Myalept (metreleptin) is a leptin analogue with the same physiologic effects as leptin.11 Metreleptin was granted a priority review and was FDA approved on February 25, 2014, as an adjunct to diet as replacement therapy to treat the complications of leptin deficiency in patients with congenital or acquired lipodystrophy.
Lipodystrophy is an orphan disease. Only an estimated few thousand patients have this disease worldwide, although robust epidemiologic data are not available.1,2 Lipodystrophy is a group of chronic, life-threatening disorders marked by abnormalities in fat tissue distribution and insufficient quantities of fat required for normal metabolic function.3 The 2 main types of lipodystrophy are generalized and partial lipodystrophy, which may be further categorized into congenital and acquired subtypes. Patients with congenital forms are born with little to no fat tissue, whereas acquired subtypes lose fat tissue over time. The loss of adipose tissue results in a deficiency in the hormone leptin, an adipocyte-derived hormone.5 A low level of leptin signals starvation and instructs the body to adapt, resulting in metabolic abnormalities and increased appetite, known as hyperphagia. Replacement of leptin does not correct the underlying fat deficiency.6 Severe lipodystrophy is associated with metabolic abnormalities including insulin resistance, hypertriglyceridemia, and hyperlipidemia, and can result in life-threatening comorbidities such as pancreatitis, progressive liver disease (ie, hepatic steatosis or cirrhosis), and/or accelerated cardiovascular diseases.5,8 Often in severe disease, traditional medications are less effective at targeting metabolic markers and do not control the average level of glycated hemoglobin (HbA1c) and lipid levels long term.1
Myalept (metreleptin) is a leptin analogue with the same physiologic effects as leptin.11 Metreleptin was granted a priority review and was FDA approved on February 25, 2014, as an adjunct to diet as replacement therapy to treat the complications of leptin deficiency in patients with congenital or acquired lipodystrophy.7,10 Metreleptin is not approved for other forms of lipodystrophy, such as partial lipodystrophy or human immunodeficiency virus (HIV)-related lipodystrophy. The safety and effectiveness of metreleptin have not been established for the treatment of liver disease (including nonalcoholic steatohepatitis [NASH]), or for use in patients with metabolic disease without concurrent evidence of generalized lipodystrophy.
The drug is available as a vial containing 11.3 mg metreleptin to deliver 5 mg per mL metreleptin when reconstituted.11 Metreleptin is only available through the Risk Evaluation and Mitigation Strategy (REMS) program for this drug due to the risk of developing neutralizing antibodies and lymphoma. The REMS program requires certification of prescribers and pharmacies and a prescription authorization form for each new prescription. Metreleptin should be administered once daily at the same time every day. Dosing for metreleptin is outlined in Table 1, and adjustments are based on clinical response.
Table 1 Metreleptin recommended dosage
Males and females <40 kg
Males >40 kg
1.25 mg (0.25 mL) to 2.5 mg (0.5 mL)
Females >40 kg
1.25 mg (0.25 mL) to 2.5 mg (0.5 mL)
FormularyWatch/Source Ref 11
Metreleptin, a first-in-class leptin analogue, represents the first FDA-approved treatment option for generalized lipodystrophy.11 Prior to FDA approval, available pharmacology options were considered off-label and prescribed to treat observed metabolic abnormalities.7 Other treatment options include lifestyle modifications, metformin, sulfonylureas, thiazolidinediones, insulin, fibrates, and statins.7,9
FDA approval was based on data from an unpublished, open-label, single-arm study of 48 patients with congenital or acquired generalized lipodystrophy and diabetes, hypertriglyceridemia, and/or increased fasting insulin.11 At baseline, 77% of patients had HbA1c values of 7% or greater and 35% had fasting triglyceride values of 500 mg/dL or greater. Dose adjustments to background medications (ie, antidiabetic agents, antihyperlipidemics) were allowed during the study.7 Metreleptin was administered subcutaneously either once or twice daily.11 Treatment was for a median duration of 2.7 years (range, 3.6 mo–10.9 yr). For patients with a baseline body weight greater than 40 kg, the weighted average daily dose was 3.2 mg for men and 6.3 mg for women. Treatment with metreleptin resulted in reductions in HbA1c and triglycerides at 1 year. Results from this trial are presented in Table 2. Greater reductions in HbA1c and triglycerides were observed in patients with worse baseline measures. In patients with an HbA1c of 7% or greater, mean reduction in HbA1c was 2.4% at 1 year. In patients with a baseline triglyceride level of 500 mg/dL or greater, median reduction in triglycerides was 1,117 mg/dL at 1 year.
