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Hype and Glory

Over at the new home of Kausfiles, Mickey Kaus wondered on Monday about all the news coming out of the ASCO (American Society for Clinical Oncology) meeting. Does it show that the hype in the famous 1998 NY Times front-page story on Judah Folkman and his cancer therapy was actually justified? Does the world owe Gina Kolata (the reporter) an apology?

You won’t catch me offering too many opinions on welfare reform over here, so I can’t resist weighing in when Mickey Kaus has some on drug discovery. Some background: the ASCO meeting is one of the most Wall Street-ocentric of the medical meetings. It’s a forum for late-stage cancer trial results to be presented, and investors watch everything for signs. The headlines from the meeting tend to be out of proportion to the actual news.

Witness the NY Times the other day, saying that Imclone’s Erbitux drug “fails” against a placebo. Nothing of the kind! (I seem to have imported some Kausfiles exclamation points.) I’m intensely sceptical of anything Imclone has to say, but these results (as the Times story pointed out about 3/4 of the way through) just failed to show Erbitux working well. Absence of evidence isn’t evidence of absence. This was a small study, and the placebo group fared much better than expected, which blew the statistical significance of the Erbitux results. It happens, and that’s why you try to run big studies when you can: a larger sample has less chance of showing this sort of jumpiness.

It’s true, though, that there’s a lot of anti-angiogenic drug news at the meeting this year. But there was a lot last year, and the year before. Angiogenesis has been the hot topic for many years now. Judah Folkman deserves the credit for pushing this idea, and for sticking with it for a long time without much company. But that was well before the Kolata article; by the time it came out, every major drug company (and plenty of minor ones) was on the case, and had been for years. There are a lot of different angiogenesis mechanisms, and a lot of room to work in.

That’s why, when I read that article, I smiled to myself at the breathless tone it took about Folkman’s peptide drug candidate (a tone that wasn’t Folkman’s fault.) Because peptides, like his Endostatin, generally make lousy drugs. For one thing, you can almost never give them orally; they have to be injected, like insulin. (The biggest reason is that your gut treats the peptides from a pharmacy exactly like it treats the ones from a hamburger: it digests them, rapidly tearing them down to amino acids.)

And angiogenesis inhibitors, like many of the other new cancer therapies, are probably going to be every-day drugs, which are no fun to inject. It’s doubtful that they’ll make the cancer disappear completely, and in some cases they’ll do well just make it stop growing. If you stop taking the drug, the tumor will probably pick right up where it left off. I can’t imagine anyone wanting to find out. (Combinations of the newer drugs with the older cytotoxic ones might deliver the knockout punch, but again, who wants to find out that it didn’t? Those will be difficult trials. . .)

Orally active small molecules are the way to go – and I don’t say that just because I get paid to discover them. They’re cheaper to make, easier to purify, and you can take them with the beverage of your choice. Entremed, the company that licensed Endostatin, is still trying to turn it into a drug (burning through heaps of Bristol-Meyers Squibb money for a few years along the way.) Meanwhile, small molecules targeting angiogenesis are already closer to being approved. I honestly don’t see what a difficult, unstable peptide is going to have that these compounds don’t.

The person associated with the Kolata article who really deserved to be whacked over the head is James Watson. He grabbed the spotlight with his ill-considered statement that “Judah is going to cure cancer in two years.” Well, it’s been four years now, and it’s not happening. Judah Folkman’s concept is already going a long way toward curing cancer, but his compound isn’t. And that’s the real problem with Kolata’s article: angiogenesis wasn’t news, and endostatin wasn’t news. Drug development is the news, but it’s slow, expensive, and doesn’t make a snappy above-the-fold very often.