Safety and efficacy of the cathepsin K inhibitor ONO-5334 in postmenopausal osteoporosis: The OCEAN study

Abstract

Osteoporosis occurs when there is an imbalance between resorption and formation of bone, with resorption predominating. Inhibitors of cathepsin K may rebalance this condition. This is the first efficacy study of a new cathepsin K inhibitor, ONO-5334. The objective of the study was to investigate the efficacy and safety of ONO-5334 in postmenopausal osteoporosis. This was a 12-month, randomized, double-blind, placebo-and active-controlled parallel-group study conducted in 13 centers in 6 European countries. Subjects included 285 postmenopausal women aged 55 to 75 years with osteoporosis. Subjects were randomized into one of five treatment arms: placebo; 50 mg twice daily, 100 mg once daily, or 300 mg once daily of ONO-5334; or alendronate 70 mg once weekly. Lumbar spine, total hip, and femoral neck BMD values were obtained along with biochemical markers of bone turnover and standard safety assessments. All ONO-5334 doses and alendronate showed a significant increase in BMD for lumbar spine, total hip (except 100 mg once daily), and femoral neck BMD. There was little or no suppression of ONO-5334 on bone-formation markers compared with alendronate, although the suppressive effects on bone-resorption markers were similar. There were no clinically relevant safety concerns. With a significant increase in BMD, ONO-5334 also demonstrated a new mode of action as a potential agent for treating osteoporosis. Further clinical studies are warranted to investigate long-term efficacy as well as safety of

A Systems Approach to Understanding Bone Cell Interactions in Health and Disease

“…Inhibitors of the protease cathepsin K inhibit the ability of osteoclasts to break down bone collagen and thus inhibit their function. Bone of animals treated with cathepsin K inhibitors are characterized by the presence of many osteoclasts, and shallow resorption lacunae lined by a layer of demineralised matrix reflecting the ability of osteoclasts to demineralise bone but not to break down the matrix (Eastell, Nagase et al 2011). …”

Cysteine Cathepsins and the Skeleton

“…Relacatib showed problems in phase I trial due to drug-drug interactions (GSK Protocol summary PSB-462795/008). ONO-5334 was well tolerated in phase II trials [123] and resulted in increased bone mineral density (BMD) similar to the bisphosphonate, alendronate, in the lumbar spine and better improvements in the femur. In contrast to bisphosphonates, balicatib and ONO-5334 did not significantly affect bone formation parameters.…”

Effects of a new conjugate drug in a rat model of postmenopausal osteoporosis

“…Unlike the other two approaches that focus on estrogen, cathepsin K inhibitors such as Odanacatib and ONO--5334 suppress action of the cathepsin K enzyme, which is one of the main enzymes involved in the digestion of bone matrix during osteoclastic resorption. This approach has been shown to improve aBMD of the lumbar spine and total hip 136 , but cannot stimulate formation of new bone. An ideal therapy for osteoporosis should promote bone formation to facilitate the recovery of lost bone, while also exhibiting few side effects.…”