MIV-711 is a novel selective cathepsin K inhibitor with beneficial effects on bone and cartilage in preclinical osteoarthritis models.
To evaluate the efficacy, safety, and tolerability of MIV-711 in participants with symptomatic, radiographic knee osteoarthritis.
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)
Six European sites.
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).
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.
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.
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.
The trial was relatively short.
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:
Vos T, Flaxman AD, Naghavi M, et al. Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012;380:2163-96. [PMID: 23245607] doi:10.1016/S0140-6736(12)61729-2 CrossrefMedlineGoogle Scholar
- 2. World Health Organization. Chronic rheumatic conditions. Geneva: World Health Organization; 2019. Accessed at www.who.int/chp/topics/rheumatic/en on 8 August 2019. Google Scholar
Frobell RB, Nevitt MC, Hudelmaier M, et al; Osteoarthritis Initiative Investigators. Femorotibial subchondral bone area and regional cartilage thickness: a cross-sectional description in healthy reference cases and various radiographic stages of osteoarthritis in 1,003 knees from the Osteoarthritis Initiative. Arthritis Care Res (Hoboken). 2010;62:1612-23. [PMID: 20496431] doi:10.1002/acr.20262 CrossrefMedlineGoogle Scholar
Barr AJ, Dube B, Hensor EM, et al. The relationship between clinical characteristics, radiographic osteoarthritis and 3D bone area: data from the Osteoarthritis Initiative. Osteoarthritis Cartilage. 2014;22:1703-9. [PMID: 25278079] doi:10.1016/j.joca.2014.06.026 CrossrefMedlineGoogle Scholar
Maschek S, Wirth W, Ladel C, et al. Rates and sensitivity of knee cartilage thickness loss in specific central reading radiographic strata from the Osteoarthritis Initiative. Osteoarthritis Cartilage. 2014;22:1550-3. [PMID: 25278063] doi:10.1016/j.joca.2014.05.015 CrossrefMedlineGoogle Scholar
Eckstein F, Collins JE, Nevitt MC, et al; FNIH OA Biomarkers Consortium. Brief report: cartilage thickness change as an imaging biomarker of knee osteoarthritis progression: data from the Foundation for the National Institutes of Health Osteoarthritis Biomarkers Consortium. Arthritis Rheumatol. 2015;67:3184-9. [PMID: 26316262] doi:10.1002/art.39324 CrossrefMedlineGoogle Scholar
Martel-Pelletier J, Pelletier JP. Is osteoarthritis a disease involving only cartilage or other articular tissues? Eklem Hastalik Cerrahisi. 2010;21:2-14. [PMID: 20302555] MedlineGoogle Scholar
Herrero-Beaumont G, Roman-Blas JA. Osteoarthritis: osteoporotic OA: a reasonable target for bone-acting agents. Nat Rev Rheumatol. 2013;9:448-50. [PMID: 23857129] doi:10.1038/nrrheum.2013.113 CrossrefMedlineGoogle Scholar
Karsdal MA, Bay-Jensen AC, Lories RJ, et al. The coupling of bone and cartilage turnover in osteoarthritis: opportunities for bone antiresorptives and anabolics as potential treatments? Ann Rheum Dis. 2014;73:336-48. [PMID: 24285494] doi:10.1136/annrheumdis-2013-204111 CrossrefMedlineGoogle Scholar
Drake FH, Dodds RA, James IE, et al. Cathepsin K, but not cathepsins B, L, or S, is abundantly expressed in human osteoclasts. J Biol Chem. 1996;271:12511-6. [PMID: 8647859] CrossrefMedlineGoogle Scholar
Dejica VM, Mort JS, Laverty S, et al. Cleavage of type II collagen by cathepsin K in human osteoarthritic cartilage. Am J Pathol. 2008;173:161-9. [PMID: 18511517] doi:10.2353/ajpath.2008.070494 CrossrefMedlineGoogle Scholar
Lindström E, Rizoska B, Henderson I, et al. Nonclinical and clinical pharmacological characterization of the potent and selective cathepsin K inhibitor MIV-711. J Transl Med. 2018;16:125. [PMID: 29743078] doi:10.1186/s12967-018-1497-4 CrossrefMedlineGoogle Scholar
Eastell R, Nagase S, Small M, et al. Effect of ONO-5334 on bone mineral density and biochemical markers of bone turnover in postmenopausal osteoporosis: 2-year results from the OCEAN study. J Bone Miner Res. 2014;29:458-66. [PMID: 23873670] doi:10.1002/jbmr.2047 CrossrefMedlineGoogle Scholar
