Effects of CB1R inverse agonist, INV ‐202, in patients with features of metabolic syndrome. A randomized, placebo‐controlled, double‐blind phase 1b study

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Abstract Aims To evaluate the clinical safety, tolerability, and pharmacokinetic and pharmacodynamic profile of the novel cannabinoid receptor‐1 (CB1R) inverse agonist, INV‐202, in adults with features of metabolic syndrome. Materials and Methods This was a multicentre, randomized, double‐blind, placebo‐controlled, 28‐day repeat‐dose (INV‐202 [25 mg] or placebo, once‐daily oral tablet), parallel‐group study in 37 participants aged 18 to 65 years (46% female, mean age 55 years, glycated haemoglobin 5.7% [39 mmol/mol], body mass index [BMI] 38.1 kg/m 2 ) with features of metabolic syndrome and glucose intolerance. An oral glucose tolerance test (OGTT) was performed at baseline and at the end of the study. Lipid profiles, weight, waist circumference and biomarkers were assessed weekly. Statistical comparisons were performed post hoc. Results INV‐202 was well tolerated with no serious or severe treatment‐emergent adverse events; the most common events related to known effects of CB1R blockade in the gastrointestinal tract. INV‐202 produced a significant mean weight loss of 3.5 kg (3.3% compared with placebo participants who gained a mean 0.6 kg [0.5%]). INV‐202 also exhibited significant reductions in waist circumference and BMI ( P ≤ 0.03). There was no significant difference in OGTT 0‐ to 3‐hour area under the curve for INV‐202 versus placebo: least squares mean 29.38 versus 30.25 h*mmol/L, with an INV‐202: placebo ratio of 97.1% (95% confidence interval 90.2, 105.6; P = 0.43). Conclusions INV‐202 was well tolerated, producing a signal for rapid weight loss with improvements in other metabolic syndrome markers in this population. These findings support further exploration and long‐term assessment of cardiometabolic effects.

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