MIV-711 for the treatment of ostheoarthritis
MIV-711 is a highly selective cathepsin K inhibitor that was invented by Medivir scientists. 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. A major goal of OA research is to identify drugs capable of slowing, stopping or even reversing 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 target both processes in order to prevent further disease progression.
Mechanism of Action
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, supporting the development of MIV-711 as a DMOAD.
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. The osteoarthritic joint is characterized by a gradual loss of cartilage together with an increasing formation of abnormal bone structures in the vicinity of the joint which can be visualized with imaging techniques. Clinically, the gradual disease progression in the joint is expressed as a continuous worsening of the disease severity in terms of pain and joint function which in turn makes the patient ever more immobile. The vicious cycle is completed as the immobility leads to life style changes that drive weight gain which in turn puts more stress on the diseased joints further accelerating joint disease progression. The overall OA disease progress also aggravates other life style related medical problems such as cardiovascular and metabolic diseases.
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 prosthetic replacement of the entire joint, 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 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 up to 28 days. The results showed that treatment with MIV-711 is safe and well tolerated at doses that cause substantial reductions of biomarkers of bone resorption and cartilage degradation. When dosed at 100 mg once daily, MIV- 711 reduced biomarkers of bone resorption and cartilage degradation by up to 98 per cent and 55 per cent, respectively, compared with placebo. These reductions in biomarkers were of a similar magnitude to the biomarker reductions observed at doses of MIV-711 that reduced the rate of joint destruction in preclinical models of OA.
The positive results from the phase I study supported the further development of MIV-711 as a DMOAD. The consistent effects of MIV-711 on biomarkers in preclinical models of OA and in human volunteers provide confidence that relevant doses of MIV-711 have been selected for evaluation in the ongoing Phase II program. Medivir is currently conducting a phase IIa study (MIV-711-201) evaluating 6 months of treatment with two doses of MIV-711 in patients with moderate knee OA. The study is fully enrolled and includes 244 patients. Completion of the trial is expected in Q3 2017. There is also an ongoing extension study (MIV-711-202) for eligible patients who have completed six months of treatment in MIV-711-201. The objective of this study is to evaluate safety, tolerability and efficacy of an additional 6 month’s treatment with MIV-711.