Beloranib Demonstrates Weight Loss in Hypothalamic Injury-Associated Obesity

The drug, a first-in-class MetAP2 inhibitor, was well-tolerated and also improved cardiovascular disease risk factors…

Zafgen has announced that ZAF-221, a randomized, double-blind, placebo-controlled Phase 2 clinical trial of beloranib, a MetAP2 inhibitor, in 14 adults with hypothalamic injury associated obesity, or HIAO, met the primary efficacy endpoint of weight reduction (p = 0.01). In addition, beloranib treatment was well-tolerated and improved cardiovascular disease risk factors.

HIAO is a rare form of medically induced obesity resulting from damage to the hypothalamus following resection of central nervous system tumors such as craniopharyngioma. The hypothalamus is a homeostatic control center in the brain that provides oversight of multiple hormonal systems, metabolic rate, hunger, and satiety. Patients affected by HIAO fail to regulate metabolism and food intake normally, resulting in rapid and intractable weight gain, treatment resistant severe obesity, and associated co-morbidities.

“We are extremely pleased with these results, which differentiate beloranib from other weight loss agents. Beloranib’s impact to restore balance to production and utilization of fat is further validated with these findings,” said Dennis Kim, M.D., Chief Medical Officer of Zafgen. “With these results in hand, we plan to pursue HIAO as an extension of our work in Prader-Willi syndrome, or PWS. We believe beloranib shows tremendous potential to improve the lives of those impacted by HIAO and PWS, and for whom there are limited effective pharmaceutical alternatives. In 2015, we aim to establish the regulatory path for a registration program with U.S. and EU regulatory authorities.”

“We are delighted by these clinical results that provide additional evidence for our hypothesis about beloranib’s mechanism and establish the drug’s unique extra-hypothalamic mode of action. Along with PWS and severe obesity in the general population, HIAO is the third indication for which we have established proof of concept for beloranib,” said Thomas Hughes, Ph.D., Chief Executive Officer of Zafgen. “We are enthusiastic to continue development of beloranib for the treatment of patients with severe and complex forms of obesity.”

Beloranib, a first-in-class MetAP2 inhibitor, that has demonstrated the potential to address weight loss and hunger reduction in patients with obesity, is being studied for the treatment of multiple indications. ZAF-221 was a randomized, double-blind, placebo controlled study of twice-weekly subcutaneous injections of 1.8 mg beloranib or placebo in patients with HIAO to evaluate weight reduction and safety over four weeks, followed by an optional four week open-label extension. Beloranib treatment resulted in mean weight loss of 3.4 kg and 6.2 kg in patients with HIAO after four and eight weeks of treatment with beloranib, respectively, in contrast to 0.3 kg mean weight loss in patients treated with placebo for four weeks (p = 0.01). Improvements in cardiovascular disease risk factors of lipids and inflammation (measured by C-reactive protein) were also observed. Beloranib 1.8 mg was well tolerated in this population, with no serious or severe adverse events reported. Safety measures such as laboratory, electrocardiogram, and vital sign measurements revealed no signals of concern, and all subjects randomized to beloranib completed the trial. This trial enrolled 14 obese patients (nine women and five men) who were confirmed by magnetic resonance imaging (MRI) to have had hypothalamic injury.

“These data represent a significant step forward in understanding the role of MetAP2 inhibition as a useful therapeutic approach to treating complex forms of obesity characterized by hypothalamic dysfunction,” said Professor Joseph Proietto, Head of Weight Control Clinic, Austin Health, Melbourne, Australia. “These results are innovative, as they represent an exceptional level of success in the pharmaceutical treatment of HIAO, and are very encouraging for our field, as well as for these patients who remain largely beyond the reach of currently marketed pharmaceutical agents.”
Zafgen News Release, Jan. 7, 2015