Zafgen’s Obesity Drug Continues to Cut The Fat in Phase 2 Trial

Xconomy Boston — 

Zafgen raised eyebrows two years ago when it showed that its injectable drug, which changes the way the body metabolizes fat, helped severely obese people in a small clinical trial lose a lot of weight in the span of a month. Today, the Cambridge, MA-based company is giving a sneak peek into its next study—and, while it’s a tiny sample size, the numbers appear to be holding up.

Cambridge, MA-based Zafgen today is releasing interim results at the 73rd American Diabetes Association Scientific Sessions from a 12-week mid-stage clinical trial testing the drug, named beloranib, in 160 severely obese patients—those with an average body mass index, or BMI, of 38. The results provide just a glimpse of the data. They account for just the first 19 patients out of the study, all female, of which only 14 were dosed with the drug rather than a placebo, according to Zafgen president and CEO Tom Hughes. But even so, they continued to show beloranib’s potential fat-zapping ability.

The five patients given the smallest dose of beloranib (0.6 milligrams) lost about 8.4 pounds over the course of 12 weeks, translating to 5.5 percent increase in total loss of body weight over placebo. The six patients on a 1.2 mg dose lost an average of 13.4 pounds, for a 7.7 percent body weight loss over placebo. And the three patients on the highest (2.4 mg) dose lost an average of 21.8 pounds, or 12.2 percent over placebo, according to Hughes.

Tom Hughes, CEO of Zafgen

“Let’s just say we’re quite pleased with that,” he says.

Zafgen was initially formed in 2008 to build off of research from the Boston Children’s Hospital which found that drugs that stopped blood vessels from forming might also help shrink fat tissue. That hypothesis turned out to be wrong, but the small-molecule drug Zafgen tested, now known as beloranib, worked in animal studies anyway—just for an entirely different reason. It changed the way the body metabolized fat.

Specifically, beloranib reduces the over-production of fat in the liver that occurs in severely obese people by inhibiting the production of an enzyme called methionine aminopeptidase 2, or MetAP2. That, in turn, causes the body to release the fat and turn it into a source of fuel. The drug is being developed as an injection just under the skin that would be administered twice a week through a small syringe under the supervision of a doctor. This method is completely different than many of the other appetite-suppressing obesity drugs, which fool the body into thinking that it is full.

Beloranib, as it showed in an earlier clinical trial, also continues to improve peoples’ levels of cardiovascular risk markers such as triglycerides, low-density lipoprotein (LDL) cholesterol, and C-reactive proteins (CRP).

Here’s how the latest study worked. Zafgen enrolled people of an average age of about 40.3 years. The patients had BMI’s anywhere from over 30 to over 50, so Zafgen could see how well each dose worked in people of varying body weight. Zafgen enrolled both men and women—though Hughes wouldn’t give the gender breakdown as of yet—and tested the drug’s safety and tolerability over the course of 12 weeks. Similar-sized groups of patients were given twice-weekly injections of beloranib at a 0.6 mg (37 patients), 1.2 mg (37 patients), or 2.4 mg (36 patients) doses, or a placebo injection (38 patients) instead, according to the release.

Hughes said that the company found that there were no new health or tolerability issues that cropped up with people taking the drug for a longer period of time (an earlier study tested the drug over a four-week period).

The most common side effects experienced by patients during the study were nausea, vomiting, diarrhea, and trouble sleeping. Hughes says that the sleeping problems primarily occurred at the highest dose level. He declined to specify how many patients total dropped out of the study. Zafgen will release the full results of the clinical trial towards the end of the summer, according to Hughes.

“Overall the effects we see in terms of diarrhea, nausea and vomiting, these are not particularly pronounced and they do not differentiate from placebo in many ways,” he says. “But it is something that is there.”

Hughes says that during treatment people would both end up eating less and changing their food preferences. He suggests that some of the gastrointestinal problems seen in patients so far, then, could reflect either dietary changes, or the fact that they’re just not taking in as much food. He also added that those side effects are “very, very modest” compared to the diarrhea, nausea and vomiting experienced by patients on mainstay diabetes drugs such as metformin.

“I think our profile overall is actually looking pretty good—and these are not safety issues,” he says.

The results are encouraging, but Zafgen knows it has to reproduce them over a larger scale, and a much longer time span, to really get the attention of regulators. The mid-stage trial was a 12-week study only because that was the longest study it could devise that was supported by the animal safety data it had at the time, according to Hughes.

Zafgen is currently running the last animal safety studies it needs to before it can begin a much longer clinical trial, and plans to start one that would evaluate the drug over the course of six months to a year. The doses in that study will be between 0.6 mg and 2.4 mg. Zafgen may explore a 1.8 mg dose going forward, but will probably keep at least two doses for the next trial, according to Hughes.

“I think we have a nice working range to move forward,” he says. “The good news is that the weight loss is rather pronounced, and it’s ongoing even towards the end of the 12 week treatment. That bodes well for continued efficacy.”

Zafgen plans to position the drug as an alternative to bariatric surgery, a procedure by which surgeons alter or block portions of a patient’s digestive system. That gives it a target population of about 15 to 18 million people in the U.S. alone, according to Hughes.

“We like that approach because it does target the therapy towards people with a clear-cut medical need and where the benefit would be easiest to address, and we think that also provides economic advantages and would help us with adoption of the drug overall,” he says.

It also wants to look at beloranib not just as a weight loss treatment, but to help curb diabetes as an alternative to what is known as metabolic surgery—bariatric surgery used to help slow symptoms of type 2 diabetes.

Hughes says Zafgen has interest from not only potential partners and acquirers, but also investors who see an IPO as a good way to cash in on Zafgen. The company has raised just under $70 million in VC money total from Atlas Ventures, Third Rock Ventures, and Alta Partners. It has enough cash to get it through the end of the year, and is currently looking to raise more. Zafgen feels good about its ability to do so.

“We’re quite aware of how favorable the IPO environment is these days, and this is something that we’re contemplating as well,” he says. “We’re quite content with our optionality right now.”