Positive efficacy findings have been reported from the bestPWS ZAF-311 study, a pivotal phase 3, double-blind, placebo-controlled trial evaluating the safety and efficacy of beloranib (Zafgen, Inc.), a MetAP2 inhibitor, in patients with Prader–Willi syndrome (PWS) during a six-month randomized treatment period. The study achieved its coprimary efficacy endpoints, as beloranib demonstrated a statistically significant reduction in both body weight and hyperphagia-related behaviors, making it the first investigational drug to have a positive effect on these hallmark features of PWS.
The bestPWS ZAF-311 study randomly assigned 107 patients to receive twice-weekly subcutaneous injections of 2.4 mg or 1.8 mg of beloranib or placebo. 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 before the suspension of dosing in October 2015. Six patients discontinued treatment early. The coprimary efficacy endpoints were an improvement in hyperphagia-related behaviors and a reduction in body weight. Patients were on average 20 years old, had an average body mass index (BMI) of 40 kg/m2, and had an average hyperphagia total score of 16.9, consistent with moderate-to-severe hyperphagia, at baseline. Treatment with 2.4-mg and 1.8-mg doses of beloranib resulted in 9.5% (P < 0.0001) and 8.2% (P < 0.0001) reductions in body weight compared with placebo, respectively. Treatment with 2.4-mg and 1.8-mg doses of beloranib also resulted in reductions of hyperphagia-related behaviors of 7.0 units (P = 0.0001) and 6.3 units (P = 0.0003) compared with placebo, respectively, as measured by the Hyperphagia Questionnaire for Clinical Trials (HQ-CT).
In December 2015, the FDA notified Zafgen that the beloranib investigational new drug (IND) application had been placed on complete clinical hold because of an imbalance in severe venous thromboembolic events, including two patient deaths. 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 a phase 2b trial of beloranib in severe obesity complicated by type-2 diabetes, expected later this quarter; and a proposal for a risk mitigation strategy for beloranib in PWS.
PWS is the most common genetic cause of life-threatening obesity. Pathologic hunger-related behaviors (hyperphagia) dominate the lives of individuals with the disorder and drive them to engage in problematic behaviors that can lead to excessive overeating, choking, and stomach rupture. Compounding the morbid obesity in PWS is a slowed metabolism; psychiatric conditions, including aggression, anxiety, and psychosis; and an increased risk for cardiopulmonary and metabolic comorbidities, all of which contribute to an increased risk for obesity-related mortality.
Source: Zafgen; January 20, 2016.