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ZGN-1061

Beneficial impact of dose-dependent ZGN-1061 on glucose tolerance

The improvements in glucose tolerance and insulin levels seen with ZGN-1061 also occurred with low dose levels which did not result in weight change and suggest these glucose homeostatic benefits can be dissociated from a weight loss effect

Zafgen has presented new data from a preclinical study evaluating ZGN-1061 in a mouse model of obesity and insulin resistance at the 53rd Annual Meeting of the European Association for the Study of Diabetes in Lisbon, Portugal. The data presented includes previously presented data from the Phase 1 clinical trial of ZGN-1061, as well as new preclinical data demonstrating the dose-dependent effect of ZGN-1061 on glucose tolerance, weight loss, and several metabolic markers in diet-induced obese mice.

“The results presented today underscore the potential of ZGN-1061 to positively impact glycaemic control, body weight and other metabolic parameters, consistent with MetAP2 inhibition," said Dr Thomas Hughes, President and Chief Executive Officer of Zafgen. “Importantly, the new preclinical data illustrate that the improvement in glucose tolerance produced by ZGN-1061 occurs independently from weight loss benefits seen with the compound. These results reinforce our confidence in the programme as we advance into a Phase 2 clinical trial of ZGN-1061 in patients with type 2 diabetes.”

At the meeting, Zafgen presented new data from a preclinical study evaluating ZGN-1061, highlights of the data include:

  • ZGN-1061 produced dose-dependent improvements in glucose tolerance and insulin levels in diet induced obese mice.
  • ZGN-1061 produced a dose-dependent reduction in body weight that was primarily due to loss of fat mass.
  • The improvements in glucose tolerance and insulin levels seen with ZGN-1061 also occurred with low dose levels which did not result in weight change and suggest these glucose homeostatic benefits can be dissociated, at least in part, from a weight loss effect or food intake effect.
  • Improvements in metabolic biomarkers, including non-esterified fatty acids, ketone bodies (β-hydroxybutyrate), and leptin, were consistent with loss of fat mass as well as increased fat mobilization and oxidation.

Zafgen also presented findings from the company’s Phase 1 clinical trial of ZGN-1061. As previously reported, 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 favourable safety profile with no evidence of pro-thrombotic effects. 

Zafgen has also initiated ZAF-1061-201, a Phase 2 clinical trial evaluating ZGN-1061 in patients with type 2 diabetes. The primary objectives of this trial are to assess glycaemic control as well as safety and tolerability. ZGN-1061 is the Company’s second-generation MetAP2 inhibitor.

“The initiation and commencement of patient dosing in this Phase 2 clinical trial represents a milestone in our ZGN-1061 development programme, as we further evaluate ZGN-1061 in patients who face numerous challenges associated with managing their type 2 diabetes,” said Dr Hughes. “ZGN-1061 has the potential to drive improvements across a number of metabolic endpoints which are not fully addressed by current diabetes treatments, and we look forward to sharing progress on enrolment of the clinical trial and reporting interim data in the first half of next year.”

The randomized, placebo-controlled Phase 2 clinical trial will evaluate three doses of ZGN-1061 for 12 weeks. The clinical trial will enrol approximately 120 patients with type 2 diabetes who are overweight or obese (BMI ≥ 27) across 23 study sites in Australia and New Zealand. Patients will be randomized to either placebo or one of three ZGN-1061 dosing arms, 0.05mg, 0.3mg and 0.9mg, which will be administered by subcutaneous injection every three days.

In addition to the primary objectives of assessing glycaemic control and safety and tolerability, the company will evaluate the effects of ZGN-1061 on multiple metabolic measures and cardiovascular risk factors, including body weight, plasma lipid fractions, and inflammation. The protocol provides for an interim analysis, expected in the first half of 2018, which will evaluate all patients who have completed the 12-week treatment period at the time of the analysis.

“We expect that this clinical trial will provide us with initial insights on how ZGN-1061 could positively impact glycaemic control and other metabolic endpoints in this difficult-to-treat patient population, and help identify an optimal dose range for use in later-stage clinical trials,” said Dr Dennis Kim, Chief Medical Officer. “We have been very encouraged with the clinical profile for ZGN-1061, which in a Phase 1 clinical trial demonstrated a favourable safety and pharmacokinetic profile as well as early efficacy signals consistent with MetAP2 inhibition.”

ZGN-1061 is a fumagillin-class, injectable small molecule second generation MetAP2 inhibitor that was advanced into development due to its unique properties that maximize impact on metabolic parameters relevant to the treatment of type 2 diabetes and other related metabolic disorders. In preclinical studies, ZGN-1061 has demonstrated promising efficacy in animal models of type 2 diabetes and obesity, with an improved pharmacokinetic profile and safety margin relative to previous molecules in the MetAP2 inhibitor class.

As demonstrated clinically for MetAP2 inhibitors, ZGN-1061 is anticipated to improve glycaemic control while also helping to restore balance to fat metabolism, enabling calories to once again be used as a productive energy source, leading to improved metabolic control and long-term weight loss. Zafgen recently completed its first Phase 1 clinical trial of ZGN-1061, and is planning to advance the compound to Phase 2 clinical testing in patients with type 2 diabetes who are overweight or obese. Zafgen holds exclusive worldwide rights for the development and commercialization of ZGN-1061.

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