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Zafgen’s Big Idea: Fight Fat by Cutting Off Its Blood Supply

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since they no longer have that handy capacity to store it away in a spare-tire around the mid-section or the hips.

So many things could go wrong with any new drug aimed at a new target, it’s hard to count. Hughes, who was one of the leaders at Novartis on a new class of diabetes drugs known as DPP4 inhibitors, has heard it all before. Skeptics thought that drug would trigger cancer-cell formation, kill important immune-system cells, and even make men sterile. None of those worries ended up derailing the product, he says.

“I remember standing in front of a lot of audiences that were incredibly skeptical and very harsh, because what we were doing hadn’t been demonstrated to work,” Hughes says. “It’s not a frightening place to be. It’s a luxury to be in a space where the skepticism exists, because it means you’re not in a saturated field, you’re in a place where there’s opportunity to lead, to drive the field, to innovate.”

So he’s confident, but he wanted to make sure I didn’t get the impression he’s delusional. “We have to be sober about what we’re doing. The fact is any new therapeutic approach is loaded with risks of all kinds,” Hughes says.

With Zafgen’s treatment, one big risk centers on exactly where that fat ends up going. If it ends up getting deposited too heavily somewhere it shouldn’t be, like the liver, or the pancreas, you could end up triggering diabetes, which most certainly isn’t an acceptable side effect for an obesity treatment. But so far, Zafgen hasn’t seen the fat-deposition problem in any of the animal tests, Hughes says.

Zafgen also wants to be careful to really understand the biology of what its drugs do to fat before it goes too far and too fast into clinical trials, he says.

One idea is based on the emerging notion that fat tissue isn’t just an innocent bystander that sits around ready to store excess calories, or to release energy when you’re running low. The fat tissue may actually be controlling its own destiny, providing a rich source stem cells that are eager to give rise to new fat tissue and perpetuate themselves. Zafgen’s drugs might break this cycle by cutting off essential nourishment to these stem cells.

The company will have a better idea of whether its approach works in people in 12 to 16 months. It will eventually seek out a partner when the time comes to run pivotal clinical trials, which will likely have to be so large that only the gigantic pharma companies of the world—like Pfizer, GlaxoSmithKline or Novartis—would have the resources to run the trials. Such large trials are needed to show that a treatment has the squeakiest of squeaky-clean safety profiles—something that regulators and consumers will almost certainly demand of a drug that could be taken by millions of people with a chronic condition that isn’t life-threatening.

Ever the scientist, even in a field populated by some highly promotional CEOs, Hughes is careful not to get too ahead of himself in saying what his company’s drugs can do.

“Let’s just say, we have a very convincing preclinical data set that supports it,” Hughes says. “We have a clinical data set using a number of different compounds that hit the same target, and lead to a very profound weight loss in animals. We have good reason to believe the mechanism we’re studying in animals is well-conserved across species. It should be operative in humans.”

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