Clinical Trials

Date: 2018-07-27

Type of information: Results

phase: 2

Announcement: results

Company: Medivir (Sweden)

Product: MIV-711

Action mechanism:

• cathepsin inhibitor. MIV-711 is being developed as a DMOAD (Disease-Modifying Osteoarthritis Drug) , i.e. a drug to slow or reverse the progression of the degeneration of joints affected by osteoarthritis.

Disease: knee osteoarthritis

Therapeutic area: Rheumatic diseases - Inflammatory diseases – Bone diseases

Country: Bulgaria, Georgia, Germany, Republic of Moldova, Romania, UK

Trial details:

• This randomised, double-blind, placebo-controlled, three-arm parallel, Phase IIa study, known as MIV-711-201, is evaluating the efficacy, safety and tolerability of MIV-711 in patients with knee osteoarthritis.
• The study enrolled 244 patients into 3 arms, each with approximately 80 patients, and is designed to compare MIV-711 dosed at 100mg or 200 mg once daily against placebo. The key objectives are to assess the effect of six months of treatment with MIV-711 on knee joint clinical pain and on knee osteoarthritis, assessed using magnetic resonance imaging, as well as the safety and tolerability of MIV-711. (NCT02705625)
• The MIV-711 phase IIa extension study included patients with moderate knee osteoarthritis who completed 6 months of treatment in the initial phase IIa clinical trial (MIV-711-201). Patients were eligible to participate in the extension study if the pain associated with their knee osteoarthritis, assessed on the numeric rating scale (NRS), did not worsen after 6 months of treatment with 200mg once daily, or if their NRS pain symptoms worsened after 6 months of treatment with placebo.

Latest news:

• • On July 27, 2018, Medivir announced positive top-line joint structure outcomes from the MIV-711 osteoarthritis phase IIa extension study (MIV-711-202). Treatment with MIV-711 over a total 12 months resulted in a continuing treatment effect on joint bone area growth and prevention of cartilage degradation.
• Of the total 50 patients in the MIV-711-202 study, 46 patients had received MIV-711 in the MIV-711-201 study, and therefore received a total of 12 months treatment with MIV-711, while 4 patients had previously received placebo. Changes in joint structure were determined using the same magnetic resonance imaging methods that were used in MIV-711-201 and were secondary endpoints in the extension study population that had previously received MIV-711. The top-line joint structure imaging outcomes from the phase IIa extension study are outlined below:

• 	Outcomes in patients who completed a total 12 months of treatment with 200mg MIV-711 once daily
  Mean change in bone area in the central medial femur	1.09% (0.09%/month)
  Mean change in cartilage thickness in the central medial femur	33mm increase

