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Zafgen Inc. (Nasdaq: ZFGN) 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 today 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 behaviors, making it the first investigational drug to demonstrate a positive impact on these two hallmark challenges of PWS.
“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,” stated Thomas Hughes, Ph.D., 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.”
PWS is the most common genetic cause of life-threatening obesity. Hyperphagia, pathologic hunger-related behaviors, dominates the lives of individuals with PWS, driving patients to engage in problematic behaviors which can lead to bodily injury, choking, and stomach rupture. 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 Merlin G. Butler, M.D., Ph.D., FFACMG, 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 behaviors 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 Efficacy and Safety Results
In the bestPWS ZAF-311 study, 107 patients were randomized to receive twice-weekly subcutaneous injections of either 2.4 mg or 1.8 mg 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 behaviors 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 BMI of 40 kg/m2, an average body weight of 100 kg, an average fat mass of 51 kg 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 analyzed the data using a mixed model repeated measures (MMRM) approach to account for missing endpoint data from the patients who did not complete the randomized treatment period of the trial.
Co-primary Endpoints
| Average Weight atBaseline (kg)1 | PercentChange inBody Weight1 | Placebo-adjustedChange inBody Weight1 | p-value | |||||
| 2.4 mg beloranib (n=37) | 105.7 | -5.30 | % | -9.45 | % | <0.0001 | ||
| 1.8 mg beloranib (n=36) | 97.5 | -4.05 | % | -8.20 | % | <0.0001 | ||
| Placebo (n=34) | 100.9 | +4.15 | % | |||||
1Endpoint results shown are Least Squares mean values.
Patients in the ZAF-311 trial were markedly obese at baseline. Patients randomized 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.
| Average HyperphagiaQuestionnaire(HQ-CT)Total Score at Baseline | Unit Change inHQ-CT TotalScore1 | Placebo-adjusted Change inHQ-CT TotalScore1 | p-value | |
| 2.4 mg beloranib (n=37) | 18.3 | -7.4 | -7.0 | 0.0001 |
| 1.8 mg beloranib (n=36) | 17.4 | -6.7 | -6.3 | 0.0003 |
| Placebo (n=34) | 15.0 | -0.4 |
1Endpoint results shown are Least Squares mean values.
The HQ-CT is a PWS-specific study instrument that provides an assessment by caregivers of the food-seeking behaviors 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 behaviors at baseline. While hyperphagia-related behaviors 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 behaviors.
Secondary Endpoints 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.
| Change inLDLCholesterol(mg/dl)1 | Change inTotalCholesterol(mg/dl)1 | Change inLeptin(μg/L)1 | Change inAdiponectin(μg/L)1 | PercentChange inCRP2 | |||
| Mean at Baseline | 101 | 174 | 6.9 | 4.6 | 7.6 μg/mL | ||
| 2.4 mg beloranib (n=37) | -17.8** | -18.0* | -24.0** | +1.9** | -53%** | ||
| 1.8 mg beloranib (n= 36) | -16.6** | -17.2* | -20.7** | +1.7** | -56%** | ||
| Placebo (n=34) | +1.8 | +1.3 | +6.9 | -0.5 | +2.5 | % | |
1Endpoint results shown are Least Squares mean values.2Endpoint results are Geometric Least Squares mean values.*p<0.001 compared to placebo** p<0.0001 compared to placebo
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 1.8 mg and 2.4 mg doses of beloranib. Lean body mass was minimally changed from baseline with a 0.5 kg loss in the 1.8 mg beloranib arm, a 0.7 kg loss in the 2.4 mg beloranib arm and an increase of 0.7 kg 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.
| Change in TotalBody Mass1 | Fat Mass Change(kg)1 | Percentage Changein Fat Mass1 | |||||
| 2.4 mg beloranib (n=37) | -5.7%* | -5.0* | -9.8%* | ||||
| 1.8 mg beloranib (n=36) | -2.9%* | -2.5* | -4.5%* | ||||
| Placebo (n=34) | + 3.4 | % | + 2.6 | + 5.9 | % | ||
1Endpoint results shown are Least Squares mean values.*p<0.0001 compared to placebo
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, 2.4 mg beloranib), ankle fracture (placebo), mental status change (1.8 mg beloranib), and pulmonary embolism (1.8 mg beloranib). Four patients withdrew due to adverse events in the 1.8 mg beloranib treatment group (abnormal behavior, anxiety, mental status changes, and pulmonary embolism) and two patients in the 2.4 mg 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 randomized 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 (1.8 mg beloranib) during the randomized 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 (2.4 mg beloranib) and two cases of deep vein thrombosis (1.8 mg and 2.4 mg beloranib) occurred during the open-label extension portion of the bestPWS study. No other deaths have occurred over the course of the beloranib program.
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.
Source: Street Insider
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