12355 An Adolescent Female With Congenital Lipodystrophy Presenting With Repeated Acute Metabolic Decompensations Rescued By A Novel Leptin Receptor Agonist

Abstract Disclosure: D.M. Chambers: None. Y. Chan: None. M.K. Crocker: None. Patient SH is a now 17-year-old female treated for generalized congenital lipodystrophy with a course complicated by severe hypertriglyceridemia, type 2 diabetes mellitus, hypertension, hepatosteatosis, and intermittent menstrual irregularity. She had been managed successfully with metreleptin for 2 years, but in 2022-2023, she developed repeated episodes of pancreatitis (4 times over a 14-month period) secondary to severe hypertriglyceridemia (serum triglycerides >8000 mg/dL). During her admissions, she had markedly increased insulin requirements (up to 12 units/kg/day) with refractory hyperglycemia despite maximal treatment with metreleptin, empagliflozin, and oral semaglutide. In the clinical context of her acute metabolic worsening, she was suspected of having a neutralizing antibody against metreleptin. Serum leptin was undetectable 1 hour after observed metreleptin doses; direct measurement of neutralizing antibodies is pending. She was transitioned from metreleptin to mibavademab, an investigational leptin receptor agonist, on an expanded use IND. She subsequently experienced significant improvements in her fasting triglyceride levels (<300 mg/dL) with no subsequent episodes of pancreatitis since starting therapy in August 2023. She has also had improvements in other aspects of her metabolic health including decreased insulin requirements with decreasing hemoglobin A1c, decreased need for adjunctive lipid and hypertension therapy, and improving menstrual regularity. Her clinical course demonstrates: 1) clinical indicators of a rare but serious loss of efficacy of metreleptin therapy; 2) adjunctive options for management of generalized lipodystrophy; and, 3) an individual experience with a novel leptin agonist therapy in the treatment of generalized lipodystrophy. Presentation: 6/3/2024