Clinical Trials

Date: 2017-06-10

Type of information: Presentation of results at a congress

phase: 1

Announcement: presentation of results at the American Diabetes Association Scientific Sessions

Company: Zafgen (USA - MA)

Product: ZGN-1061

Action mechanism:

• enzyme inhibitor/methionine aminopeptidase 2 (MetAP2) inhibitor. ZGN-1061 is a fumagillin-class, injectable small molecule second generation MetAP2 inhibitor that modulates the activity of key cellular processes that control the body's ability to make and store fat, and utilize fat and glucose as an energy source.
• In preclinical studies, ZGN-1061 has demonstrated promising efficacy and potency in animal models of obesity, with an improved pharmacokinetic profile and safety margin relative to previous molecules in the MetAP2 class. ZGN-1061 is anticipated to help reduce hunger and restore balance to fat metabolism, enabling calories to once again be used as a productive energy source, leading to weight loss and improved metabolic control.

Disease: patients with type 2 diabetes who are overweight or obese

Therapeutic area: Metabolic diseases

Country:

Trial details: The Phase 1 clinical trial included a single ascending dose (SAD) phase, which enrolled healthy volunteers, and a multiple ascending dose (MAD) phase, which evaluated twice-weekly administration of ZGN-1061 in overweight or obese patients over four weeks. The SAD phase was comprised of six dosing cohorts ranging from 0.2 mg to 4.8 mg and the MAD phase was comprised of three dosing cohorts of 0.2 mg, 0.6 mg and 1.8 mg. The SAD phase included 39 volunteers (ZGN-1061 N=28, placebo N=11), 90% male and average body mass index (BMI) of 26 kg/m2; and the MAD phase included 29 patients (ZGN-1061 N=22, placebo N=7), 76% male and average BMI of 33 kg/m2. Patients in the MAD phase were domiciled while receiving treatment and were subjected to inpatient safety monitoring for most of the clinical trial's 28-day duration.

Latest news:

