MIV-711 for the treatment of ostheoarthritis

Introduction

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.

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. 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.

Project overview

MIV-711 is being developed as a disease-modifying osteoarthritis drug (DMOAD), and Medivir previously conducted a successful clinical phase I trial in healthy volunteers. Positive top line data from the phase IIa study MIV-711-201 were reported in September. Patients receiving MIV-711 once daily at both 100 and 200 mg doses experienced approximately 65% reductions in femoral joint bone area progression in the 6-month period compared to those receiving placebo (unadjusted p-values for both doses < 0.005). Similar to previous epidemiological cohort studies, the OA patients who received placebo in this study showed a 1% increase in medial femur joint bone area over the treatment period. MIV-711 also showed a benefit on cartilage degradation, with the 100mg group experiencing a 70% reduction in median loss of femoral cartilage thickness relative to placebo group, and the 200mg group even showing a small increase in median cartilage thickness. MIV-711 did not show a statistically significant effect on patient-reported numerical rating scale (NRS) pain following 6 months of treatment, the primary endpoint of the study. Nevertheless, consistent tendencies favouring both the 100mg and 200mg groups were observed across patient-reported pain and other patient-reported symptoms. The study data also indicate that both MIV-711 doses showed acceptable safety and tolerability for this patient population. The independent Drug Monitoring Committee held its second and final scheduled meeting during the MIV-711-202 study. The DMC reviewed all safety data from the phase IIa studies, including unblinded data from the initial study and data to date from the extension study. Based on this review, the DMC has recommended that the extension study should go ahead as planned. MIV-711-202 remains on track to be completed during the first half of 2018 as expected. With clinical data demonstrating MIV-711’s potential to be the first disease modifying drug for osteoarthritis, Medivir has retained strategic advisors to seek a partner for the future development of MIV-711.

MIV-711 – Poster presentation at the Annual Meeting of the American College for Rheumatology in San Diego, USA (PDF)

Cathepsin K - Poster presentation at the OARSI 2016 World Congress, April 2016 (PDF)

Page updated 9 November 2017