solvents like tetrahydrofuran or (God help you) ether for things like toluene and ethyl acetate. They'll try to get rid of those low-temperature dry-ice cooled reactions, because they'd much rather work in a regular ice bath if possible. All those chromatography steps will be attacked, because they hate running columns on that scale, and who doesn't? Crystallization, precipitations, filtering through a plug of silica gel - anything but running a long column and cutting fractions. If you're a considerate medicinal chemist, you'll have thought about these issues beforehand rather than just throwing the whole problem over the wall when you're done with it. That's why I never use HMPA, because either my reaction can do without it, or we can do without my reaction.

When the quantities involved get serious, some people will step in and see if the entire approach needs to be torn up. There are drugs out there that have had five or ten different routes to them over the years. You don't want to make the whole program depend on finding a new one, but it's worth some work on the side. By this time, the chemistry is moving on to another world in the pilot plant, where the hard-hatted crew worry about issues like starting on the top floor reactor so they can gravity-filter into the room below. When you start thinking about the viscosity of your reaction mixture and the shape of the pipes it's going to be running through, you've moved into the world of chemical engineering.

But meanwhile, people like me are back in the med-chem labs, starting another project on a totally different series of molecules. We're weighing out a hundred milligrams of this and that, trying things out in five-mL flasks to see if they work. It starts again.

Comments (19) + TrackBacks (0) | Category: Life in the Drug Labs

April 11, 2006

Ariad's Day in Court

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Posted by Derek

It's been a while since I wrote about Ariad and their suit against Eli Lilly, but the time has come again. Back in 2002, the company was granted (after sixteen years of prosecution) a patent with broad claims around the transcription factor NF-kappaB. I mentioned that one the other day as a good example of a protein that's involved in more things than human beings can keep track of, so you can imagine where these claims could take you.

In Ariad's case, they're planning on taking them to the bank. As I wrote at the time:

Ariad had a lawsuit fueled and on the pad, and as soon as their patent was issued, they launched. In fact, the Business Wire press release about the lawsuit went out before the one about the patent, which shows you where Ariad's priorities are. They claim that two of Lilly's biggest products, Evista for osteoporosis and Xigris for sepsis, both work through NF-kB (and there's little doubt that they do, at least partially.) Therefore they're demanding royalties, and pronto. Lilly had ignored Ariad's previous requests for a licensing deal, according to the Wall St. Journal, which moved them up to the exalted position of First Target. The other fifty companies can presumably expect the same treatment if they don't get on Ariad's good side.

And back in 2003, when the suit finally seemed to be cleared to go to trial, I wrote that it might get there during 2004, which shows you how much I overestimate our legal system. Or perhaps how I underestimate Lilly's legal team, which I'm sure has kept things spinning out as expensively as possible. After all, Ariad lost over fifty million dollars last year - perhaps Lilly were hoping they'd go out of business before things went to court.

Actually, that's not likely, since Ariad is merely the licensee. The assignees on the orginal patent are Harvard, MIT, and the Whitehead Institute, none of which will be going to be going out of business any time soon. I would very much like to know how much of their money is going into this fight, as opposed to Ariad's (more on this in a minute).

So here we go; arguments started this week. The implications, as I said back in those older posts, are potentially very large. Patenting big swaths of important biochemical pathway space has the potential to turn drug development into even more of an expensive nightmare than it already is. As this thorough overview in Science mentions, there are over 200 drugs that could plausibly be said to work (at least partially) through NF-kB signaling, from aspirin on up. You can add all sorts of development candidates for arthritis, cancer, diabetes and many other indications to that list. That article includes this interesting note:

Ariad's chances of winning, at first glance, appear small. "It's probably somewhat less than 20%," says Philip Nadeau, a biotech analyst at investment bank Cowen & Co., which counts Ariad among its clients. "These broad patents in general seem to be tough to defend when brought to court." But among the inventors on the NF-B patent are David Baltimore, now president of the California Institute of Technology in Pasadena, fellow Nobel laureate Phillip Sharp of MIT, and well-known Harvard molecular biologist Thomas Maniatis. Their very presence on the patent, and possibly in court, could be decisive. "You've got very prominent scientists who are the inventors," notes Rochelle Seide, a patent attorney with Arent Fox in New York. "That sells very well before a jury." (These inventors have not commented publicly on the patent or lawsuit and declined to do so for this story.)