Rünger TM, Adami S, Benhamou CL, et al. Morphea-like skin reactions in patients treated with the cathepsin K inhibitor balicatib. J Am Acad Dermatol. 2012;66:e89-96. [PMID: 21571394] doi:10.1016/j.jaad.2010.11.033 CrossrefMedlineGoogle Scholar
Eisman JA, Bone HG, Hosking DJ, et al. Odanacatib in the treatment of postmenopausal women with low bone mineral density: three-year continued therapy and resolution of effect. J Bone Miner Res. 2011;26:242-51. [PMID: 20740685] doi:10.1002/jbmr.212 CrossrefMedlineGoogle Scholar
Jensen AB, Wynne C, Ramirez G, et al. The cathepsin K inhibitor odanacatib suppresses bone resorption in women with breast cancer and established bone metastases: results of a 4-week, double-blind, randomized, controlled trial. Clin Breast Cancer. 2010;10:452-8. [PMID: 21147688] doi:10.3816/CBC.2010.n.059 CrossrefMedlineGoogle Scholar
Lindström E, Rizoska B, Tunblad K, et al. The selective cathepsin K inhibitor MIV-711 attenuates joint pathology in experimental animal models of osteoarthritis. J Transl Med. 2018;16:56. [PMID: 29523155] doi:10.1186/s12967-018-1425-7 CrossrefMedlineGoogle Scholar
Lindstrom E, Grabowska U, Jerling M, et al. MIV-711, a highly selective cathepsin K inhibitor, reduces biomarkers of bone resorption and cartilage degradation in healthy subjects. Osteoarthritis Cartilage. 2014;22:S197. doi:10.1016/j.joca.2014.02.376 CrossrefMedlineGoogle Scholar
Hunter D, Nevitt M, Lynch J, et al; FNIH OA Biomarkers Consortium. Longitudinal validation of periarticular bone area and 3D shape as biomarkers for knee OA progression? Data from the FNIH OA Biomarkers Consortium. Ann Rheum Dis. 2016;75:1607-14. [PMID: 26483253] doi:10.1136/annrheumdis-2015-207602 CrossrefMedlineGoogle Scholar
Bowes MA, Vincent GR, Wolstenholme CB, et al. A novel method for bone area measurement provides new insights into osteoarthritis and its progression. Ann Rheum Dis. 2015;74:519-25. [PMID: 24306109] doi:10.1136/annrheumdis-2013-204052 CrossrefMedlineGoogle Scholar
Barr AJ, Dube B, Hensor EM, et al. The relationship between three-dimensional knee MRI bone shape and total knee replacement—a case control study: data from the Osteoarthritis Initiative. Rheumatology (Oxford). 2016;55:1585-93. [PMID: 27185958] doi:10.1093/rheumatology/kew191 CrossrefMedlineGoogle Scholar
Neogi T, Bowes MA, Niu J, et al. Magnetic resonance imaging-based three-dimensional bone shape of the knee predicts onset of knee osteoarthritis: data from the Osteoarthritis Initiative. Arthritis Rheum. 2013;65:2048-58. [PMID: 23650083] doi:10.1002/art.37987 CrossrefMedlineGoogle Scholar
Bowes MA, Guillard GA, Vincent GR, et al. Precision, reliability, and responsiveness of a novel automated quantification tool for cartilage thickness: data from the Osteoarthritis Initiative. J Rheumatol. 2019. [PMID: 30988122] doi:10.3899/jrheum.180541 CrossrefMedlineGoogle Scholar
Eckstein F, Kwoh CK, Boudreau RM, et al; OAI investigators. Quantitative MRI measures of cartilage predict knee replacement: a case-control study from the Osteoarthritis Initiative. Ann Rheum Dis. 2013;72:707-14. [PMID: 22730370] doi:10.1136/annrheumdis-2011-201164 CrossrefMedlineGoogle Scholar
Bingham CO, Buckland-Wright JC, Garnero P, et al. Risedronate decreases biochemical markers of cartilage degradation but does not decrease symptoms or slow radiographic progression in patients with medial compartment osteoarthritis of the knee: results of the two-year multinational Knee Osteoarthritis Structural Arthritis Study. Arthritis Rheum. 2006;54:3494-507. [PMID: 17075851] MedlineGoogle Scholar
Reginster JY, Badurski J, Bellamy N, et al. Efficacy and safety of strontium ranelate in the treatment of knee osteoarthritis: results of a double-blind, randomised placebo-controlled trial. Ann Rheum Dis. 2013;72:179-86. [PMID: 23117245] doi:10.1136/annrheumdis-2012-202231 CrossrefMedlineGoogle Scholar
