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.

Activin A more prominently regulates muscle mass in primates than does GDF8.

Growth and differentiation factor 8 (GDF8) is a TGF-ß superfamily member, and negative regulator of skeletal muscle mass. GDF8 inhibition results in prominent muscle growth in mice, but less impressive hypertrophy in primates, including man. Broad TGF-ß inhibition suggests another family member negatively regulates muscle mass, and its blockade enhances muscle growth seen with GDF8-specific inhibition. Here we show that activin A is the long-sought second negative muscle regulator. Activin A specific inhibition, on top of GDF8 inhibition, leads to pronounced muscle hypertrophy and force production in mice and monkeys. Inhibition of these two ligands mimics the hypertrophy seen with broad TGF-ß blockers, while avoiding the adverse effects due to inhibition of multiple family members. Altogether, we identify activin A as a second negative regulator of muscle mass, and suggest that inhibition of both ligands provides a preferred therapeutic approach, which maximizes the benefit:risk ratio for muscle diseases in man.

Myostatin blockade with a fully human monoclonal antibody induces muscle hypertrophy and reverses muscle atrophy in young and aged mice.

BACKGROUND: Loss of skeletal muscle mass and function in humans is associated with significant morbidity and mortality. The role of myostatin as a key negative regulator of skeletal muscle mass and function has supported the concept that inactivation of myostatin could be a useful approach for treating muscle wasting diseases. METHODS: We generated a myostatin monoclonal blocking antibody (REGN1033) and characterized its effects in vitro using surface plasmon resonance biacore and cell-based Smad2/3 signaling assays. REGN1033 was tested in mice for the ability to induce skeletal muscle hypertrophy and prevent atrophy induced by immobilization, hindlimb suspension, or dexamethasone. The effect of REGN1033 on exercise training was tested in aged mice. Messenger RNA sequencing, immunohistochemistry, and ex vivo force measurements were performed on skeletal muscle samples from REGN1033-treated mice. RESULTS: The human monoclonal antibody REGN1033 is a specific and potent myostatin antagonist. Chronic treatment of mice with REGN1033 increased muscle fiber size, muscle mass, and force production. REGN1033 prevented the loss of muscle mass induced by immobilization, glucocorticoid treatment, or hindlimb unweighting and increased the gain of muscle mass during recovery from pre-existing atrophy. In aged mice, REGN1033 increased muscle mass and strength and improved physical performance during treadmill exercise. CONCLUSIONS: We show that specific myostatin antagonism with the human antibody REGN1033 enhanced muscle mass and function in young and aged mice and had beneficial effects in models of skeletal muscle atrophy.