Abstract
BACKGROUND: Monlunabant, a novel cannabinoid receptor 1 (CB1R) inverse agonist, has shown encouraging weight loss efficacy and tolerability. We aimed to evaluate the efficacy and safety of monlunabant in individuals with obesity and metabolic syndrome. METHODS: This 16-week, randomised, double-blind, placebo-controlled, dose-ranging phase 2a trial, conducted at 25 outpatient research centres in Canada, enrolled adults with obesity and metabolic syndrome. Participants were randomly assigned (1:1:1:1) by means of an interactive response system to once-daily oral tablets of monlunabant 10 mg, 20 mg, 50 mg, or placebo. The participants, site staff, sponsor, and contract research organisation were masked to treatment allocation. The primary endpoint was mean bodyweight (kg) change from baseline at week 16 versus placebo, assessed in all eligible randomised participants, whereas the safety analysis was done in all randomised participants who received at least one dose of trial product. The estimator for the primary estimand was analysed using a mixed model for repeated measures, assuming missing data are missing at random. This trial is registered with ClinicalTrials.gov (NCT05891834) and is complete. FINDINGS: From Sept 8, 2023, to Jan 26, 2024, 409 individuals were screened for eligibility. In total, 243 individuals were randomly assigned to monlunabant 10 mg (n=61), monlunabant 20 mg (n=61), monlunabant 50 mg (n=60), and placebo (n=61); 242 participants received treatment, including 167 (69%) females and 75 (31%) males. 183 (76%) of 242 participants completed the trial: 50 (82%) of 61 received monlunabant 10 mg, 42 (70%) of 60 received monlunabant 20 mg, 34 (57%) of 60 received monlunabant 50 mg, and 57 (93%) of 61 received placebo. At week 16, participants receiving monlunabant showed statistically significant weight loss compared with those receiving placebo (least squares mean difference vs placebo of -6·4 kg [95% CI -8·0 to -4·9] for monlunabant 10 mg, -6·9 kg [-8·5 to -5·3] for monlunabant 20 mg, and -8·0 kg [-9·7 to -6·4] for monlunabant 50 mg). Adverse events were mostly mild to moderate gastrointestinal and psychiatric disorders and were seen in 42 (69%) of 61 participants in the monlunabant 10 mg group, 47 (78%) of 60 participants in the monlunabant 20 mg group, 55 (92%) of 60 participants in the monlunabant 50 mg group, and 42 (69%) of 61 participants in the placebo group. Withdrawals due to adverse events appeared dose-dependent, occurring in eight (13%) participants who received monlunabant 10 mg, 16 (27%) who received monlunabant 20 mg, 25 (42%) who received monlunabant 50 mg, and none who received placebo, driven by nausea, anxiety, diarrhoea, irritability, and sleep disorder. No deaths were reported. INTERPRETATION: Participants receiving monlunabant showed statistically significant and clinically meaningful weight loss compared with those receiving placebo for all tested doses. Only slightly greater weight loss was observed at higher doses, whereas adverse events appeared dose dependent. Further investigation is needed to assess the safety and efficacy of lower doses of monlunabant, to evaluate its potential as a medication for obesity. FUNDING: Inversago Pharma (a Novo Nordisk company).