BOSTON – Prader-Willi syndrome patients lost more than 4% of their body weight over a 26-week period with the investigative antiobesity drug beloranib, compared with a similar gain in patients taking placebo, in the phase III bestPWS trial.
Hunger-related behavior was also reduced, along with total and LDL cholesterol levels and other cardiometabolic risk factors, lead investigator Dr. Merlin G. Butler reported at the annual meeting of the Endocrinology Society.
However, because of concerns over venous thromboembolic events in patients on beloranib, the trial was halted before all patients reached 26 weeks of treatment.
“bestPWS is the first phase III clinical trial to show statistically and clinically significant weight loss and improvement in hyperphagia-related behaviors in PWS [Prader-Willi syndrome] patients. The reduction in hyperphagia-related behaviors in the beloranib-treated groups represents a clinically meaningful benefit to patients,” Dr. Butler said.
Beloranib is a novel, first-in-class injectable molecule that works by inhibiting MetAP2, an enzyme that modulates the activity of cellular processes that are important in the control of metabolism. Its benefits in preclinical studies and a phase II trial in reducing body weight and decreasing hyperplasia fueled optimism regarding the therapeutic value in Prader-Willi syndrome, the most common genetic cause of morbid obesity. Although rare, Prader-Willi syndrome is life threatening and life limiting, with most of those affected dying before the age of 50.
“There are currently no treatment options for the intractable obesity and hyperphagia in Prader-Willi syndrome,” said Dr. Butler of the University of Kansas Medical Center, Kansas City, Kan.
In the bestPWS trial, 107 patients were randomized 2:1 to receive twice-weekly subcutaneous injections of beloranib or placebo for 26 weeks: 36 received 1.8 mg and 37 received 2.4 mg of beloranib, and 34 received placebo. Seventy-four patients completed the treatment. The coprimary efficacy endpoints were improvement in hyperphagia-related behaviors and reduction in body weight. Secondary endpoints included improvements in total body fat mass, lipids, and, as markers of cardiometabolic risk, total cholesterol and LDL cholesterol levels.
Baseline demographic and clinical characteristics were comparable in the three trial arms, with an average age of 20 years, average body mass index of 40 kg/m2, average body weight of 100 kg, average fat mass of 51 kg, and average Hyperphagia Questionnaire for Clinical Trials (HQ-CT) total score of 16.9.
Patients in the placebo arm displayed an increase in body weight of about 4% over the 26-week trial. In contrast, patients treated with beloranib lost weight (4.1% and 5.3% in the 1.8-mg and 2.4-mg arms, respectively; both P less than .0001, compared with placebo). The weight loss in the two treatment arms did not differ significantly. Beloranib was also associated with improvements in body composition, total cholesterol, and LDL cholesterol, high-sensitivity C-reactive protein, leptin, and adiponectin, compared with placebo.
Both beloranib doses also appreciably reduced hunger-associated behaviors, with reductions of 6.7-7.4 points with beloranib, compared with a reduction of 0.4 with placebo.
Adverse events most commonly included injection-site bruising, aggression, and hyperphagia; they were generally mild and transient.
There were five serious adverse events. Those that occurred in the treatment arms were psychiatric disorders, which are common background comorbidities in Prader-Willi patients, and so are not necessarily treatment related. In the bestPWS trial, two deep vein thrombosis events and two fatal pulmonary embolism events occurred. After the first pulmonary embolism death, the trial was discontinued; at that point, 27 randomized patients had not completed the full 26-week course.
Overall, 11 venous thrombotic events, including pulmonary embolism, deep vein thrombosis, and superficial thrombophlebitis, have occurred in the roughly 400 patients who have so far received beloranib in the course of its development, including the adverse events in the bestPWS trial. None of these events has occurred in those receiving placebo.
Even in light of these sobering events, Dr. Butler said he remains optimistic. “In addition to the reduction in body weight and decrease in excessive eating behaviors previously reported from this study, [these data] demonstrate important reductions in cardiometabolic risk factors and further support a strong rationale for continued evaluation of beloranib as a potential treatment for Prader-Willi syndrome,” said Dr. Butler.
Beloranib is currently on clinical hold while the potential for a prothrombotic effect of beloranib and a heightened risk for Prader-Willi syndrome patients are assessed, Dr. Butler said.
Dr. Butler disclosed study funding by Zafgen, the manufacturer of Beloranib.