Merck & Co. has discontinued development of its cathepsin K inhibitor odanacatib, citing an increased risk of cardiovascular events for the osteoporosis drug. The decision was an expensive setback for the company: the drug spent 12 years in clinical development and its pivotal trial enrolled more than 16,000 patients.

Researchers first started working on cathepsin K inhibitors in 1995, after discovering that osteoclasts — which resorb bone tissue as part of the continual bone-remodelling process — secrete cathepsin K protease to degrade the bone protein matrix. Currently approved bone strengthening 'anti-resorptive' drugs slow down osteoclast activity through a variety of mechanisms, but in so doing they also lower the activity of bone-building osteoblast cells. By blocking secreted cathepsin K, drug developers hoped they could prevent bone resorption without affecting the ability of osteoblasts to build bone.

Merck's phase III data suggest that odanacatib did indeed have efficacy, increasing bone mineral density and reducing the risk of fractures (Ther. Adv. Musculoskelet. Dis. 7, 103–109; 2015). But it also increased the risk of stroke, the company reported in September at the annual meeting of the American Society for Bone Mineral Research (ASBMR). The mechanistic underpinnings of this risk remain unknown, the company said. There is currently only one other cathepsin K inhibitor in clinical trials: Medivir advanced its MIV-711 into phase II trials for osteoarthritis in January 2016.

Several other cathepsin inhibitors have previously fallen by the wayside. Novartis dropped its balicatib in 2006 because of dermatological adverse events, and GlaxoSmithKline dropped its relacatib in 2007, possibly because of off-target toxicity. Sanofi dropped its dual cathepsin S/K inhibitor SAR114137 in 2012 for undisclosed reasons, but researchers are now studying the drug as a repurposing candidate for Chagas disease under the NIH's New Therapeutic Uses programme.

The osteoporosis community is still excited, however, over the prospects of Amgen and UCB's first-in-class sclerostin-targeting romosozumab, which is currently under review for approval (Nat. Rev. Drug Discov. 15, 445–446; 2016).