SAN DIEGO—At the recent Endocrine Society Annual Meeting on March 7, biopharmaceutical company Zafgen Inc. shared positive efficacy and safety data from its recently completed Phase 2 trial of beloranib in patients with hypothalamic injury-associated obesity (HIAO).
HIAO is a rare form of medically induced obesity that results from damage to the hypothalamus after resection of central nervous system tumors, such as craniopharyngiomas, or from strokes, brain trauma or radiation therapy of the brain. Given that the hypothalamus oversees hormonal systems, metabolism, hunger and satiety, patients with HIAO cannot regulate their metabolism and food intake normally, which can lead to rapid, intractable weight gain, severe treatment-resistant obesity and associated co-morbidities.
This novel, first-in-class small-molecule therapy works by targeting the methionine aminopeptidase 2 (MetAP2) enzyme, which controls the body’s production and use of fatty acids. MetAP2 inhibitors reduce hunger and the production of new fatty acid molecules by the liver, helping stimulate the use of stored fat for energy. Zafgen licensed the compound from Chong Kun Dang Pharmaceutical Corp., and holds worldwide rights for its development and commercialization (exclusive of South Korea).
“We are very pleased with the results from this latest study of patients with HIAO, which demonstrated proof of concept for both the safety and effectiveness of beloranib on body weight and cardiovascular risk markers in this patient population,” Dr. Thomas Hughes, Zafgen’s CEO, commented in a statement. “These positive results also indicate that the efficacy of beloranib in HIAO patients is similar to that observed in conventionally obese patients, as beloranib treatment leads to meaningful and statistically significant weight loss in both patient populations.”
The Phase 2, randomized, double-blind, placebo-controlled trial sought to evaluate the safety, efficacy and tolerability of beloranib 1.8 mg administered via subcutaneous injection twice weekly for four weeks, followed by an optional four-week open-label extension. Fourteen patients were enrolled, and all had radiographic evidence of hypothalamic damage with subsequent rapid, significant weight gain. After four weeks of treatment, patients randomized to beloranib lost -3.4 ± 0.6 kg, while those on placebo lost -0.25 ± 0.8 kg. Results from the extension did not suggest any waning of beloranib’s effects within the eight weeks of treatment. Known markers of beloranib response, which include lipid parameters and markers of inflammation, were improved at both four and eight weeks of treatment.
There were no early discontinuations of the trial due to adverse events, severe adverse events or serious adverse events in the patients receiving beloranib, nor were any clinically significant abnormal laboratory measures, vital signs or electrocardiography findings seen. The most common adverse events associated with beloranib treatment were dizziness, headache and nasopharyngitis, which were generally mild and transient.
In a previous Phase 2 study of beloranib, whose results were announced at Obesity Week 2013, the compound demonstrated significant weight loss and improvements in cardiometabolic risk markers in 147 obese patients over 12 weeks of treatment, which was the largest and longest beloranib trial at that time. In that trial, participants receiving 0.6 mg, 1.2 mg or 2.4 mg of beloranib lost on average -5.5 ± 0.5 kg, -6.9 ± 0.6 kg and -10.9 ± 1.1 kg, respectively, versus -0.4 ± 0.4 kg for those on placebo. Beloranib was generally well tolerated, with progressive and ongoing weight loss, a reduced sense of hunger and improved cardiometabolic risk markers. Previous studies demonstrated improvements in LDL cholesterol, HDL cholesterol and triglycerides, which were confirmed in this study. The study also demonstrated the drug’s ability to lower blood pressure.
In an analyst comment on the latest beloranib results, Joseph P. Schwartz of Leerink Partners noted that the improvement seen in cardiometabolic and inflammation biomarkers, “coupled with weight loss data, further de-risks beloranib’s late-stage development, mainly: a) Ph. 3 pivotal trial in Prader-Willi syndrome, which is expected to report data by YE15, and b) [Zafgen’s] ongoing regulatory discussions with FDA/EMA on the design of first-of-its-kind pivotal program in HIAO. Cardiometabolic parameters in particular bode well for the Ph. 3 proof-of-concept study in obese [patients] with type II diabetes expected to read out top-line data in 4Q15.”
With regard to the reported adverse events, Schwartz commented that “In line with previously known effects on the CNS, this may be something to manage, although in serious orphan diseases like [Prader-Willi syndrome] and HIAO, it shouldn’t change meaningfully the risk/benefit profile or how many [patients] may be eligible candidates for the drug, in our view.”
He added that the study’s “differentiation of ‘sense of hunger’ from ‘drive to eat’ enables the investigators to conclude beloranib’s mechanistic effect on extrahypothalamic pathways. [Management] remains committed to further rationalizing this effect of beloranib on hyperphagia causing weight loss (independent from a fully functional hypothalamus) with additional preclinical and translational work.”