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T2DM medications

Zafgen’s ZGN-1061 demonstrates safety and effectiveness for T2DM

Trial met all primary objectives, demonstrated efficacy and safety and established minimally effective dose of 0.9 mg for ZGN-1061

Zafgen has announced positive full results from the its Phase 2 clinical trial of ZGN-1061, designed to demonstrate proof-of-concept efficacy and safety in patients with type 2 diabetes and establish a minimally effective dose. The trial met all of its primary endpoints at the 0.9mg dose, and 12-week data demonstrated a favourable safety and tolerability profile, with no treatment-related serious adverse events and no cardiovascular (CV) safety signals observed. Data for this trial and two supportive nonclinical studies for ZGN-1061 were presented as late-breaker abstracts at the American Diabetes Association (ADA) 78th Scientific Sessions in Orlando, FL.

“These positive Phase 2 data show clinically relevant efficacy, favorable safety profile and dose responsive results in line with our expectations for this proof-of-concept trial in patients with type 2 diabetes,” said Dr Thomas E Hughes, President and Chief Scientific Officer, Zafgen. “Statistically significant lowering of glucose levels and A1C was observed, with a curve continuing to show potential for A1C lowering beyond 12 weeks. Of particular interest, the safety data in this clinical trial were unremarkable and highly differentiated from our first generation MetAP2 inhibitor, with no CV safety signals observed.”

ZGN-1061 demonstrated a statistically significant reduction in A1C at 0.9mg versus placebo at Week eight (p<0.01) and Week 12 (p<0.001). A1C lowering results from the trial establishes the 0.9mg dose as a minimally effective dose, with progressive A1C lowering to 12 weeks with no signs of waning of effect. The 0.9mg dose in this trial represents approximately 50% target engagement of MetAP2. These results were well-supported by several relevant metabolic biomarkers, including postprandial and fasting plasma glucose, FGF21, adiponectin and leptin.

ZGN-1061 was generally safe and well-tolerated, with primarily mild to moderate adverse events (AEs) and an overall high study completion rate (95%). The most frequent AEs were injection site bruising, upper respiratory infection, and diarrhoea that was mild and self-limiting. Serious adverse events – upper abdominal pain and skin ulcer – were reported by two patients on treatment and deemed not related to study drug by the principal investigator. Importantly, there were no elevations in D-dimer concentrations across the dosing groups as compared to baseline or placebo and no CV safety signals observed.

In addition to the Phase 2 clinical data for ZGN-1061, Zafgen is also reporting supportive non-clinical data for ZGN-1061, including data on combination treatment with ZGN-1061 and liraglutide, and data on treatment with ZGN-1061 in non-alcoholic steatohepatitis (NASH). Non-clinical data on treatment with both ZGN-1061 and liraglutide suggest that combination therapy with these glucose-lowering agents may yield additive improvement in glycaemic control and weight loss, demonstrating the effect of two complementary mechanisms – MetAP2 and GLP-1.

From non-clinical data in a NASH model, the researchers observed that ZGN-1061 markedly reduced liver weight, NAS score and markers of liver damage (ALT and AST). These NASH-related data, combined with previous gene expression data with ZGN-1061 and clinical liver fat content data from Zafgen’s first generation MetAP2 inhibitor, suggest potential clinical value in treating liver-specific metabolic conditions. It is estimated that up to 70 percent of people with type 2 diabetes have concomitant NASH.

“The clinical data announced today for ZGN-1061 reinforce our excitement about the potential of our second-generation MetAP2 inhibition platform to address advanced, complex type 2 diabetes, while also providing a potential safety read-through to our rare disease programs with high unmet medical need, starting with Prader-Willi syndrome,” said Jeffrey Hatfield, CEO of Zafgen. “Zafgen’s MetAP2 inhibition platform approach is also supported by the combination therapy and NASH nonclinical studies for ZGN-1061, opening the door for potential additional value in the treatment of type 2 diabetes.”

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