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.

The Role of the Melanocortin System in Metabolic Disease: New Developments and Advances

“…Again, these outcomes are not off-target effects, but rather main physiological functions of melanocortins. These problems have thus far prevented the use of antiobesity drugs that target the activation of MC4R in the clinic [154, 218]. …”

Bench-top to clinical therapies: A review of melanocortin ligands from 1954 to 2016

“…The modified peptide, 16-(tetrazol-5-yl)hexadecanoyl-Oeg-Gly-Ser-Gln-His-Dap[bis(carboxymethyl)amino]acetyl-Nle-c[Glu-Hyp-DPhe-Arg-Trp-Lys]-NH 2 (Figure 6), has K i of 2700, 71, 0.58, and 13 nM at the hMC1R, hMC3R, hMC4R, hMC5R, respectively [286]. These in vitro results did not translate into clinically relevant effects on body weight in obese, otherwise healthy, patients [287]. A four day multi-dose, randomized, double-blind, placebo-controlled trial tested multiple concentrations administered subcutaneously up to 3.0 mg/day [287].…”

“…These in vitro results did not translate into clinically relevant effects on body weight in obese, otherwise healthy, patients [287]. A four day multi-dose, randomized, double-blind, placebo-controlled trial tested multiple concentrations administered subcutaneously up to 3.0 mg/day [287]. Analysis of the pharmacokinetic parameters indicated the compound possessed a long (>200 hour) t 1/2 half-life, but did not alter body weight.…”

Ultraviolet radiation, vitamin D and the development of obesity, metabolic syndrome and type-2 diabetes

“…69 However, sub-cutaneous treatment of overweight-to-obese men with another MC4R agonist, MC4-NN2-0453, had no effect on weight loss and induced a significant number of adverse events including skin problems (benign melanocytic nevus and pigmentation), headache and sexual dysfunction, which resulted in termination of the trial. 70 …”