Original Research21 January 2020
A Randomized Controlled Trial
    Author, Article, and Disclosure Information
    Visual Abstract. Disease-Modifying Effects of a Novel Cathepsin K Inhibitor in Osteoarthritis

    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.



    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:



    • 1. Vos TFlaxman ADNaghavi Met alYears 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. Lancet2012;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
    • 3. Frobell RBNevitt MCHudelmaier Met alOsteoarthritis Initiative InvestigatorsFemorotibial 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
    • 4. Barr AJDube BHensor EMet alThe relationship between clinical characteristics, radiographic osteoarthritis and 3D bone area: data from the Osteoarthritis Initiative. Osteoarthritis Cartilage2014;22:1703-9. [PMID: 25278079] doi:10.1016/j.joca.2014.06.026 CrossrefMedlineGoogle Scholar
    • 5. Maschek SWirth WLadel Cet alRates and sensitivity of knee cartilage thickness loss in specific central reading radiographic strata from the Osteoarthritis Initiative. Osteoarthritis Cartilage2014;22:1550-3. [PMID: 25278063] doi:10.1016/j.joca.2014.05.015 CrossrefMedlineGoogle Scholar
    • 6. Eckstein FCollins JENevitt MCet alFNIH OA Biomarkers ConsortiumBrief 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 Rheumatol2015;67:3184-9. [PMID: 26316262] doi:10.1002/art.39324 CrossrefMedlineGoogle Scholar
    • 7. Martel-Pelletier JPelletier JPIs osteoarthritis a disease involving only cartilage or other articular tissues? Eklem Hastalik Cerrahisi2010;21:2-14. [PMID: 20302555] MedlineGoogle Scholar
    • 8. Herrero-Beaumont GRoman-Blas JAOsteoarthritis: osteoporotic OA: a reasonable target for bone-acting agents. Nat Rev Rheumatol2013;9:448-50. [PMID: 23857129] doi:10.1038/nrrheum.2013.113 CrossrefMedlineGoogle Scholar
    • 9. Karsdal MABay-Jensen ACLories RJet alThe coupling of bone and cartilage turnover in osteoarthritis: opportunities for bone antiresorptives and anabolics as potential treatments? Ann Rheum Dis2014;73:336-48. [PMID: 24285494] doi:10.1136/annrheumdis-2013-204111 CrossrefMedlineGoogle Scholar
    • 10. Drake FHDodds RAJames IEet alCathepsin K, but not cathepsins B, L, or S, is abundantly expressed in human osteoclasts. J Biol Chem1996;271:12511-6. [PMID: 8647859] CrossrefMedlineGoogle Scholar
    • 11. Dejica VMMort JSLaverty Set alCleavage of type II collagen by cathepsin K in human osteoarthritic cartilage. Am J Pathol2008;173:161-9. [PMID: 18511517] doi:10.2353/ajpath.2008.070494 CrossrefMedlineGoogle Scholar
    • 12. Lindström ERizoska BHenderson Iet alNonclinical and clinical pharmacological characterization of the potent and selective cathepsin K inhibitor MIV-711. J Transl Med2018;16:125. [PMID: 29743078] doi:10.1186/s12967-018-1497-4 CrossrefMedlineGoogle Scholar
    • 13. Eastell RNagase SSmall Met alEffect 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 Res2014;29:458-66. [PMID: 23873670] doi:10.1002/jbmr.2047 CrossrefMedlineGoogle Scholar
    • 14. Rünger TMAdami SBenhamou CLet alMorphea-like skin reactions in patients treated with the cathepsin K inhibitor balicatib. J Am Acad Dermatol2012;66:e89-96. [PMID: 21571394] doi:10.1016/j.jaad.2010.11.033 CrossrefMedlineGoogle Scholar