Table 2 Study results
Number of patients
Change from baseline at 1 year
Fasting triglycerides (mg/dL)
348 (176, 769)
-184 (-643, -21)
Median % change
-55% (-77%, -20%)
Abbreviations: Q, quartile; SD, standard deviation
FormularyWatch/Source Ref 11
The most commonly reported adverse reactions included headache, hypoglycemia, decreased weight, and abdominal pain.7,11 Two patients developed pancreatitis and 3 patients developed lymphoma, but it is unclear if these reactions were related to the drug or the disorder. Neutralizing antibodies developed in 84% of patients. Adverse events associated with the neutralizing antibodies include loss of efficacy, worsening metabolic control, and severe infections.
Inherent limitations of single-arm, open-label studies make efficacy and safety assessments challenging.7 Important questions remain unanswered, such as how much did diet and background medications (eg, antidiabetics, antihyperlipidemics) impact observed outcomes. Although the trial demonstrated improvement in surrogate markers, direct impact on mortality and comorbidities have not been measured.
The metreleptin single-arm study resulted in reductions of important metabolic markers such as HbA1c and triglycerides.12 Data were limited and inherent limitations of single-arm, open-label studies make it difficult to ascertain the full impact of metreleptin in this population. Additional questions remain as to the impact of metreleptin on serious safety concerns, such as lymphoma and neutralizing antibodies, which are included as boxed warnings. Although rigorous data are limited, the combination of diet and treatment with antidiabetic and antihyperlipidemic agents has demonstrated improvements in metabolic abnormalities in patients with generalized lipodystrophy. The unique mechanism of action may impact issues associated with hyperphagia. Therefore, metreleptin addresses an unmet need for generalized forms of lipodystrophy, particularly in those who require a greater improvement in metabolic abnormalities than can be met with unlabeled treatment options.11
The current wholesale acquisition cost (WAC) and average wholesale price (AWP) for 1 vial containing 11.3 mg (5 mg/mL) metreleptin are $1,472.00 and $1,766.40, respectively.13 In the trial, the reported weighted average daily doses in patients greater than 40 kg were 3.2 mg for men (estimated cost range/adult/year, $152,150–$182,575) and 6.3 mg for women (estimated cost range/adult/year, $299,545–$359,455). In January 2015, Aegerion will take control of metreleptin’s commercialization and will raise the cost to meet the ultra-orphan indication.16
Until the approval of metreleptin, there were no approved medications for the treatment of metabolic abnormalities associated with lipodystrophy.7,12 A 2013 consensus statement published by the American Association of Clinical Endocrinologists (AACE) cited lifestyle modifications, metformin, sulfonylureas, thiazolidinediones, insulin, fibrates, and statins as options for disease management.9 The role of metreleptin, however, was not discussed. Notably, off-label treatment is complicated by hyperphagia, which is associated with leptin deficiency.1 As a leptin analogue, metreleptin offers the unique capabilities of treating metabolic abnormalities while affecting mechanisms associated with underlying hyperphagia.
Metreleptin represents the only FDA-approved medication specifically for patients with generalized lipodystrophy in combination with a reduced diet.11 The most notable metabolic improvements were seen in patients with elevated metabolic levels at baseline. Long-term metreleptin safety and efficacy data, however, are needed to answer outstanding concerns.10 In February 2014, FDA required 7 postmarketing studies for metreleptin, including a long-term product exposure registry of metreleptin patients, a study to assess immunogenicity (antibody formation), and an assessment and analysis of spontaneous reports of serious risks related to the use of metreleptin. An additional 8 studies were requested.
The unique mechanism of action of metreleptin may help to address issues with hyperphagia. The observed reduction in important markers such as HbA1c and triglycerides may result in long-term improvements in comorbid diseases complicated by these metabolic abnormalities in generalized forms of lipodystrophy. The greatest improvements with metreleptin were observed in patients with severe metabolic abnormalities at baseline. Long-term clinical trial data are warranted to characterize metreleptin safety and to assess observed improvements in the incidences of pancreatitis, liver disease, cardiovascular disease, and mortality associated with complications. There are limited data and potential risks associated with metreleptin treatment in other forms of lipodystrophy, such as partial lipodystrophy or HIV-related lipodystrophy, for the treatment of liver disease (NASH), or for use in patients with metabolic disease (ie, diabetes, hypertriglyceridemia) without concurrent evidence of generalized lipodystrophy. Metreleptin does address a significant unmet need for pediatric and adult patients with congenital or acquired generalized lipodystrophy.
Dr Roeges is a clinical pharmacist with the Drug Intelligence Department at Cataman.
Disclosure information: The author reports no financial disclosures as related to products discussed in this article.
Dr Roeges is a clinical pharmacist with the Drug Intelligence Department at Catamaran.