A double-blind, randomized, placebo-controlled, phase 2 trial examined the efficacy and safety of monlunabant in adults with diabetic kidney disease

INTRODUCTION: Diabetic kidney disease (DKD) is a significant complication of diabetes, and an unmet need remains for new therapeutic options. Here, we investigated the efficacy and safety of monlunabant, a second-generation cannabinoid receptor 1 inverse agonist, in individuals with DKD. METHODS: This phase 2, randomized, double-blind, placebo-controlled, multicenter study, enrolled adults with DKD. Participants were randomized (1:1:1) to receive oral tablets of monlunabant 10 mg or 25 mg, or placebo once daily for 16 weeks. The primary endpoint was the change in urine albumin-to-creatinine ratio (UACR) from baseline to week 16. Secondary endpoints included changes in urine protein-to-creatinine ratio (UPCR) and estimated glomerular filtration rate (eGFR). RESULTS: In total, 254 participants formed the full analysis set (85, 86, and 83 in the 10 mg, 25 mg, and placebo groups, respectively). At week 16, the estimated geometric least squares mean ratios to baseline for UACR were 0.58, 0.51, and 0.71 in the 10 mg, 25 mg, and placebo groups, respectively. Monlunabant 25 mg did not show statistically significant differences compared to placebo (estimated treatment ratio [ETR] 0.72, 95% confidence interval (0.46 to 1.14)). Therefore, formal testing was not performed for 10 mg compared to placebo (ETR 0.82 (0.53 to 1.27)). Secondary endpoints showed similar trends, with no differences in UPCR or eGFR, when compared to placebo. The most frequently reported adverse events were mild to moderate gastrointestinal disorders, driven by nausea, vomiting, and diarrhea. Participant withdrawals increased with monlunabant dose. CONCLUSIONS: Our study failed to establish proof of concept of monlunabant in DKD, as the effect on UACR at week 16 was not significantly different from placebo. However, greater than anticipated variability and a large placebo response affect interpretation. TRIAL REGISTRATION: Registered at ClinicalTrials.gov with study number NCT05514548.