Preclinical, randomized phase 1, and compassionate use evaluation of REGN4461, a leptin receptor agonist antibody for leptin deficiency

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. Therapies that restore leptin-LEPR signaling may resolve these metabolic sequelae. We developed a fully human monoclonal antibody (mAb), REGN4461 (mibavademab), that activates the human LEPR in the absence or presence of leptin. In obese leptin knockout mice, REGN4461 normalized body weight, food intake, blood glucose, and insulin sensitivity. In a mouse model of generalized lipodystrophy, REGN4461 alleviated hyperphagia, hyperglycemia, insulin resistance, dyslipidemia, and hepatic steatosis. In a phase 1, randomized, double-blind, placebo-controlled two-part study, REGN4461 was well tolerated with an acceptable safety profile. Treatment of individuals with overweight or obesity with REGN4461 decreased body weight over 12 weeks in those with low circulating leptin concentrations (<8 ng/ml) but had no effect on body weight in individuals with higher baseline leptin. 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. Description LEPR agonist antibody REGN4461 (mibavademab) improves metabolic consequences of leptin deficiency. Editor’s summary Genetic deficiency of leptin signaling is often treated with the leptin analog metreleptin; however, some individuals show immunogenicity to the drug. Altarejos et al. show that monoclonal antibody (mAb)–based leptin receptor agonism is an alternative strategy for treating leptin deficiency. mAb administration lowered food intake and improved body weight and metabolic parameters in mouse models of leptin deficiency or generalized lipodystrophy. The mAb was well tolerated and improved weight in low-leptin, high-BMI individuals in phase I testing. Treatment of one patient with atypical partial lipodystrophy and a known immune response to metreleptin additionally improved hepatosteatosis and circulating triglycerides. —Catherine Charneski