FRI058 Treatment With Mibavademab, A Novel Leptin Receptor Agonist, Is Associated With Improvement In Metabolic Parameters In Individuals With Generalized Lipodystrophy

Disclosure: B. Olenchock: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. S. Podgrabinska: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. C. Hou: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. B. Musser: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. J. Mendell: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. A. Harman: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. R.J. Sanchez: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. K. Miller: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. P. Parasoglou: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. S. Hectors: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. S. Karnik: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. O.E. Pagovich: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. R. SinhaRoy: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. C.A. Harris: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. B. Akinci: Advisory Board Member; Self; Regeneron Pharmaceuticals, Amryt Pharmaceuticals. Consulting Fee; Self; Amryt Pharmaceuticals, Regeneron Pharmaceuticals, Third Rock Ventures, AstraZeneca, Lilly USA, LLC, Novartis Pharmaceuticals, Novo Nordisk, Boehringer Ingelheim, Servier, Sanofi-Aventis, MSD. I. Yildirim simsir: None. S. Ozen: None. E. Sorkina: Advisory Board Member; Self; Amryt Pharmaceuticals, Regeneron Pharmaceuticals. A. Garg: Consulting Fee; Self; Aegerion Pharmaceuticals, Regeneron Pharmaceuticals. Grant Recipient; Self; Aegerion Pharmaceuticals, Pfizer, Inc., Regeneron Pharmaceuticals, Amryt Pharmaceuticals, Ionis Pharmaceuticals Inc. R.J. Vargas Gonzalez: None. D.M. Weinreich: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. G. Herman: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. E.A. Oral: Consulting Fee; Self; Regeneron Pharmaceuticals, Third Rock Ventures, Amryt Pharmaceuticals, Rejuvenate Inc, Ionis Pharmaceuticals. Grant Recipient; Self; Gemphire Theraputics, Amryt Pharmaceuticals, Ionis Pharmaceuticals. R.J. Brown: Grant Recipient; Self; Regeneron Pharmaceuticals. Background: Generalized lipodystrophy (GLD) is characterized by the deficiency of adipose tissue and consequently, low levels of the adipose-derived hormone leptin. Leptin deficiency in GLD leads to metabolic abnormalities which are often refractory to treatment with conventional agents. Recombinant human leptin, the only approved therapeutic, improves metabolic abnormalities of GLD, however, daily dosing is required and there is a risk of immunogenicity. There is an unmet need for effective therapies in GLD that are safe, administered less frequently, and can treat patients who have developed neutralizing antibodies to recombinant leptin. Mibavademab is an investigational human leptin receptor agonist monoclonal antibody. We report here the safety, tolerability and pharmacodynamic (PD) responses to mibavademab in a Phase 2 trial (NCT04159415) in patients with GLD. Methods: Patients ≥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 one of two fixed sequence arms comprising sequential 8-week treatment periods (Arm A: placebo, low-dose mibavademab, high-dose mibavademab; Arm B: low-dose mibavademab, high-dose mibavademab, high-dose mibavademab). Patients in each arm received an IV loading dose of placebo or mibavademab followed by weekly SC administration of study drug tiered by body weight (≥50 kg or <50 kg). Both arms were followed by an open-label high-dose mibavademab treatment period. Safety, pharmacokinetics, and PD of mibavademab were assessed. Primary efficacy endpoints, glycated hemoglobin (HbA1c) and fasting triglycerides (TGs) were measured at Week 8 and at predetermined time points thereafter until study completion. Results: 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. After 8 weeks of low-dose mibavademab, drug levels were significantly lower than predicted in the active arm, and clinically meaningful differences were not observed for any of the primary efficacy endpoints as compared to placebo. In an exploratory pooled analyses after 28 weeks of mibavademab administration, serum drug concentrations were significantly higher than observed at Week 8, and clinically significant reductions from baseline in HbA1c (mean: -1.9%, SD: 2.0) and in TGs (median: -102.1 mg/dL, IQR: 1355.5 mg/dL, -49.3% [57.2%]). Mibavademab was generally well tolerated with no serious adverse events related to administration. Conclusions: Treatment with high-dose mibavademab for up to 28 weeks was associated with clinically meaningful improvements in metabolic parameters, and was generally well-tolerated. Mibavademab represents a potential new therapeutic option for patients with GLD. Presentation: Friday, June 16, 2023