FDA Approves BMS Drug for Rare Fat Disorder

FDA Approves BMS Drug for Rare Fat Disorder

CHEMICAL NAMES

1. Leptin (human), N-methionyl-

2. N-methionylleptin (human)

STRUCTURAL FORMULA

MVPIQKVQDD TKTLIKTIVT RINDISHTQS VSSKQKVTGL DFIPGLHPIL 50
TLSKMDQTLA VYQQILTSMP SRNVIQISND LENLRDLLHV LAFSKSCHLP 100
WASGLETLDS LGGVLEASGY STEVVALSRL QGSLQDMLWQ LDLSPGC 147

Disulfide bridge location
97-147
http://www.ama-assn.org/resources/doc/usan/metreleptin.pdf
MOLECULAR FORMULA C714H1167N191O221S6

MOLECULAR WEIGHT 16.16 kDa

MANUFACTURER Amylin Pharmaceuticals, Inc.

CODE DESIGNATION r-metHuLeptin

metreleptin

An analog of human leptin, metreleptin, has been approved in Japan and is currently under review by the FDA in the US for the treatment of diabetes and/or hypertriglyceridemia, in patients with rare forms of lipodystrophy, syndromes characterized by abnormalities in adipose tissue distribution, and severe metabolic abnormalities. Bristol-Myers Squibb has submitted a New Drug Approval (NDA) for metreleptin to the US Food and Drug Administration (FDA) Office of Orphan Products Development. In a three-year study of metreleptin in patients with lipodystrophy organized by the National Institute of Diabetes and Digestive and Kidney Diseases at the National Institutes of Health, metreleptin treatment was associated with a significant decrease in blood glucose (A1c decreased from 9.4% at baseline to 7.0% at study end) and triglyceride concentration (from 500 mg/dl at baseline to 200 mg/dl at study end). The Juvenile Diabetes Research Foundation has also partnered with Amylin Pharmaceuticals and researchers at the University of Texas Southwestern Medical Center to study whether metreleptin can be used to improve the treatment of type 1 diabetes.

N-Methionylleptin (human)
Recombinant human OB protein, purified to homogenicity as a 16-kDa monomer

Treatment of obesity and related disorders (metabolic homeostasis regulator)

LAUNCHED 2013 IN JAPAN BI SHINOGI

186018-45-1 CAS NO

BLA STN125390

• Brand name: Myalept
• Generic name: metreleptin
• Company: Amylin Pharmaceuticals, Inc.
• Treatment for: Lipodystrophy

Feb 25, 2014	FDA Approves Myalept to Treat Generalized Lipodystrophy
Dec 12, 2013	FDA Advisory Committee Votes on Investigational Medicine Metreleptin
Apr  3, 2012	Amylin Completes Biologics License Application for Metreleptin to Treat Diabetes and/or Hypertriglyceridemia in Patients With Rare Forms of Lipodystrophy
Dec 20, 2010	Amylin Submits Clinical and Nonclinical Sections of Rolling Biologics License Application for Metreleptin to Treat Rare Forms of Lipodystrophy

http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM377929.pdf

LEPTIN
Structure of the obese protein leptin-E100.

FDA approves Myalept to treat rare metabolic disease

On Feb. 24, 2014, the U.S. Food and Drug Administration approved 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.Generalized lipodystrophy is a condition associated with a lack of fat tissue. Patients with congenital generalized lipodystrophy are born with little or no fat tissue. Patients with acquired generalized lipodystrophy generally lose fat tissue over time. Because the hormone leptin is made by fat tissue, patients with generalized lipodystrophy have very low leptin levels. Leptin regulates food intake and other hormones, such as insulin.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 very high levels of triglycerides in the blood (hypertriglyceridemia) that can lead to inflammation of the pancreas.

“Myalept is the first approved therapy indicated for treating the complications associated with congenital or acquired generalized lipodystrophy and provides a needed treatment option for patients with this orphan disease,” said Mary Parks, M.D., 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, an analog of leptin made through recombinant DNA technology, were 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 (a measure of blood sugar control), fasting glucose, and triglycerides.

Anti-drug 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 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. Myalept is contraindicated in patients with general obesity. Myalept is not approved for use in patients with HIV-related lipodystrophy or in patients with metabolic disease, including diabetes mellitus and hypertriglyceridemia, without concurrent evidence of generalized lipodystrophy.

Because of the risks associated with the development of neutralizing antibodies and lymphoma, Myalept is available only through the Myalept Risk Evaluation and Mitigation Strategy (REMS) Program. Under this REMS program, prescribers must be certified with the program by enrolling in and completing training. Pharmacies must be certified with the program and only dispense Myalept after receipt of the Myalept REMS Prescription Authorization Form for each new prescription.

