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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: Twitter: Dereklowe

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« How Much Basic Research? | Main | One More On Basic Research and the Clinic »

September 13, 2004

A Real-World Can O' Worms

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Posted by Derek

Here's another example of academica and industry, and how it can be hard to divide out the credit. There's a family of nuclear receptor proteins known as PPARs, a very important (and difficult to unravel) group. The whole field got started years ago, when it was noticed that some compounds had a very particular effect on the livers of rats and mice: they made the cells in them produce a huge number of organelles called peroxisomes.

Eventually, a protein was found that seemed to mediate this effect, and it was called the Peroxisome Proliferator-Activated Receptor, thus PPAR. It was thought that there might be some other similar proteins. At this point, their functions were completely unknown.

Meanwhile, off at a Japanese drug company, a class of compounds (thiazolidinediones) had been found to lower glucose in diabetic animal models. The original plan, if I recall correctly, had been to stich together a dione compound with a Vitamin E structure, and as it turns out the reasoning behind this idea was faulty in every way. But the Japanese group had hit on a whole series of interesting structures that lowered glucose in a way that had never been seen before. No one had a clue about how they worked, but all sorts of theories were proposed, tested, and discarded.

The activity was unusual enough that many other drug companies jumped into the thiazolidinedione game. It turned out, as various companies sought out patentable chemical space, that the Vitamin-E-like side chain wasn't essential, but the thiazolidinedione head group was a good thing to have. (It's since been superseded.) The Japanese group was in the lead, with a compound that was eventually named trogliazone, but SmithKline Beecham (as it was then) and Eli Lilly weren't far behind, with rosiglitazone and pioglitazone. There were a number of contenders from other companies fell out of the race for various reasons. The three left standing went all the way into human trials, and no one still had any idea of how they worked.

We're up to the early 1990s now. Off in another part of the scientific world, a number of research groups were digging into PPAR biology. It looked like there were three PPARs, designated alpha, gamma, and delta (known as PPAR beta in Europe.) They all had binding sites that looked like small molecules in the cell should fit into them, but no one had really established what they might be. All three seemed as if they might be important in pathways dealing with fatty acids, not that that narrows it down very much.

As best I can reconstruct things, in a very short period in the mid-1990s, it became clear that PPAR gamma was a big player in fat cells (adipocytes). Many labs were working on this, but two academic groups that were very much in the thick of things (and still are) were those of Bruce Spiegelman from Harvard and Ron Evans from the Salk Institute. Then a group at Glaxo Wellcome (as it was then), also doing research in the field, found out that the glitazone drugs were actually ligands for PPAR-gamma, and immediately hypothesized that it was the mechanism by which they lowered glucose. From what I've been told, Glaxo's management didn't immediately believe this, but it turned out to be right on the money. Glaxo is still a major player in the PPAR world, turning out a huge volume of both basic and applied research.

All three PPAR-gamma drugs made it to market. So, who gets the credit? It's hard enough to figure out even inside the academic sphere - the two groups I mentioned had plenty of competition here and abroad, and insights came from all over. But (as far as I can tell) none of them were the first to make the connection between PPAR-gamma and diabetes therapy. So does Glaxo get the credit (they do have a few key patents to show for it all.)

And if we're doling out credit, who's going to line up for blame? As it happened, the very first PPAR-gamma compound to market, troglitazone, showed some unexpected liver toxicity once it found a broader audience. It was eventually pulled from the market in a hail of lawsuits. Rosiglitazone and pioglitazone (Avandia and Actos, by brand) are still out there, having survived the loss of the first compound, but not without a period of suspicion and breath-holding.

Any more troubles to share? Later PPAR drugs have shown all kinds of weird effects, including some massive clinical failures late in human trials. The money that's been made from the two on the market probably hasn't made up yet for all the cash that the industry has spent trying to figure out what's going on, and the story takes on more complexity every year. (Glaxo, for their trouble, has never made a dime off one of their own PPAR compounds.)

It's to the point now that some companies are, it seems, throwing up their hands about the whole field, while others continue to plow ahead. And by now, the number of research papers from academia will make your head hurt. PPARs seem to be involved in everything you can imagine, from diabetes to cancer to wound healing, and who knows what else. The whole thing is going to keep a lot of people busy for a long time yet. And anyone who thinks they can clearly and fairly apportion the credit, the spoils, the blame and the Bronx cheers is dreaming.

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