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Data evaluating Beloranib in Prader-Willi Syndrome

bestPWS Study is the first Phase 3 pivotal trial to show significant weight-loss and improvement in hyperphagia-related behaviours in PWS patients
Beloranib demonstrated a statistically significant reduction in fat mass at both 1.8 mg and 2.4 mg dose levels

Zafgen has announced new data from the bestPWS ZAF-311 study, a pivotal, double-blind, placebo-controlled Phase 3 trial evaluating the safety and efficacy of beloranib, a MetAP2 inhibitor, in patients with Prader-Willi syndrome (PWS) during the six-month randomized treatment period. Data presented during ENDO 2016, the Endocrine Society's 98th Annual Meeting & Expo, showed that beloranib was associated with improvement in total cholesterol, LDL cholesterol and other cardiometabolic risk factors, and a reduction in fat mass when compared to placebo.

As previously reported, the bestPWS study achieved its co-primary efficacy endpoints, as beloranib demonstrated a statistically significant reduction in both body weight and hyperphagia-related behaviours, making it the first investigational drug to demonstrate a positive impact on these two hallmark challenges of PWS.

Patients with PWS also have higher rates of psychiatric conditions including aggression, anxiety and psychosis. Compounding the obesity in PWS is markedly low metabolism, abnormal body composition with higher fat mass and low lean mass, and higher risk for cardiopulmonary and metabolic co-morbidities, all of which contribute to a higher risk of obesity-related mortality.

"Prader-Willi syndrome is a life-limiting and life-threatening condition with no available treatment options that significantly impact affected individuals and their families," said Dr Merlin G Butler, Professor of Psychiatry, Behavioral Sciences and Pediatrics, Director, Division of Research and Genetics, Departments of Psychiatry & Behavioral Sciences and Pediatrics at the University of Kansas Medical Center. "In addition to the reduction in body weight and decrease in excessive eating behaviours previously reported from this study, the data presented today demonstrate important reductions in cardiometabolic risk factors and further support a strong rationale for continued evaluation of beloranib as a potential treatment for PWS."

BestPWS ZAF-311 outcomes

In the bestPWS ZAF-311 study, 107 patients were randomised to receive twice-weekly subcutaneous injections of either 2.4mg or 1.8mg of beloranib or placebo. Seventy-four patients completed the full 26 weeks of treatment per the study protocol, and 27 patients completed at least 75 percent of the randomized treatment period prior to the suspension of dosing in the trial in October 2015. There were six patients who discontinued early. The co-primary efficacy endpoints for this trial were improvement in hyperphagia-related behaviours and reduction in body weight. Secondary endpoints in this trial included improvement in total body fat mass and improvement in lipids and markers of cardiometabolic risk (TC and LDL). Patients in the trial were on average 20 years old, had an average BMI40, an average body weight of 100kg, an average fat mass of 51kg and an average hyperphagia total score of 16.9, consistent with moderate to severe hyperphagia, at the beginning of randomized treatment.

These baseline characteristics were well-balanced across treatment arms. In agreement with the FDA, Zafgen has analysed the data using a mixed model repeated measures (MMRM) approach to account for missing endpoint data from the patients who did not complete the randomised treatment period of the trial.

Patients in the ZAF-311 trial were markedly obese at baseline. Patients randomised to receive placebo displayed substantial (4.15%) increase in body weight over the course of the six months of randomized treatment. Body weight gain in this patient population was anticipated, and typically occurs throughout life generally due to a lack of effective treatments for managing obesity. Patients treated with beloranib, in contrast to placebo, experienced a reduction in weight, with the 2.4 mg dose arm displaying a 5.3 percent reduction from baseline, with a placebo-adjusted weight loss of 9.45 percent.

