Efficacy and safety of tofacitinib as monotherapy in Japanese patients with active rheumatoid arthritis: a 12-week, randomized, phase 2 study

Yoshiya Tanaka, Tsutomu Takeuchi, Hisashi Yamanaka, Hiroyuki Nakamura, Shigeyuki Toyoizumi, Samuel Zwillich, Yoshiya Tanaka, Tsutomu Takeuchi, Hisashi Yamanaka, Hiroyuki Nakamura, Shigeyuki Toyoizumi, Samuel Zwillich

Abstract

Objectives: To evaluate oral tofacitinib versus placebo for treatment of active rheumatoid arthritis in Japanese patients with inadequate response to disease-modifying antirheumatic drugs.

Methods: In this double-blind, placebo-controlled, randomized, parallel-group, 12-week, phase 2 study (clinicaltrials.gov NCT00687193), 317 patients received tofacitinib: 1, 3, 5, 10, or 15 mg as monotherapy or placebo twice daily (BID).

Primary endpoint: response rate by American College of Rheumatology (ACR) ≥ 20% improvement criteria (ACR20) at week 12.

Results: ACR20 response rates: 37.7% (20/53), 67.9% (36/53), 73.1% (38/52), 84.9% (45/53), and 90.7% (49/54) with tofacitinib: 1, 3, 5, 10, and 15 mg BID, respectively, versus 15.4% (8/52) with placebo (p < 0.01; all doses). Dose-dependent ACR20 responses with tofacitinib versus placebo occurred from week 2 onward (p < 0.05). Changes from baseline in 28-joint disease activity score using erythrocyte sedimentation rate improved with tofacitinib versus placebo from week 4 (p < 0.01; all doses). Six tofacitinib patients experienced treatment-related serious adverse events (AEs). Most common treatment-emergent AEs: nasopharyngitis (10% vs 12%) and hyperlipidemia (5% vs 0%). Serum creatinine, hemoglobin, and total-, low-, and high-density lipoprotein-cholesterol levels increased with tofacitinib.

Conclusions: Tofacitinib produced dose-dependent ACR20 responses and reduced disease activity. The safety profile was consistent with that reported from global monotherapy trials.

Keywords: Japan; Monotherapy; Randomized controlled trial; Rheumatoid arthritis; Tofacitinib.

Figures

Figure 1.. Patient disposition. AEs were categorized…
Figure 1.. Patient disposition. AEs were categorized according to whether they were considered related to study drug or not. AE adverse event, BID twice daily.
Figure 2.. Response rates for patients receiving…
Figure 2.. Response rates for patients receiving tofacitinib monotherapy or placebo over time. (a) ACR20 response (± SE), FAS, LOCF. (b) DAS28-4(ESR) 3.2–p < 0.05 versus placebo. ACR20 American College of Rheumatology 20% improvement criteria, BID twice daily, DAS28-4(ESR) 28-joint disease activity score using erythrocyte sedimentation rate, FAS full analysis set, HAQ-DI Health Assessment Questionnaire-Disability Index, HDA high disease activity, LDA low disease activity, LOCF last observation carried forward, MDA medium disease activity, SE standard error.

