title: Investigation of safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple doses of a long-acting α-MSH analog in healthy overweight and obese subjects.
abstract: MC4-NN2-0453 is a novel, long-acting, selective, melanocortin-4-receptor agonist developed for treatment of obesity. This first-human-dose, randomized, double-blind, placebo-controlled trial investigated the safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple doses of MC4-NN2-0453 in overweight to obese but otherwise healthy subjects. The trial included a single-dose part of ascending subcutaneous 0.03-1.50 mg/kg doses in overweight to obese but otherwise healthy men, and a multiple-dose part of ascending subcutaneous 0.75-3.0 mg/day doses in obese but otherwise healthy men/women. The single-dose part included 7 cohorts of 8 subjects, randomized 6:2 to active drug/placebo; the multiple-dose part included 4 cohorts of 20 subjects, randomized 16:4 to active drug/placebo. MC4-NN2-0453 was well tolerated and raised no safety concerns except for nonserious skin-related adverse events, this along with lack of weight loss effect led to premature termination of the trial. Headache, sexual-arousal disturbance, and penile erection were also reported. Single-dose pharmacokinetics showed dose-linearity and dose-proportionality. Maximum plasma concentration was observed after 50-100 hours, which then declined with a of approximately 250 hours. Plasma concentration reached steady state after 4 weeks for 0.75 and 1.5 mg/day multiple-dose cohorts, and the was similar to single dose. There were no significant pharmacodynamic effects, including effect on body weight.
authors.affiliation: Covance, Evansville, IN, USA.
authors.forename: Jane E
authors.initials: JE
authors.lastname: Royalty
authors.forename: Gitte
authors.initials: G
authors.lastname: Konradsen
authors.forename: Ole
authors.initials: O
authors.lastname: Eskerod
authors.forename: Birgitte S
authors.initials: BS
authors.lastname: Wulff
authors.forename: Birgit S
authors.initials: BS
authors.lastname: Hansen
mesh_terms: D000293:Adolescent; D000328:Adult; D019440:Anti-Obesity Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D017495:Hyperpigmentation / Q000139:chemically induced; D008297:Male; D008875:Middle Aged; D009508:Nevus, Pigmented / Q000139:chemically induced; D009765:Obesity / Q000188:drug therapy* / Q000378:metabolism; D050177:Overweight / Q000188:drug therapy* / Q000378:metabolism; D044105:Receptor, Melanocortin, Type 4 / Q000037:antagonists & inhibitors; D055815:Young Adult; D000521:alpha-MSH / Q000008:administration & dosage* / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
chemical_list: D019440:Anti-Obesity Agents; C470072:MC4R protein, human; D044105:Receptor, Melanocortin, Type 4; D000521:alpha-MSH
keywords: alpha-melanocyte-stimulating hormone; obesity; pharmacodynamics; pharmacokinetics