Phase I clinical study
Relacatib: Its effect on the metabolism of ibuprofen, paracetamol and atorvastatin was determined in a phase I trial. Although early data showed great potential, late clinical studies were not carried out due to potential drug-drug interactions. Balicatib: Results from a phase I study showed a dose-dependent increase in lumbar spine (+4.4%) and hip (+2.2%) bone BMD, as well as a dose-dependent decrease in bone resorption-related markers (serum CTX 61% and urine NTX 55%). The study of the drug was eventually discontinued due to safety concerns after patients with balicatib were found to have symptoms of scleroderma. A three-phase I trial of odanacatib was conducted to examine safety, tolerability, pharmacokinetics and pharmacodynamics. Three results showed that no serious adverse effects occurred in the short-term study and that odanacatib was well tolerated. A recent report studied safety, tolerability, pharmacokinetics and pharmacodynamics in 44 healthy volunteers (36 men and 8 postmenopausal women) and again showed relatively good tolerability.
Phase II clinical study
ONO-5334: As seen in the Phase I clinical study of balicatib, both ONO-5334 and alendronate reduced biochemical markers of bone resorption by 50-70%, with only ONO-5334 at the highest at 300 mg/day At doses, there was a modest reduction in markers of bone formation. Additional studies found that ONO-5334 treatment at 300 mg/day resulted in a sustained increase in bone mineral density (lumbar spine +6.7%, hip +3.4%, femur +3.7%) and reduced serum CTX and urine NTX levels, but Markers of bone formation were not significantly reduced. Notably, discontinuation of treatment after 24 months of treatment resulted in higher urinary NTX and serum TRAP5b levels than baseline, suggesting reversibility of proteinase K inhibitors. However, a review of clinical trials did not reveal any clinical trials involving ONO-5334.
Phase III clinical study
Odanacatib is still the most studied at present, and the research results show that it has great potential research value, Fig5. Of final concern is the difference between odanacatib and placebo-treated patients, with odanacatib having an increased risk of cardiovascular and cerebrovascular disease (though not reaching statistical significance), according to the 2016 Bone and Mineral Annual Meeting in America, adjudicated Atrial fibrillation and atrial flutter events were more common in Odanacatib-treated patients, but the difference did not reach statistical significance. Based on these analyses, the study sponsor eventually withdrew from the Odanacatib study. Although there are many difficulties in the study of proteinase K inhibitors, it also provides a new idea for the study of osteoporosis treatment. Proteinase K inhibitors are a new direction for the treatment of osteoporosis. While currently available antiresorptive agents reduce osteoclast activity and number, resulting in reduced bone resorption, they can lead to reduced bone formation. Proteinase K inhibitors have less effect on bone formation while reducing bone resorption. However, unlike the primary biological target of phosphates, which are osteoclasts, proteinase K inhibitors have the potential to affect other tissues, and this potential risk has limited the development of all proteinase K inhibitors except Odanacatib.