New data from Zafgen's ZGN-433 Phase 1b study on obesity presented at ADA 2011

Zafgen, Inc., a pharmaceutical company pioneering novel obesity therapeutics to help the body regain and sustain a lean, healthy state by targeting imbalances in fat metabolism, today announced new data from a Phase 1b study of ZGN-433, a selective methionine aminopeptidase 2 inhibitor (MetAP2), which showed a significant improvement in cardiovascular risk markers in severely obese subjects. Treatment with ZGN-433 was associated with rapid and significant improvements in low-density lipoprotein (LDL) cholesterol, triglycerides and C-reactive protein (CRP) levels, with no evidence of major tolerability or safety issues. The study results build on the positive Phase 1b safety and weight loss data presented earlier this year, further demonstrating that MetAP2 inhibition treatment is a promising new approach for treating severe obesity. The data will be presented in a poster session at the American Diabetes Association's 71^st Annual Scientific Sessions in San Diego on June 26 at noon P.D.T.

"This short-term treatment of less than four weeks with ZGN-433 improved multiple cardiovascular risk factors important in obesity and diabetes," said Thomas Hughes, Ph.D., president and chief executive officer, Zafgen, Inc. "The study also confirmed preclinical findings that MetAP2 inhibition leads to changes in fat metabolism and adipose tissue-derived hormones leptin and adiponectin, both hormones controlling energy balance and fat metabolism. Management of cardiovascular disease risk is critical in the setting of weight management, making these findings very significant for the future development and potential use of MetAP2 inhibitors in the treatment of obesity."

The Phase 1b trial was a randomized, double-blind, placebo-controlled study to evaluate the safety, tolerability and efficacy of intravenously administered ZGN-433 in severely obese women with a body mass index (BMI) of 37.8±0.6 kg/m². Individuals received ZGN-433 at 0.1 mg/m², 0.3 mg/m², 0.9 mg/m² or placebo twice weekly by intravenous administration over a four-week period. Patients were allowed to eat normally and were not counselled to change their exercise habits. The trial enrolled 31 subjects. Twenty-six people completed the study.

After 26 days of treatment, subjects had decreased LDL cholesterol levels by 22 percent in the group that received 0.9 mg/m² of ZGN-433 versus a two percent increase in the placebo group. Blood pressure did not change with treatment. No treatment-related serious adverse events were observed. Consistent with results seen in obese mouse models, treatment with ZGN-433 at a dose of 0.9 mg/m² increased β-hydroxybutyrate, an indicator of fat oxidation, by 188 percent (p<0.05), increased plasma adiponectin concentrations by 59 percent (p<0.005) and increased the ratio of adiponectin/leptin by 241 percent.

In addition, Zafgen announced the company is initiating a second trial for ZGN-433 in obese females. The Phase 1b study will demonstrate the safety and tolerability of ZGN-433 at fixed doses of 3.0 mg or 6.0 mg twice weekly for four weeks, in patients with starting BMI up to 50 kg/m². In earlier Phase 1b obesity studies, the highest dose tested was 0.9 mg/m², or approximately 1.9 mg twice weekly.

"Zafgen's second Phase 1b study will allow us to test ZGN-433 at higher dose levels with the goal of demonstrating maximal efficacy at safe doses," said James Vath, head of drug discovery and development, Zafgen, Inc. "We are pleased to be further advancing Zafgen's MetAP2 inhibitor program in development for the treatment of severe obesity, and look forward to initiating Phase 2 trials in obese patients and obese diabetic patients in the coming year."

Research continues to show that obese and lean individuals metabolize fat differently. Studies indicate that once a person becomes obese, the body undergoes certain metabolic changes and is "programmed" to make and store more fat, making it much more difficult to reduce body weight. These metabolic adaptations that take place in obese people impair the normal release and breakdown of fatty acids from adipose tissue. Simultaneously, the body becomes much more efficient in diverting calories from food and storing them as fat.

Source: Zafgen, Inc.