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Inhibition treatment

MetAP2 inhibitor improves cardiovascular risk markers

Severely obese patients could benefit from Inhibition treatment
Company plans to initiate Phase 2 trials in obese and obese diabetic patients

New data from a Phase 1b study of ZGN-433, a selective methionine aminopeptidase 2 inhibitor (MetAP2, Zafgen Inc.), has 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.

According to the company, the study results build on the positive Phase 1b safety and weight loss data presented earlier in 2011, further demonstrating that MetAP2 inhibition treatment is a promising new approach for treating severe obesity. The data was be presented at the American Diabetes Association’s 71st Annual Scientific Sessions, San Diego, CA.


Zafgen’s approach to treating obesity focuses on targeting imbalances in fat metabolism to restore control of key metabolic processes, releasing stored fat, which then is used by the body as fuel. MetAP2 inhibitor treatment works by re-establishing balance to the ways the body processes fat, leading to substantial loss of excess body weight and improved glucose tolerance in people who are obese. 


“This short-term treatment of less than four weeks with ZGN-433 improved multiple cardiovascular risk factors important in obesity and diabetes” Thomas Hughes

“This short-term treatment of less than four weeks with ZGN-433 improved multiple cardiovascular risk factors important in obesity and diabetes,” said Dr Thomas Hughes, President and CEO, Zafgen. “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 randomised, double-blind, placebo-controlled study to evaluate the safety, tolerability and efficacy of intravenously administered ZGN-433 in severely obese women with a BMI of 37.8±0.6 . 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% in the group that received 0.9 mg/m2 of ZGN-433 versus a 2% increase in the placebo group (p=0.02). Additionally, CRP, a well-recognized risk factor for cardiovascular disease that is increased in obese patients, decreased 64% in the group that received 0.9 mg/m2 of ZGN-433 versus 12% for placebo (p<0.001). 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% (p<0.05), increased plasma adiponectin concentrations by 59% (p<0.005) and increased the ratio of adiponectin/leptin by 241% (p=0.001). Insulin and glucose were not affected by treatment in this non-diabetic study population. 


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 3.0mg or 6.0mg twice weekly for four weeks, in patients with starting BMI up to 50. In earlier Phase 1b obesity studies, the highest dose tested was 0.9mg/m2, or approximately 1.9mg 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” James Vath

Research continues to show that obese and lean individuals metabolise 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. 


“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. “We are pleased to be further advancing Zafgen’s MetAP2 inhibitor programme 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.”

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