• cathepsin K inhibitor;
  • osteoporosis;
  • pharmacokinetics;
  • pharmacodynamics;
  • bone resorption;
  • ONO-5334


• 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.


• 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.


To investigate the safety, pharmacokinetics and pharmacodynamics of the new cathepsin K inhibitor, ONO-5334.


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.


Across the doses tested, mean ONO-5334 Cmax occurred 0.5–1.0 h after dosing and the the t1/2 ranged from 9.1 to 22 h. Linear increases in Cmax 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) Cmax 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.


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.