References

    1. Smolen JS, Aletaha D, Bijlsma JW, Breedveld FC, Boumpas D, Burmester G, et al. Treating rheumatoid arthritis to target: recommendations of an international task force. Ann Rheum Dis. 2010;69((4)):631–7.
    1. Saag KG, Teng GG, Patkar NM, Anuntiyo J, Finney C, Curtis JR, et al. American College of Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis. Arthritis Rheum. 2008;59((6)):762–84.
    1. Strand V, Singh JA. Improved health-related quality of life with effective disease-modifying antirheumatic drugs: evidence from randomized controlled trials. Am J Manag Care. 2007;13((Suppl 9)):S237–51.
    1. Koike R, Harigai M, Atsumi T, Amano K, Kawai S, Saito K, et al. Japan College of Rheumatology 2009 guidelines for the use of tocilizumab, a humanized anti-interleukin-6 receptor monoclonal antibody, in rheumatoid arthritis. Mod Rheumatol. 2009;19((4)):351–7.
    1. Koike R, Takeuchi T, Eguchi K, Miyasaka N. Update on the Japanese guidelines for the use of infliximab and etanercept in rheumatoid arthritis. Mod Rheumatol. 2007;17((6)):451–8.
    1. Miyasaka N, Takeuchi T, Eguchi K. Guidelines for the proper use of etanercept in Japan. Mod Rheumatol. 2006;16((2)):63–7.
    1. Lipsky PE, van der Heijde DM, St Clair EW, Furst DE, Breedveld FC, Kalden JR, et al. Infliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-tumor necrosis factor trial in rheumatoid arthritis with concomitant therapy study group. N Engl J Med. 2000;343((22)):1594–602.
    1. Weinblatt ME, Kremer JM, Bankhurst AD, Bulpitt KJ, Fleischmann RM, Fox RI, et al. A trial of etanercept, a recombinant tumor necrosis factor receptor: Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate. N Engl J Med. 1999;340((4)):253–9.
    1. Weinblatt ME, Keystone EC, Furst DE, Moreland LW, Weisman MH, Birbara CA, et al. Adalimumab, a fully human anti-tumor necrosis factor alpha monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: the ARMADA trial. Arthritis Rheum. 2003;48((1)):35–45.
    1. Finckh A, Simard JF, Gabay C, Guerne PA. Evidence for differential acquired drug resistance to anti-tumour necrosis factor agents in rheumatoid arthritis. Ann Rheum Dis. 2006;65((6)):746–52.
    1. Yamanaka H, Seto Y, Tanaka E, Furuya T, Nakajima A, Ikari K, et al. Management of rheumatoid arthritis: the 2012 perspective. Mod Rheumatol. 2013;23((1)):1–7.
    1. Tanaka Y, Yamaoka K. JAK inhibitor tofacitinib for treating rheumatoid arthritis: from basic to clinical. Mod Rheumatol. 2012;23:415–24.
    1. Tanaka Y, Maeshima K, Yamaoka K. In vitro and in vivo analysis of a JAK inhibitor in rheumatoid arthritis. Ann Rheum Dis. 2012;71((Suppl 2)):i70–4.
    1. Meyer DM, Jesson MI, Li X, Elrick MM, Funckes-Shippy CL, Warner JD, et al. Anti-inflammatory activity and neutrophil reductions mediated by the JAK1/JAK3 inhibitor, CP-690,550, in rat adjuvant-induced arthritis. J Inflamm (Lond) 2010;7((1)):41.
    1. Rochman Y, Spolski R, Leonard WJ. New insights into the regulation of T cells by γc family cytokines. Nat Immunol Rev. 2009;9((7)):480–90.
    1. Fleischmann R, Kremer J, Cush J, Schulze-Koops H, Connell CA, Bradley JD, et al. Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis. N Engl J Med. 2012;367((6)):495–507.
    1. Kremer JM, Li ZG, Hall S, Fleischmann R, Genovese M, Martin-Mola E, et al. Tofacitinib (CP-690,550), an oral JAK inhibitor, in combination with traditional DMARDS: Phase 3 study in patients with active rheumatoid arthritis with inadequate response to DMARDs. Ann Rheum Dis. 2011;70((Suppl 3)):170.
    1. Lee EB, Fleischmann RM, Hall S, van Vollenhoven RF, Bradley J, Gruben D, et al. Radiographic, clinical and functional comparison of tofacitinib monotherapy versus methotrexate in methotrexate-nave patients with rheumatoid arthritis. Arthritis Rheum. 2012;64((Suppl 10)):S1049.
    1. Burmester GR, Blanco R, Charles-Schoeman C, Wollenhaupt J, Zerbini C, Benda B, et al. Tofacitinib (CP-690,550) in combination with methotrexate in patients with active rheumatoid arthritis with an inadequate response to tumour necrosis factor inhibitors: a randomised phase 3 trial. Lancet. 2013;381((9865)):451–60.
