Date: 2016-07-19
Type of
information: Halting of the trial
phase: 2b
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: severe obesity complicated by type 2 diabetes
Therapeutic
area: Metabolic diseases
Country: Australia
Trial
details:
- • ZAF-203 is a Phase 2b clinical trial designed to determine the long-term weight loss benefits of MetAP2 inhibitor treatment with beloranib in patients with severe obesity complicated by type 2 diabetes, which began randomized treatment in December 2014. The trial aims to demonstrate efficacy and safety over a 12 month period, with an interim six-month analysis. Patients in the study are randomized to receive twice weekly subcutaneous injections of placebo, 1.2 mg or 1.8 mg of beloranib during the treatment period of 12 months. The primary efficacy endpoint is change in total body weight from baseline to the end of randomized treatment. Key secondary endpoints include changes in glycemic control, lipid parameters and inflammatory markers. Additional assessments include sense of hunger and quality of life impact for patients. (NCT02324491)
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 June 11, 2016, Zafgen announced new data from the ZAF-203 clinical trial evaluating beloranib, a MetAP2 inhibitor, for the treatment of severe obesity complicated by type 2 diabetes. Data presented during the American Diabetes Association's 76th Scientific Sessions showed that beloranib was associated with improvement in body composition, including a significant decrease in body weight, fat mass, reduction in waist and hip circumference, and improvements in liver fat, as well as glycemic control parameters including HbA1c, fasting plasma glucose (FPG), post-prandial glucose, beta-cell function, and insulin sensitivity, when compared to placebo.
As previously reported, the ZAF-203 clinical trial achieved its primary efficacy endpoint, as beloranib demonstrated a statistically significant reduction in body weight compared to placebo. Patients enrolled in both the 1.8 mg and 1.2 mg treatment arms also met a key secondary endpoint, with patients in each dose arm achieving, on average, an absolute reduction in HbA1c following six months of treatment of 2.0 percent compared to a reduction of 0.6 percent for placebo.
ZAF-203 Efficacy and Safety Results:
In the ZAF-203 clinical trial, 152 patients were randomized and received twice-weekly subcutaneous injections of either 1.8 mg or 1.2 mg of beloranib or placebo, in addition to a diet and exercise regimen. Sixty-six patients comprised the pre-specified primary analysis population, completing six months of treatment in compliance with the protocol prior to the Company's suspension of dosing in the trial at the time the FDA placed a partial clinical hold on the beloranib IND in October 2015.
The primary analysis population were a mean age of 55, had a body mass index (BMI) of 39.0 kg/m2, fat mass of 36-42 percent, and average HbA1c levels of 8.3 percent at baseline.
Primary Endpoint
|
Average Weight at
Baseline (kg) |
*Change in
Body Weight |
*Percent Change
in Body Weight |
*p-value |
| 1.8 mg beloranib (n=19) |
109.1 |
-14.2 |
-12.7 |
<0.0001 |
| 1.2 mg beloranib (n=25) |
120.4 |
-15.0 |
-13.5 |
<0.0001 |
| Placebo (n=22) |
103.2 |
-3.8 |
-3.1 |
|
|
|
|
|
|
*Endpoint results shown are Least Squares mean values. p-value is the test of the difference from placebo. Similar results were obtained for the 152-patient intent to treat (ITT) population using a mixed-model repeated measures (MMRM) statistical method.
95% (p<0.0001) and 92% (p<0.0001) of patients enrolled in the 1.8 mg and 1.2 mg treatment arms achieved a 5% reduction in body weight, versus 27% of placebo-treated patients
74% (p<0.0001) and 64% (p<0.0001) of patients enrolled in the 1.8 mg and 1.2 mg treatment arms achieved a 10% reduction in body weight, versus 5% of placebo-treated patients
Secondary Endpoints : Beloranib treatment was associated with statistically significant and clinically meaningful reductions in HbA1c and several other glycemic control parameters.
|
Average HbA1c
at
Baseline |
*Average HbA1c
at
Week 26 |
*Absolute
Change in
HbA1c |
*p-value |
| 1.8 mg beloranib (n=19) |
|
8.2 |
% |
|
6.3 |
% |
|
-2.0 |
% |
<0.0001 |
| 1.2 mg beloranib (n=25) |
|
8.5 |
% |
|
6.3 |
% |
|
-2.0 |
% |
<0.0001 |
| Placebo (n=22) |
|
8.1 |
% |
|
7.7 |
% |
|
-0.6 |
% |
|
|
|
|
|
|
|
|
|
|
|
|
*Endpoint results shown are Least Squares mean values. p-value is the test of the difference from placebo.