    • 15. Eisman JABone HGHosking DJet alOdanacatib in the treatment of postmenopausal women with low bone mineral density: three-year continued therapy and resolution of effect. J Bone Miner Res2011;26:242-51. [PMID: 20740685] doi:10.1002/jbmr.212 CrossrefMedlineGoogle Scholar
    • 16. Jensen ABWynne CRamirez Get alThe 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 Cancer2010;10:452-8. [PMID: 21147688] doi:10.3816/CBC.2010.n.059 CrossrefMedlineGoogle Scholar
    • 17. Lindström ERizoska BTunblad Ket alThe selective cathepsin K inhibitor MIV-711 attenuates joint pathology in experimental animal models of osteoarthritis. J Transl Med2018;16:56. [PMID: 29523155] doi:10.1186/s12967-018-1425-7 CrossrefMedlineGoogle Scholar
    • 18. Lindstrom EGrabowska UJerling Met alMIV-711, a highly selective cathepsin K inhibitor, reduces biomarkers of bone resorption and cartilage degradation in healthy subjects. Osteoarthritis Cartilage2014;22:S197. doi:10.1016/j.joca.2014.02.376 CrossrefMedlineGoogle Scholar
    • 19. Hunter DNevitt MLynch Jet alFNIH OA Biomarkers ConsortiumLongitudinal validation of periarticular bone area and 3D shape as biomarkers for knee OA progression? Data from the FNIH OA Biomarkers Consortium. Ann Rheum Dis2016;75:1607-14. [PMID: 26483253] doi:10.1136/annrheumdis-2015-207602 CrossrefMedlineGoogle Scholar
    • 20. Bowes MAVincent GRWolstenholme CBet alA novel method for bone area measurement provides new insights into osteoarthritis and its progression. Ann Rheum Dis2015;74:519-25. [PMID: 24306109] doi:10.1136/annrheumdis-2013-204052 CrossrefMedlineGoogle Scholar
    • 21. Barr AJDube BHensor EMet alThe 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
    • 22. Neogi TBowes MANiu Jet alMagnetic resonance imaging-based three-dimensional bone shape of the knee predicts onset of knee osteoarthritis: data from the Osteoarthritis Initiative. Arthritis Rheum2013;65:2048-58. [PMID: 23650083] doi:10.1002/art.37987 CrossrefMedlineGoogle Scholar
    • 23. Bowes MAGuillard GAVincent GRet alPrecision, reliability, and responsiveness of a novel automated quantification tool for cartilage thickness: data from the Osteoarthritis Initiative. J Rheumatol2019. [PMID: 30988122] doi:10.3899/jrheum.180541 CrossrefMedlineGoogle Scholar
    • 24. Eckstein FKwoh CKBoudreau RMet alOAI investigatorsQuantitative MRI measures of cartilage predict knee replacement: a case-control study from the Osteoarthritis Initiative. Ann Rheum Dis2013;72:707-14. [PMID: 22730370] doi:10.1136/annrheumdis-2011-201164 CrossrefMedlineGoogle Scholar
    • 25. Bingham COBuckland-Wright JCGarnero Pet alRisedronate 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 Rheum2006;54:3494-507. [PMID: 17075851] MedlineGoogle Scholar
    • 26. Reginster JYBadurski JBellamy Net alEfficacy and safety of strontium ranelate in the treatment of knee osteoarthritis: results of a double-blind, randomised placebo-controlled trial. Ann Rheum Dis2013;72:179-86. [PMID: 23117245] doi:10.1136/annrheumdis-2012-202231 CrossrefMedlineGoogle Scholar
    • 27. Altman RAsch EBloch Det alDevelopment 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 Rheum1986;29:1039-49. [PMID: 3741515] CrossrefMedlineGoogle Scholar
    • 28. Jensen MPMcFarland CAIncreasing the reliability and validity of pain intensity measurement in chronic pain patients. Pain1993;55:195-203. [PMID: 8309709] CrossrefMedlineGoogle Scholar
