Clinical Trials

Date: 2016-07-19

Type of information: Halting of the trial

phase: 3

Announcement: halting of the development

Company: Zafgen (USA - MA)

Product: ZGN-440 (beloranib)

Action mechanism: enzyme inhibitor/methionine aminopeptidase 2 (MetAP2) inhibitor. Beloranib is a potent inhibitor of methionine aminopeptidase 2, or MetAP2, an enzyme that modulates the activity of key cellular processes that control metabolism. MetAP2 inhibitors work, at least in part, by directing MetAP2 binding to cellular stress mediators, and, thus, reducing the tone of signals that drive lipid synthesis by the liver and fat storage throughout the body. In this manner, MetAP2 inhibition increases metabolism of fat as an energy source. Zafgen holds exclusive worldwide rights (exclusive of South Korea) for the development and commercialization of beloranib. Zafgen exclusively licensed beloranib from Chong Kun Dang (CKD) Pharmaceutical Corp. of South Korea.

Disease: Prader-Willi syndrome

Therapeutic area: Rare diseases - Genetic diseases - Metabolic diseases

Country: USA

Trial details:

• BestPWS is a six-month trial consisting of randomized, double-blind, placebo controlled, twice-weekly subcutaneous injections of 1.8 mg or 2.4 mg of beloranib or placebo in 108 patients with PWS. The primary efficacy endpoints for this trial are hyperphagia-related behaviors and body weight. Secondary endpoints include changes in total body fat mass, LDL-c, HDL-c, C-reactive protein (CRP) which is a marker of systemic inflammation, among others, and quality of life. (NCT02179151)

   

Latest news:

• •  On July 19, 2016, Zafgen announced that, following a comprehensive review of its assets and clinical programs, as well as feedback from regulatory authorities, the Company is refocusing its resources on development of a differentiated second-generation MetAP2 inhibitor, ZGN-1061, in severe and complicated obesity. "Given the heightened complexity and future cost of beloranib development, balanced against the emerging product profile of ZGN-1061, we believe that the long-term opportunity for ZGN-1061 is more robust than for beloranib, said Thomas Hughes, Ph.D., President and Chief Executive Officer of Zafgen. Given our deep knowledge of this new and exciting drug class, and our strong cash position, we believe we are well-positioned to advance ZGN-1061 as a potential new treatment for prevalent obesity-related indications". To address the beloranib  clinical hold, Zafgen recently held a Type A meeting with the FDA to discuss the clinical and preclinical data for beloranib as well as a proposed risk mitigation strategy for beloranib in Prader-Willi syndrome. Following its discussions with the FDA and review of other considerations, Zafgen has determined that the obstacles, costs and development timelines to obtain marketing approval for beloranib are too great to justify additional investment in the program, particularly given the promising emerging profile of ZGN-1061. The Company is therefore suspending further development of beloranib in order to focus its resources on ZGN-1061. Zafgen is currently screening patients to initiate a Phase 1 clinical trial evaluating ZGN-1061 for safety, tolerability, and weight loss efficacy over four weeks of treatment, and currently expects Phase 1 clinical data by the end of the first quarter of 2017. Based on the clinical data demonstrating beloranib's significant effect on body weight and glycemic control in patients with severe obesity complicated by type 2 diabetes, Zafgen plans to focus later-stage development of ZGN-1061 in severe and complicated obesity.
• • On April 3, 2016, Zafgen 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 (see below) 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. • On January 20, 2016, Zafgen announced positive efficacy results from the bestPWS ZAF-311 study evaluating the safety and efficacy of beloranib 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). 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. 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 Baseline (kg)	*Percent Change in Body Weight			*Placebo-adjusted Change in Body Weight			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	%
  *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.

