Zafgen Inc. will funnel its latest $45 million financing into development of its rapidly advancing obesity candidate, beloranib. The financing round included a number of new investors as well as existing investor Alta Partners, which led Zafgen’s Series D round in 2012. Zafgen recently reported Phase II results showing that beloranib led to significant weight loss and cardiometabolic risk reduction in 147 obese participants.

“This particular financing round is really important to us,” Zafgen CEO Thomas Hughes told BioWorld Today. He said that the funding will take the company through “some pretty important clinical activities” including advancement into Phase IIb, and possibly Phase III studies in severe obesity or Prader Willi syndrome.

Beloranib is a selective methionine aminopeptidase 2 (MetAP2) inhibitor, the first in its class, with a mechanism entirely different from the current big three of obesity ­– Arena Pharmaceuticals Inc.’s Belviq (lorcaserin), Vivus Inc.’s Qsymia (phentermine/topiramate) and Orexigen Therapeutics Inc.’s Contrave (naltrexone/bupropion). Blocking MetAP2 is believed to reduce the production of new fatty acid molecules by the liver and help to convert stored fats into useful energy.

The premise underlying the technology is that obese and lean individuals metabolize fat differently, with obese bodies “programmed” to create and store more fat through metabolic adaptations that impair the normal release and breakdown of fatty acids from adipose tissue.

According to Zafgen, adipose tissue traps fat, storing and not releasing it very efficiently, preserving the obese state. Rather than reducing food intake, which doesn’t really unlock that fat, Zafgen is targeting the underlying abnormality, attempting to normalize the metabolism of fat in the cell.

Hughes said that beloranib is differentiated by its competitors in the marketplace based on the nature of weight loss resulting. “We don’t see that with other agents,” Hughes said, explaining that severely obese patients have far too much weight to lose to be successfully managed with an agent that gives single-digit-percentage weight loss per year. “We feel we can offer the type of weight loss and speed of weight loss appropriate for that class of patient,” Hughes said.

In its randomized, double-blind, placebo-controlled Phase II study in 122 obese subjects receiving twice-weekly beloranib injections, Zafgen observed average weight losses of 5.5 kg, 6.9 kg and 10.9 kg for respective doses of 0.6 mg, 1.2 mg or 2.4 mg. Weight loss was progressive, with reduced hunger and improved cardiometabolic risk markers. Patients were counseled to eat normally with no changes in diet or exercise. The drug was generally well tolerated with no serious adverse events.

Zafgen started up in 2011 with initial financing of $33 million from Atlas Venture and Third Rock Ventures. (See BioWorld Today, July 7, 2011.)

The company closed a Series C for about $20 million as it was preparing to launch its clinical program. Atlas and Third Rock returned in 2012 for a Series D raise of $21 million. Alta partners joined the syndicate at that time. (See BioWorld Today, Dec. 5, 2012.)

Altogether, Hughes said that Zafgen is “in for $104 million.”

Looking ahead, Zafgen’s need for future financing will depend on strategic choices made for marketing the drug. The options include the broad indication of severe obesity and the orphan indication of Prader Willi syndrome.

Prader Willi syndrome is a rare chromosomal disorder that causes, among other symptoms, excessive eating and life-threatening obesity.

The orphan option would allow the company to successfully commercialize the drug using funds already raised. If successful in Prader Willi syndrome, the drug would then provide a source of nondilutive capital to finance the expensive, large-scale trials necessary to achieve approval in a broader obesity indication.

“We have a very good match of that drug with that particular patient population. . . . It is something we are considering if for no other reason than on a compassionate basis. We have an unusually exciting set of opportunities ahead of us. We’re working to navigate all of those.”

Zafgen does have other agents in its pipeline, although it has been mum publicly on the nature of those programs.

Hughes said they relate particularly to metabolic diseases, in which Zafgen aims to become an industry leader. “We’ve been carrying out medicinal chemistry programs for some time. I would say watch this space.”