A Food and Drug Administration (FDA) advisory panel has voted 11 to 1 in favor of the use of metreleptin (Myalept, Bristol-Myers Squibb/AstraZeneca) for the treatment of pediatric and adult patients with generalized lipodystrophy.
However, the FDA's Endocrinologic and Metabolic Drugs Advisory Committee also 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."
Panel members generally agreed that the drug might be useful in patients with partial lipodystrophy, but the data provided by Bristol-Myers Squibb were insufficient to demonstrate efficacy in that more heterogeneous patient group, particularly against a background of potential increased risks for lymphoma and immunogenicity.
If approved by FDA, metreleptin would be available only via a risk evaluation and mitigation strategy (REMS), which requires prescriber and pharmacy certification and special documentation.
Lipodystrophy: Lack of Fat
"Lipodystrophy" refers to a group of rare syndromes characterized by selective loss of adipose 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. Metabolic abnormalities typically seen in all subtypes include severe insulin resistance, diabetes mellitus, hypertriglyceridemia, and hepatic steatosis, or fatty liver. Patients will often have large abdomens as a result of hepatosplenomegaly. Hyperphagia is also a common characteristic.
Current treatment involves agents that address the metabolic complications, including diet, metformin, sulfonylureas, insulin, fibrates, and statins. There are no treatments specifically approved for the lipodystrophy itself.
Benefit Clearer for Generalized Type
Efficacy data, presented by Jean L. Chan, MD, from Bristol-Myers Squibb, came from 2 studies conducted at the US National Institutes of Health (NIH) involving a total of 72 patients and an additional 28 patients from a trial funded by the company.
All 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, comprising primarily those with generalized lipodystrophy (48 vs 24 with partial lipodystrophy), 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.
Results were more variable in the sponsor-funded study, which included just 5 patients with generalized lipodystrophy and 23 with partial lipodystrophy. Greater improvements with metreleptin were seen among patients with lower baseline leptin levels in both groups.
Along with the concern about 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.
Safety Concerns
In addition to the 100 lipodystrophy patients, safety data were also included from other trials, including 5 that involved 784 obese individuals, conducted during the 1990s when metreleptin's previous owner, Amgen, was seeking that indication for the drug (and later abandoned the effort due to lack of efficacy).
Dr. Golden described safety concerns that prompted the REMS designation: there were 3 cases of lymphoma among the NIH study subjects, although it is unclear whether those were related to metreleptin. Nearly all patients developed antibodies to metreleptin, and neutralizing antibodies were seen in a small number of patients from the obesity trials and in 1 lipodystrophy patient who experienced worsening metabolic status and later developed sepsis. Pancreatitis was also seen in a total of 7 patients.
The numbers are too small to draw firm conclusions regarding the role of metreleptin in any of the adverse events, Dr. Golden noted.
Mixed Support
In general, panel members felt that, as long as there was close monitoring via the REMS, the benefits of metreleptin outweighed the potential risks for patients with generalized lipodystrophy, but that there were just too many unknowns with partial lipodystrophy, even with the monitoring.
Wyndham Wilson, MD, senior investigator and deputy chief of the lymphoid malignancy branch at the National Cancer Institute, Bethesda, Maryland, voted in support of metreleptin's use for generalized lipodystrophy.
"I felt that there was adequate evidence that this drug was clinically beneficial," he said, adding that he recommends postmarketing surveillance for tumors, evidence of worsening of metabolic syndrome caused by neutralizing antibodies, severe infections, and "any other adverse effects that are unexpected."
Dennis R. Ownby, MD, section chief of allergy and immunology at Georgia Regents University, Augusta, also voted yes for the generalized-lipodystrophy indication. "It's a miserable disease, and while this is not a perfect therapy, it is a therapy that offers benefit."
Joining the majority in voting no for the partial-lipodystrophy indication was committee chair Robert J. Smith, MD, professor of medicine (endocrinology) at Albert Medical School of Brown University, Providence, Rhode Island, who said: "I was much more concerned about the partial-lipodystrophy group than the generalized-lipodystrophy [one] in terms of how much efficacy data we have and the uncertainties in the data."
Added Dr. Smith, "I suspect that there are patients with the diagnosis of partial lipodystrophy who would benefit from metreleptin, but I haven't seen enough data to make me comfortable with knowing how to define who those patients are."
Some panel members said that they would like to see data from a trial in which the partial-lipodystrophy patients were limited to certain characteristics, such as low leptin levels and HbA1c and triglyceride levels above a defined cutoff. Two panelists suggested that the sponsor and the FDA might explore ways to design an ethically acceptable randomized trial.
The FDA is expected to announce its decision by February 24.
Members of FDA advisory panels are vetted for conflicts of interest and waivers are granted for participation if necessary. No waivers were granted for this hearing.
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Cite this: Leptin Analog Endorsed for Generalized Lipodystrophy - Medscape - Dec 12, 2013.
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