Tofacitinib

Zusammenfassung

Tofacitinib wurde 2012 als erster oral applizierbare Januskinase-Inhibitor zur Behandlung der Rheumatoiden Arthritis in den USA zugelassen. Die Wirksamkeit als Monotherapie als auch in Kombination mit etablierten Medikamenten ist durch mehreren Phase III Studien belegt. In diesem Artikel wird das therapeutische Potenzial dieses Wirkprinzips diskutiert und die aktuelle Datenlage zur Effektivität und Sicherheit einer Tofacitinib-Therapie mit Fokus auf eine mögliche Zulassung in der EU beurteilt.

Abstract

Tofacitinib is the first Janus kinase inhibitor which was approved for the therapy of rheumatoid arthritis in the USA. Several phase III studies proved the efficacy of Tofacitinib as monotherapy or in combination with established medication. This article discusses the therapeutic potential of this new pharmacological approach and the current data on efficacy and safety of Tofacinib therapy with special emphasis on a prospective approval in the EU.

Schlüsselwörter

Tofacitinib - Januskinase-Inhibitor - Rheumatoide Arthritis - Immunsuppression - Autoimmunerkrankungen

Keywords

tofacitinib - janus kinase inhibitor - rheumatoid arthritis - immunosuppression - autoimmune diseases

• Literatur

• 1 Baker SJ, Rane SG, Reddy EP. Hematopoietic cytokine receptor signaling. Oncogene 2007; 26: 6724-6737
• 2 Burmester GR, Blanco R, Charles-Schoeman C 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: 451-460
• 3 Changelian PS, Flanagan ME, Ball DJ et al. Prevention of organ allograft rejection by a specific Janus kinase 3 inhibitor. Science 2003; 302: 875-878
• 4 Cohen S, Zwillich SH, Chow V et al. Co-administration of the JAK inhibitor CP-690,550 and methotrexate is well tolerated in patients with rheumatoid arthritis without need for dose adjustment. Br J Clin Pharmacol 2009; 69: 143-151
• 5 EMA/248755/2013. Refusal of the marketing authorisation for Xeljanz (tofacitinib). 2013. http://www.ema.europa.eu/ema/pages/includes/document/open_document.jsp?webContentId=WC500142485 [cited 2013 September 11].
• 6 EULAR. Updated EULAR Recommendations on Management of Rheumatoid Arthritis (RA). 2013. www.eular.org/myUploadData/files/EULAR%20RA%20recommendations%20FINAL.pdf [cited 2013 September 11].
• 7 FDA. FDA News Release: FDA approves Xeljanz for rheumatoid arthritis. 2012. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm327152.htm [cited 2013 September 11].
• 8 Felson DT, Anderson JJ, Boers M et al. American College of Rheumatology. Preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum 1995; 38: 727-735
• 9 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
• 10 Fox DA. Kinase inhibition-a new approach to the treatment of rheumatoid arthritis. N Engl J Med 2012; 367: 565-567
• 11 Fransen J, van Riel PL. The Disease Activity Score and the EULAR response criteria. Clin Exp Rheumatol 2005; 23: 93-S99
• 12 Fries JF, Spitz P, Kraines RG et al. Measurement of patient outcome in arthritis. Arthritis Rheum 1980; 23: 137-145
• 13 Gupta P, Alvey C, Wang R 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: 109-115
• 14 Johnston JA, Kawamura M, Kirken RA et al. Phosphorylation and activation of the Jak-3 Janus kinase in response to interleukin-2. Nature 1994; 370: 151-153
• 15 Kremer J, Li Z, Hall S 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. 03) 170
• 16 Kudlacz E, Perry B, Sawyer P et al. The novel JAK-3 inhibitor CP-690550 is a potent immunosuppressive agent in various murine models. Am J Transplant 2004; 4: 51-57
• 17 McInnes IB, Schett G. The pathogenesis of rheumatoid arthritis. N Engl J Med 2011; 365: 2205-2219
• 18 Meyer DM, Jesson MI, Li X 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: 41
• 19 Milici AJ, Kudlacz EM, Audoly L et al. Cartilage preservation by inhibition of Janus kinase 3 in two rodent models of rheumatoid arthritis. Arthritis Res Ther 2008; 10: R14
• 20 Musso T, Johnston JA, Linnekin D et al. Regulation of JAK3 expression in human monocytes: phosphorylation in response to interleukins 2, 4, and 7. J Exp Med 1995; 181: 1425-1431
• 21 O'Shea JJ, Pesu M, Borie DC et al. A new modality for immunosuppression: targeting the JAK/STAT pathway. Nat Rev Drug Discov 2004; 3: 555-564
• 22 Ory PA. Interpreting radiographic data in rheumatoid arthritis. Ann Rheum Dis 2003; 62: 597-604
• 23 Pfizer. Tofacitinib for Treatment of Rheumatoid Arthritis (NDA 203214). Advisory Meeting, 2012. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ArthritisAdvisoryCommittee/UCM302960.pdf [cited 2013 September 11].
• 24 Pfizer. Xeljanz® (Tofacitinib), Prescribing Information. 2012. http://www.xeljanz.com or http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203214Orig1s000TOC.cfm [cited 2013 September 11].
• 25 Riese RJ, Krishnaswami S, Kremer J. Inhibition of JAK kinases in patients with rheumatoid arthritis: scientific rationale and clinical outcomes. Best Pract Res Clin Rheumatol 2010; 24: 513-526
• 26 Schneider M, Lelgemann M, Abholz H-H, Blumenroth M, Flügge C, Gerken M, Jäniche H, Kunz R, Krüger K, Mau W, Specker C, Zellner M. Interdisziplinäre Leitlinie: Management der frühen rheumatoiden Arthritis. 3rd. Edition ed. Berlin, Heidelberg, New York: Springer Verlag; 2011
• 27 Scott DL, Wolfe F, Huizinga TW. Rheumatoid arthritis. Lancet 2010; 376: 1094-1108
• 28 Sharp JT, Lidsky MD, Collins LC et al. Methods of scoring the progression of radiologic changes in rheumatoid arthritis. Correlation of radiologic, clinical and laboratory abnormalities. Arthritis Rheum 1971; 14: 706-720
• 29 Smolen JS, Steiner G. Therapeutic strategies for rheumatoid arthritis. Nat Rev Drug Discov 2003; 2: 473-488
• 30 van der Heijde D. How to read radiographs according to the Sharp/van der Heijde method. J Rheumatol 2000; 27: 261-263
• 31 van der Heijde D, Tanaka Y, Fleischmann R 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: 559-570
• 32 van Vollenhoven RF, Fleischmann R, Cohen S et al. Tofacitinib or adalimumab versus placebo in rheumatoid arthritis. N Engl J Med 2012; 367: 508-519
• 33 van Vollenhoven RF. Treatment of rheumatoid arthritis: state of the art 2009. Nat Rev Rheumatol 2009; 5: 531-541
• 34 Vijayakrishnan L, Venkataramanan R, Gulati P. Treating inflammation with the Janus kinase inhibitor CP-690,550. Trends Pharmacol Sci 2011; 32: 25-34
• 35 Witthuhn BA, Silvennoinen O, Miura O et al. Involvement of the Jak-3 Janus kinase in signalling by interleukins 2 and 4 in lymphoid and myeloid cells. Nature 1994; 370: 153-157