mibavademab (REGN4461) / Regeneron, Sanofi - LARVOL DELTA

KYRIAD: A Study to Investigate Mibavademab in Adult Women With Functional Hypothalamic Amenorrhea (clinicaltrials.gov) - P2 | N=34 | Not yet recruiting | Sponsor: Regeneron Pharmaceuticals

New P2 trial • Women's Health

Advances of pharmacological therapies in lipodystrophy syndromes: current evidence and future directions. (PubMed, Expert Rev Endocrinol Metab) - "Dietary modification, exercise, lifestyle management, and metreleptin therapy are the mainstay of treatment, while conventional therapies are used to target specific complications...There is currently no cure for lipodystrophy syndromes. Emerging therapies are being investigated to expand therapeutic options and improve long-term outcomes of this complex disorder."

Journal • Review • Lipodystrophy • Metabolic Disorders • Rare Diseases

Efficacy and Safety of Mibavademab in Adult and Pediatric Patients With Generalized Lipodystrophy (clinicaltrials.gov) - P3 | N=28 | Not yet recruiting | Sponsor: Regeneron Pharmaceuticals

New P3 trial • Lipodystrophy • Metabolic Disorders • Pediatrics

A Study Evaluating Mibavademab Treatment of Obesity Due to Leptin (LEP) Gene Mutations in Children, Adolescents and Adults (clinicaltrials.gov) - P3 | N=4 | Not yet recruiting | Sponsor: Regeneron Pharmaceuticals

New P3 trial • Genetic Disorders • Obesity

The Impact of Mibavademab, a Novel Leptin Receptor Agonist, on Metabolic Parameters in Individuals with Generalized Lipodystrophy (ENDO 2025) - P2 | "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."

Clinical • Diabetes • Dyslipidemia • Hypertriglyceridemia • Lipodystrophy • Metabolic Disorders • LEP • LEPR

A Study of the Safety of Mibavademab in Pediatric and Adult Participants Switching From Metreleptin to Mibavademab for the Treatment of Generalized Lipodystrophy (GLD) (clinicaltrials.gov) - P3 | N=9 | Active, not recruiting | Sponsor: Regeneron Pharmaceuticals | Recruiting ➔ Active, not recruiting | Trial completion date: Jun 2027 ➔ Nov 2026 | Trial primary completion date: Mar 2027 ➔ Jul 2026

Enrollment closed • Trial completion date • Trial primary completion date • Lipodystrophy • Metabolic Disorders • Pediatrics

Leptin- And Incretin-based Combination Therapy In Lipodystrophy: A Promising Metabolic Strategy? (ENDO 2025) - "Metreleptin (ML) remains the cornerstone of treatment for generalized lipodystrophy (GL); however, its efficacy in partial lipodystrophy (PL) can be limited, highlighting the need for alternative or incremental therapies to achieve optimal metabolic control...P3 (25-year-old, LMNA related GL (with T10I variant), treated with mibavademab for 4 years): after adding dulaglutide for 5 months, HbA1c reduced from 8.9% to 7.3%, with stable BMI (14.4 kg/m²) and no change in TG (265 to 273 mg/dL)...In summary, combined leptin-based and incretin-based therapies may enhance metabolic outcomes in lipodystrophy. Future randomized controlled trials are needed to evaluate the efficacy of incretin-based therapies either with or without leptin pathway treatments to confidently determine the extent of benefit of combination therapy in lipodystrophy."

Combination therapy • Late-breaking abstract • Lipodystrophy • Metabolic Disorders • Pancreatitis • Rare Diseases • LEP • LEPR • LMNA

Select Upcoming 2025 Milestones (GlobeNewswire) - "Report additional data from Phase 1/2 study for DB-OTO (AAV-based gene therapy) in patients with hearing deficit due to variants of the otoferlin gene (mid-2025); Report results from Phase 3 study for pozelimab (C5 antibody) in combination with cemdisiran in myasthenia gravis (second half 2025)....Report results from Phase 2 study for semaglutide in combination with trevogrumab (myostatin antibody) with and without garetosmab (Activin A antibody) in obesity (second half 2025); Report results from Phase 2 study for mibavademab (LEPR agonist antibody) in combination with tirzepatide in obesity (second half 2025); Report results from Phase 3 study for garetosmab (Activin A antibody) in fibrodysplasia ossificans progressiva (FOP) (second half 2025)."

