Effect of ONO-5334 on Bone Mineral Density and Biochemical Markers of Bone Turnover in Postmenopausal Osteoporosis: 2-Year Results From the OCEAN Study

Abstract

Cathepsin K inhibitors, such as ONO-5334, are being developed for the treatment of postmenopausal osteoporosis. However, their relative effects on bone resorption and formation, and how quickly the effects resolve after treatment cessation, are uncertain. The aim of this study was to examine the efficacy and safety of 24-month treatment with ONO-5334 and to assess the effect of treatment cessation over 2 months. We studied 197 postmenopausal women with osteoporosis or osteopenia with one fragility fracture. Patients were randomized to ONO-5334 50 mg twice daily, 100 mg or 300 mg once daily, alendronate 70 mg once weekly (positive control), or placebo for 24 months. After 24 months, all ONO-5334 doses were associated with increased bone mineral density (BMD) for lumbar spine, total hip, and femoral neck (p < 0.001). ONO-5334 300 mg significantly suppressed the bone-resorption markers urinary (u) NTX and serum and uCTX-I throughout 24 months of treatment and to a similar extent as alendronate; other resorption marker levels remained similar to placebo (fDPD for ONO-5334 300 mg qd) or were increased (ICTP, TRAP5b, all ONO-5334 doses). Levels of B-ALP and PINP were suppressed in all groups (including placebo) for approximately 6 months but then increased for ONO-5334 to close to baseline levels by 12 to 24 months. On treatment cessation, there were increases above baseline in uCTX-I, uNTX, and TRAP5b, and decreases in ICTP and fDPD. There were no clinically relevant safety concerns. Cathepsin K inhibition with ONO-5334 resulted in decreases in most resorption markers over 2 years but did not decrease most bone formation markers. This was associated with an increase in BMD; the effect on biochemical markers was rapidly reversible on treatment cessation.

Modulation of osteoclast differentiation and bone resorption by Rho GTPases

“…They indeed show encouraging results with decreased bone resorption and preserved bone formation. [111][112][113][114][115] An alternative approach Polarized osteoclasts have the unique ability to resorb bone (1). Then, the sealing zone (SZ) is disassembled and osteoclasts can spread under a Rac/ Rho effect (2).…”

An oral cathepsin K inhibitor ONO-5334 inhibits N- terminal and C- terminal collagen crosslinks in serum and urine at similar plasma concentrations in postmenopausal women

“…In a 2-year phase II study in osteopenia/osteoporosis (OCEAN), ONO-5334 increased bone mineral density (BMD) at all measured sites at doses of 50 mg twice daily (BID) and 300 mg once daily (OD). A dose of 100 mg OD had less efficacy on BMD compared to 50 mg BID and 300 mg OD [16][17][18].…”

Future directions for new medical entities in osteoporosis

“…The dose-ranging OCEAN trial compared another cathepsin K inhibitor, ONO-3443 (Table 2), administered daily, with placebo or weekly alendronate in nearly 200 post-menopausal women with osteoporosis [61,62]. Again, markers of bone resorption were markedly reduced whereas markers of bone formation were either maintained or slightly elevated at 2 years, depending on the dose and, contrarily to alendronate serum TRAP5b was increased, which is consistent with an increased number of viable osteoclasts when cathepsin K is inhibited (see above).…”