• 	Hyperphagia Questionnaire (HQ-CT) Score at Baseline	*Unit Change in HQ-CT Score	*Placebo- adjusted Change in HQ-CT Score	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
  *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. • On December 2, 2015, Zafgen received verbal notice from the FDA that its beloranib investigational new drug (IND) application has been placed on complete clinical hold, affecting the ongoing open label extension (OLE) portion of the pivotal Phase 3 ZAF-311 bestPWS clinical trial in patients with Prader-Willi syndrome (PWS). A complete clinical hold is an order that the FDA issues to a sponsor to suspend all clinical work requested under the Company's IND application. As previously announced, the Company continues to expect top-line results of the randomized portion of the ZAF-311 clinical trial in the first quarter of 2016.  
• • On December 2, 2015, Zafgen provided an update on the open label extension (OLE) portion of the pivotal Phase 3 ZAF-311 bestPWS clinical trial evaluating beloranib in patients with Prader-Willi syndrome (PWS). On December 1, 2015, the Company learned that a patient receiving beloranib as part of the OLE portion of the study was diagnosed with bilateral pulmonary emboli and has died. "Our thoughts are with the patient and their family at this time," said Dr. Thomas Hughes, Chief Executive Officer of Zafgen. "Patient safety remains our top priority and we are investigating the circumstances around this event. We are also engaging in discussions with the FDA while we determine the next steps with the beloranib program." As previously announced, the Company continues to expect top-line results of the randomized portion of the ZAF-311 clinical trial in the first quarter of 2016.
• • On October 22, 2015,  Zafgen announced a clinical update for beloranib. After review of its ongoing clinical trials, the Company has elected to proceed with efficacy and safety data analysis and close the randomized portion of its Phase 3 ZAF-311 clinical trial of beloranib in patients with Prader-Willi syndrome (PWS) and its ZAF-203 Phase 2b clinical trial of beloranib in patients with severe obesity complicated by type 2 diabetes. Zafgen believes that a sufficient number of patients have completed randomized treatment in both clinical trials to assess the efficacy of beloranib and help inform next steps for the beloranib program. Following the partial clinical hold announced last week, the Company believes it can best preserve the integrity of the data in each clinical trial by closing the randomized portion of the clinical trials early. The Company, based on consultation with the FDA, expects ZAF-311 to remain a pivotal clinical trial. The Company expects to report top-line results from both the ZAF-311 and ZAF-203 clinical trials in the first quarter of 2016. Zafgen will continue the six-month open label extension (OLE) of the ZAF-311 clinical trial in PWS to obtain important ongoing efficacy and safety data. As previously planned, the Company is continuing to offer an open-ended, unblinded extension study after patients have completed six months of OLE. In consultation with the FDA , a full assessment of the safety and efficacy data from ZAF-311 will be performed to inform the design of ZAF-312, the Company's second PWS Phase 3 clinical trial. The FDA has informed the Company that it will review the ZAF-311 clinical trial results on the basis of an abbreviated data package.
• • On October 16, 2015, Zafgen announced that it received verbal notice from the FDA that beloranib has been placed on partial clinical hold. This partial clinical hold impacts ongoing or planned clinical trials. As previously reported, Zafgen learned of a death in the ongoing Phase 3 bestPWS study (ZAF-311) of beloranib in Prader-Willi Syndrome (PWS). While the cause of death remains unknown, the patient's treatment assignment has been unblinded and it is now known that the patient was receiving beloranib. Due to previously reported thromboembolic events in ongoing and prior clinical trials of beloranib and the unknown nature of the death, the FDA gave verbal notice of a partial clinical hold to institute measures to ensure patient safety. Patients currently participating in the ZAF-311 study will be screened for existing thrombotic disease prior to receiving further study drug and regularly monitored through the completion of the study.
• • On May 28, 2015, Zafgen announced that the Company has completed enrollment of ZAF-311, also known as the Beloranib Efficacy Safety and Tolerability in Prader-Willi syndrome (bestPWS) study, a Phase 3 clinical trial of beloranib for the treatment of patients with Prader-Willi syndrome (PWS). The objective of the study is to evaluate the efficacy and safety of beloranib in PWS patients over 6 months of randomized treatment, followed by a six-month open label extension. The trial includes 108 patients with PWS enrolled across 15 sites in the U.S.; the planned enrollment target number was 102 patients. At the time of screening, patients enrolled in the trial are, on average, ~20 years old, morbidly obese (BMI ~40 kg/m2), roughly equal number of males and females, and have a hyperphagia total score consistent with moderate to severe hyperphagia. Thus, the enrolled population is representative of the general PWS population and what was intended for this Phase 3 clinical trial.

Is general: Yes