The US Food and Drug Administration (FDA) has approved Amylin Pharmaceuticals' Myalept (metreleptin for injection) as replacement therapy to treat the complications of leptin deficiency, in addition to diet, in patients with congenital generalized or acquired generalized lipodystrophy.
This is the first approved therapy for treating the complications associated with congenital or acquired generalized lipodystrophy and follows an 11 to 1 vote in favor of the use of metreleptin in pediatric and adult patients with this condition by an FDA advisory committee in December 2013.
However, the Endocrinologic and Metabolic Drugs Advisory Committee voted 10 to 2 against metreleptin's use for "metabolic disorders associated with partial lipodystrophy, including hypertriglyceridemia and/or diabetes mellitus inadequately controlled on a current therapy and/or evidence of hepatic steatosis." The drug might be useful in partial lipodystrophy, but the data provided were insufficient to demonstrate efficacy in that more heterogeneous patient group, the panel felt.
The FDA stresses that metreleptin is not approved for patients with HIV-related lipodystrophy or in patients with metabolic disease, including diabetes mellitus and hypertriglyceridemia, without concurrent evidence of generalized lipodystrophy. And it is contraindicated in patients with general obesity.
Myalept will be available only through a risk evaluation and mitigation strategy (REMS) program, which requires prescriber and pharmacy certification and special documentation.
In general, panel members said in December that, as long as there was close monitoring via the REMS, they felt that the benefits of metreleptin would outweigh the potential risks for patients with generalized lipodystrophy, but that there were just too many unknowns with partial lipodystrophy, even with monitoring.
Seven Postmarketing Trials Required
Lipodystrophy refers to a group of rare syndromes characterized by selective loss of fat tissue. Patients 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.
Both types can be familial or acquired. The latter is believed to result from an autoimmune process, although no specific one has been identified.
Patients with both types of generalized lipodystrophy often develop severe insulin resistance at a young age and may have diabetes mellitus that is difficult to control or hypertriglyceridemia that can lead to inflammation of the pancreas.
Current treatment involves agents that address the metabolic complications, including diet, metformin, sulfonylureas, insulin, fibrates, and statins, but prior to metreleptin there were no treatments specifically approved for the lipodystrophy itself.
Indeed metreleptin will be a "much-needed treatment option for patients with this orphan disease," according to Mary Parks, MD, deputy director of the Office of Drug Evaluation II in the FDA's Center for Drug Evaluation and Research.
The safety and effectiveness of Myalept was evaluated in an open-label, single-arm study that included 48 patients with congenital or acquired generalized lipodystrophy who also had diabetes mellitus, hypertriglyceridemia, and/or elevated levels of fasting insulin. The trial showed reductions in HbA1c, fasting glucose, and triglycerides.
However, the FDA notes in its approval notice that antidrug antibodies with neutralizing activity to leptin and/or Myalept "may develop, which could result in severe infections or loss of treatment effectiveness."
T-cell lymphoma has also been reported in patients with acquired generalized lipodystrophy, both treated and not treated with Myalept, "so healthcare professionals should carefully consider the benefits and risks of treatment with Myalept in patients with significant hematologic abnormalities and/or acquired generalized lipodystrophy."
The agency is therefore requiring 7 postmarketing studies for Myalept, including a long-term prospective observational study (product exposure registry) of patients treated with Myalept, a study to assess for immunogenicity, and an assessment and analysis of spontaneous reports of potential serious risks related to the use of Myalept. And an additional 8 studies are being requested as postmarketing commitments.
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Cite this: Myalept (Metreleptin) Approved for Generalized Lipodystrophy - Medscape - Feb 25, 2014.