And that's going to be interesting. Ariad would presumably like to have these luminaries in court, testifying on its behalf. Will they? These people surely know what the implications of an Ariad victory will be for industrial (and even academic) research. Do they really want this suit to succeed? I wish I knew.

A separate question is whether the institutions involved want it to succeed, and those answers might well be different. They all stand to gain some revenue from Lilly if Ariad wins - although, let's be honest, what's another few million or so to Harvard? Presumably there's even more money in the offing if Ariad starts to lean on everyone else, though. And since it's these sorts of institutions that discover more of these fundamental pathways, they might not be averse to a system that lets them profit from them - let the lesser outfits take their chances, eh? Pecunia non olet?

Lilly's defense seems as if it'll be that (first) their drugs were in development long before NFkB was even discovered, and (second) that, as in the Rochester/COX-2 ruling, that the identification of a biochemical pathway does not equal finding a drug that affects it. Those are both good arguments, and (like other observers) I expect Lilly to win. Of course, no matter what happens, there's going to be an appeal, so it could be years before we hear the last of this. (The Metabolite case that's been before the Supreme Court could well have a bearing on this, too. I'll have more on that in another post; I've been neglecting that one).

But along the way, it'll be interesting to see how the issue is reported. My fear is that the whole thing might end up being framed as a battle between disinterested, truth-seeking academic researchers and rapacious pharma drug peddlers. Let's hope not - there's only so much that my stomach can take.

Comments (22) + TrackBacks (1) | Category: Patents and IP

April 10, 2006

Linkorama

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Posted by Derek

I have Schedule D to wrestle with tonight, so it's time for some linking and blogroll additions. I'll start with a relatively new blog from a pharma consultant, Eye on FDA, and that'll do it from the industrial side this time.

The rest are from academia, some pure chemistry sites such as Dylan Stiles', which I've already linked to. I enjoy his site a lot, but one thing that it tells me is something that I already knew - namely, that I'm not 25 any more. Another blogging chem grad student is Paul Bracher, at Harvard. Another site for hard-core organic chemistry fans is Totally Synthetic. I did just this sort of thing for my PhD, and it's a lot more fun to read about than it is to do. Another blog from inside academia, this time from a post-doc, is Interfacial Science. Another post-doc can be found at Post Doc Ergo Propter Doc.

I can also recommend Nature's venture into chem-blogging, the group-written Sceptical Chymist. (That's the name I put on my first notebook in my first-year Quantitative Analysis course, actually - Robert Boyle is definitely worth remembering).

And finally, there's Peter Rost, famously ex-Pfizer. You're unlikely to find very many points of agreement between his worldview and mine, but you can see for yourself here.

Comments (6) + TrackBacks (0) | Category: Blog Housekeeping

April 9, 2006

New Frontiers in Self-Deception

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Posted by Derek

One of the big uses for human gene chips has been the search for biomarkers: genes that are up- or down-regulated in disease states. The hope is that gene expression changes will be the early warning signs of diseases, and could also help refine their diagnosis beyond what can be done by traditional means.

Cancer is the obvioius place to start. As I've said in the past, there's no one disease by that name - just thousands of broadly similar diseases that we don't adequately distinguish between. We'll have to get down to the genetic and protein-expression levels to see the important differences. The process has already begun, as a look at the Iressa story shows.

Nothing good comes easy, though, and the field may have gotten ahead of itself. That's what a new paper in PNAS maintains, anyway. The authors, from the Weizmann Institute in Israel, point out that the various predictive gene lists proposed for different kinds of cancers have a lot of disquieting problems. For one thing, the lists for the same types of cancer don't seem to overlap very much. And in those cases, if you take the two and switch them (applying one group's list to the other group's patients) their success rates fall sharply.

The problems remain after all attempts to massage them away. Some possible reasons for them might be the different gene chips technologies used by different groups or different methods of analyzing the data, but these don't seem to be nearly enough to account for all the trouble. A bigger problem is the dependence of the results of these studies on the particular patients who were entered into them. There seems to be a major problem with unstable results based on the training set used to generate the lists.

This latest paper lays this out in mathematical terms, and the results aren't real pretty. The published gene lists were derived from dozens, or at most a couple of hundred patients. But in order to have an overlap of at least 50% between two lists of candidate marker genes, with a confidence of 95%, the authors calculate that the number of patients needs to be in the low thousands. The existing proposals are almost certainly completely inadequate. The search goes on, but it just got harder, and a lot more expensive.

