Clinical and translational pharmacology of the cathepsin K inhibitor odanacatib studied for osteoporosis

Abstract

Cathepsin K (CatK) is a cysteine protease abundantly expressed by osteoclasts and localized in the lysosomes and resorption lacunae of these cells. CatK is the principal enzyme responsible for the degradation of bone collagen. Odanacatib is a selective, reversible inhibitor of CatK at sub‐nanomolar potency. The pharmacokinetics of odanacatib have been extensively studied and are similar in young healthy men, postmenopausal women, and elderly men and were qualitatively similar throughout Phase 1 development and in‐patient studies. Following 3 weeks of 50 mg once weekly dosing the geometric mean AUC0‐168hr was 41.1 μM•hr, the C168hr was 126 nM and the harmonic mean apparent terminal half‐life was 84.8 hr. Odanacatib exposure increased in a less than dose proportional manner due to solubility limited absorption. It is estimated that approximately 70% of the absorbed dose of odanacatib is eliminated via metabolism, 20% is excreted as unchanged drug in the bile or feces, and 10% is excreted as unchanged drug in the urine. The systemic clearance was low (approximately 13 mL/min). Odanacatib decreases the degradation of bone matrix proteins and reduces the efficiency of bone resorption with target engagement confirmed by a robust decrease in sCTx (approx. 60%), uNTx/Cr (approx. 50%) and total urine DPD/Cr (approx. 30%), with an increase in serum 1CTP (approx. 55%). The 50 mg weekly dosing regimen evaluated in Phase 3 achieved near maximal reduction in bone resorption throughout the treatment period. The extensive clinical program for odanacatib, together with more limited clinical experience with other CatK inhibitors (balicatib and ONO‐5334), provides important insights into the clinical pharmacology of CatK inhibition and the potential role of CatK in bone turnover and mineral homeostasis. Key findings include the ability of this mechanism to: 1) provide sustained reductions in resorption markers, increases in BMD, and demonstrated fracture risk reduction; 2) be associated with relative formation‐sparing effects such that sustained resorption reduction is achieved without accompanying meaningful reductions in bone formation; and 3) lead to increases in osteoclast number as well as other osteoclast activity (including build‐up of CatK enzyme) which may yield transient increases in resorption following treatment discontinuation and the potential for non‐monotonic responses at sub‐therapeutic doses.

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