    • 29. Alghadir AHAnwer SIqbal Aet alTest-retest reliability, validity, and minimum detectable change of visual analog, numerical rating, and verbal rating scales for measurement of osteoarthritic knee pain. J Pain Res2018;11:851-6. [PMID: 29731662] doi:10.2147/JPR.S158847 CrossrefMedlineGoogle Scholar
    • 30. Salaffi FStancati ASilvestri CAet alMinimal clinically important changes in chronic musculoskeletal pain intensity measured on a numerical rating scale. Eur J Pain2004;8:283-91. [PMID: 15207508] CrossrefMedlineGoogle Scholar
    • 31. Heimann TMeinzer HPStatistical shape models for 3D medical image segmentation: a review. Med Image Anal2009;13:543-63. [PMID: 19525140] doi:10.1016/j.media.2009.05.004 CrossrefMedlineGoogle Scholar
    • 32. Davies RHTwining CJCootes TFet alBuilding 3-D statistical shape models by direct optimization. IEEE Trans Med Imaging2010;29:961-81. [PMID: 19887309] doi:10.1109/TMI.2009.2035048 CrossrefMedlineGoogle Scholar
    • 33. Williams TGHolmes APWaterton JCet alAnatomically corresponded regional analysis of cartilage in asymptomatic and osteoarthritic knees by statistical shape modelling of the bone. IEEE Trans Med Imaging2010;29:1541-59. [PMID: 20378463] doi:10.1109/TMI.2010.2047653 CrossrefMedlineGoogle Scholar
    • 34. Bowes MAMaciewicz RAWaterton JCet alBone area provides a responsive outcome measure for bone changes in short-term knee osteoarthritis studies. J Rheumatol2016;43:2179-82. [PMID: 27909144] CrossrefMedlineGoogle Scholar
    • 35. Bellamy NBuchanan WWGoldsmith CHet alValidation 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 Rheumatol1988;15:1833-40. [PMID: 3068365] MedlineGoogle Scholar
    • 36. Bennell KLBowles KAPayne Cet alLateral wedge insoles for medial knee osteoarthritis: 12 month randomised controlled trial. BMJ2011;342:d2912. [PMID: 21593096] doi:10.1136/bmj.d2912 CrossrefMedlineGoogle Scholar
    • 37. Drake MTClarke BLOursler MJet alCathepsin K inhibitors for osteoporosis: biology, potential clinical utility, and lessons learned. Endocr Rev2017;38:325-50. [PMID: 28651365] doi:10.1210/er.2015-1114 CrossrefMedlineGoogle Scholar
    • 38. Kraus VBBurnett BCoindreau Jet alOARSI FDA Osteoarthritis Biomarkers Working GroupApplication of biomarkers in the development of drugs intended for the treatment of osteoarthritis. Osteoarthritis Cartilage2011;19:515-42. [PMID: 21396468] doi:10.1016/j.joca.2010.08.019 CrossrefMedlineGoogle Scholar
    • 39. Kraus VBCollins JEHargrove Det alOA Biomarkers ConsortiumPredictive validity of biochemical biomarkers in knee osteoarthritis: data from the FNIH OA Biomarkers Consortium. Ann Rheum Dis2017;76:186-95. [PMID: 27296323] doi:10.1136/annrheumdis-2016-209252 CrossrefMedlineGoogle Scholar
    • 40. Karsdal MAByrjalsen IAlexandersen PCSMC021C2301/2 investigatorsTreatment of symptomatic knee osteoarthritis with oral salmon calcitonin: results from two phase 3 trials. Osteoarthritis Cartilage2015;23:532-43. [PMID: 25582279] doi:10.1016/j.joca.2014.12.019 CrossrefMedlineGoogle Scholar
    • 41. Garnero PAronstein WSCohen SBet alRelationships 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 Cartilage2008;16:660-6. [PMID: 17993283] CrossrefMedlineGoogle Scholar