Tofacitinib - An Oral Janus Kinase Inhibitor

Tofacitinib (CP-690,550) is an oral Janus Kinase Inhibitor. While biologics interfere with intercellular communication, the new small molecules interfere with intracellular communication.


Tofacitinib in Patients with Active Rheumatoid Arthritis: A 12-Week Phase 2b Study

Y. Tanaka and colleagues compared efficacy, safety, and tolerability of 5 doses of tofacitinib monotherapy vs placebo for treatment of rheumatoid arthritis in Japanese pts with inadequate response to DMARDs. The primary endpoint, however, has been ACR20 response rate at week 12 . All tofacitinib doses were superior compared with placebo and a clear dose-response has been observed. ACR50 and ACR70 response rates also showed a dose-response at Wk 12. The most common adverse events were nasopharyngitis, hyperlipidemia, and increased LDL; these were reported to be mild in severity.

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Tofacitinib (CP-690,550), An Oral Janus Kinase Inhibitor, As Monotherapy in Japanese Patients with Active Rheumatoid Arthritis: A 12-Week Phase 2b Study.
Y. Tanaka1, T. Takeuchi2, H. Yamanaka3, M. Suzuki4, H. Nakamura4, S. Toyoizumi4, J. D. Bradley5 and S. H. Zwillich5. 1University of Occupational & Environmental Health, Kitakyushu, Fukuoka, Japan, 2Keio University School of Medicine, Tokyo, Japan, 3Institute of Rheumatology, Tokyo Women’s Medical University, Tokyo, Japan, 4Pfizer Inc., Tokyo, Japan, 5Pfizer Inc., Groton, CT
Conclusion: When used as monotherapy, tofacitinib dosed 1 mg BID demonstrated superior ACR20 response rates compared with placebo at week 12. Doses of tofacitinib 5, 10, and 15 mg BID demonstrated superiority to placebo in DAS28-4(ESR) 2.6. The safety profile of tofacitinib monotherapy was manageable in Japanese patients with longstanding active rheumatoid arthritis.


Tofacitinib in Combination with Methotrexate Reduced the Progression of Structural Damage in Patients with Rheumatoid Arthritis: a 24-Month Phase 3 Study

Désirée van der Heijde and colleagues compared efficacy, reduction of structural damage progression, and safety of tofacitinib vs placebo in pts with active rheumatoid arthtitis with inadequate response to methotrexate (MTX). Tofacitinib significantly reduced progression of structural damage vs placebo in patients with active rheumatoid arthtitis on methotrexate.

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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.
Désirée van der Heijde1, Y. Tanaka2, Roy Fleischmann3, Edward C. Keystone4, et al.
1Department of Rheumatology, Leiden University Medical Center, Leiden, Netherlands, 2University of Occupational & Environmental Health, Kitakyushu, Fukuoka, Japan, 3University of Texas Southwestern Medical Center, etc.
Conclusion: In this P3 study, tofacitinib significantly reduced progression of structural damage vs PBO in pts with active RA on MTX. Consistent with other studies, tofacitinib demonstrated significant and clinically meaningful reductions in signs and symptoms of RA and physical function. No new safety signals were detected.


Tofacitinib in Combination with Traditional Disease-Modifying Anti-Rheumatic Drugs: Phase 3 Study

V. Strand and colleagues compared efficacy and safety of tofacitinib vs placebo in pts with active rheumatoid arthritis with an inadequate response to one DMARD (traditional or biologic). The study showed statistically significant and clinically meaningful improvements in multiple patient-reported outcomes vs placebo at month 3.

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Tofacitinib (CP-690,550) in Combination with Traditional Disease-Modifying Anti-Rheumatic Drugs: Phase 3 Study Patient-Reported Outcomes in Patients with Active Rheumatoid Arthritis and An Inadequate Response to Disease-Modifying Anti-Rheumatic Drugs.
V. Strand1, J. M. Kremer2, Z. G. Li3, S. Hall4, Roy M. Fleischmann5, M. C. Genovese6, et al.
1Stanford University, Palo Alto, CA, 2Albany Medical College and The Center for Rheumatology, Albany, NY, 3Peking University People’s Hospital, etc.
Conclusion: In this Phase 3 study of tofacitinib in combination with traditional DMARDs, treatment with 5 and 10 mg BID resulted in consistent statistically significant and clinically meaningful improvements in multiple patient-reported outcomes vs placebo at month 3.