Comments (4) + TrackBacks (0) | Category: Cancer

April 6, 2006

How Not to Do It: Distilling HMPA

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Posted by Derek

Dylan Stiles has a post up on distilling HMPA, which will be familiar to anyone who's worked with the solvent. The problem is, HMPA doesn't come dry, and it has be be dry to be any good. You can take the wimpy way out and dump a load of dessicant into a fresh bottle, but the only way to be sure is to distill the stuff.

Well, that's one of the problems with it. The other one, as Stiles mentions, is that it's carcinogenic. His advice - not to soak your genitalia in it - is sound. And that prompts me to update an old post from a few years ago here, to get it into the "How Not to Do It" archives. Longtime readers may recall it, but it's worth bringing back:

One fine afternoon in graduate school, I was peacefully advancing the cause of science when one of the guys from down the hall came into my lab. "What's HMPA smell like?" he asked. "Holy (excreta)!" I answered, "You think I know? Probably like it tastes, I guess." He told me that one of our recent postdocs was distilling it, and he was afraid that the smell in the lab was, well, HMPA, odd as that might sound.

I went down the hall to investigate, and came upon the single stupidest distillation rig I've ever encountered. There it was, a two-liter round-bottom flask with a heating mantle on it, boiling and bumping away on the high vacuum line. (OK, fair enough, if you're going to distill the stuff, you might as well get it over with.) On top of this lunking load of toxic solvent was the smallest still head in the group, a tiny little 14/20 short-path job that looked, in that context, to be about the size of the cherry on top of a triple banana split. This thing wasn't even slowing the hot HMPA vapors down much. My friend had a right to be suspicious, because yes, that smell probably was the springtime-fresh aroma of HMPA itself.

Unfortunately, I can't say much about the bouquet of this caricinogenic substance. You'd have to track down our Spanish post-doc and ask him; he was basically showering in the stuff. I stayed out in the hall while I ranted at him, and as he informed me that this was how they did it in Barcelona. "Well, go to Barcelona and do it!" I shouted, looking around to see if there were drops of solvent starting to run down the walls yet.

I left him peacefully distilling away, confident in his technique. Sometimes I wonder what's become of the guy. . .

(Note: no slur is intended on Spanish post-docs - I've worked with lunatics from all over the world, and as far as I can see, none of us are safe. Besides, if there were any country where people didn't make idiotic mistakes, they'd have taken over the world long ago, you'd think. . .)

Update: I should add that I haven't used HMPA myself in at least fifteen years. It's a no-win solvent in drug research. For one thing, it can be quite difficult to remove from your samples, and you have to make sure that it's all gone before you assay anything. If your reaction will only work with HMPA in it, it's as good as dead, because no scale-up group will use it. And if it'll work with something else besides HMPA, well, you should have just used that to start with and saved yourself the trouble.

Comments (27) + TrackBacks (0) | Category: How Not to Do It

April 5, 2006

Which World Do We Live In, Anyway?

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Posted by Derek

Keeping up with the literature? I'm clearly not, although I regularly (or semi-regularly) read nearly a dozen journals. There's too much stuff coming out, and has been for a long time. Even harder than just "keeping up" is integrating what you read into some sort of coherent whole. I'm pretty sure that only the greatest scientists have ever done a really good job on that front.

These thoughts are prompted by a recent paper in PNAS by some statisticians at Columbia and Yale. They reference the GeneWays project, an attempt at text-mining the biomedical literature for relevant information. To me, what the project looks like is an automated version of what I've done with papers at various points in my career - sit down and rewrite them into a condensed version that gets across their key points. Doing that forces you to read and comprehend the whole thing, in detail, and explain it to yourself in terms that you understand. It's labor-intensive, but worthwhile when you really have to absorb something you're unfamiliar with.

Here's a look at some of the information typically extracted out of a paper. As you can see, they're going for the basics - what interacts with what. This may seem like trivializing the papers involved, but it's a good first step, as any look into the molecular and cell biology literature will confirm. If you'd like to experience this for yourself, try running the term "NF-{kappa}B" through a search engine like PubMed, pretending as if you had rashly agreed to do a review article on its various biological activities. There are, as of this evening, nine hundred and thirteen pages of search results. Next week there will be more.

The PNAS article uses the GeneWays data set to look at how scientific information is dealt with over time. They searched out statements about the same pair of substances - things like "Kinase W phosphorylates (or does not phosphorylate) Protein X". Then they tracked how these cascaded through the literature. There are, of course, plenty of opportunities for honestly conflicting statements about the same actors, given the variables involved.