• • On June 10, 2017, Zafgen announced the presentation of new data for ZGN-1061, its second-generation MetAP2 inhibitor, in two late-breaking posters at the American Diabetes Association's 77th Annual Scientific Sessions (ADA). The data show that ZGN-1061 treatment causes improvements across multiple metabolic measures consistent with MetAP2 inhibition, demonstrates rapid drug absorption and clearance, and has a favorable safety profile with no evidence of prothrombotic effects. Phase 1 Clinical Trial Data: Poster 144-LB, "Single and Multiple Dose Evaluation of a Novel MetAP2 Inhibitor: Results of a Randomized, Double-Blind, Placebo-Controlled Clinical Trial," details the full results from the Phase 1 clinical trial of ZGN-1061, including new efficacy data related to secondary endpoints. The multiple ascending dose (MAD) phase evaluated twice-weekly administration of ZGN-1061 in overweight or obese patients (ZGN-1061 N=22, placebo N=7; average BMI of 33 kg/m2). Patients in the MAD phase were domiciled while receiving treatment and were subjected to inpatient safety monitoring for most of the clinical trial's 28-day duration.
• Data from the clinical trial are highlighted below: As previously reported, on average, patients treated with ZGN-1061 for four weeks lost weight relative to placebo-treated patients (-4.6 lbs, -2.2 lbs, and -3.8 lbs for 0.2 mg, 0.6 mg, and 1.8 mg, respectively vs. -0.51 lbs for placebo). Body weight loss was steady and progressive during treatment with ZGN-1061 and rebounded post-treatment, supporting a drug effect. ZGN-1061 produced improvements in waist circumference relative to placebo. In addition, treatment with ZGN-1061 resulted in a trend for reduced food intake relative to placebo. The clinical trial demonstrated trends for reductions in LDL-cholesterol, and high-sensitivity C-reactive protein (hsCRP). Notably, there were greater reductions in mean LDL-cholesterol and hsCRP in ZGN-1061-treated subjects with abnormally elevated LDL or hsCRP at baseline. The clinical trial also showed a trend for reductions in leptin and increases in adiponectin with ZGN-1061 compared to placebo, reflective of favorable changes in adipose function and signaling.
• ZGN-1061 is rapidly metabolized and cleared following administration, with a much shorter half-life than beloranib, minimizing exposure to the compound while driving desired metabolic effects. Single and repeat doses of ZGN-1061 were generally safe and well tolerated. There were no severe adverse events (AEs), no serious AEs (SAEs), and no AEs leading to early withdrawal from the clinical trial. As previously reported, there was no prothrombotic effect observed with ZGN-1061. No treatment emergent venous thromboembolisms (VTEs), no clinically meaningful D-dimer elevations indicative of thrombosis and no elevations in mean D-dimer levels were observed in the dosing groups compared to baseline or placebo. There were no clinically significant changes in coagulation laboratory parameters or other key biomarkers of interest, including von Willebrand factor and soluble thrombomodulin.
• Preclinical Efficacy and Safety Differentiation Data: Preclinical data presented at the meeting demonstrated that ZGN-1061 showed similar effects on diabetes, obesity, and other metabolic endpoints, but with a greatly improved safety profile in comparison to the Company's prior development compound, beloranib. In poster 143-LB, "The MetAP2 Inhibitor ZGN-1061 Improves Glycemia and has Weight Loss Efficacy with an Improved Safety Profile in Preclinical Models," Zafgen presented results from a study comparing ZGN-1061, beloranib and vehicle in a mouse model of obesity and insulin resistance, as well as in vitro and in vivo data demonstrating the impact of ZGN-1061 versus beloranib on multiple thrombotic markers. Highlights of the data include:
• ZGN-1061 showed statistically significant improvements in glycemic control, insulin sensitivity, body weight, body fat, lipids and cardiometabolic biomarkers compared to vehicle, and these improvements were comparable to those seen for beloranib.
• ZGN-1061 is rapidly metabolized and cleared following administration, with a much shorter half-life than beloranib, minimizing exposure to the compound while driving desired metabolic effects.
• ZGN-1061 displays a reduced impact on endothelial cells compared to beloranib, and on several thrombotic markers, including P21, thrombomodulin, and plasminogen activator inhibitor-1 (PAI-1), in vitro, as well as thrombin time and D-dimer in vivo. ZGN-1061 has improved safety margins for morbidity and coagulopathy, with a 200-fold margin for ZGN-1061 compared to approximately 4-fold for a clinically equivalent dose of beloranib.
• • On May 4, 2017, Zafgen announced positive topline data from its Phase 1 clinical trial of ZGN-1061. The compound demonstrated rapid drug absorption and clearance in line with pre-specified criteria established for the molecule, and was well-tolerated and safe, with no evidence of prothrombotic effects. Patients in the clinical trial experienced mean weight loss of up to approximately one pound per week.
• Zafgen plans to advance ZGN-1061 into a Phase 2 clinical trial in the second half of this year in patients with type 2 diabetes who are overweight or obese. On average, patients treated with ZGN-1061 for four weeks lost weight relative to placebo-treated patients (-4.6 lbs, -2.2 lbs, and -3.8 lbs for 0.2 mg, 0.6 mg, and 1.8 mg, respectively vs. -0.51 lbs for placebo), with trends for improvements observed in waist circumference, food intake, low density lipoprotein-cholesterol, C-reactive protein, adiponectin and leptin. ZGN-1061 demonstrated rapid drug exposure and clearance for all dose levels, in line with prospectively established criteria. Effective concentrations of drug were reached in circulation based on measurements of drug binding to the MetAP2 target enzyme.
• • On September 20, 2016, Zafgen announced that the company has recently initiated dosing in the multiple ascending dose cohorts of its ongoing Phase 1 clinical trial of ZGN-1061. The initiation of the MAD portion was triggered following a review of the initial safety and tolerability data from the first two cohorts of the single ascending dose portion of the clinical trial.

Is general: Yes