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Disease-Modifying Effects of a Novel Cathepsin K Inhibitor in Osteoarthritis: A Randomized Controlled Trial
Philip G Conaghan1, Michael A Bowes2, Sarah R Kingsbury1
1Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds and NIHR Leeds Biomedical Research Centre, Leeds, United Kingdom (P.G.C., S.R.K.).
Background:
MIV-711 is a novel selective cathepsin K inhibitor with beneficial effects on bone and cartilage in preclinical osteoarthritis models.
Objective:
To evaluate the efficacy, safety, and tolerability of MIV-711 in participants with symptomatic, radiographic knee osteoarthritis.
Design:
26-week randomized, double-blind, placebo-controlled phase 2a study with a 26-week open-label safety extension substudy. (EudraCT: 2015-003230-26 and 2016-001096-73).
Setting:
Six European sites.
Participants:
244 participants with primary knee osteoarthritis, Kellgren-Lawrence grade 2 or 3, and pain score of 4 to 10 on a numerical rating scale (NRS).
Intervention:
MIV-711, 100 (n = 82) or 200 (n = 81) mg daily, or matched placebo (n = 77). Participants (46 who initially received 200 mg/d and 4 who received placebo) received 200 mg of MIV-711 daily during the extension substudy.
Measurements:
The primary outcome was change in NRS pain score. The key secondary outcome was change in bone area on magnetic resonance imaging (MRI). Other secondary end points included cartilage thickness on quantitative MRI and type I and II collagen C-telopeptide biomarkers. Outcomes were assessed over 26 weeks.
Results:
Changes in NRS pain scores with MIV-711 were not statistically significant (placebo, -1.4; MIV-711, 100 mg/d, -1.7; MIV-711, 200 mg/d, -1.5). MIV-711 significantly reduced medial femoral bone area progression (P = 0.002 for 100 mg/d and 0.004 for 200 mg/d) and medial femoral cartilage thinning (P = 0.023 for 100 mg/d and 0.125 for 200 mg/d) versus placebo and substantially reduced bone and cartilage biomarker levels. Nine serious adverse events occurred in 6 participants (1 in the placebo group, 3 in the 100 mg group, and 2 in the 200 mg group); none were considered to be treatment-related.
Limitation:
The trial was relatively short.
Conclusion:
MIV-711 was not more effective than placebo for pain, but it significantly reduced bone and cartilage progression with a reassuring safety profile. This treatment may merit further evaluation as a disease-modifying osteoarthritis drug.
Primary Funding Source:
Medivir.
Insights
MIV-711 did not improve pain in knee osteoarthritis patients but significantly slowed bone and cartilage degeneration. This cathepsin K inhibitor shows promise as a disease-modifying osteoarthritis drug with a good safety profile.
Area of Science:
- Orthopedics
- Pharmacology
- Radiology
Background:
- MIV-711 is a novel selective cathepsin K inhibitor.
- Preclinical models show MIV-711 benefits bone and cartilage in osteoarthritis.
- Osteoarthritis (OA) is a degenerative joint disease affecting millions worldwide.
Purpose of the Study:
- To evaluate MIV-711's efficacy, safety, and tolerability in knee OA patients.
- Assess MIV-711's impact on pain, bone area, and cartilage thickness.
- Investigate MIV-711's effect on collagen biomarkers.
Main Methods:
- 26-week, randomized, double-blind, placebo-controlled phase 2a study.
- 244 participants with symptomatic knee OA (Kellgren-Lawrence grade 2-3).
- MIV-711 (100 or 200 mg daily) or placebo, followed by an open-label extension.
Main Results:
- No significant difference in pain reduction (NRS) between MIV-711 and placebo.
- MIV-711 significantly reduced medial femoral bone area progression (P <= 0.004).
- MIV-711 reduced medial femoral cartilage thinning and biomarker levels; safety profile was reassuring.
Conclusions:
- MIV-711 did not demonstrate efficacy for pain relief in knee OA.
- MIV-711 significantly reduced structural progression (bone and cartilage) in knee OA.
- MIV-711 warrants further investigation as a potential disease-modifying osteoarthritis drug.