Myalept is also approved with a Medication Guide and instructions for use that provides patients with important information about the medication. The guide will be distributed each time a patient fills a prescription.

The FDA is requiring seven studies (post-marketing requirements) for Myalept, including a long-term prospective observational study (product exposure registry) of patients treated with Myalept, a study to assess for the immunogenicity (antibody formation) of Myalept, and an assessment and analysis of spontaneous reports of potential serious risks related to the use of Myalept. Eight additional studies are being requested as post-marketing commitments.

In clinical trials, the most common side effects observed in patients treated with Myalept were low blood sugar (hypoglycemia), headache, decreased weight, and abdominal pain.

Myalept is marketed by San Diego-based Amylin Pharmaceuticals, L.L.C.

For more information:

• FDA: Approved Drugs
• FDA: Drug Innovation 

Metreleptin is an analogue of the human hormone leptin being developed by Amylin Pharmaceuticals (a subsidiary of Bristol-Myers Squibb) for the subcutaneous treatment of metabolic disorders including lipodystrophy. The compound is expected to improve insulin sensitivity, hypertriglyceridaemia and hyperglycaemia in patients with lipodystrophy who are unresponsive to conventional treatment.

Metreleptin has been approved in Japan as a leptin therapy for the treatment of lipodystrophy. Amylin has also completed a submission for regulatory approval to the US FDA for metreleptin in the treatment of diabetes mellitus and/or hypertriglyceridaemia in patients with rare forms of lipodystrophy.

Clinical development of the drug is also underway in the USA for the treatment of type 1 diabetes. Amgen was previously assessing the use of metreleptin as a treatment for amenorrhoea; however, it appears that development in this indication has been discontinued. This article summarizes the milestones in the development of metreleptin leading to this first approval for lipodystrophy.

Metreleptin is a leptin replacement therapy first launched in Japan in 2013 for the treatment of congenital lipodystrophy. Amylin filed for approval in the U.S. in 2010 for the treatment of diabetes and/or hypertriglyceridemia in patients with rare forms of lipodystrophy. In 2013, the Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) recommended the approval for the treatment of pediatric and adult patients with generalized lipodystrophy , but not for partial lipodystrophy.

Phase II clinical studies are also under way at Beth Israel Deaconess Medical Center for the treatment of lipodystrophy syndrome associated with AIDS. The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) is conducting phase II clinical trials for the treatment of nonalcoholic steatohepatitis. Phase II are ongoing at the National Institute for Diabetes and Digestive and Kidney Diseases for the treatment of non-alcoholic fatty liver disease (NAFLD) associated with lipodystropy. Early clinical studies had also been ongoing for the treatment of leptin deficiencies.

The University Texas Southwestern Medical Center at Dallas is evaluating metreleptin for the treatment of type 1 diabetes. Beth Israel Deaconess Medical Center is conducting phase II clinical trials for the treatment of amenorrhea. Amgen had been conducting clinical trials for this indication and for the treatment of type 1 diabetes and depression; however no recent development has been reported for this research.

In 2011, Amylin and Takeda put on hold their clinical trials with metreleptin in combination with pramlintide for the treatment of obesity in order to investigate an antibody-related laboratory finding. Amylin is currently evaluating the compound as monotherapy for the treatment of obesity. The companies had been conducting phase II clinical trials of metreleptin not in combination with pramlintide for the treatment of obesity; however, no recent development has been reported for this research.

Originally developed at the Rockefeller University, an exclusive license to metreleptin was granted to Amgen in 1995. In 2009, the drug candidate was licensed to Takeda by Amylin worldwide for the treatment of obesity. In 2010, orphan drug designation was assigned in the U.S. for the treatment of metabolic disorders secondary to lipodystrophy and for the treatment of leptin deficiency secondary to generalized lipodystrophy and partial familial lipodystrophy.

In 2012, orphan drug designation was assigned in Japan for the treatment of diabetes or hyperlipidemia due to lipoatrophy. In 2012, orphan drug designation was assigned in the E.U. for the treatment of Barraquer-Simons syndrome, Berardinelli-Seip syndrome, familial partial lipodystrophy and Lawrence syndrome. In 2014, AstraZeneca acquired the global rigths for development, manufacture and commercialization of the product.

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EP2195034A2

Other exemplary leptins for use in the methods and compositions described herein include, but are not limited to, the amino acid sequence for mature, recombinant methionyl human leptin (herein called rmetHu-Leptin 1-146 or Metreleptin) having the amino acid sequence:

MVPIQKVQDDTKTLIKTΓVTRINDISHTQSVSSKQKVTGLDFIPGLHPILTLSKMDQTLA VYQQILTSMPSRNVIQISNDLENLRDLLHVLAFSKSCHLPWASGLETLDSLGGVLEASG YSTEWALSRLQGSLQDMLWQLDLSPGC (SEQ ID NO:274).