    1. van Vollenhoven RF, Fleischmann R, Cohen S, Lee EB, García Meijide JA, Wagner S, et al. Tofacitinib or adalimumab versus placebo in rheumatoid arthritis. N Engl J Med. 2012;367((6)):508–19.
    1. van der Heijde D, Tanaka Y, Fleischmann R, Keystone E, Kremer J, Zerbini C, et al. Tofacitinib (CP-690,550) in patients with rheumatoid arthritis receiving methotrexate: twelve-month data from a twenty-four-month phase III randomized radiographic study. Arthritis Rheum. 2013;65((3)):559–70.
    1. Tanaka Y, Suzuki M, Nakamura H, Toyoizumi S, Zwillich SH. Phase II study of tofacitinib (CP-690,550) combined with methotrexate in patients with rheumatoid arthritis and an inadequate response to methotrexate. Arthritis Care Res (Hoboken) 2011;63((8)):1150–8.
    1. Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988;31((3)):315–24.
    1. Gupta P, Alvey C, Wang R, Dowty ME, Fahmi OA, Walsky RL, et al. Lack of effect of tofacitinib (CP-690,550) on the pharmacokinetics of the CYP3A4 substrate midazolam in healthy volunteers: confirmation of in vitro data. Br J Clin Pharmacol. 2012;74((1)):109–15.
    1. Radboud University Nijmegen Medical Centre : Disease activity score in rheumatoid arthritis.
    1. Fries JF, Spitz PW, Young DY. The dimensions of health outcomes: the health assessment questionnaire, disability and pain scales. J Rheumatol. 1982;9((5)):789–93.
    1. Cella D, Yount S, Sorensen M, Chartash E, Sengupta N, Grober J. Validation of the functional assessment of chronic illness therapy fatigue scale relative to other instrumentation in patients with rheumatoid arthritis. J Rheumatol. 2005;32((5)):811–9.
    1. Ghoreschi K, Jesson MI, Li X, Lee JL, Ghosh S, Alsup JW, et al. Modulation of innate and adaptive immune responses by tofacitinib (CP-690,550) J Immunol. 2011;186((7)):4234–43.
    1. Fleischmann R, Cutolo M, Genovese MC, Lee EB, Kanik KS, Sadis S, et al. Phase IIb dose-ranging study of the oral JAK inhibitor tofacitinib (CP-690,550) or adalimumab monotherapy versus placebo in patients with active rheumatoid arthritis with an inadequate response to disease-modifying antirheumatic drugs. Arthritis Rheum. 2012;64((3)):617–29.
    1. Kremer JM, Cohen S, Wilkinson BE, Connell CA, French JL, Gomez-Reino J, et al. A phase IIb dose-ranging study of the oral JAK inhibitor tofacitinib (CP-690,550) versus placebo in combination with background methotrexate in patients with active rheumatoid arthritis and an inadequate response to methotrexate alone. Arthritis Rheum. 2012;64((4)):970–81.
    1. Kremer JM, Bloom BJ, Breedveld FC, Coombs JH, Fletcher MP, Gruben D, et al. The safety and efficacy of a JAK inhibitor in patients with active rheumatoid arthritis: results of a double-blind, placebo-controlled phase IIa trial of three dosage levels of CP-690,550 versus placebo. Arthritis Rheum. 2009;60((7)):1895–905.
    1. Kawashiri SY, Kawakami A, Yamasaki S, Imazato T, Iwamoto N, Fujikawa K, et al. Effects of the anti-interleukin-6 receptor antibody, tocilizumab, on serum lipid levels in patients with rheumatoid arthritis. Rheumatol Int. 2011;31((4)):451–6.
    1. Koike T, Harigai M, Inokuma S, Ishiguro N, Ryu J, Takeuchi T, et al. Postmarketing surveillance of tocilizumab for rheumatoid arthritis in Japan: interim analysis of 3881 patients. Ann Rheum Dis. 2011;70((12)):2148–51.
    1. Nishimoto N, Miyasaka N, Yamamoto K, Kawai S, Takeuchi T, Azuma J, Kishimoto T. Study of active controlled tocilizumab monotherapy for rheumatoid arthritis patients with an inadequate response to methotrexate (SATORI): significant reduction in disease activity and serum vascular endothelial growth factor by IL-6 receptor inhibition therapy. Mod Rheumatol. 2009;19((1)):12–19.

Source: PubMed

Szponzorok és közreműködők

Egészségi állapot

Kábítószer-beavatkozások

3
Iratkozz fel