Preclinical studies suggest that MIV-711, a selective and reversible cathepsin K inhibitor, has beneficial effects on bone and cartilage. This phase 2a randomized controlled trial examined the efficacy, safety, and tolerability of MIV-711 in participants with symptomatic, radiographically confirmed osteoarthritis of the knee.
Abstract
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.
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Author, Article, and Disclosure Information
Philip G. Conaghan,
Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds and NIHR Leeds Biomedical Research Centre, Leeds, United Kingdom (P.G.C., S.R.K.)
Imorphics, Manchester, United Kingdom (M.A.B., A.B., G.G.)
Medivir, Huddinge, Sweden (B.R., N.S., P.G., Å.J., C.W., R.B., J.Ö.)
Presented in part at the 2017 American College of Rheumatology Annual Meeting, San Diego, California, 3–8 November 2017; the 2018 American College of Rheumatology Annual Meeting, Chicago, Illinois, 19–24 October 2018; and the 2018 Osteoarthritis Research Society International World Congress on Osteoarthritis, Liverpool, United Kingdom, 26–29 April 2018.
Disclaimer: The views expressed in this article are those of the authors and not necessarily those of the U.K. National Health Service, the U.K. National Institute for Health Research, or the U.K. Department of Health.
Acknowledgment: The authors thank the other principal investigators (Sara Armani of Parexel Berlin Early Phase Clinical Unit and Inga Bodrug of LLC ARENSIA Exploratory Medicine Republican Clinical Hospital) as well as all of the clinical staff and study coordinators at each site for their contributions. The authors also thank Karin Tunblad, Torbjörn Larsson, Åsa Holmgren, Alli Manninen, and Karin Göhlin of Medivir for their contributions. Support for third-party writing assistance for this article, furnished by Megan Christian, was provided by Prism Ideas.
Financial Support: By Medivir. Drs. Conaghan and Kingsbury are supported in part by the U.K. National Institute for Health Research through the Leeds Biomedical Research Centre.
Disclosures: Dr. Conaghan reports personal fees from Medivir during the conduct of the study and personal fees from AbbVie, Bristol-Myers Squibb, Eli Lilly, EMD Serono, Flexion Therapeutics, Galapagos, GlaxoSmithKline, Novartis, Pfizer, Samumed, and Stryker outside the submitted work. Dr. Bowes reports employment with Imorphics and stock options in Stryker. Dr. Kingsbury reports personal fees from Medivir during the conduct of the study. Dr. Guillard reports a contract to perform image analysis for Imorphics during the conduct of the study. Dr. Rizoska reports employment with Medivir outside the submitted work. Ms. Jansson reports personal fees from Medivir during the conduct of the study and outside the submitted work. Dr. Bethell reports personal fees from Medivir during the conduct of the study and outside the submitted work. Dr. Öhd reports full-time employment with Medivir during the conduct of the study. Authors not named here have disclosed no conflicts of interest. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M19-0675.
Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that her spouse has stock options/holdings with Targeted Diagnostics and Therapeutics. Darren B. Taichman, MD, PhD, Executive Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Christina C. Wee, MD, MPH, Deputy Editor, reports employment with Beth Israel Deaconess Medical Center. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Yu-Xiao Yang, MD, MSCE, Deputy Editor, reports that he has no financial relationships or interest to disclose.
Data Sharing Statement: The authors have indicated that they will not be sharing data.
Corresponding Author: Philip G. Conaghan, PhD, Leeds Institute of Rheumatic and Musculoskeletal Medicine, Chapel Allerton Hospital, Chapeltown Road, Leeds LS7 4SA, United Kingdom; e-mail, P.
Current Author Addresses: Drs. Conaghan and Kingsbury: Leeds Institute of Rheumatic and Musculoskeletal Medicine and NIHR Leeds Biomedical Research Centre, 2nd Floor Chapel Allerton Hospital, Chapeltown Road, Leeds LS7 4SA, United Kingdom.
Drs. Bowes, Brett, and Guillard: Imorphics, Worthington House, Towers Business Park, Wilmslow Road, Manchester M20 2HJ, United Kingdom.
Drs. Rizoska, Graham, Wadell, Bethell, and Öhd; Mr. Sjögren; and Ms. Jansson: Medivir, PO Box 1086, 141 22 Huddinge, Sweden.
Author Contributions: Conception and design: P.G. Conaghan, M.A. Bowes, S.R. Kingsbury, P. Graham, C. Wadell, R. Bethell, J. Öhd.
Analysis and interpretation of the data: P.G. Conaghan, M.A. Bowes, S.R. Kingsbury, A. Brett, G. Guillard, B. Rizoska, N. Sjögren, P. Graham, Å. Jansson, C. Wadell, R. Bethell, J. Öhd.
Drafting of the article: P.G. Conaghan, M.A. Bowes, S.R. Kingsbury, B. Rizoska, J. Öhd.
Critical revision of the article for important intellectual content: P.G. Conaghan, M.A. Bowes, S.R. Kingsbury, A. Brett, P. Graham, Å. Jansson, J. Öhd.
Final approval of the article: P.G. Conaghan, M.A. Bowes, S.R. Kingsbury, A. Brett, G. Guillard, B. Rizoska, N. Sjögren, P. Graham, Å. Jansson, C. Wadell, R. Bethell, J. Öhd.
Provision of study materials or patients: C. Wadell.
Statistical expertise: N. Sjögren.
Obtaining of funding: J. Öhd.
Administrative, technical, or logistic support: M.A. Bowes, C. Wadell.
Collection and assembly of data: P.G. Conaghan, M.A. Bowes, P. Graham, Å. Jansson, C. Wadell, J. Öhd.
This article was published at Annals.org on 31 December 2019.
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