Positive efficacy results have been reported from a phase 2b trial (ZAF-203) evaluating beloranib (Zafgen), a MetAP2 inhibitor, in the treatment of severe obesity complicated by type-2 diabetes. The study achieved its primary efficacy endpoint, as treatment with 1.8-mg and 1.2-mg doses of beloranib resulted in 12.7% (P < 0.0001) and 13.5% (P < 0.0001) reductions in body weight, respectively, compared with a reduction of 3.1% for placebo. Patients treated with beloranib also met a key secondary endpoint, with patients in each arm achieving an average absolute reduction in hemoglobin A1c of 2.0% compared with a reduction of 0.6% for placebo.
In January 2016, Zafgen announced that a pivotal phase 3 trial (ZAF-311) of beloranib in patients with Prader-Willi syndrome (PWS) had achieved its coprimary endpoints, demonstrating statistically significant weight loss and improvement in hyperphagia-related behaviors at both the 2.4-mg and 1.8-mg dose levels. Zafgen plans to present the FDA with the data from the ZAF 203 and ZAF-311 trials, along with a proposal for a risk-mitigation strategy for beloranib in patients with PWS, in an effort to resolve a complete clinical hold the FDA placed on the drug in December 2015.
The agency’s action was in response to a death in Zafgen’s phase 3 study of PWS patients, which was subsequently determined to have been caused by a pulmonary embolism. Shortly afterward, another patient receiving beloranib died, also from a pulmonary embolism.
In the new data from the ZAF-203 trial, Zafgen reported that the most common adverse events (AEs) included upper respiratory tract infection, diarrhea, and injection-site bruising. Ten patients in the beloranib groups (five in each of the 1.8-mg and 1.2-mg groups) withdrew because of AEs compared with two patients in the placebo group.
Nine serious adverse events (SAEs) occurred––one in the 1.8-mg group, six in the 1.2-mg group, and two in the placebo group. One of the SAEs was a pulmonary embolism in the 1.2-mg treatment group. During the venous thromboembolism (VTE) screening process that followed a partial clinical hold placed on beloranib in October 2015, two additional VTEs were identified in patients in the ZAF-203 trial: deep vein thrombosis in a patient who had received 1.8 mg of beloranib, and superficial thrombophlebitis in a patient who had received the 1.2-mg dose.
Beloranib is a first-in-class injectable small-molecule therapy that works by inhibiting MetAP2, an enzyme that modulates the activity of key cellular processes that control metabolism. Once a person becomes obese, the body undergoes certain metabolic changes and becomes “programmed” to create and store more fat, making it difficult to reduce body weight. Beloranib is believed to help reduce hunger and to restore a balance to fat metabolism, thereby allowing calories to again be used as an energy source, according to Zafgen.