PII-074 - PHARMACOKINETICS OF MIBAVADEMAB (MIBA) IN HEALTHY PARTICIPANTS: RESULTS FROM A RANDOMIZED, PHASE 1, TWO-PART, FIRST-IN-HUMAN STUDY.

J. Mendell¹, A. Gewitz¹, Y. Wang¹, L. Harnisch¹, B. Olenchock¹, H. Pan¹, S. Podgrabinska¹, W. Zheng¹, A. Zhao¹, F. Vanhoutte², J. Davis¹; ¹Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA, ²SGS Clinical Pharmacology Unit, Antwerp, Belgium.

Background: Leptin is a circulating adipose-derived hormone that controls energy expenditure and glucose/lipid metabolism by binding to leptin receptors (LEPR); leptin is critical for body weight homeostasis and is a target for obesity. The safety and tolerability of MIBA, a LEPR agonist antibody, was evaluated in overweight (OW)/obese adults in a two-part study (NCT03530514); here, we report MIBA pharmacokinetics (PK).

Methods: Part A: healthy lean/OW adults (N=56, body mass index [BMI]: 18.5 to < 30.0 kg/m2) were randomized to 7 single dose cohorts (0.3, 1.0, 3.0, 10, or 30 mg/kg IV and 300 or 600 mg SC) of MIBA or placebo (PBO). Part B: healthy OW/obese adults (N=56, BMI: 25–40 kg/m2) assigned to 4 cohorts based on BMI, sex and leptin were treated with MIBA 15 mg/kg IV followed by 10 mg/kg IV every 3 weeks for 4 doses or PBO. Concentrations of total MIBA and total soluble LEPR (sLEPR), to assess for binding of MIBA or upregulation of LEPR, were measured in serum.

Results: In Part A, MIBA PK profiles showed 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. Tmax was ~3 (300 mg) to ~7 days (600 mg) in the SC cohorts. In Part B, MIBA concentrations were lower in low vs. high baseline leptin ( < 5 vs >5 ng/mL) subjects due to greater target-mediated clearance. Total sLEPR increased with MIBA, with small differences between low vs. high leptin subjects. No treatment-emergent anti-drug antibodies were observed.

Conclusion: In healthy adults, MIBA exhibited a well-characterized PK profile and showed a greater target-mediated clearance in low baseline leptin OW/obese subjects.