First-in-Human Study of Safety, Pharmacodynamics of LB54640, An Oral Melanocortin-4 Receptor Agonist

Background: Central regulation of energy balance plays a major role in obesity management and it is mediated by POMC and Arg/NPY neurons in hypothalamus. POMC neurons are known to suppress appetite and to increase energy expenditure mediated by a-MSH, which is an agonist at the anorectic melanocortin-4 receptors. LB54640, an oral, selective MC4R agonist with low molecular weight, has the potential to induce weight loss. Methods: This was a randomized, double-blind, placebo-controlled, single and multiple ascending dose study to assess the safety, tolerability, PK/PD of LB54640 in people with obesity and overweight. Single oral doses of LB54640 from 10 to 400 mg were tested in the SAD cohort. In the MAD cohort, 61 subjects in 7 dose groups received either LB54640 (10 - 600 mg) or placebo at least once for 28 days. Results: Baseline demographics were generally well balanced between treatment groups (in the MAD cohort, mean age 43.5 ± 10.28 years; gender male 66.7 %, female 33.3 %. The BMIs and the body weights ranged between 32.94 ± 4.65 kg/m2 and 97.28 ± 16.97 kg.). A doseresponse relationship in body weight reduction was noted starting at 200 mg. The mean percent change from baseline to 28 days in the 200 mg, 400 mg, 600 mg dose groups were -1.3 %, -2.5 %, -3.0 %, vs. -0.08 % in the placebo group. People given LB54640 showed decreasing trends in waist circumference. The mean change from baseline to 28 days in the 200 mg, 400 mg, 600 mg dose groups and placebo group were -0.7 cm, -9.1 cm, -4.1 cm, vs. -0.5 cm in placebo. In the 400 mg and 600 mg dose groups, small but favorable changes in fasting lipid, glucose profile and body fat mass were observed after 28 days of treatment. At day 28, the mean change in total body fat mass in the placebo, the 400mg, 600 mg dose groups were 0.85 kg, -0.02 kg, -1.46 kg. There were no serious adverse events. Particularly, no skin pigmentation, adrenal AEs were observed. The most common AEs were nausea/vomiting and the grade of all AEs was mild to moderate. No clinically significant abnormalities were observed in blood pressure and heart rate measurements. Conclusions: LB54640 was generally well tolerated in people with obesity and overweight in doses ranging from 10 mg to 600 mg. Additionally, body weight displayed a dose-dependent reduction up to -3.0% in the highest dose group for 28 days, showing the potential for LB54640 to be an effective treatment for weight management.