Clinical data • Myasthenia Gravis • Obesity • Rare Diseases

A Study of Tirzepatide (LY3298176) Plus Mibavademab Compared With Tirzepatide Alone in Adult Participants With Obesity (clinicaltrials.gov) - P2 | N=360 | Active, not recruiting | Sponsor: Eli Lilly and Company | Recruiting ➔ Active, not recruiting

Enrollment closed • Genetic Disorders • Obesity

Regeneron Provides Business Updates and Highlights from Broad Clinical Pipeline at the 43rd Annual J.P. Morgan Healthcare Conference (GlobeNewswire) - "Results are expected from the Phase 3 AERIFY study in the second half of 2025, with a potential BLA submission to follow...Phase 2 study testing combinations of tirzepatide and mibavademab is ongoing, with initial data expected from both in the second half of 2025."

P2 data • P3 data • Chronic Obstructive Pulmonary Disease • Obesity

A Study of the Safety of Mibavademab in Pediatric and Adult Participants Switching From Metreleptin to Mibavademab for the Treatment of Generalized Lipodystrophy (GLD) (clinicaltrials.gov) - P3 | N=8 | Recruiting | Sponsor: Regeneron Pharmaceuticals | Not yet recruiting ➔ Recruiting

Enrollment open • Lipodystrophy • Metabolic Disorders • Pediatrics

Study of REGN4461, a Leptin Receptor Agonist Antibody, in Patients With Generalized Lipodystrophy (clinicaltrials.gov) - P2 | N=16 | Completed | Sponsor: Regeneron Pharmaceuticals | Active, not recruiting ➔ Completed

Trial completion • Lipodystrophy • Metabolic Disorders

A Study of the Safety of Mibavademab in Pediatric and Adult Participants Switching From Metreleptin to Mibavademab for the Treatment of Generalized Lipodystrophy (GLD) (clinicaltrials.gov) - P3 | N=8 | Not yet recruiting | Sponsor: Regeneron Pharmaceuticals

New P3 trial • Lipodystrophy • Metabolic Disorders • Pediatrics

LEAP: A Study to Examine the Effects of the Leptin Receptor (LEPR) Agonist Antibody REGN4461 in Adult Patients With Familial Partial Lipodystrophy (FPLD) (clinicaltrials.gov) - P2 | N=20 | Terminated | Sponsor: Regeneron Pharmaceuticals | Completed ➔ Terminated; Sponsor Decision

Trial termination • Lipodystrophy • Metabolic Disorders

A Study of Tirzepatide (LY3298176) Plus Mibavademab Compared With Tirzepatide Alone in Adult Participants With Obesity (clinicaltrials.gov) - P2 | N=360 | Recruiting | Sponsor: Eli Lilly and Company | Not yet recruiting ➔ Recruiting

Enrollment open • Genetic Disorders • Obesity

An Adolescent Female With Congenital Lipodystrophy Presenting With Repeated Acute Metabolic Decompensations Rescued By A Novel Leptin Receptor Agonist (ENDO 2024) - "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...She was transitioned from metreleptin to mibavademab, an investigational leptin receptor agonist, on an expanded use IND...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."

Late-breaking abstract • Cardiovascular • Diabetes • Dyslipidemia • Hypertension • Hypertriglyceridemia • Lipodystrophy • Metabolic Disorders • Pancreatitis • Type 2 Diabetes Mellitus • Women's Health • LEP • LEPR

Changes In Metabolic Parameters For Mibavademab, A Novel Leptin Receptor Agonist, In Individuals With Generalized Lipodystrophy (ENDO 2024) - "Abstract is embargoed at this time."

Clinical • Late-breaking abstract • Lipodystrophy • Metabolic Disorders • LEP • LEPR

Changes In Metabolic Parameters For Mibavademab, A Novel Leptin Receptor Agonist, In Individuals With Generalized Lipodystrophy (ENDO 2024) - P2 | "Notably, four patients were previously treated with metreleptin, three with documented anti-metreleptin neutralizing antibodies. In this cohort of patients with GLD, treatment with high dose mibavademab for 12 weeks led to further improvements in HbA1c and fasting triglycerides and was generally well tolerated. Mibavademab may emerge as a potential new therapeutic option for patients with GLD."