74% (p<0.01) and 72% (p<0.01) of patients enrolled in the 1.8 mg and 1.2 mg treatment arms achieved the treatment goal of <7% HbA1c at six months, versus 23% of placebo-treated patients
63% (p<0.01) and 68% (p <0.01) of patients enrolled in the 1.8 mg and 1.2 mg treatment arms achieved the treatment goal of ?6.5% HbA1c at six months, versus 18% of placebo-treated patients
At Week 26, least squares mean HbA1c in beloranib-treated patients was 6.3%.
Patients treated with beloranib demonstrated statistically significant decreases from baseline in fasting plasma glucose compared to placebo at all time points (p<0.01 for both doses). Clinically meaningful reductions from baseline in mean postprandial plasma glucose concentrations were observed with both beloranib doses compared to placebo. The overall area under the curve for postprandial plasma glucose was decreased at all post-baseline assessments with either 1.8 or 1.2 mg of beloranib versus placebo. In addition, after 26 weeks, there was a significant improvement in ?-cell function (HOMA2 %B) with both doses of beloranib compared to placebo. Furthermore, insulin sensitivity (HOMA2 %S) was significantly improved in patients that received the 1.2 mg dose of beloranib compared to placebo.
These observed improvements in HbA1c and improvements in other markers of glycemic control, including reduced fasting plasma glucose, reduced postprandial glucose, improved ?-cell function, and improved insulin sensitivity, occurred without any attendant increase in the risk of hypoglycemia.
In this clinical trial, beloranib treatment was also associated with statistically significant improvements in body composition which was measured using bioimpedance.
Patients treated with 1.8 mg and 1.2 mg beloranib had consistent reduction in fat mass that was statistically significant compared to placebo at Week 12 and Week 26. Furthermore, in those treated with beloranib, fat mass accounted for approximately 75 percent of weight loss, which is consistent with that observed with other interventions including diet and exercise. In this clinical trial, there was also a small but significant reduction in lean mass in beloranib-treated subjects compared to no change in placebo-treated subjects.
|
Change in Fat Mass |
Change in Lean Mass |
| 1.8 mg beloranib (n=19) |
-21.7 %
p<0.001 |
-5.7%
p<0.05 |
| 1.2 mg beloranib (n=25) |
-24.1%
p<0.001 |
-5.0%
p<0.05 |
| Placebo (n=22) |
|
-7.4 |
% |
|
0.6 |
% |
|
|
|
|
|
|
|
Beloranib-treated patients also had improvements in waist and hip circumference, liver fat, leptin, and adiponectin compared with placebo (p<0.05).
The most common adverse events (AEs) in the clinical trial were upper respiratory tract infection, diarrhea, and injection site bruising. These were generally mild and transient in nature and occurred at comparable incidence rates between beloranib and placebo treated patients. Ten patients in the beloranib groups (five in each of the 1.8 mg and 1.2 mg groups) withdrew due to AEs compared to two patients in the placebo group. Consistent with prior beloranib clinical trials in conventional obesity, the most common causes of AEs leading to early withdrawal were sleep related, leading to four withdrawals from the clinical trial. In the clinical trial, there were a total of nine serious adverse events (SAEs) identified in eight patients, one in the 1.8 mg group, six in the 1.2 mg group, and two in the placebo group. As previously disclosed, one of the SAEs was a pulmonary embolism in the 1.2 mg treatment group. During the VTE screening process that followed the FDA's partial clinical hold on the beloranib IND in October 2015, two additional VTEs were identified in patients in this clinical trial: deep vein thrombosis in a patient who had received 1.8 mg of beloranib, and superficial thrombophlebitis in a patient who had received 1.2 mg of beloranib.
- • 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 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 September 9, 2015, Zafgen announced it has completed enrollment of ZAF-203, a Phase 2b clinical trial of beloranib in the treatment of patients with both severe obesity and type 2 diabetes. The trial enrolled 152 patients across 16 sites in Australia. The Company remains on track to release six-month interim data in a subset of 95 patients in late 2015 or very early 2016. The baseline characteristics of the study population on average are as follows: 54 years of age, body mass index (BMI) of 40 kg/m2, body weight of 115 kg, HbA1c of 8.3% and fasting glucose of 193 mg/dl, with 43% of the patients being female.
- • On December 15, 2014, Zafgen announced that the Company has initiated a Phase 2b clinical trial with beloranib, in the treatment of patients with both severe obesity and type 2 diabetes. The trial is a randomized, double-blind, placebo-controlled design in severely obese adults with a BMI between 30 and 60 kg/m2, and type 2 diabetes. The trial will aim to demonstrate weight loss over a 6 - 12 month period, along with improvements in glycemic control, and is expected to enroll 150 patients at approximately 15 sites across Australia. Patients enrolled will be randomized to receive placebo, 1.2 mg or 1.8 mg of beloranib, twice weekly subcutaneous injections during the randomized treatment period of 12 months.
Is
general: Yes
