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

Xconomy Boston — 

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, … Next Page »

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