Efficacy and Safety of CP‐945,598, a Selective Cannabinoid CB1 Receptor Antagonist, on Weight Loss and Maintenance

Abstract

Three double‐blind, placebo‐controlled, three‐parallel‐group, multicenter phase 3 trials were conducted to assess the efficacy and safety of CP‐945,598 for weight loss and weight‐loss maintenance. Two trials were designed to be 2 years in duration (in obese and overweight patients) and one as a 1‐year study (in obese and overweight patients with type 2 diabetes). However, the 2‐year trials and the CP‐945,598 development program were terminated before completion due to changing regulatory perspectives of CB1 receptor‐related drugs. In total, 1,253 and 2,536 participants in the two 2‐year multinational and North American studies were randomized to 10‐mg CP‐945,598 (n = 360; 718); 20‐mg CP‐945,598 (n = 534, 1,084) and placebo (n = 359, 734), respectively; and 975 participants were randomized to 10‐mg CP‐945,598 (n = 318); 20‐mg CP‐945,598 (n = 320); and placebo (n = 337) in the 1‐year multinational diabetes trial. Baseline demographics were similar between treatment groups within each trial. One year of treatment with CP‐945,598 resulted in a dose‐related mean percentage reduction from baseline body‐weight in all trials. A significant proportion of all participants also achieved 5% and 10% weight loss after 1 year. In participants with mainly well‐controlled type 2 diabetes, the combination of lifestyle and CP‐945,598 induced substantial improvements in glycemic control. The most frequent adverse events (AEs) for CP‐945,598 were: diarrhea, nausea, nasopharyngitis, and headache. Self‐reported experiences of anxiety and suicidal thoughts were higher with CP‐945,598 than placebo, as were the incidence of depression and depressed mood. However, the reported increases in psychiatric symptoms were not consistently dose dependent.

A PET study comparing receptor occupancy by five selective cannabinoid 1 receptor antagonists in non-human primates

“…The preclinical observations have been validated in humans by extensive clinical studies with rimonabant, confirming weight loss and improved lipid and glucose metabolism in treated obese humans (Van Gaal et al, 2005; Després et al, 2005; Pi-Sunyer et al, 2006). Similar findings have also been reported with taranabant and otenabant (Aronne et al, 2010; 2011). The clinical trials have, however, additionally revealed adverse psychiatric side effects, particularly depression, which has led to withdrawal of the drugs from clinical use (Beyer et al, 2010).…”

Effect of weight reduction on glycated haemoglobin in weight loss trials in patients with type 2 diabetes

“…Eighteen of the studies were randomized controlled trials of mainly dietary interventions . There were 30 randomized, placebo‐controlled trials of obesity drugs, including orlistat, cetilistat, sibutramine, topiramate, rimonabant, taranabant, CP‐945,598, and lorcaserin . All but one of the drug trials included the dietary advice of reduced energy intake in all treatment groups.…”

Maximizing retention in long‐term clinical trials of a weight loss agent: use of a dietitian support team

“…This retention programme was implemented proactively and was successful at improving upon the reported 53% 1‐year retention rate in the Rio‐North American study, which studied a similar weight loss drug in patients with similar BMI but without diabetes in the USA and Canada, also over a 1‐year time period 1, 19, and even improved upon the retention rate of Phase 3 trials conducted with more recently approved weight loss agents 2, 3, 4, 5.…”