Bone Abstracts

Introduction: Cathepsin K is necessary for bone matrix resorption. Excessive resorption associated with osteoporosis and osteoarthritis can be reduced by cathepsin K inhibition. MIV-711, a highly selective cathepsin K inhibitor, successfully attenuates both bone resorption and cartilage degradation in non-clinical studies.

Aim: To determine safety, tolerability, pharmacokinetics and pharmacodynamics of MIV-711 during multiple oral dosing to postmenopausal women.

Methods: This was a double-blind, placebo-controlled, randomized study in 12 healthy postmenopausal females (eight on active drug and four on placebo). A dose of 100 mg MIV-711 or placebo was administered once daily for 28 days and investigated for adverse events, clinical chemistry and haematology, vital signs, ECG parameters, and biomarkers. Data are expressed as means±S.E.M.

Results: Compared with placebo there was a statistically significant sustained reduction in serum CTX-I levels, a biomarker of bone resorption, with day 28 trough levels 67±3% lower than baseline. Urinary excretion of bone resorption markers CTX-I and NTX-I were significantly reduced with day 28 levels 98±1 and 76±1% lower than baseline, respectively. Urinary excretion of CTX-II, a biomarker of cartilage degradation, was 55±9% lower than baseline on day 28. MIV-711 had minimal effects on biomarkers of bone formation. Other exploratory biomarkers were also measured. Pharmacokinetic results agreed with previous data in healthy volunteers. MIV-711 was well tolerated with no safety concerns. Adverse events included skin reactions at ECG electrode sites, headache and gastrointestinal symptoms with comparable incidence after active drug or placebo.

Conclusions: MIV-711 effectively suppresses serum levels of CTX-I and urinary excretion of CTX-I, NTX-I and CTX-II. MIV-711 once daily for 28 days was safe and well tolerated in healthy postmenopausal females. These results support further development of MIV-711 for bone and cartilage related disorders such as osteoarthritis with a potential clinical dose of MIV-711 between 50 and 100 mg once daily.