† Pharmacokinetics of Mibavademab in Healthy Participants: Results from a Randomized, Phase 1, Two-Part, First-in-Human Study

Background/Synopsis Leptin is a circulating adipose-derived hormone that controls energy expenditure and glucose/lipid metabolism by binding to leptin receptors (LEPRs); leptin is critical for body weight homeostasis and is a target for replacement therapy in treating obesity due to leptin deficiency. Objective/Purpose To report the pharmacokinetics (PK) of mibavademab, a LEPR agonist antibody, from a two-part first-in-human study (NCT03530514) evaluating the safety and tolerability of mibavademab in overweight/obese adults. Methods Part A: healthy lean/overweight adults (n=56, body mass index [BMI]: 18.5–<30.0 kg/m2) were randomized 3:1 to seven single dose cohorts (0.3, 1.0, 3.0, 10, or 30 mg/kg intravenous [IV] and 300 or 600 mg subcutaneous [SC]) of mibavademab or placebo. Part B: healthy overweight/obese adults (n=56, BMI: 25–40 kg/m2) assigned to four cohorts 6:1 (cohort 1) or 3:1 (cohorts 2–4) based on BMI, sex, and leptin were treated with mibavademab 15 mg/kg IV followed by 10 mg/kg IV every 3 weeks for four doses, or placebo. Concentrations of total mibavademab and total soluble LEPR (sLEPR) in serum were measured to assess for binding of mibavademab or upregulation of LEPR. Results In Part A, mibavademab PK profiles exhibited a brief distribution (IV dosing) or absorption phase (SC dosing), followed by concurrent linear elimination, predominant at 30 mg/kg IV, and target-mediated elimination phases. Estimated mean clearance was 22.6 mL/day/kg at 1 mg/kg IV and 2.42 mL/day/kg at 30 mg/kg IV. Time to maximum concentration was ∼3 (300 mg) to ∼7 days (600 mg) in the SC cohorts. In Part B, mibavademab concentrations were lower in participants with low versus high baseline leptin (<5 vs >5 ng/mL) due to greater target-mediated clearance in the former. Total sLEPR increased with mibavademab treatment, with small differences between low versus high leptin participants. No treatment-emergent anti-drug antibodies were observed in participants treated with mibavademab. Conclusions In healthy adults, mibavademab exhibited a well-characterized PK profile and showed a greater target-mediated clearance in low baseline leptin overweight/obese participants. External Funding Yes Funding Sources Regeneron Pharmaceuticals, Inc. Leptin is a circulating adipose-derived hormone that controls energy expenditure and glucose/lipid metabolism by binding to leptin receptors (LEPRs); leptin is critical for body weight homeostasis and is a target for replacement therapy in treating obesity due to leptin deficiency. To report the pharmacokinetics (PK) of mibavademab, a LEPR agonist antibody, from a two-part first-in-human study (NCT03530514) evaluating the safety and tolerability of mibavademab in overweight/obese adults. Part A: healthy lean/overweight adults (n=56, body mass index [BMI]: 18.5–<30.0 kg/m2) were randomized 3:1 to seven single dose cohorts (0.3, 1.0, 3.0, 10, or 30 mg/kg intravenous [IV] and 300 or 600 mg subcutaneous [SC]) of mibavademab or placebo. Part B: healthy overweight/obese adults (n=56, BMI: 25–40 kg/m2) assigned to four cohorts 6:1 (cohort 1) or 3:1 (cohorts 2–4) based on BMI, sex, and leptin were treated with mibavademab 15 mg/kg IV followed by 10 mg/kg IV every 3 weeks for four doses, or placebo. Concentrations of total mibavademab and total soluble LEPR (sLEPR) in serum were measured to assess for binding of mibavademab or upregulation of LEPR. In Part A, mibavademab PK profiles exhibited a brief distribution (IV dosing) or absorption phase (SC dosing), followed by concurrent linear elimination, predominant at 30 mg/kg IV, and target-mediated elimination phases. Estimated mean clearance was 22.6 mL/day/kg at 1 mg/kg IV and 2.42 mL/day/kg at 30 mg/kg IV. Time to maximum concentration was ∼3 (300 mg) to ∼7 days (600 mg) in the SC cohorts. In Part B, mibavademab concentrations were lower in participants with low versus high baseline leptin (<5 vs >5 ng/mL) due to greater target-mediated clearance in the former. Total sLEPR increased with mibavademab treatment, with small differences between low versus high leptin participants. No treatment-emergent anti-drug antibodies were observed in participants treated with mibavademab. In healthy adults, mibavademab exhibited a well-characterized PK profile and showed a greater target-mediated clearance in low baseline leptin overweight/obese participants.