Clinical • Late-breaking abstract • Diabetes • Dyslipidemia • Hypertriglyceridemia • Lipodystrophy • Metabolic Disorders • LEP • LEPR

Qualitative Interviews Describing the Patient Experience of Individuals with Generalized Lipodystrophy Enrolled in a Clinical Trial of Mibavademab (ENDO 2024) - P2 | "All participants who reported symptoms of hunger, pain, fatigue, and extreme body temperature, or the clinical biomarker of hyperglycemia before entering the study reported improvements in each of these after treatment. In addition, all participants reported being either satisfied or very satisfied with treatment. This qualitative research provides insight into the patient experience for individuals with GLD and provides an opportunity to further understand and complement the clinical trial results.Unless otherwise noted, all abstracts presented at ENDO must not be released to the press or the public until the date and time of presentation."

Clinical • Interview • Diabetes • Fatigue • Lipodystrophy • Metabolic Disorders • Pain • Sleep Disorder • LEP • LEPR

LEAP: A Study to Examine the Effects of the Leptin Receptor (LEPR) Agonist Antibody REGN4461 in Adult Patients With Familial Partial Lipodystrophy (FPLD) (clinicaltrials.gov) - P2 | N=20 | Completed | Sponsor: Regeneron Pharmaceuticals | Active, not recruiting ➔ Completed | Trial completion date: Jun 2025 ➔ Apr 2024 | Trial primary completion date: Dec 2024 ➔ Oct 2023

Trial completion • Trial completion date • Trial primary completion date • Lipodystrophy • Metabolic Disorders

A Study of Tirzepatide (LY3298176) Plus Mibavademab Compared With Tirzepatide Alone in Adult Participants With Obesity (clinicaltrials.gov) - P2 | N=360 | Not yet recruiting | Sponsor: Eli Lilly and Company

New P2 trial • Genetic Disorders • Obesity

Pharmacokinetics and pharmacodynamics of mibavademab (a leptin receptor agonist): Results from a first-in-human phase I study. (PubMed, Clin Transl Sci) - P1 | "No treatment-emergent anti-mibavademab antibodies were observed in any mibavademab-treated participant. Results from this study collectively inform further development of mibavademab to treat conditions associated with leptin deficiency."

Journal • P1 data • PK/PD data • Leptin Receptor Deficiency Obesity • Obesity • LEP • LEPR

LEAP: A Study to Examine the Effects of the Leptin Receptor (LEPR) Agonist Antibody REGN4461 in Adult Patients With Familial Partial Lipodystrophy (FPLD) (clinicaltrials.gov) - P2 | N=20 | Active, not recruiting | Sponsor: Regeneron Pharmaceuticals | Recruiting ➔ Active, not recruiting | N=40 ➔ 20

Enrollment change • Enrollment closed • Lipodystrophy • Metabolic Disorders

Preclinical, randomized phase 1, and compassionate use evaluation of REGN4461, a leptin receptor agonist antibody for leptin deficiency. (PubMed, Sci Transl Med) - "Deficiency in the adipose-derived hormone leptin or leptin receptor signaling causes class 3 obesity in individuals with genetic loss-of-function mutations in leptin or its receptor LEPR and metabolic and liver disease in individuals with hypoleptinemia secondary to lipoatrophy such as in individuals with generalized lipodystrophy. Furthermore, compassionate-use treatment of a single patient with atypical partial lipodystrophy and a history of undetectable leptin concentrations associated with neutralizing antibodies to metreleptin was associated with noteable improvements in circulating triglycerides and hepatic steatosis. Collectively, these translational data unveil an agonist LEPR mAb that may provide clinical benefit in disorders associated with relatively low leptin concentrations."

Clinical • Journal • P1 data • Preclinical • Diabetes • Dyslipidemia • Genetic Disorders • Hepatology • Leptin Receptor Deficiency Obesity • Lipodystrophy • Metabolic Disorders • Obesity • LEP • LEPR

LEAP: A Study to Examine the Effects of the Leptin Receptor (LEPR) Agonist Antibody REGN4461 in Adult Patients With Familial Partial Lipodystrophy (FPLD) (clinicaltrials.gov) - P2 | N=40 | Recruiting | Sponsor: Regeneron Pharmaceuticals | Trial completion date: Feb 2024 ➔ Jun 2025 | Trial primary completion date: Jul 2023 ➔ Dec 2024

Trial completion date • Trial primary completion date • Lipodystrophy • Metabolic Disorders • LEP