The HQ-CT is a PWS-specific study instrument that provides an assessment by caregivers of the food-seeking behaviours exhibited by patients. The scale provides a composite value from nine questions, each rated on a scale of zero to four units (total range of score of zero to 36). Patients in the ZAF-311 trial were enrolled only if their baseline HQ-CT total score was greater than 12 units, representing moderate-to-severe hyperphagia related behaviours at baseline. While hyperphagia-related behaviours were stable over six months of treatment in the placebo arm, both the 2.4 mg and 1.8 mg beloranib arms showed highly statistically significant reductions in HQ-CT total score, indicative of reduced hunger-associated behaviours.

In this study, beloranib was associated with improvements in total cholesterol and LDL cholesterol as well as other markers of cardiometabolic risk compared to placebo. The mean change in HDL cholesterol and triglycerides showed no significant change from baseline for each treatment arm. The reduction in leptin levels and increase in adiponectin levels seen in PWS patients receiving both dose levels of beloranib is consistent with altered fatty acid mobilization and lipid utilization.

Body composition was measured using dual-energy X-ray absorptiometry (DXA) scan. Patients treated with beloranib demonstrated a significant reduction in total body mass and fat mass at both the 1.8mg and 2.4mg doses of beloranib. Lean body mass was minimally changed from baseline with a 0.5kg loss in the 1.8mg beloranib arm, a 0.7kg loss in the 2.4mg beloranib arm and an increase of 0.7kg in the placebo arm. Approximately 90 percent of loss in total body mass with beloranib was due to loss of body fat, indicating preferential loss of fat with minimal change in lean mass.

The most common adverse events (AEs) in this study were injection site bruising, aggression, and hyperphagia, generally of mild severity and transient in nature. Of these, only injection site bruising was notable as being reported more frequently in patients taking beloranib compared to placebo. There were a total of five serious adverse events (SAEs); aggression (placebo, 2.4mg beloranib), ankle fracture (placebo), mental status change (1.8mg beloranib), and pulmonary embolism (1.8mg beloranib). Four patients withdrew due to adverse events in the 1.8mg beloranib treatment group (abnormal behaviour, anxiety, mental status changes, and pulmonary embolism) and two patients in the 2.4mg beloranib group (injection site pain and psychotic disorder).

Many of these adverse events, specifically psychiatric disorders, are commonly observed as background comorbidities in PWS patients. At the end of the randomised treatment period, there were no clinically significant abnormal patterns regarding laboratory values, vital signs, or electrocardiography (ECG) findings. As previously disclosed, across the completed trials comprising the beloranib clinical program, there has been an association of venous thromboembolic events reported in patients treated with beloranib versus placebo, including one fatal case of pulmonary embolism (1.8mg beloranib) during the randomised portion of the bestPWS study that was reported in October 2015.

No other venous thromboembolic events were reported during the blinded randomized portion of the bestPWS study. As previously reported, a second patient death associated with pulmonary embolism (2.4mg beloranib) and two cases of deep vein thrombosis (1.8mg and 2.4mg beloranib) occurred during the open-label extension portion of the bestPWS study. No other deaths have occurred over the course of the beloranib programme.

"These data further support the efficacy profile of beloranib in PWS, and advance our understanding of the potential of our MetAP2 inhibitor platform to impact metabolic disorders," said Dr Thomas Hughes, Chief Executive Officer of Zafgen. "We believe these data also provide greater perspective on the benefit/risk relationship of beloranib in this high-risk patient population and we look forward to discussing these results with the FDA."

Zafgen plans to present to the FDA the data from the ZAF-311 clinical trial, and previously reported data from the ZAF-203 Phase 2b clinical trial of beloranib in obesity complicated by type 2 diabetes, as well as a proposal for a risk mitigation strategy for beloranib in PWS in an effort to resolve the full clinical hold the FDA placed on the beloranib IND in December 2015.

Zafgen holds exclusive worldwide rights (exclusive of South Korea) for the development and commercialization of beloranib. Zafgen exclusively licensed beloranib from Chong Kun Dang Pharmaceutical Corporation (CKD Pharma) of South Korea.

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