A randomized phase 2a efficacy and safety trial of the topical J anus kinase inhibitor tofacitinib in the treatment of chronic plaque psoriasis

Abstract

BACKGROUND: Tofacitinib (CP-690,550) is a novel Janus kinase inhibitor in development as an oral formulation for the treatment of several inflammatory diseases including psoriasis. OBJECTIVES: This phase 2a study aimed to assess the efficacy, systemic safety, local tolerability and systemic pharmacokinetics of topical tofacitinib in mild-to-moderate plaque psoriasis. METHODS: Two tofacitinib ointment formulations were evaluated in this multicentre, double-blind, vehicle-controlled trial (NCT01246583). Seventy-one patients were randomized 2 : 1 : 2 : 1 to 2% tofacitinib ointment 1, vehicle 1, 2% tofacitinib ointment 2 and vehicle 2, each administered twice daily for 4 weeks to a single fixed 300 cm(2) treatment area containing a target plaque with or without one or more nontarget plaques and normal skin. RESULTS: The primary endpoint of percentage change from baseline in the Target Plaque Severity Score at week 4 demonstrated statistically significant improvement for ointment 1 [least squares mean (LSM) -54.4%] vs. vehicle 1 (LSM -41.5%), but not ointment 2 (LSM -24.2%) vs. vehicle 2 (LSM -17.2%). Secondary endpoints (target plaque area and Itch Severity Item) improved similarly for tofacitinib ointment vs. corresponding vehicle. Adverse event (AE) occurrence was similar across treatment groups. All AEs were mild or moderate and none were serious or led to subject discontinuation. One application-site AE (erythema) was reported. Tofacitinib mean systemic exposure was minimal and was greater for ointment 1 than for ointment 2. CONCLUSIONS: Tofacitinib ointment 1 was well tolerated and efficacious compared with vehicle for the treatment of plaque psoriasis. Further study of topical tofacitinib for psoriasis treatment is warranted.

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References 26

1. 1.

   Gudjonsson JE, Elder JT, Goldsmith LA, Katz SI, Gilchrest BA, Paller A, Leffell DJ, Wolff K. Psoriasis. Fitzpatrick's Dermatology in General Medicine. 2012;197-232.

   Not in our library

2. 2.

   Papp K, Gulliver W, Lynde C, et al. Canadian guidelines for the management of plaque psoriasis: overview. J Cutan Med Surg. 2011;15:210-19.

   Not in our library10.2310/7750.2011.10066

3. 3.

   Williams SC. New biologic drugs get under the skin of psoriasis. Nat Med. 2012;18:638.

   Not in our library10.1038/nm0512-638

4. 4.
   Anti-inflammatory activity and neutrophil reductions mediated by the JAK1/JAK3 inhibitor, CP-690,550, in rat adjuvant-induced arthritis · 2010

   No notice
5. 5.

   Ghoreschi K, Jesson MI, Li X, et al. Modulation of innate and adaptive immune responses by tofacitinib (CP-690,550). J Immunol. 2011;186:4234-43.

   Not in our library10.4049/jimmunol.1003668

6. 6.

   Murray PJ. The JAK-STAT signaling pathway: input and output integration. J Immunol. 2007;178:2623-9.

   Not in our library10.4049/jimmunol.178.5.2623

7. 7.

   O'Sullivan LA, Liongue C, Lewis RS, et al. Cytokine receptor signaling through the Jak-Stat-Socs pathway in disease. Mol Immunol. 2007;44:2497-506.

   Not in our library10.1016/j.molimm.2006.11.025

8. 8.

   Rosengren S, Corr M, Firestein GS, Boyle DL. The JAK inhibitor CP-690,550 (tofacitinib) inhibits TNF-induced chemokine expression in fibroblast-like synoviocytes: autocrine role of type I interferon. Ann Rheum Dis. 2012;71:440-7.

   Not in our library10.1136/ard.2011.150284

9. 9.

   Boy MG, Wang C, Wilkinson BE, et al. Double-blind, placebo-controlled, dose-escalation study to evaluate the pharmacologic effect of CP-690,550 in patients with psoriasis. J Invest Dermatol. 2009;129:2299-302.

   Not in our library10.1038/jid.2009.25

10. 10.

    Papp K, Menter A, Strober B, et al. Efficacy and safety of tofacitinib, an oral JAK inhibitor, in the treatment of psoriasis: a Phase 2b randomized placebo-controlled dose-ranging study. Br J Dermatol. 2012;167:668-77.

    Not in our library10.1111/j.1365-2133.2012.11168.x

11. 11.