But there are probably even more reasons for such assertions to reinforce each other, as the authors point out. The statements could indeed be true, and relatively easy to verify, through experiments with a low error rate. Or some of the later statements could be unverified restatements of the earlier ones: "As is well known. . .". There's also the way that some substances have of interacting with so many things that statements about their involvement with some other molecule have better than even odds of being true just by chance - some kinases come to mind.

So they used a probabalistic model, with parameters for each step along the way. These include possibilities like discarding negative data, performing (or not performing) an independent experiment before publishing a statement, the probabilities of getting false positives or false negatives in such experiments, the probabilities that positive (or negative) data are actually published and the probabilities that other scientists actually read them before publishing their own work, etc.

They come up with a whole range of hypothetical chains through the literature. Turning the dials on the model in different ways can give you strongly conforming virtual scientists, who believe everything they read, strongly argumentative ones who are fond of reversing earlier data, scientists who go with the flow until someone brave publishes a contrary instance and then switch to follow that, and many others. Then there's the style they call "mild scepticism":

"In this hypothetical world, scientists do read their peer's articles and try to compare their own results to the published ones but tend to trust their own results more than the data published by their peers. Patterns that resemble the mild skepticism were prevalent in our real-world data set, but analysis revealed the presence of all five hypothetical patterns."

Putting some numbers on that, it appears from the real publication data that scientists tend to weight their own personal results about ten times more than those that they read in the literature. (I'd love to see this broken down by author, I can tell you). They also found, as I'd expect, that postive statements make up more than 95% of the whole data set. (The authors seem a bit baffled by this - negative results are famously difficult to publish, guys). They also found very high correlations within individual chains of statements - reversals are rare indeed.

What they found completely unnerving was that, given their assumptions, the real-world data are explained equally well by two possible research universes: one where false-positive and false-negative rates are low, and there's a huge perponderance of positive statements among the set of true ones. The other one is a world with very high error rates, in which a given positive statement is much more likely to be false than it is to be true:

"Another major question also remains open: In which of the two alternative universes discovered in our analysis are we living? Our results indicate that the optimistic and pessimistic realities are almost equally likely given currently available data."

Comments (13) + TrackBacks (0) | Category: The Scientific Literature

April 4, 2006

Once More Into the Patent Breech

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Posted by Derek

Man, is everyone going at it hammer and tongs in the comments sections to the last two posts. There are a lot of good issues being raised, along with some interesting invective. But (as several people have noted), we're conflating several issues here.

On the subject of me-too drugs, I've already said a lot of what I have to say on the subject, and it can be found in that category over on the right. Looking over the comments, I tend to agree with SRC's take on the subject, although I'm pretty sure that my blood pressure doesn't go up as high as his does. A point that he makes, that many of these drugs are the sign of roughly simultaneous development (rather than sequential) is something a lot of people don't think about.

That said, there are some sequential me-toos, of varying degrees of utility. I've gone on about Clarinex/Claritin and Nexium/Prilosec here before, because I think that those are the two most egregious within-the-same-company examples. See this post on Sepracor for some others - come to think of it, they're involved in the Clarinex example, too, much to Schering-Plough's sorrow. It's fine with me if insurance companies decide that they don't want to pay for these things without a clear demonstration of medical need. If the market isn't big enough, companies won't develop such drugs. I'm in favor of as many pricing signals being sent as possible, all up and down the business.

Then there's the whole "how much does the federal research budget subsidize Big Pharma?" question. I'm going to have to pull that one out and deal with it - again - but not tonight. I continue to think that if you haven't been through the process, it can be difficult to realize just how long, twisty, and expensive the path between a great initial paper in Nature and a great drug on the market really is.

But these two issues have become thoroughly tangled up with the "can patents be improved" question. There have been some good suggestions scattered throughout the comments: longer granted terms for unmet medical needs, for example. If you try to apply these things too slickly, you open the way into terrible arguments, but for conditions where there isn't an existing therapy, the case should be clear. But isn't this exactly what the Orphan Drug Act is supposed to already do for us? There may not be as much uncaptured benefit here as we're thinking.