  These outcomes compare favorably with the outcomes from a historical control group: the patients in the initial phase IIa study treated with placebo for six months. These patients experienced a mean increase of joint bone area in the central medial femur of 0.95%, or a monthly rate of increase in joint bone area of 0.16%/month, and a mean decrease in cartilage thickness in the central medial femur of 66mm. Although there were only four patients in extension study who had previously received placebo in the initial study, the effects of treatment with MIV-711 200mg on both joint structure and clinical symptoms in these patients were consistent with the positive effects that had previously been seen after 6 months of treatment with MIV-711 200mg in the initial study. As previously announced, the extension study met the primary endpoint, demonstrating that MIV-711 200mg had an acceptable safety and tolerability profile with 6 months of additional treatment with 200 mg MIV-711 following the initial phase IIa study (MIV-711-201) 6-month treatment period (12 months in total). Medivir plans to submit full data from the MIV-711-202 study for presentation at a future scientific meeting.
• • On November 9, 2017, Medivir  announced that data from the initial phase IIa study of MIV-711 in patients with moderate knee osteoarthritis were presented as a late-breaking poster at the 2017 annual meeting of the American College for Rheumatology (ACR). The presentation, entitled “MIV-711, a Novel Cathepsin K Inhibitor Demonstrates Evidence of Osteoarthritis Structure Modification: Results from a 6 Month Randomised Double-Blind Placebo-Controlled Phase IIa Trial”, was made by Professor Philip Conaghan, Professor of Musculoskeletal Medicine at the University of Leeds in the UK and lead investigator on the study. The principal conclusions of the study were as follows:
• -Treatment with MIV-711 did not result in a statistically significant reduction in knee pain relative to placebo-treated patients, but there was consistent tendency favoring patients treated with MIV-711 in all symptom measures. In addition, analgesic use showed a tendency to be lower in both of the MIV-711 treated arms.
• -Treatment with MIV-711 resulted in substantial joint protective effects after 6 months of treatment, reducing both joint bone area growth and cartilage loss compared to placebo.
• -Administration of MIV-711 resulted in substantial and sustained reductions in biomarkers related to bone and cartilage degeneration, serum CTX-I and urine CTX-II respectively. The effects of MIV-711 on these biomarkers indicate robust engagement of MIV-711 with its biological target, cathepsin K, throughout the duration of treatment.
• -MIV-711 had an acceptable safety and tolerability profile at both doses.
• Taken together, the data from the MIV-711-201 study are consistent with joint structure disease modification already after 6 months’ treatment. Further evaluation of MIV-711 in longer and larger DMOAD trials is therefore warranted.
• • On December 8, 2016, Medivir announced that the independent Data Monitoring Committee (DMC) has had its third meeting. Based on the review of the accumulated safety data after the first 150 subjects had completed 3 months of treatment, the DMC has recommended that the phase IIa trial of osteoarthritis should continue without any modifications.It is expected that data from MIV-711-201 will be available in the third quarter of 2017 and that data from the extension study will be available in the first half of 2018.
• • On October 27, 2016, Medivir announced that its first phase IIa trial of MIV-711 for the treatment of osteoarthritis has been fully enrolled. It is expected that data from the study will available in the third quarter of 2017.
• In addition, the second planned meeting of the independent Drug Monitoring Committee (DMC) has taken place, and concluded by again recommending that the trial should go ahead.
• • On September 23, 2016, Medivir announced that the independent Data Monitoring Committee (DMC) has recommended continuation of the ongoing randomized, double-blind phase IIa study (MIV-711-201) based on a review of unblinded safety data. The first patient has been enrolled into an open label phase IIa extension study, MIV-711-202. The objective of MIV-711-201 is to evaluate the safety, tolerability and efficacy of six months of treatment with MIV-711 in patients with moderate knee osteoarthritis. As part of the study, an independent DMC is periodically scheduled to review the unblinded safety data from the trial. The DMC’s voting members are two expert physicians and one biostatistician. The possible recommendations from such a review, based on the analysis of the accumulated safety data, could be 1) Go ahead, 2) Go ahead but with modification, 3) Suspend enrollment or 4) Stop enrollment. Based on the review of the accumulated safety data after the first 50 subjects had completed three months of treatment, the DMC has recommended that the phase IIa trial of osteoarthritis should go ahead.
• In addition, the first patient has been enrolled in an open label extension study that will enroll approximately 50 patients from MIV-711-201. All patients in the study will receive 200mg MIV-711 once daily. Patients will be eligible to roll over into the extension if they have a favorable response to MIV-711 treatment, or if their disease has worsened following placebo treatment. The first objective of the study is to assess the safety and tolerability of six additional months of treatment with MIV-711, as well as its effect on knee joint structure assessed using magnetic resonance imaging (MRI), in patients who have shown evidence of a response to MIV-711 treatment. The other objective of the study is to explore the safety, tolerability and efficacy of six months of treatment with MIV-711 in patients previously on placebo whose osteoarthritis has worsened over the preceding six month period.
• • On January 29, 2016, Medivir announced the enrolment of the first patient into a randomized double-blind phase IIa clinical study of the in-house developed cathepsin K inhibitor MIV-711 in patients with moderate knee osteoarthritis. The phase IIa study will enrol 240 patients into 3 arms, each with approximately 80 patients, and compare MIV-711 dosed at 100mg or 200 mg once daily against placebo. The key objectives are to assess the effect of six months of treatment with MIV-711 on knee joint clinical pain and on knee OA, assessed using magnetic resonance imaging, as well as the safety and tolerability of MIV-711.
• Approximately SEK 140 m of Medivir´s cash is allocated for this phase IIa program through 2017, of which approximately SEK 25 m was spent during 2015.

Is general: Yes