Altman R, Asch E, Bloch D, et al. Development of criteria for the classification and reporting of osteoarthritis. Classification of osteoarthritis of the knee. Diagnostic and Therapeutic Criteria Committee of the American Rheumatism Association. Arthritis Rheum. 1986;29:1039-49. [PMID: 3741515] CrossrefMedlineGoogle Scholar
Jensen MP, McFarland CA. Increasing the reliability and validity of pain intensity measurement in chronic pain patients. Pain. 1993;55:195-203. [PMID: 8309709] CrossrefMedlineGoogle Scholar
Alghadir AH, Anwer S, Iqbal A, et al. Test-retest reliability, validity, and minimum detectable change of visual analog, numerical rating, and verbal rating scales for measurement of osteoarthritic knee pain. J Pain Res. 2018;11:851-6. [PMID: 29731662] doi:10.2147/JPR.S158847 CrossrefMedlineGoogle Scholar
Salaffi F, Stancati A, Silvestri CA, et al. Minimal clinically important changes in chronic musculoskeletal pain intensity measured on a numerical rating scale. Eur J Pain. 2004;8:283-91. [PMID: 15207508] CrossrefMedlineGoogle Scholar
Heimann T, Meinzer HP. Statistical shape models for 3D medical image segmentation: a review. Med Image Anal. 2009;13:543-63. [PMID: 19525140] doi:10.1016/j.media.2009.05.004 CrossrefMedlineGoogle Scholar
Davies RH, Twining CJ, Cootes TF, et al. Building 3-D statistical shape models by direct optimization. IEEE Trans Med Imaging. 2010;29:961-81. [PMID: 19887309] doi:10.1109/TMI.2009.2035048 CrossrefMedlineGoogle Scholar
Williams TG, Holmes AP, Waterton JC, et al. Anatomically corresponded regional analysis of cartilage in asymptomatic and osteoarthritic knees by statistical shape modelling of the bone. IEEE Trans Med Imaging. 2010;29:1541-59. [PMID: 20378463] doi:10.1109/TMI.2010.2047653 CrossrefMedlineGoogle Scholar
Bowes MA, Maciewicz RA, Waterton JC, et al. Bone area provides a responsive outcome measure for bone changes in short-term knee osteoarthritis studies. J Rheumatol. 2016;43:2179-82. [PMID: 27909144] CrossrefMedlineGoogle Scholar
Bellamy N, Buchanan WW, Goldsmith CH, et al. Validation study of WOMAC: a health status instrument for measuring clinically important patient relevant outcomes to antirheumatic drug therapy in patients with osteoarthritis of the hip or knee. J Rheumatol. 1988;15:1833-40. [PMID: 3068365] MedlineGoogle Scholar
Bennell KL, Bowles KA, Payne C, et al. Lateral wedge insoles for medial knee osteoarthritis: 12 month randomised controlled trial. BMJ. 2011;342:d2912. [PMID: 21593096] doi:10.1136/bmj.d2912 CrossrefMedlineGoogle Scholar
Drake MT, Clarke BL, Oursler MJ, et al. Cathepsin K inhibitors for osteoporosis: biology, potential clinical utility, and lessons learned. Endocr Rev. 2017;38:325-50. [PMID: 28651365] doi:10.1210/er.2015-1114 CrossrefMedlineGoogle Scholar
Kraus VB, Burnett B, Coindreau J, et al; OARSI FDA Osteoarthritis Biomarkers Working Group. Application of biomarkers in the development of drugs intended for the treatment of osteoarthritis. Osteoarthritis Cartilage. 2011;19:515-42. [PMID: 21396468] doi:10.1016/j.joca.2010.08.019 CrossrefMedlineGoogle Scholar
Kraus VB, Collins JE, Hargrove D, et al; OA Biomarkers Consortium. Predictive validity of biochemical biomarkers in knee osteoarthritis: data from the FNIH OA Biomarkers Consortium. Ann Rheum Dis. 2017;76:186-95. [PMID: 27296323] doi:10.1136/annrheumdis-2016-209252 CrossrefMedlineGoogle Scholar
Karsdal MA, Byrjalsen I, Alexandersen P; CSMC021C2301/2 investigators. Treatment of symptomatic knee osteoarthritis with oral salmon calcitonin: results from two phase 3 trials. Osteoarthritis Cartilage. 2015;23:532-43. [PMID: 25582279] doi:10.1016/j.joca.2014.12.019 CrossrefMedlineGoogle Scholar
Garnero P, Aronstein WS, Cohen SB, et al. Relationships between biochemical markers of bone and cartilage degradation with radiological progression in patients with knee osteoarthritis receiving risedronate: the Knee Osteoarthritis Structural Arthritis randomized clinical trial. Osteoarthritis Cartilage. 2008;16:660-6. [PMID: 17993283] CrossrefMedlineGoogle Scholar
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.