Zafgen Inc (NASDAQ:ZFGN), a biopharmaceutical company dedicated to significantly improving the health and well-being of patients affected by obesity and complex metabolic disorders, announced positive efficacy results 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 a six-month randomized treatment period. The clinical trial 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 in PWS.
Treatment with the 2.4 mg and the 1.8 mg doses of beloranib resulted in 9.45 percent (p<0.0001) and 8.20 percent (p<0.0001) reductions in body weight relative to placebo, respectively. Treatment with the 2.4 mg and the 1.8 mg doses of beloranib also resulted in reductions of hyperphagia-related behaviors of 7.0 units (p=0.0001) and 6.3 units (p=0.0003) relative to placebo, respectively, as measured by the Hyperphagia Questionnaire for Clinical Trials (HQ-CT).
“This clear efficacy outcome is a crucial first step in moving discussions forward with the Food and Drug Administration regarding continued development of beloranib,” stated Thomas Hughes, Ph.D., Chief Executive Officer of Zafgen. “While we take the previously reported adverse events very seriously, we now have the robust data to provide greater perspective on the benefit/risk relationship of beloranib in this high-risk patient population. We thank our investigators, and the patients and their families for participating in the bestPWS ZAF-311 clinical trial.”
PWS is the most common genetic cause of life-threatening obesity. Pathologic hunger-related behaviors, known as hyperphagia, dominate the lives of individuals with PWS, and drive patients to engage in problematic behaviors which can lead to excessive overeating, choking, and stomach rupture. Compounding the morbid obesity in PWS is slowed metabolism, psychiatric conditions including aggression, anxiety, and psychosis, higher risk for cardiopulmonary and metabolic co-morbidities; all of which contribute to a higher risk of obesity-related mortality.
“Prader-Willi syndrome significantly impacts the quality of life of affected individuals and their families, as it drives patients to engage in excessive overeating, or hyperphagia, and may also lead to morbid obesity, which can be life-threatening if not controlled,” said Merlin G. Butler, M.D., Ph.D., FFACMG, Professor of Psychiatry, Behavioral Sciences and Pediatrics, Director, Division of Research and Genetics, Department of Psychiatry, Behavioral Sciences and Pediatrics at the Kansas University Medical Center. “There are no treatment options for these life-limiting problems, so I believe the significant improvements seen in both hyperphagia and obesity in patients receiving beloranib during this six-month clinical trial are clinically meaningful and support a strong rationale for continued evaluation of beloranib as a potential treatment for PWS.”
On December 2, 2015, the Food and Drug Administration (FDA) notified Zafgen that the beloranib investigational new drug (IND) application had been placed on complete clinical hold due to an imbalance in severe venous thromboembolic events, including two patient deaths. In order to address the clinical hold, Zafgen plans to present to the FDA the efficacy and safety data from the bestPWS ZAF-311 study, data from the Phase 2b trial of beloranib in severe obesity complicated by type 2 diabetes, ZAF-203, expected later this quarter, and a proposal for a risk mitigation strategy for beloranib in PWS.
“We are actively working to better understand the mechanisms and incidence of underlying thromboembolic disease in PWS, as well as the potential impact of beloranib treatment on thrombosis in order to develop a strategy for risk mitigation in this underserved patient population,” Dr. Hughes said. “We plan to continue our dialog with the FDA given the robust efficacy results seen in the ZAF-311 trial.”
BestPWS ZAF-311 Efficacy and Safety Results
The bestPWS ZAF-311 study randomized 107 patients 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 trial 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. Patients in the trial were on average 20 years old, had an average BMI of 40 kg/m2 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 the treatment arms. In agreement with the FDA, Zafgen has analyzed the data using a mixed model repeated measures (MMRM) approach to account for the missing endpoint data of the patients who did not complete the clinical trial.
|Average Weight at|
|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|
|*Endpoint results shown are Least Squared mean values.|
Patients in the ZAF-311 trial were markedly obese at baseline. Patients randomized to receive placebo displayed substantial (4.15%) gain 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 lack of effective treatments for managing obesity. Patients treated with beloranib, in contrast to placebo, lost 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.
Score at Baseline
|*Unit Change in|
|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|
|*Endpoint results shown are Least Squared 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.
The most common adverse events (AEs) were injection site bruising, aggression, and hyperphagia, generally of mild and transient 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 in the course of the beloranib program.
Zafgen plans to present the full safety and efficacy data set from the bestPWS Phase 3 trial, including impact on body composition, cardiovascular disease risk markers, metabolic endpoints, and quality of life measures at upcoming medical meetings. (Original Source)
Shares of Zafgen Inc closed yesterday at $5.62 . ZFGN has a 1-year high of $55.36 and a 1-year low of $5.34. The stock’s 50-day moving average is $6.62 and its 200-day moving average is $23.79.
On the ratings front, Zafgen has been the subject of a number of recent research reports. In a report issued on December 3, Suntrust Robinson Humphrey analyst Edward Nash downgraded ZFGN to Hold, with a price target of $7, which implies an upside of 24.6% from current levels. Separately, on December 2, Leerink Swann’s Joseph Schwartz maintained a Buy rating on the stock and has a price target of $11.
According to TipRanks.com, which ranks over 7,500 financial analysts and bloggers to gauge the performance of their past recommendations, Edward Nash and Joseph Schwartz have a total average return of 24.8% and 12.8% respectively. Nash has a success rate of 50.0% and is ranked #255 out of 3580 analysts, while Schwartz has a success rate of 42.1% and is ranked #199.
The street is mostly Bullish on ZFGN stock. Out of 5 analysts who cover the stock, 3 suggest a Buy rating and 2 recommend to Hold the stock. The 12-month average price target assigned to the stock is $16.00, which represents a potential upside of 184.7% from where the stock is currently trading.
Zafgen Inc is a biopharmaceutical company dedicated to improving the health and well-being of patients affected by obesity. Beloranib is the Company’s product candidate.