Clinical Trials

Date: 2013-10-09

Type of information: Presentation of results at a congress

phase: 1b

Announcement: presentation of results at the American Society for Bone and Mineral Research (ASBMR) Annual Meeting in Baltimore, USA.

Company: Medivir (Sweden)

Product: MIV-711

Action mechanism:

• cathepsin inhibitor. MIV-711 is a cathepsin K inhibitor intended to treat skeletal disorders that feature high bone resorption such as osteoporosis, rheumatoid arthritis and bone metastases. Cathepsin K is an enzyme that is important to the metabolism of bone and cartilage, and accordingly, inhibition of cathepsin K is expected to have a positive effect on these diseases.

Disease: bone disorders characterized by excessive bone resorption such as osteoporosis, osteoarthritis and bone metastases.

Therapeutic area: Rheumatic diseases - Inflammatory diseases – Bone diseases

Country:

Trial details:

• A double-blind, placebo-controlled, randomized study was designed to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of single oral doses of 20 to 600 mg of MIV-711 in healthy male and female subjects (N=27). MIV-711 was given as an oral capsule and at each dosing occasion, 7 subjects received MIV-711 and 2 received placebo.
• In the phase 1a study, MIV-711 has been administered as single ascending oral doses to healthy volunteers, followed by repeated once daily doses for 7 days, with the aim to explore the safety, tolerability and pharmacokinetics. In addition effect on biomarkers relevant for bone and cartilage degradation have been followed. MIV-711 will also be studied in postmenopausal women following once daily oral dosing for 14 days.
• In the phase Ib trial, repeated single daily doses will be administered to groups of healthy volunteers including post-menopausal women. Safety, tolerability, pharmacokinetics and efficacy on biomarkers will be evaluated during 7-14 days’ treatment.

Latest news:

• • On October 9, 2013, Medivir has announced further results from the phase I clinical study on the cathepsin K inhibitor MIV-711 for the treatment of osteoarthritis and other bone related disorders. The 7 day data was presented on October 6th at the American Society for Bone and Mineral Research (ASBMR) Annual Meeting in Baltimore, USA. The key conclusions from the study are: •Serum levels of the bone resorption marker CTX-I were suppressed in a dose-dependent manner with up to 55% at 24 hours post last dose on Day 7 •Urinary excretion of the cartilage degradation marker CTX-II was reduced in a dose-dependent manner with up to 72% post last dose on Day 7.
• Similar effects were seen in post-menopausal women dosed once daily for 28 days at 100 mg. MIV-711was generally safe and well tolerated at all doses and durations tested. A double-blind, placebo-controlled, randomized study was designed to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of multiple oral doses of 50, 100 and 200 mg of MIV-711 given once daily for 7 days in healthy male and female subjects (n=27). MIV-711 was given as an oral capsule and at each dosing occasion, 7 subjects received MIV-711 and 2 received placebo. In a separate cohort, 100 mg MIV-711 was given once daily for 28 days to postmenopausal women with 8 subjects receiving MIV-711 and 4 placebo. Seven days of once daily treatment with MIV-711 decreased serum levels of the bone resorption biomarker, CTX-I, in a dose dependent manner. Compared to baseline, 50 mg MIV-711 reduced CTX-I by 40 ± 7%, 100 mg by 54 ± 4%, and 200 mg by 55 ± 8% at 24 h post final dose. MIV-711 also decreased urinary excretion of the cartilage degradation biomarker, CTX-II, in a dose dependent manner. In the last sample collected 12-24 hours after the last dose on Day 7, the rate of CTX-II excretion was reduced by 31 ± 11%, 58 ± 10% and 72 ± 9% in subjects receiving 50 mg, 100 mg and 200 mg MIV-711 respectively as compared to baseline. In a last cohort of post-menopausal women 28 day once daily treatment with 100 mg MIV-711 decreased serum CTX-I levels on Day 28 by 67 ± 3% compared to baseline at 24 h post final dose. Urinary excretion of the bone resorption biomarkers CTX-I and NTX-I was reduced by 98 ± 1% and 76 ± 1% respectively as compared to baseline. Treatment with 100 mg MIV-711 for 28 days also decreased urinary excretion of the cartilage degradation biomarker, CTX-II, by 55 ± 9% compared to baseline.MIV-711 was generally well tolerated at all doses tested (50, 100 and 200 mg once daily for 7 days and 100 mg for 28 days) with no significant changes in haematology, clinical chemistry, vital signs or ECG parameters. The overall incidence of drug-related adverse events was similar across all dose levels of MIV-711 and was comparable to placebo. MIV-711 was rapidly absorbed after being administered as an oral capsule and mean Cmax values and AUC increased in a slightly more than proportional manner over the 50 to 200 mg OD dose range. • On May 21,  2013, Medivir has announced that data from a first in man study on the investigational cathepsin K inhibitor MIV-711 for the treatment of osteoarthritis and osteoporosis was presented at the European Calcified Tissue Society (ECTS) Annual Meeting in Lisbon, Portugal. Effect on bone resorption biomarker: MIV-711 decreased serum levels of the bone resorption biomarker, CTX-I, in a dose dependent manner. Maximal reduction occurred with 600 mg (79 ± 4% reduction at 24 h post dose) and at 100 mg of MIV-711 CTX-I levels were reduced by 51 ± 4% at 24 h post dose compared to baseline levels. Anticipating a target reduction of circulating CTX-I levels of approximately 50%, the results indicate that low doses will be sufficient for the desired pharmacological effects. Safety and pharmacokinetics: MIV-711 was well tolerated at all doses tested (20 - 600mg). No serious adverse events occurred and most commonly reported adverse events were skin reactions (predominantly at electrode sites which appeared both after active drug and placebo), GI symptoms, headache and musculoskeletal pain. No apparent effects were seen on vital signs and no significant changes in hematology or clinical chemistry were observed. MIV-711 was rapidly absorbed after being administered as an oral capsule and mean Cmax values and AUC increased proportionally with increasing dose. The pharmacokinetic and pharmacodynamic data support once-daily dosing with MIV-711.
• MIV-711 is currently being evaluated in a phase Ib multiple ascending dose study for up to 4 weeks. The top line data will be available around mid-year, while further phase I data will be presented at a scientific conference later this year. • On August 21, 2012, Medivir has reported that a clinical phase Ib trial of the company’s candidate drug (CD) MIV-711 has commenced. MIV-711’s clinical phase I program was initiated in May (See below). Phase Ia was recently completed, in which increasing single doses were administered to healthy volunteers to evaluate safety, tolerability, pharmacokinetics and efficacy on biomarkers. The results were very promising and support Medivir assessment that it will be possible to administer MIV-711 in a low single daily dose. The company expectd to be able to compile the complete phase I trial’s results by the end of this year. • On May 28, 2012, Medivir has announced that a phase I clinical trial has been initiated with its investigational drug, MIV-711, a cathepsin K inhibitor for the treatment of bone disorders characterized by excessive bone resorption such as osteoporosis, osteoarthritis and bone metastases. The design of the study will allow Medivir to explore how MIV-711 affects biomarkers known to be relevant for measuring bone and cartilage turnover. It will also provide the company with valuable information regarding potential therapeutic dose levels to be used in future studies. The results from this study are expected in the first quarter of 2013. • On March 19, 2012, Medivir has announced that it will file an application to a European regulatory agency to begin phase I clinical trials with MIV-711, a cathepsin K inhibitor for the treatment of bone disorders such as osteoporosis, osteoarthritis or bone metastases. Based on the encouraging results of the preclinical safety and toxicology studies carried out with MIV-711, a decision has been taken to initiate clinical development of MIV-711and an application for clinical trial authorization will be filed. The first clinical study is planned to commence as soon authorization has been granted.

 

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