I wonder if there could be a (presumably shorter) fixed patent term that only starts once a compound comes to market, to deal with those long-gestation-period drugs that companies worry about getting involved with. You could also imagine adding onto a patent's term if the company agrees to do further studies (data to be made completely available,) which discover further utility (especially against competitor compounds?) But there's lots of arguing room in any scheme like that, too. And I could easily imagine companies carefully timing their investigations in order to stretch the patent out in the most lucrative way possible. (There was a similar suggestion in there for time limits to various milestones, tied to patent terms).

Coming up with incentives that can't be easily gamed isn't trivial, and it's a problem that's much larger than the patent debate.

Comments (16) + TrackBacks (0) | Category: Patents and IP

April 3, 2006

More On Doing Away With Patents

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Posted by Derek

Many of the folks commenting on that last post know what they're talking about, but not everyone who opines on drug industry patents does. (My fear, as I said yesterday, is that Boldrin and Levine might be in that category). So I thought I'd lay out some of the ground rules that people outside the pharmaceutical world might not be familiar with.

First off: it is not difficult to figure out what is in someone else's pill. Modern instrumental techniques make can make this an about an afternoon's work - a couple of days for a tougher one. And as for the formulation - all the stuff in there other than the active ingredient itself - that's usually easy to reverse-engineer, too. For any practical purpose, without a patent there is no barrier here.

Next, while the process of producing a given drug is often the subject of separate patents, there are still, in most cases, multiple ways to skin the chemical cat. Generic drug companies like Teva and Ranbaxy, among others, are famous for being able to come up with processes that are equivalent (and in some cases superior) to the patented ones. It's rare that there's a barrier to innovation here.

Third, it should be remembered that patents must thoroughly disclose the subject of their claims. Patents on drug substances must provide specific, detailed instructions on how to make the compounds in question and on their physical properties. One "skilled in the art" should be able to step right up and whip up a batch - and in fact, those skilled in the art often do, to get a look at the competition's compounds or to try to improve on them. It can be hard to see which of the claimed compounds is the one that's being developed, true - but by the time it gets into the clinic it's often clear, and by the time it gets to the FDA, all must be revealed.

And finally, please, please take some time to understand the difference between an academic discovery and a finished drug that makes it to market. Talking about how "gosh, most medicines are found through government-funded research anyway, right?" will not convince anyone who's done drug development that you know what you're talking about.

There, that should help clear out some of the underbrush. Workable suggestions for something other than patents on drug substances, anyone?

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April 2, 2006

Down With Patents, Eh?

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Posted by Derek

I see that Against Intellectual Monopoly by Michele Boldrin and David Levine is about to be released. This is a provocative work, parts of which have appeared in articles over the last couple of years. The first few chapters are available online (still with some typos, I've noticed).

What makes this a bomb-throwing sort of book, from the perspective of a drug company researcher like me, is that the authors recommend abolishing the patent system as we know it. They have a chapter (PDF) on the drug industry specifically, as you'd expect. Looking it over, I find it a peculiar mix of compelling argument and things that make me hold my head and moan. For instance, the authors, in all their discussion of the German and Italian drug industries, don't seem to take into account the way these industries have been able to make money over here.

I'm open to the idea that there might be other ways to encourage innovation than the patent system we have now. But Boldrin and Levine seem to have bought into the whole it's-the-government-that-finds-drugs idea, which never fails to drive me insane. (See this category for more on the same topic here).

Here's just one example of a hold-my-head section:

Much of the case for drug patents rests on the high cost of bringing drugs to market. Most studies have been sponsored by the pharmaceutical industry and are so quite suspect. The Consumer Project on Technology examined the cost of clinical trials for orphan drugs – good data are available for these drugs because they are eligible for special government benefits. A pharmaceutical industry sponsored study estimated the average cost of clinical trials for a drug at about $24.5 million 1995 dollars. However, for orphan drugs where better data are available, the average cost of clinical trials was only about $6.5 million 1995 dollars – yet there is no reason to believe that these clinical trials are in any way atypical.

There aren't? How about the fact that they're often first-in-class therapies, and thus can have a lower efficacy standard (better than nothing!) to meet? Or the fact that they're orphan drugs, meaning that there's a limited patient population available to start with? There are cardiovascular drugs that have been through trials in more patients than the total market size of some orphan therapies. No, there are some deficiencies here.

For a worried take on Boldrin and Levine's work, see Arnold Kling, and for its application to the drug industry, this post at Samizdata. Here's some more discussion on the same topic.

Comments (52) + TrackBacks (2) | Category: Patents and IP