Safety, Tolerability, Pharmacokinetics and Exploratory Pharmacodynamics of Melanin-Concentrating Hormone Receptor-1 Antagonist RGH-706 in Healthy and Overweight or Obese Men

Aim: This Phase 1 program evaluated the safety, tolerability, pharmacokinetics and exploratory pharmacodynamics of the novel melanin-concentrating hormone receptor-1 antagonist RGH-706. Methods: Study A was a first-in-man, randomized trial comprising a double-blind, placebo-controlled single-ascending-dose part (0.1–162.5 mg) and a two-way crossover food-effect assessment at 62.5 mg in healthy men. Study B was a double-blind, placebo-controlled, single- and multiple-ascending-dose study in overweight or obese (otherwise healthy) men receiving a single dose followed by 14 days of once-daily dosing (2.5–22.5 mg/day). Safety assessments included clinical evaluations, ECGs and mood and sleep scales. RGH-706 concentrations in plasma and urine samples were measured by validated methods. Pharmacokinetics was characterized using non-compartmental analysis. Study B evaluated exploratory pharmacodynamic measures including appetite-related outcomes, food preference, test-meal food and macronutrient intake, body composition and metabolic biomarkers. Results: In Study A (n = 68), systemic exposure increased approximately dose proportionally up to 62.5 mg and more than proportionally above, with tmax between 2.5 and 3.5 h and a bi-exponential disposition with a 29–35 h terminal half-life. Food ingestion had a negligible effect on exposure and renal clearance was also negligible. In Study B (n = 36), RGH-706 showed moderate accumulation with steady state reached within 8 days. Exploratory pharmacodynamic measures showed a trend towards lower total energy intake, preference for fatty foods and weight gain, primarily with the lower doses of 2.5 and 7.5 mg/day. RGH-706 was well tolerated across all doses and conditions in both studies. Conclusions: RGH-706 was safe, well tolerated and exhibited well-characterized pharmacokinetics. The pharmacodynamic data support further exploration of RGH-706 in weight management.