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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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October 24, 2002

Of All Sad Words. . .

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Posted by Derek

If you want a good example of how something that seems completely sensible can backfire in drug development, look no further than the story of leptin. I remember when this peptide hormone was discovered in rodents in 1995: the news really made a splash among groups working on obesity and metabolic therapies.

If you raised antibodies to leptin and treated mice with then, taking the protein out of circulation, the animals ate like mad. And on the other hand, injecting extra leptin made them turn up their noses at food, even when they should be eating (which for mice and rats is at night - or whenever their dark phase is in the animal rooms.) It turned out that two well-known mutant mice strains (ob/ob and db/db) were actually mutants of leptin function. The first has bollixed-up leptin protein, the second has a problem with its leptin receptors. Both animals eat heavily and put on serious weight (they're rather odd-looking.) It all fell together.

So you can see how everyone got revved up. Here (after many false starts) was the real eating hormone! Under our noses all along! Some companies took at whack at finding small molecules to affect the leptin receptor, but that didn't pan out well. Trying to find a small-molecule drug to tackle a receptor built for a large peptide is usually a losing proposition (which is why people, these many years later, still have to inject themselves with insulin.)

But Amgen was out in the lead with the protein itself. It wasn't going to be an oral medication, but a real wonder-drug for the terminally obese would be worth injecting, right? While they developed it, the research went on, furiously - and some oddities began to emerge. You'd think, from the rodent data, that really obese humans would be leptin deficient, too. Wrong - not only did they have leptin, they usually had well over the normal amounts. Ahem.

That was disturbing. You're clearly not going to accomplish much by giving more of the stuff to someone who has plenty of it already. The picture that began to form was similar to the role of insulin in Type II diabetes (the adult-onset kind.) Type IIs have plenty of insulin, at least in the first phases of their disease. In fact, they have more than normal. The problem is, their tissues have become resistant to its effects, so the pancreas compensates by pumping out more and more of it. (This can go on for years, until the beta-cells finally start to break down under the strain of constant pedal-to-the-floor insulin secretion - and at that point, your diabetic troubles really start to catch up with you.)

Obese humans are resistant to leptin. No one's sure how that happens, or why (no one's really sure how people get resistant to insulin, either, although there's sure no shortage of theories.) Amgen soldiered on into the clinic, and (despite pulling out all the stops) failed to find any real effects. The craze was over.

These days, everyone in the drug industry who studies metabolism knows about leptin, respects its central role in feeding behavior - and sighs at bit at what might have been.

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