Memorandum

FDA approves AZ's Myalept (metreleptin) for the orphan indication of generalized lipodystrophy, but (as expected) not for partial lipodystrophy – February 25, 2014

Today, AstraZeneca announced the FDA approval of its leptin analog Myalept (metreleptin) for the treatment of the complications of leptin deficiency in patients with congenital or acquired generalized lipodystrophy, but not partial lipodystrophy - this decision is consistent with the FDA Advisory Committee's 11-1 vote to approve the drug for generalized lipodystrophy and 2-10 vote against approving it for partial lipodystrophy due to the limited ability to define a patient group for whom the benefits convincingly outweigh the risks (risks include immunogenicity and, to a lesser degree, lymphoma). Lipodystrophy is a rare orphan disease associated with the absence of subcutaneous fat, leptin deficiency, and devastating metabolic abnormalities such as extreme insulin resistance, hypertriglyceridemia, liver disease, and severe hunger. The press release specifically notes that AZ is working to complete the transfer of the Biologics License Application (BLA) for Myalept from BMS as part of AZ's acquisition of the two companies' previously shared diabetes assets (completed earlier this month). Myalept will be available as a subcutaneous injection in an 11.3 mg vial that requires reconstitution and is subject to a REMS program. The news update specifically notes that Myalept is not approved for patients with diabetes not associated with congenital leptin deficiency, and is contraindicated in patients with general obesity not associated with leptin deficiency - as a reminder, patients with general obesity commonly have too much rather than too little leptin and do not respond to leptin treatment due to leptin resistance, so should not be subject to the adverse immunogenic effects of metreleptin when there is no benefit.  We certainly see today's approval as a noteworthy milestone for AZ, as it is the company's first major US regulatory approval following the closure of the acquisition of BMS' diabetes business earlier this month.  Presumably, AZ will leverage its relationship with endocrinologists (from Bydureon, Byetta, and Symlin) to build awareness of metreleptin to treat lipodystrophy.  Unfortunately, plans for metreleptin are not what they once were; in late 2011, Amylin and Takeda announced that they would discontinue development of pramlintide/metreleptin, which was once an investigational therapy for the treatment of obesity. This followed a commercial reassessment of the therapy. In brighter news, BMS/AZ/Amylin and the JDRF are conducting a phase 1 trial investigating metreleptin's potential for type 1 diabetes (ClinicalTrials.gov Identifier: NCT01268644) - the collaborators plan to communicate results and next steps in the next few months.