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Metreleptin, a Leptin Analog, for Generalized Lipodystrophy Found Favorable by FDA

Dec 26, 2013
 
A new treatment for lipodystrophy may be on the horizon….

Lipodystrophy is a condition in which the adipose tissue degenerates in a certain area of the body and is often linked to repeated injections in one area; the condition is also linked to decreased circulating levels of leptin. This can be a problem for diabetics although rotating sites of injections can assist with decreasing lipodystrophy which can leave a small lump or dent in the skin and can also impact the absorption of medications (i.e. insulin) injected into that area.
 
Bristol-Myers Squibb/AstraZeneca have been working on getting approval of a leptin analog for reducing lipodystrophy, metreleptin (Myalept®), and recently met with the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee on December 11, 2013 to determine the fate of their drug. The advisory committee voted 11 to 1 in favor of the use of metreleptin in the treatment of generalized lipodystrophy in the adult and pediatric population but the committee voted against its use in "metabolic disorders associated with partial lipodystrophy, including hypertriglyceridemia and/or diabetes mellitus inadequately controlled on a current therapy and/or evidence of hepatic steatosis."
 
While Bristol-Myers Squibb/AstraZeneca’s 130 page briefing document for the December 11th meeting has data supporting metreleptin’s safety and efficacy, the studies were small and did not have enough data to support its use in partial lipodystrophy patients according to some committee members who voted to limit metreleptin’s indication to generalized lipodystrophy treatment. 
 
Efficacy data was collected from 2 open label studies that involved 72 patients treated with metreleptin with key endpoints assessing metreleptin’s efficacy in improving metabolic abnormalities in lipodystrophy patients (i.e. change over time in patient’s HbA1c, fasting plasma glucose (FPG), TG, and liver function). Researchers report that changes in these areas were "substantial and clinically meaningful" with change in HbA1c (baseline to 12 months) was -1.4 ± 0.2%, (mean ± SE 95% CI: -0.9, -1.8); FPG (change at 12 months): -42 ± 12 mg/dL (95% CI: -18, -65); TG (change at 12 months): concentration change was 673 ± 223 mg/dL, while %TG change was 32 ± 8% (95% CI: -17, -47).  The researchers also noted that improvements of mean AST and ALT were noted at month 4 and continued through month 12.
 
As for safety data, 100 participants were assessed either through the NIH study or the FHA101 study.  There were minor observations of adverse events noted however enough so that if the FDA were to approve metreleptin for generalized lipodystrophy, it would be under a risk evaluation and mitigation strategy (REMS), where prescribers and pharmacies would require special documentation and certification.  This is based on 3 patients developing lymphoma, even though 2 of those patients had pre-existing lymphoma and/or bone marrow abnormalities and 5 cases of treatment emergent adverse events (TEAEs) of acute pancreatitis.  It is important to note though that those 5 patients had a previous history of pancreatitis and hypertriglyceridemia.
 
With the advisory committee’s support for approval of metreleptin for generalized lipodystrophy, it is now in the hands of the FDA for final approval. The FDA is expected to make its final decision by February 24, 2014.
 
Practice Pearls:
  • Lipodystrophy is characterized by a loss of adipose tissue and resultant leptin deficiency as well as ectopic deposition of TG in the liver and muscle.
  • Lipodystrophy is often associated with injections in the same area such as insulin injections in diabetes but can be reduced with rotation of site of injection.
  • Lipodystrophy is also associated with severe metabolic abnormalities (primarily hypertriglyceridemia),  severe insulin resistance and use of antiretroviral drugs.
  • The advisory committee’s support for approval of metreleptin for generalized lipodystrophy is now in the hands of the FDA for final approval, anticipated February 24, 2014.
Endocrinologic and Metabolic Drugs Advisory Committee Briefing Document: METRELEPTIN (BLA STN125390).  Bristol-Meyers Squibb and Astra Zeneca.  Background document: BMS-986109.