Tofacitinib in the Treatment of Rheumatoid Arthritis: Open-Label, Long-Term Extension Studies up to 36 Months

J. Wollenhaupt and colleagues reported the safety and tolerability of tofacitinib and the durability of clinical response up to 36 months in long-term extension studies in patients with active rheumatoid arthritis. A total of 3227 patients were treated for a total duration of 3118 patient-years. Tofacitinib demonstrated a well-tolerated safety profile and sustained long-term efficacy over a period of 36 months.

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Tofacitinib (CP-690,550), An Oral Janus Kinase Inhibitor, in the Treatment of Rheumatoid Arthritis: Open-Label, Long-Term Extension Studies up to 36 Months.
J. Wollenhaupt1, J. C Silverfield2, E. B. Lee3, S. Wood4, K. Soma5, L. Wang5, H. Nakamura6, Y. Komuro6, C. I. Nduaka5, D. Gruben5, S. H. Zwillich5 and J. D. Bradley5.
1Teaching Hospital of the University of Hamburg, Hamburg, Germany, 2Tampa Medical Group, P.A., Tampa, FL, 3Hanyang University Hospital, Seoul, 4Pfizer Inc., Groton, NJ, 5Pfizer Inc., Groton, CT, 6Pfizer Inc., Tokyo, Japan
Conclusion: Treatment with tofacitinib at doses of 5 or 10 mg BID in pts with RA demonstrated a well-tolerated safety profile and sustained long-term efficacy over a 36-mo period.


Tofacitinib (CP-690,550), An Oral Janus Kinase Inhibitor, or Adalimumab Versus Placebo in Patients with Rheumatoid Arthritis on Background Methotrexate: A Phase 3 Study

R.F. van Vollenhoven and colleagues compared the efficacy and safety of tofacitinib and an active comparator, adalimumab, vs placebo in patients with active rheumatoid arthritis with inadequate response to methotrexate. Efficacy of tofacitinib and Adalimumab were similar, when given on methotreaxate background.

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Tofacitinib (CP-690,550), An Oral Janus Kinase Inhibitor, or Adalimumab Versus Placebo in Patients with Rheumatoid Arthritis on Background Methotrexate: A Phase 3 Study.
R.F. van Vollenhoven1, R. M. Fleischmann2, S. B. Cohen3, E. B. Lee4, G. Meijide5, S. Wagner6, S. Forejtova7, S. H. Zwillich8, D. Gruben8, T. Koncz9, G. Wallenstein8, S. Krishnaswami8, J. D. Bradley8, B. Wilkinson8 and the ORAL Standard investigators10.
1Karolinska Institute, Stockholm, Sweden, 2Metroplex Clinical Research Center, Dallas, TX, 3Metroplex Clinical Research
Conclusion: Tofacitinib demonstrated rapid, significant, and clinically meaningful reductions in signs and symptoms of RA and physical function. No new tofacitinib safety signals were detected. Efficacy results with tofacitinib and ADA, when both were given on MTX background, were similar.


Tofacitinib: Analysis of Infections and All-Cause Mortality Across Phase 3 and Long-Term Extension Studies in Patients with Rheumatoid Arthritis

S. Cohen and colleagues showed data on infection and mortality for patients with rheumatoid arthritis, pooled from P3 and long-term extension studies. The safety profile of tofacitinib was consistent with the previous experience and no new safety signals were observed.


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Tofacitinib (CP-690,550), An Oral Janus Kinase Inhibitor: Analysis of Infections and All-Cause Mortality Across Phase 3 and Long-Term Extension Studies in Patients with Rheumatoid Arthritis.
S. Cohen1, S. C. Radominski2, P. Asavatanabodee3, S. P. Wood4, K. Soma4, C. I. Nduaka4, L. Wang4, D. Gruben4, H. Valdez5, S. H. Zwillich4 and J. Bradley4.
1Metroplex Clinical Research Centre, Dallas, TX, 2Universidade Federal do Paraná, Curitiba, Brazil, 3Phramongkutklao Hospital and College of Medicine, Bangkok, Thailand, 4Pfizer Inc., Groton, CT, 5Pfizer Inc., New York, NY
Conclusion: In P3 and LTE studies, mortality rates were consistent with the expected rate in pts with active RA, including those receiving therapy with other DMARDs. The safety profile of tofacitinib with regard to infection AEs was consistent with the previously reported P2 experience and no new safety signals were observed.