    Burmester G, Blanco R, Charles-Schoemann C, et al. Tofacitinib (CP-690,550), an oral Janus kinase inhibitor, in combination with methotrexate, in patients with active rheumatoid arthritis with an inadequate response to tumor necrosis factor-inhibitors: a 6-month Phase 3 study. Arthritis Rheum. 2011;63(Suppl. 10):S279.

    Not in our library

12. 12.

    van der Heijde D, Tanaka Y, Fleischmann R, et al. Tofacitinib (CP-690,550), an oral Janus kinase inhibitor, in combination with methotrexate reduced the progression of structural damage in patients with rheumatoid arthritis: a 24-month Phase 3 study. Arthritis Rheum. 2011;63(Suppl. 10):S107.

    Not in our library

13. 13.

    Kremer JM, Li ZG, Hall S, et al. Tofacitinib (CP-690,550), an oral Janus kinase inhibitor, in combination with traditional DMARDS: a Phase 3 efficacy and safety study in patients with active rheumatoid arthritis with an inadequate response to DMARDs. Ann Rheum Dis. 2011;70:170.

    Not in our library

14. 14.

    Fleischmann R, Cutolo M, Genovese MC, 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;64:617-29.

    Not in our library10.1002/art.33383

15. 15.

    Kremer JM, Cohen S, Wilkinson BE, 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;64:970-81.

    Not in our library10.1002/art.33419

16. 16.

    Fleischmann R, Kremer J, Cush J, et al. Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis. N Engl J Med. 2012;367:495-507.

    Not in our library10.1056/nejmoa1109071

17. 17.

    van Vollenhoven RF, Fleischmann R, Cohen S, et al. Tofacitinib or adalimumab versus placebo in rheumatoid arthritis. N Engl J Med. 2012;367:508-19.

    Not in our library10.1056/nejmoa1112072

18. 18.

    Sandborn WJ, Ghosh S, Panes J, et al. Tofacitinib, an oral Janus kinase inhibitor, in active ulcerative colitis. N Engl J Med. 2012;367:616-24.

    Not in our library10.1056/nejmoa1112168

19. 19.

    Racz E, Prens EP. Molecular pathophysiology of psoriasis and molecular targets of antipsoriatic therapy. Expert Rev Mol Med. 2009;11:e38.

    Not in our library10.1017/s146239940900129x

20. 20.

    Hirahara K, Ghoreschi K, Laurence A, et al. Signal transduction pathways and transcriptional regulation in Th17 cell differentiation. Cytokine Growth Factor Rev. 2010;21:425-34.

    Not in our library10.1016/j.cytogfr.2010.10.006

21. 21.

    Nestle FO, Kaplan DH, Barker J. Psoriasis. N Engl J Med. 2009;361:496-509.

    Not in our library10.1056/nejmra0804595

22. 22.

    Mak RK, Hundhausen C, Nestle FO. Progress in understanding the immunopathogenesis of psoriasis. Actas Dermosifiliogr. 2009;100(Suppl. 2):2-13.

    Not in our library10.1016/s0001-7310(09)73372-1

23. 23.

    Punwani N, Scherle P, Flores R, et al. Preliminary clinical activity of a topical JAK1/2 inhibitor in the treatment of psoriasis. J Am Acad Dermatol. 2012;67:658-64.

    Not in our library10.1016/j.jaad.2011.12.018

24. 24.

    van der Velden, Pasch MC, Van Erp PE, et al. Treatment of plaque psoriasis with the two-compound product calcipotriol/betamethasone dipropionate versus both monotherapies: an immunohistochemical study. J Dermatolog Treat. 2010;21:13-22.

    Not in our library10.3109/09546630903214175

25. 25.

    Veien NK, Bjerke JR, Rossmann-Ringdahl I, Jakobsen HB. Once daily treatment of psoriasis with tacalcitol compared with twice daily treatment with calcipotriol. A double-blind trial. Br J Dermatol. 1997;137:581-6.

    Not in our library10.1111/j.1365-2133.1997.tb03790.x

26. 26.

    Zhu X, Wang B, Zhao G, et al. An investigator-masked comparison of the efficacy and safety of twice daily applications of calcitriol 3 microg/g ointment vs. calcipotriol 50 microg/g ointment in subjects with mild to moderate chronic plaque-type psoriasis. J Eur Acad Dermatol Venereol. 2007;21:466-72.

    Not in our library10.1111/j.1468-3083.2006.01913.x

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• JAK3 as an Emerging Target for Topical Treatment of Inflammatory Skin Diseases · 2016
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• Reversal of Alopecia Areata Following Treatment With the JAK1/2 Inhibitor Baricitinib · 2015
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• Update on psoriasis immunopathogenesis and targeted immunotherapy · 2015
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