Cannabinoid 1 receptor (CB1R) inverse agonists are emerging as a potential obesity therapy. However, the physiological mechanisms by which these agents modulate human energy balance are incompletely elucidated. Here, we describe a comprehensive clinical research study of taranabant, a structurally novel acyclic CB1R inverse agonist. Positron emission tomography imaging using the selective CB1R tracer [(18)F]MK-9470 confirmed central nervous system receptor occupancy levels ( approximately 10%-40%) associated with energy balance/weight-loss effects in animals. In a 12-week weight-loss study, taranabant induced statistically significant weight loss compared to placebo in obese subjects over the entire range of evaluated doses (0.5, 2, 4, and 6 mg once per day) (p < 0.001). Taranabant treatment was associated with dose-related increased incidence of clinical adverse events, including mild to moderate gastrointestinal and psychiatric effects. Mechanism-of-action studies suggest that engagement of the CB1R by taranabant leads to weight loss by reducing food intake and increasing energy expenditure and fat oxidation.

FOSAMAX® PLUS D is a once‐weekly alendronate (ALN) 70‐mg / vitamin D3 (vit‐D3) 5600 IU combination tablet developed by Merck & Co., Inc. A single‐dose, open‐label, randomized, 2‐period, crossover study was conducted to test bioequivalence between FOSAMAX® PLUS D combination tablets and co‐administration of corresponding doses of ALN 70‐mg (FOSAMAX®) and vit‐D3 5600 IU (2x 2800 IU) as individual tablets in healthy male and female Asian subjects to support registration in Taiwan. Results: the 90%CI of the GMR for ALN AUC0‐∞ fell within the pre‐specified bioequivalence bounds of 0.8 to 1.25, but slightly exceeded 1.25 for ALN AUC0‐last and Cmax. The 90% CI of the GMR for vit‐D3, unadjusted for endogenous vit‐D3, was also contained within the pre‐specified bioequivalence bounds. Thus, the combination tablet was bioequivalent based on ALN AUC0‐∞ and vit‐D3 unadjusted for endogenous levels. However, it was not bioequivalent to co‐administration with respect to ALN AUC0‐last and Cmax . In conclusion, the small differences between the combination tablet and co‐administration of individual doses for ALN AUC0‐last and Cmax are not considered to be clinically significant, as slightly increased ALN concentrations are unlikely to meaningfully affect the safety profile. TFDA accepted these results and considered them supportive for registration of the combination tablet in Taiwan.