Beloranib safe, effective in adults with Prader-Willi syndrome

Adults with Prader-Willi syndrome randomly assigned the MetAP2 inhibitor beloranib for 6 months saw a significant reduction in both body weight and hyperphagia-related behaviors when compared with those assigned placebo, according to phase 3 trial results released by the drug’s developer, Zafgen.

In announcing results from the 6-month randomized, double-blind trial, Thomas Hughes, PhD, CEO of Zafgen, noted the investigational drug is the first to demonstrate a positive impact on both body weight and hyperphagia. The study results follow an FDA complete clinical hold on an investigational new drug application for beloranib, announced in December, due to an imbalance in severe venous thromboembolic events, including two patient deaths.

"This clear efficacy outcome is a crucial first step in moving discussions forward with the Food and Drug Administration regarding continued development of beloranib," Hughes said in a press release. "While we take the previously reported adverse events very seriously, we now have the robust data to provide greater perspective on the benefit/risk relationship of beloranib in this high-risk patient population. We thank our investigators, and the patients and their families for participating in the bestPWS ZAF-311 clinical trial."

In the bestPWS ZAF-311 study, researchers randomly assigned 107 adults with Prader-Willi syndrome to twice-weekly subcutaneous injections of either 2.4 mg or 1.8 mg of beloranib or placebo (mean age, 20 years; mean baseline BMI, 40 kg/m²; mean baseline hyperphagia score, 16.9). Seventy-four patients completed the full 26 weeks of treatment per the trial protocol, and 27 patients completed at least 75% of the randomized treatment period prior to the suspension of dosing in the trial in October 2015; six patients discontinued early. Researchers used a mixed model repeated measures analysis to account for the missing endpoint data of the patients who did not complete the clinical trial.

Patients assigned the 2.4-mg dose saw a 9.45% reduction in body weight (P < .0001) and a reduction in hyperphagia-related behaviors of 7 units (P = .0001) compared with placebo; patients assigned the 1.8-mg dose saw an 8.2% reduction in body weight (P < .0001) and a 6.3-unit reduction in hyperphagia-related behaviors vs. placebo (P = .0003).

The most common adverse events were injection site bruising, aggression and hyperphagia, generally of mild and transient nature. Of these, only injection site bruising was notable as being reported more frequently in patients taking beloranib compared with placebo.

In order to address the clinical hold, Zafgen plans to present to the FDA the efficacy and safety data from the bestPWS ZAF-311 study, data from the phase 2b trial of beloranib in severe obesity complicated by type 2 diabetes, ZAF-203, expected later this quarter, and a proposal for a risk mitigation strategy for beloranib in PWS.

"We are actively working to better understand the mechanisms and incidence of underlying thromboembolic disease in PWS, as well as the potential impact of beloranib treatment on thrombosis in order to develop a strategy for risk mitigation in this underserved patient population," Hughes said. "We plan to continue our dialogue with the FDA given the robust efficacy results seen in the ZAF-311 trial."