MIV-711, a highly selective cathepsin K inhibitor, reduces biomarkers of bone resorption and cartilage degradation in healthy subjects

Purpose: Excessive bone resorption and cartilage degradation are key features of osteoarthritis (OA). Biomarkers reflecting these processes are reduced in non-clinical studies performed with the selective cathepsin K inhibitor MIV-711. In addition, MIV-711 has provided structural benefit on bone and cartilage in animal models of OA. This abstract presents results on biomarkers after multiple dosing as part of a First in Man study with MIV-711. Methods: A double-blind, placebo-controlled, randomized study in 27 healthy subjects of both genders. Multiple ascending doses of 50, 100 or 200 mg MIV-711 were given in the fasting state, once daily for 7 days. An additional cohort consisting of 12 postmenopausal women (PMW) dosed for 28 days with either placebo or 100 mg MIV-711 once daily was also studied. Biomarkers reflecting cartilage degradation (CTX-II) and bone resorption (CTX-I, NTX-I) were measured. Results: In the 7-day cohorts, MIV-711 decreased serum CTX-I levels in a dose-dependent manner. At 24 h post final dose, serum CTX-I levels were reduced by 40%, 54% and 55% compared to baseline in response to 50 mg, 100 mg and 200 mg MIV-711 respectively. By contrast, serum CTX-I levels were 6% higher in placebo-treated subjects compared to baseline. Urinary levels of CTX-II were also reduced in a dose-dependent fashion at this time point by 31%, 58% and 72% vs. baseline, respectively. By contrast, urine CTX-II levels were 30% higher in placebo-treated subjects on Day 7 compared to baseline. After 28-day treatment in PMW, serum CTX-I levels were reduced by 67% while urinary CTX-II levels were reduced by 55% compared to baseline. In addition, urine levels of CTX-I and NTX-I were reduced by 98% and 76% on Day 28 compared to baseline respectively. The time-course of these effects on biomarkers and the comparison to placebo can be found in Table 1 below. Overall, MIV-711 was safe and well tolerated over the 28 day period. Conclusions: Multiple doses of MIV-711 up to 200 mg administered once daily to healthy subjects for 7 days produced dosedependent decreases in biomarkers of bone resorption and cartilage degradation. These results were confirmed in 28 day studies when given to PMW. MIV-711 was also safe and well-tolerated. These data support the further development of MIV-711 for bone and cartilage related disorders such as osteoporosis and osteoarthritis. (Table presented).