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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: Twitter: Dereklowe

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February 5, 2004

Sic Transit Gloria Mundi

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Posted by Derek

So Entremed is finally giving up on its celebrated peptide drug candidates, angiostatin and endostatin. I'm sorry to see what the company, and its employees have been through, but I'm even sorrier when I think about what cancer patients have been through during this story. Especially those of them who read that (in)famous New York Times story back in 1998, with the (in)famous James Watson quote about curing cancer in two years. (He might as well wear a sign: Loosest Cannon in the Room - Come Here For Quotes!)

I wrote about this whole issue back on my Lagniappe site a couple of years ago, which led to an interesting exchange with Mickey Kaus about whether the Times article had been vindicated or not. Kaus is a wonderful political journalist, but would be the first to admit that he's no pharmaceutical expert, and his take was that the focus on angiogenesis made the Times article look better, in retrospect. My contention was that angiogenesis was already known to be a good area to work in. This was thanks in good part, it's true, to Judah Folkman, who was also a main subject of the article. But the emphasis on angiostatin and endostatin was perverse.

By the time the Times ran their front-page above-the-fold horn-honker, legions of people had already decided that Folkman was on to something. And they were working on better compounds to try the theory out. The problem with Folkman's peptides was that they were, well, peptides, and unusually painful ones to work with, at that. Angiostatin and endostatin are not that easy to produce, to purify, to store, or to dose, as opposed to the small molecules that were also already in clinical trials.

Once you dose peptides, they get hammered, chain-sawed, and burned down to the ground. I love coming up with verbs to describe the process, I have to admit. If you saw a plot of blood levels after dosing a typical peptide drug, you'd see just what I mean. It takes a pretty specialized protein to circulate around after an i.v. dose without getting enzymatically ripped to shreds, and as for oral dosing, you can forget it. The gut is very efficient at grinding every protein it sees down to its component amino acids.

So Entremed's compounds were flying into a stiff breeze from the beginning. And, as so often happens, anti-angiogenesis as a cancer therapy has turned out to be more complicated than anyone thought. (If you work in the drug industry, you could take that last phrase and turn it into a keyboard macro to save time. It's practically our motto.) There are many, many possible targets in the field, and we're not that sure which ones are most likely to work. And a lot of them are so biologically similar that it's hard to make selective drugs that work against them, anyway, thus many clinical candidates turn out to have a large and ill-defined footprint. To add to the confusion, different types of tumors express different amounts of these various target proteins, and their relative importance is surely all over the place as well. Not that we know yet, of course. And I'm only talking about the cases where vascularization is thought to be important; many other sorts of tumors are poor candidates for anti-angiogeneic therapies right from the start.

No, these compounds have been doomed for years, as far as I can see. They were long shots even when the Times sent Entremed on its insane ride up to nearly $100/share. I remember scoffing at the article when it came out, and I remember trying to go short the company's stock (couldn't get the shares to borrow.) But while all this was happening, people were getting their hopes up, desperate patients who thought that this might be their chance for survival. How many of them who read that article are still alive today?

I'm normally a pretty optimistic person, but I make an exception for my work. We should never let people get their hopes up. Not until we're really, really sure. We don't know enough. This whole situation wasn't Entremed's fault, and it certainly wasn't Judah Folkman's. This one gets chalked up to the New York Times.

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