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MIV-711, a highly selective cathepsin K inhibitor, reduces biomarkers of bone resorption and cartilage degradation in healthy subjects
  April 2014 Osteoarthritis & Cartilage Supplement
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 dose-dependent 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.

MIV-711 - a cathepsin K inhibitor
Osteoarthritis (OA) is the most common form of joint disease, with up to 40% of the population over the age of 65 suffering from the disease. MIV-711 was first synthesized by Medivir scientists, and has the potential to be a future disease-modifying treatment for OA
Therapy /Disease area
Osteoarthritis is the most common form of joint disease and is characterised by pain and varying degrees of inflammation in one or more joints. The joints most commonly affected are the knees, hips and hands. Typically, the patient experiences pain in conjunction with movement or when the joint is supporting weight. Some patients also experience swelling and pain, even when the joint isn't being used. Imaging of the affected joints shows signs of cartilage loss and abnormal bone structures in the vicinity of the joint.
The incidence of osteoarthritis is increasing, as the population ages and obesity becomes more common. The total affected population is estimated to reach 95 million by 2020 in the seven major markets. The only treatments currently available are symptomatic i.e. pain relief combined with physiotherapy and weight loss. In more severe cases, surgical intervention, including replacement of the entire joint with a prosthetic, is necessary. There is, therefore, a substantial need for treatments that can stop the progress of both cartilage breakdown and bone deformation in affected joints
A major goal of OA research is to identify drugs capable of impacting the progression of the disease, referred to as Disease Modifying Osteoarthritis Drugs (DMOADs). Recent scientific work suggests that two separate processes, bone resorption and cartilage degradation, are involved in the development and progression of OA. Future treatments for OA should, therefore, target both processes in order to prevent the progression of the disease. Cathepsin K is a protease that breaks down collagen, a protein that plays an important role in the structural integrity of both bone and cartilage. Medivir's research has shown that inhibition of cathepsin K can reduce the rate of joint destruction in preclinical models of osteoarthritis. MIV-711 therefore has the potential to be a DMOAD. MIV-711 is a highly selective cathepsin K inhibitor that was invented by Medivir scientists. A successful clinical phase I trial in healthy volunteers has been conducted. The trial evaluated the safety, tolerability, pharmacokinetics and pharmacodynamics (effect on biomarkers of bone and cartilage turnover) of different doses of MIV-711 or placebo, administered once daily for between one and 28 days. The results showed that treatment with MIV-711 is safe and well tolerated at doses that reduce biomarkers of bone resorption and cartilage degradation. When dosed at 100 mg once daily, MIV- 711 reduced the biomarkers for bone resorption and cartilage degradation by up to 98 per cent and 55 per cent, respectively, compared with placebo. The positive results from the phase I study support the further development of MIV-711 as a DMOAD. The current goal for the project is to complete a phase IIa study in 240 osteoarthritis patients


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