Serum and urine bone resorption markers and pharmacokinetics of the cathepsin K inhibitor ONO‐5334 after ascending single doses in post menopausal women

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Cathepsin K plays a critical role in bone resorption where it degrades the major organic components of bone and cartilage. • Therefore inhibitors of cathepsin K may offer clinical benefit in metabolic bone diseases characterized by accelerated bone resorption including osteoporosis. WHAT THIS STUDY ADDS • This phase I study in post menopausal women provides the first safety, tolerability, pharmacokinetic and pharmacodynamic data for single doses of the cathepsin K inhibitor, ONO‐5334. • Morning administration of ONO‐5334 showed rapid and dose‐dependent suppression in bone resorption. • This study shows that ONO‐5334 is safe, well tolerated and suppresses bone resorption and therefore shows potential as a new treatment for osteoporosis. AIMS To investigate the safety, pharmacokinetics and pharmacodynamics of the new cathepsin K inhibitor, ONO‐5334. METHODS A double‐blind, placebo‐controlled, randomized studywas carried out in 52 healthy post menopausal females. Single ascending doses of ONO‐5334 (3–600 mg) were evaluated in six cohorts. The effect of food was studied at ONO‐5334 100 mg. RESULTS Across the doses tested, mean ONO‐5334 C max occurred 0.5–1.0 h after dosing and the the t 1/2 ranged from 9.1 to 22 h. Linear increases in C max and AUC(0,∞) were observed in the 3–300 mg and 3–600 mg dose range, respectively. After food, the geometric mean ratio (95% CI) C max and AUC(0,∞) for ONO‐5334 were 0.78 (0.31, 1.94) and 0.95 (0.67, 1.35)‐fold greater than fasted, respectively. ONO‐5334 significantly reduced serum bone resorption markers within 4 h vs . placebo. Statistical significance was achieved for ONO‐5334 doses ≥30 mg for C‐terminal telopeptide of type 1 collagen (CTX) and ≥300 mg for N‐terminal telopeptide of type 1 collagen (NTX). Statistical significance was still evident at 24 h for ONO‐5334 100 mg with serum CTX and 600 mg with serum NTX. The maximum suppression in serum CTX occurred at 4 h post dose with difference compared with placebo of −32%, −59%, −60% and −66% for 30, 100, 300 and 600 mg ONO‐5334, respectively. Second morning urine void 24 h post dose showed statistically significant suppression of urinary CTX and NTX at 100 mg and above vs . placebo. ONO‐5334 600 mg showed statistically significant suppression up to 72 h for serum CTX, urinary CTX and urinary NTX and 48 h for serum NTX vs . placebo. Adverse events were transient with no evidence of dose relationship. CONCLUSIONS ONO‐5334 displayed linear plasma pharmacokinetics over the (predicted therapeutic) dose range, 3–300 mg, with clear suppression of urinary bone resorption markers at doses ≥100 mg for serum markers at 24 h. ONO‐5334 was well tolerated up to 600 mg day –1 when administered to healthy post menopausal women.