FRI069 Treatment With Mibavademab, A Novel Leptin Receptor Agonist, Is Associated With Improvement In Weight And Associated Comorbidities In Congenital Leptin Deficiency

Disclosure: E. Ozsu: None. L. Akin: None. M. Aydin: None. M. Berberoglu: None. D. Stein: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. O. Pagovich: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. B. Olenchock: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. S. Podgrabinska: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. C.A. Harris: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. J. Mendell: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. R. SinhaRoy: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. J. Altarejos: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. B. Akinci: Advisory Board Member; Self; Amryt Pharmaceuticals, Regeneron, Third Rock Ventures. Consulting Fee; Self; Third Rock ventures, Regeneron, Amryt Pharmaceuticals. Speaker; Self; Astra Zeneca, Lilly, MSD, Novartis, Novo Nordisk, Sanofi Aventis. E.A. Oral: Advisory Board Member; Self; Third Rock Ventures, Regeneron, Rejuveneate Bio. Consulting Fee; Self; Amryt Pharmaceuticals, Regeneron. Grant Recipient; Self; Regeneron, Novo Nordisk, GI Dynamics, Ionis Pharmaceuticals, Fractyl, Rhythm Pharmaceuticals. Other; Self; Amryt Pharmaceuticals. Background: Congenital leptin deficiency (CLD) is a form of extreme obesity caused by biallelic pathogenic variants in the leptin gene. Recombinant human leptin normalizes weight and neuroendocrine/metabolic abnormalities in CLD, however, daily dosing is required with a risk of immunogenicity. Mibavademab is an investigational human leptin receptor agonist monoclonal antibody. Case report: A Turkish male infant came to medical attention due to rapid weight gain at 2 months of age and work-up led to identification of homozygous variant in the leptin gene causing CLD. He was treated with Metreleptin for 11 months starting at age 2. When weight regain despite Metreleptin therapy was noted, neutralizing antibody (Nab) was found to be strongly positive. He continued to gain weight rapidly causing impaired mobility, and required nightly oxygen with BIPAP. He was hospitalized frequently with upper respiratory tract infections and needed ICU care four times during the 5(th) year of his life. At age 5 years and 9 months and body weight of 89.9 kg (BMI SD:5.7), the compassionate use application to use Mibavademab was approved by the local ethics board and the Ministry of Health. The patient received an intravenous loading dose of Mibavademab followed by weekly subcutaneous (SC) administration of Mibavademab. SC dose and diet intake were carefully adjusted based on drug levels, and intended vs. observed weight loss. Results: Weight reduction was first observed in the first week of treatment, which was rapid with an average velocity of 7.1 kg/month until month 7. Upon dose adjustment, velocity decreased to 3.1 kg/month. Weight stabilization was achieved at month 11 at a weight of 28.9 kg (BMI SD:1.0) while using Mibavademab every two weeks. Overall, drug levels were significantly higher than projected in the first 28 weeks and then brought to predicted stable levels upon dose adjustments. Despite the rapid weight loss, improved mobility and age-appropriate growth were observed. There were no signs of precocious puberty. Glucose tolerance, insulinemia, and liver parameters all improved favorably over treatment period and there were no safety signals. The patient discontinued BIPAP treatment and sleep assumed a normal pattern without hypoxia. Conclusions: Compassionate treatment with Mibavademab for up to 60 weeks was associated with improvements in body weight and metabolic parameters, and was well-tolerated in a young child with CLD and Nab against metreleptin. Substantial benefits in mobility, social engagement, and respiratory status were also noted without adverse events. Mibavademab represents a potential new therapeutic option for patients with CLD and this first experience will provide guidance for treatment of similar patients. Presentation: Friday, June 16, 2023