Zafgen Weight Loss Drug Shows Promise in First Human Test

1/5/11Follow @xconomy

People working on new drugs for obesity had a pretty crummy 2010 on the whole, but now an intriguing startup in Cambridge, MA, called Zafgen is starting the new year with a bang.

Zafgen is announcing today that its experimental weight loss drug for severe obesity was well-tolerated, and able to help people lose about 1 kilogram (2.2 pounds) of body weight each week in its first study in humans. The trial only lasted one month—and obesity drugs need to show sustained benefit for at least a year—but even in early days among the first 24 people tested, the weight loss effect was significantly better than a placebo. Side effects included mild headaches and dizziness at high doses. Detailed findings will be presented at the Keystone Symposia on Obesity in Keystone, CO, on January 15.

“While the long-term safety and efficacy of the compound remain to be established, there is nothing in the industry drug pipeline this advanced that has shown this kind of efficacy,” said Steven Smith, a diabetes and obesity expert at the Sanford-Burnham Medical Research Institute in Orlando, FL, said in a Zafgen statement. Smith was involved in the study design and interpretation.

If this drug can continue to deliver these kinds of results in further testing, it could be a potent new option for one of the biggest threats to public health in the U.S. An estimated 20 million people in the U.S. are considered severely obese, with a body mass index of 35 and above—for a person who’s 5-foot-6, a BMI of 35 means a weight of 216 pounds. Carrying all that extra weight puts people at risk for lots of chronic ailments like arthritis, heart disease, depression, and diabetes, to name a few.

Despite the growing problem, obesity drug developers have struggled to seize the opportunity. Mountain View, CA-based Vivus (NASDAQ: VVUS) and San Diego-based Arena Pharmaceuticals have failed to win FDA clearance for new treatments, as they were unable to strike the right balance of squeaky-clean safety and potent effectiveness in the past year. One other company, San Diego-based Orexigen Therapeutics (NASDAQ: OREX), is hopeful it will win FDA clearance for a new drug this month. But Zafgen’s drug helped people lose about two to four times as much weight by the same early point in time, when compared to what researchers saw in other studies. More invasive treatments like gastric bypass surgery are the only things that have been shown to help people lose more weight, the company said.

Tom Hughes

Tom Hughes

“We’re really excited,” says Zafgen CEO Tom Hughes.

We first wrote in detail about Zafgen in this space two years ago, when the company thought it had hit upon a novel idea of fighting obesity by cutting off the blood supply to fat tissue. Two big-name venture firms in Boston—Third Rock Ventures and Atlas Venture—recruited Hughes out of Novartis to pursue this intriguing concept. Further animal studies suggested the original hypothesis of how the drug worked was wrong, and that it probably worked instead by re-setting the way the body metabolizes fat.

Regardless of how the drug’s supposed to work at the metabolic level, Zafgen saw it produce consistent weight loss in animal studies. And the compound, a small molecule drug called ZGN-433 that’s designed to hit a target called MetAP2, had already been tested at much higher doses as a cancer treatment by South Korea-based CKD Pharma. That meant Zafgen had a pretty good idea of its safety and absorption profile. So the startup plowed ahead last year with this first clinical trial to see if the massive amount of weight loss seen in animals could be reproduced in people.

Here’s how the study was set up. Zafgen and its investigators recruited 24 severely obese women in Australia, and randomly assigned them to get either a low, medium, or high dose of the new drug, or a placebo. The treatment was given as an intravenous infusion twice a week, for four weeks. Patients were allowed to eat normally, and weren’t counseled to combine drug treatment with exercise—which is often done in other studies, and can muddy up the final results. People in this Zafgen-sponsored study had a body-mass index of 32 to 45.

Researchers saw the best results at the highest of the three doses—0.9 milligrams per square meter of body surface area. People taking the Zafgen drug lost about 3.1 percentage points more of their body weight than those on a placebo after the first month, researchers said. Interestingly, scientists also saw progress on other important secondary measurements in the study. Hunger declined. So did the amount of triglyceride fats in the blood, along with so-called “bad” LDL cholesterol.

Sharp-eyed watchers of the obesity drug field might wonder what the big deal is about 3.1 percentage points of extra weight loss over placebo. The FDA, after all, has said it wants to see obesity drugs deliver an average of 5 percentage points of improved weight loss over placebo. But the FDA’s threshold is something developers need to reach after a full year of study. When Vivus and Orexigen’s drugs were compared with placebos after just their first month of study, Hughes says, they typically only offered a little more than 1 percentage point of weight loss advantage over placebo. So if Zafgen’s drug can continue at its current pace of weekly weight loss, it could help patients drop 20 to 40 percent of their weight in a six to nine month course of therapy, Hughes says.

That, of course, will need to be proven in further studies. Zafgen is already working on plans for a bigger, mid-stage clinical trial to confirm the weight loss results, Hughes says. The company has also reformulated its product into a more convenient form, an injection that can deliver the drug just under the skin, instead of via an IV infusion.

Zafgen envisions testing its drug in patients with the most severe forms of obesity—people with body mass indexes of 35 and above—and it’s likely to be the kind of thing taken under a doctor’s close supervision, Hughes says. Animal studies suggest the drug ought to work as well in men as it does in women, but Zafgen’s first study only enrolled women because they represent two-thirds of all severely obese people, and about 80 to 90 percent of that group that actually seeks medical treatment, Hughes says.

The company has enough cash to keep operating through this year, and to get its important Phase 2 clinical trial started, Hughes says. Zafgen is considering whether to develop the drug more on its own, or to seek help from a partner.

There’s no doubt this will give Hughes something of substance to talk about next week at the mother of all biotech partnering meetings—the JP Morgan Healthcare Conference in San Francisco. Hughes, not surprisingly, was keeping all his options open when asked about the future business strategy around this compound.

“Within a few months, we’ll know best path forward for the program,” he says.

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