Odanacatib (MK-0822): A Comprehensive Review of a Potent Cathepsin K Inhibitor—From Blockbuster Efficacy to Discontinuation

Executive Summary

Odanacatib (MK-0822) represents one of the most compelling and cautionary case studies in modern pharmaceutical development. Developed by Merck & Co., this investigational small molecule was a highly potent and selective inhibitor of Cathepsin K, an enzyme central to osteoclastic bone resorption. Its mechanism of action was heralded as a significant advancement over existing osteoporosis therapies. Unlike traditional antiresorptive agents such as bisphosphonates, which suppress bone turnover by reducing the number and viability of osteoclasts, Odanacatib was designed to inhibit only the final enzymatic step of bone matrix degradation. This novel "formation-sparing" approach aimed to preserve osteoclast signaling to bone-forming osteoblasts, thereby uncoupling bone resorption from formation and tipping the remodeling balance toward a net gain in bone mass.

The clinical development program for Odanacatib yielded exceptionally strong efficacy data. In extensive Phase II studies and the pivotal, 16,000-patient Phase III Long-Term Odanacatib Fracture Trial (LOFT), the drug demonstrated robust, progressive increases in bone mineral density (BMD) over five years. More importantly, it achieved highly statistically significant reductions in the risk of vertebral, hip, and non-vertebral fractures. The anti-fracture efficacy was so profound that the LOFT trial's independent Data Monitoring Committee recommended its early termination in 2012, a rare event that signaled the arrival of a potential blockbuster therapy.