Pharmacodynamic Effects on Biochemical Markers of Bone Turnover and Pharmacokinetics of the Cathepsin K Inhibitor, ONO‐5334, in an Ascending Multiple‐Dose, Phase 1 Study

Abstract

Selective inhibitors of cathepsin K, which has a major role in the degradation of bone collagen, are potential new treatments for osteoporosis. The pharmacokinetics and the pharmacodynamic effects on biochemical markers of bone turnover of the new cathepsin K inhibitor, ONO-5334, were investigated in a multiple ascending dose, phase 1 study. A total of 120 healthy postmenopausal women were enrolled, and doses of 10 to 600 mg once daily and 50 and 300 mg twice daily were evaluated in 15- and 28-day multiple-dosing cohorts. Plasma ONO-5334 concentration reached steady state within 2 days. Twenty-four hours after the last dose in the 15-day multiple-dose cohort, 100, 300, and 600 mg once daily reduced urinary C-terminal telopeptide of type I collagen by a mean (± standard deviation) 44.9% ± 13.6%, 84.5% ± 4.4%, and 92.5% ± 1.3%, respectively. The 28-day cohort showed similar effects. There were far smaller effects on bone-specific alkaline phosphatase (B-ALP), tartrate-resistant acid phosphatase 5b (TRAP5b), or osteocalcin (OC) (measured after 28 days). ONO-5334 was well tolerated up to 600 mg/d and for up to 28 days of multiple dosing. Multiple dosing with ONO-5334 100 mg resulted in considerable suppression of bone resorption markers with no appreciable effects on bone formation markers (B-ALP, OC) or osteoclast number (TRAP5b).

Bone turnover markers in serum and urine as diagnostic, prognostic and monitoring biomarkers of bone metastasis

“…However, the peripheral concentrations of these markers under different clinical situations and treatment conditions do not always reflect the expected data. The relationship to the really observed bone mass and other circulating bone turnover markers has often been found contrary to their assumed regulative effect on osteoblasts [43][44][45][46]. Thus, the influence of biological factors (age, menopausal and hormonal status, renal function) on the concentration of both analytes in serum/plasma [47,48], the still not fully understood molecular processes in the bone [49,50], but also simply unresolved analytical problems [51] may currently be reasons for these substantial interpretation difficulties of the two analytes in serum/plasma.…”

New understanding and treatments for osteoporosis

“…Mutations in CATHEPSIN K gene cause pycnodysostosis, a rare bone disease characterized by osteosclerosis and suppressed bone resorption [75]. Three inhibitors of cathepsin K are balicatib, whose development was stopped because of adverse effects due to lack of specificity inhibition of other cathepsins, odanacatib, and ONO5334 [76,77].…”

Bone biology, signaling pathways, and therapeutic targets for osteoporosis

“…ONO-5334 is another cathepsin K inhibitor that has completed phase I and II clinical trials [65,66]. The phase II OCEAN clinical trial [66] demonstrated that this agent decreased bone resorption similar to alendronate, with little or no change in bone formation, in a dose ranging study.…”