Most recent update: Friday, October 19, 2018 - 08:09

Bariatric News - Cookies & privacy policy

You are here

Prader-Willi syndrome

Zafgen presents ZGN-1258 data for Prader-Willi syndrome

ZGN-1258 is Zafgen’s second-generation, novel investigational MetAP2 inhibitor for the treatment of rare metabolic disorders, including Prader-Willi syndrome

Zafgen, a clinical-stage biopharmaceutical company leveraging its proprietary knowledge of MetAP2 systems biology to develop novel therapies for patients affected by a range of metabolic diseases, has announced results from three non-clinical, Investigational New Drug (IND)-enabling studies of ZGN-1258 presented at the 2018 Foundation for Prader-Willi Research (FPWR) Family Conference in Las Vegas.

ZGN-1258 is Zafgen’s second-generation, novel investigational MetAP2 inhibitor for the treatment of rare metabolic disorders, including Prader-Willi syndrome (PWS), designed to decrease hyperphagia, change the way the body metabolizes fat, and reduce fat mass. Together, these studies demonstrate nonclinical efficacy and safety for ZGN-1258 and support further development.

PWS is a rare, genetic form of life-threatening obesity characterized by unrelenting pathologic hunger (hyperphagia) leading to dangerous food-seeking behaviour, and there is currently no approved treatment for hyperphagia. People with PWS are also impacted by slowed metabolism, psychiatric conditions and higher risk for cardiopulmonary and metabolic co-morbidities. Our best estimate of prevalence is approximately 1:40,000 people. People with PWS have a shortened life expectancy of approximately 32 years.

The data presented includes:

  • ZGN-1258 effects on body weight and food intake of hyperphagia and obesity;
  • ZGN-1258 effects on other behavioral manifestations commonly observed in PWS, such as low physical activity, anxiety, and obsessive-compulsive behaviors; and
  • ZGN-1258 differentiation on nonclinical safety measures.

“We are excited to connect with the PWS community at the Annual FPWR Conference and to highlight the progress we’ve made in advancing ZGN-1258 for the treatment of PWS, as we work to meet a critical need for patients and families affected by this serious, life-threatening disease,” said Dr Dennis Kim, Chief Medical Officer, Zafgen. “Collectively, the body of evidence we are building with our nonclinical, IND-enabling studies for ZGN-1258 demonstrate an efficacy profile that matches our first generation MetAP2 inhibitor – from reduction in hyperphagia and body weight to increases in activity and reduction in anxiety- and compulsive-like behaviours – as well as differentiation on nonclinical safety measures. These nonclinical studies may provide important read-throughs to the potential impact of ZGN-1258 for people living with PWS.”

The hyperphagia associated with PWS can be extremely debilitating, causing individuals to struggle with concentration, social interaction, school and work, and the overwhelming desire for food can result in dangerous behaviors. The condition also impacts the patients' caregivers and the entire family, who also live under conditions that restrict access to food and may limit social freedom and flexibility. The studies being presented not only provide important nonclinical data related to the compound’s effects on body weight, food intake, and behavioural manifestations, but also combined show the potential for MetAP2 inhibition to address multiple factors of a rare, complex disease that in turn could have a considerable impact on people with PWS and their families.

In one poster, the effects of ZGN-1258 are characterised in mouse models of hyperphagia and obesity: mice with diet-induced obesity (DIO), leptin-deficient ob/ob mice, and mice with hypothalamic injury associated (via gold thioglucose (GTG)) obesity. All three models have elements of hyperphagia in disease presentation, and the GTG and ob/ob models represent impaired hypothalamic function as a contributor to hyperphagia, which may translate to hypothalamic dysregulation seen in PWS. ZGN-1258 administered daily produced a dose-dependent reduction in intake of the high-fat diet and body weight in DIO mice; dose-dependent reduction in food intake and weight and normalization of the hyperphagic phenotype in ob/ob mice; and reduced food intake and weight in mice with GTG-induced obesity. Across the models and doses, the vast majority of endpoints were highly statistically significant (p<0.001).

In a second poster, in three mouse models that share features with PWS, ZGN-1258 demonstrates improvement in behavioral manifestations commonly observed in PWS, including low physical activity, anxiety and obsessive-compulsive behaviours. ZGN-1258 treatment produced statistically significant, robust weight loss in obese, leptin-deficient ob/ob mice, and a smaller but statistically significant reduction in body weight in normal weight Magel2-null mice, which have a chromosome 15 mutation similar to PWS, as well as in normal weight FMR1 knockout (KO) mice, with characteristics of anxiety and compulsive behaviours (all p<0.05). Measurements of anxiety-like behavior were reduced in all three mouse models (p<0.05). Most interestingly, ZGN-1258 treatment produced an observable, significant, dose-dependent improvement in locomotor activity in all mouse models.

A third poster showed a comparison of the effects of ZGN-1258 and Zafgen’s first generation MetAP2 inhibitor on safety measures, including measures of thrombotic risk, demonstrating a highly differentiated profile for ZGN-1258 on endothelial cell effects. In toxicology models, ZGN-1258 doses approximately 100-fold greater than the projected clinical exposure had only a mild and transient effect on D-dimer and platelets, demonstrating a significantly improved safety profile and none of the prolonged endothelial cell effects associated with cardiovascular safety risk seen with the prior compound.

“Advancing a second generation MetAP2 inhibitor to help patients and families affected by PWS is at the core of Zafgen’s mission and dedication to a community that inspires us to innovate, and we are thrilled to be able to share these important data at the Annual FPWR Conference,” said Jeffrey Hatfield, Chief Executive Officer, Zafgen. “Our MetAP2 inhibition programs address the most serious, complex metabolic diseases, like PWS, and the consistency of efficacy and differentiated safety data that we are seeing not only within the ZGN-1258 program, but also across our pipeline with ZGN-1061 for type 2 diabetes, gives us tremendous confidence as we bring forward these much-needed treatments.”

Zafgen also presented the study design for PATH for PWS, a natural history study co-sponsored by FPWR and Zafgen that is intended to help better understand serious medical events in PWS in at least 500 patients over a four-year period, as well as evaluate how PWS related behaviours change over time. The data from this study will inform the development and clinical trial design of potential new treatments for PWS, including ZGN-1258. The PATH for PWS study has begun enrolling participants.

Want more stories like this? Subscribe to Bariatric News!

Bariatric News
Keep up to date! Get the latest news in your inbox. NOTE: Bariatric News WILL NOT pass on your details to 3rd parties. However, you may receive ‘marketing emails’ sent by us on behalf of 3rd parties.