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

1/28/09Follow @xconomy

Public health leaders increasingly fret about the epidemic in fatness that has left two-thirds of adults in this country overweight or obese. They urge people to drop the Big Macs and hit the treadmill. But there are some exciting ideas emerging within the biotech and pharmaceutical arenas about what might be done when all that fails. I learned about one such idea during a fascinating conversation a couple weeks ago with Tom Hughes, the CEO of Cambridge, MA-based Zafgen.

Hughes, 49, is a trim, lanky guy who stands over 6 feet tall, wears thin wire-rimmed glasses, and speaks in complete paragraphs. He was recruited out of a top research job at Novartis into this startup by its backers, Atlas Venture and Third Rock Ventures.

Hughes told me that Zafgen is currently testing a batch of new compounds that are made to shrink fat tissue by choking off its blood supply. This method has its roots in a similar approach, used for shrinking tumors, that was developed by the late Judah Folkman and his colleague Maria Rupnick at Children’s Hospital in Boston. Folkman and Rupnick’s ideas were once considered nutty—and then were proven right.

Zafgen’s technique is different than those underlying all the other anti-obesity drugs in clinical trials now. Most such treatments are designed to work on receptors in the brain, making people feel full, or to block the absorption of fat. Zafgen’s drugs, on the other hand, are built on the belief that if you cut off the growth of blood vessels supplying the body’s fatty parts (aka adipose tissue), then they will shrink. Instead of storing excess calories as fat the body will find some other way to burn them off, like by fidgeting.

The idea, Hughes says, “is not mainstream, by any means.”

Zafgen still has a lot to prove, but Hughes says he has plans for a big year in which the company will put its notion to the test. He’s looking to license in a drug candidate that was designed to block blood vessel formation in tumors, and which is far enough along in its development that it could enter clinical trials as an obesity treatment this year. The company is also developing a batch of new compounds with improved activity against its chosen molecular target (which Hughes isn’t disclosing just yet.) And Zafgen scientists are working up studies to really try to answer how this type of drug affects fatty tissue.

The company’s animal studies, conducted in a variety of species of mice and rats, so far show a similar pattern. Not much happens in the first few days for animals on a blood-vessel-blocking drug. Then they start losing weight fast, about 25 percent of their body weight in a few weeks. During that period, they eat less. Then once they reach a stable, lean body mass, the animals start eating more food without gaining back the weight. The hypothesis is that the animals are simply finding a way to burn off the fat, 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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