FDA
12th December 2013

FDA Panel Supports Metreleptin for Generalized Lipodystrophy

In a meeting yesterday, FDA’s Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) recommended the investigational medicine metreleptin (Amylin Pharmaceuticals, Bristol Myers Squibb) for the treatment of pediatric and adult patients with generalized lipodystrophy (LD) in a vote of 11 to 1.

FDA Panel Supports Metreleptin for Generalized Lipodystrophy

In a meeting yesterday, FDA’s Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) recommended the investigational medicine metreleptin (Amylin Pharmaceuticals, Bristol Myers Squibb) for the treatment of pediatric and adult patients with generalized lipodystrophy (LD) in a vote of 11 to 1.

Consequently, in a vote of 2 to 10, EMDAC did not recommend metreleptin in patients with metabolic disorders associated with partial LD [including hypertriglyceridemia and/or diabetes mellitus inadequately controlled on a current therapy, and/or evidence of hepatic steatosis (fatty liver disease)].

This vote represents the committee’s interpretation that there was greater evidence of benefit/risk profile for patients with generalized LD than with partial LD.

LD is a group of rare syndromes often associated with severe metabolic abnormalities and significant morbidity and mortality. LD is characterized by abnormal or degenerative conditions of the body’s adipose tissue, and can be congenital or acquired. Acquired LD is believed to result from an autoimmune process, although no specific one has been identified. Individuals with “generalized” lipodystrophy have no adipose tissue and typically low or absent leptin levels, whereas “partial” lipodystrophy is characterized by loss of adipose tissue, abnormal ectopic-fat deposition, and variable leptin levels.

Metreleptin is an investigational recombinant analog of the human hormone leptin, and has received orphan designation from the FDA and the European Medicines Agency (EMA). 

Efficacy data, presented by Jean L. Chan, MD, from Bristol-Myers Squibb, came from 2 studies conducted at the U.S. National Institutes of Health (NIH) involving a total of 72 patients and an additional 28 patients from a trial funded by the company. The studies were single arm and open label, since the use of a placebo was deemed unethical. This was cited as a significant limitation in the data by both the sponsor and FDA reviewers.

Of the 72 NIH patients (48 patients with general LD, 24 with partial LD), there was a 1.4-percentage-point drop in HbA1c and a 45% reduction in triglycerides at 1 year compared with baseline means of 8.2% and 1041 mg/dL, respectively. Liver volume dropped by approximately a third at 1 year, and significant reductions were also seen in liver-enzyme levels. Steatohepatitis was also improved among 27 patients in whom liver biopsies were performed, Dr. Chan reported.

In the sponsor-funded study involving 28 patients (5 patients with generalized LD, 23 with partial LD), results were more variable; however, greater improvements with metreleptin were seen among patients with lower baseline leptin levels in both groups.

Along with the concern about possible safety concerns and the single-arm design, FDA reviewer Julie Golden, MD, also faulted the studies for missing data, confounding by use of other medications, and compliance problems. The optimal trial design would be a randomized, placebo-controlled study in patients with inadequately controlled HbA1c or triglycerides on optimal therapy, she noted.

The sponsoring companies acknowledge the committee’s feedback and will continue to work with the FDA to identify the appropriate patients with partial LD who may benefit from metreleptin.

Current treatment of LD involves agents that address the associated metabolic complication, including diet, metformin, sulfonylureas, insulin, fibrates, and statins. There are no treatments specifically approved for the lipodystrophy itself.

The FDA is not bound by the EMDAC’s decision but normally follows its recommendation.

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