SUN-253 The Impact of Mibavademab, a Novel Leptin Receptor Agonist, on Metabolic Parameters in Individuals with Generalized Lipodystrophy

Abstract Disclosure: R.J. Brown: Regeneron Pharmaceuticals, Chiesi Pharmaceuticals, Pfizer, Inc., Marea. O. Pagovich: Regeneron Pharmaceuticals. S. Podgrabinska: Regeneron Pharmaceuticals. J. Zhao: Regeneron Pharmaceuticals. R. Barrier: Regeneron Pharmaceuticals. B. Musser: Regeneron Pharmaceuticals. R. Dingman: Regeneron Pharmaceuticals. J. Mendell: Regeneron Pharmaceuticals. R.J. Sanchez: Regeneron Pharmaceuticals. S. Hectors: Regeneron Pharmaceuticals. B. Akinci: Amryt Pharmaceuticals (now Chiesi Famaceutici), Alnylam, Regeneron Pharmaceuticals, Third Rock Ventures, AstraZeneca, Novo Nordisk, Boehringer Ingelheim, Sanofi, Bilim Ilac, ARIS, Servier. I. Yildirim Simsir: None. S. Ozen: None. E. Shestakova: None. E. Mishina: None. A. Garg: Chiesi, Regeneron Pharmaceuticals, Zvelt Pharmaceuticals, Quintiles, Akcea Therapeutics, Intercept Pharmaceuticals. R.J. Vargas Gonzalez: None. B.A. Olenchock: Regeneron Pharmaceuticals. E.A. Oral: Regeneron Pharmaceuticals, Amryt Pharmaceuticals (now part of Chiesi Rare Disease group), Ionis Pharmaceuticals Inc., Third Rock Ventures (now formed Marea Therapeutics), Rejuvenate Bio, Novo Nordisk, Rhythm Pharmaceuticals, Fractyl, Morphic Medical (formerly GI Dynamics). Generalized lipodystrophy (GLD) is characterized by a near-total loss of adipose tissue and low levels of leptin, an adipocyte-derived hormone that modulates glucose and lipid metabolism, food intake, and energy expenditure. Mibavademab, an investigational human leptin receptor agonist monoclonal antibody, is not structurally related to endogenous leptin and activates the leptin receptor in the absence or presence of leptin. Therefore, anti-drug antibodies that would cross-react with and potentially neutralize endogenous leptin are not developed. Previously, we reported safety and efficacy with at least 28 weeks of medium-dose mibavademab and 12 weeks of high-dose mibavademab from a phase 2 trial (NCT04159415). Here we report safety and efficacy with high-dose mibavademab for up to 52 weeks. Patients aged ≥12 years with acquired or congenital GLD were randomized to mibavademab or placebo. After a single-blind placebo run-in, patients were randomized 1:1 to 1 of 2 fixed sequence arms comprising sequential 8-week treatment periods (Arm A: placebo, low-dose mibavademab, medium-dose mibavademab; Arm B: low-dose mibavademab, medium-dose mibavademab, medium-dose mibavademab). Patients in each arm received an intravenous loading dose of placebo or mibavademab followed by weekly subcutaneous administration of study drug. Both arms were followed by an open-label high-dose mibavademab treatment period (OLTP5). Safety, pharmacokinetics, and pharmacodynamics of mibavademab were assessed. Glycated hemoglobin (HbA1c) and fasting triglycerides (TGs) were measured at Week 8 (primary efficacy endpoint) and at predetermined time points until study completion. Sixteen patients with GLD and baseline diabetes (mean HbA1c 9.6%, range 6.0-12.2%) or hypertriglyceridemia (median TGs 669 mg/dL, range 107-2899 mg/dL) were randomized and completed ≥28 weeks of mibavademab treatment. Eight patients who entered OLTP5 were treated with high-dose mibavademab. Patients received a median of 51 doses of high-dose mibavademab, with a median duration of 49.9 weeks exposure. After 52 weeks of high-dose treatment, drug concentrations were maintained above target range, and clinically significant reductions from baseline were observed in HbA1c (mean change: -2.12%, SD: 2.95) and fasting TGs (median percent change: -74.6%, Q1, Q3: -92.4, -66.3). High-dose mibavademab was generally well tolerated. Treatment with high-dose mibavademab for up to 52 weeks was associated with sustained and clinically meaningful improvements in metabolic parameters, and was generally well tolerated. Mibavademab may be a new therapeutic option for patients with GLD. Presentation: Sunday, July 13, 2025