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Long-term safety of tofacitinib up to 9.5 years: a comprehensive integrated analysis of the rheumatoid arthritis clinical development programme

Author

RMD Open. 2020 Oct;6(3):e001395. doi: 10.1136/rmdopen-2020-001395.

Stanley B Cohen 1, Yoshiya Tanaka 2, Xavier Mariette 3, Jeffrey R Curtis 4, Eun Bong Lee 5, Peter Nash 6, Kevin L Winthrop 7, Christina Charles-Schoeman 8, Lisy Wang 9, Connie Chen 10, Kenneth Kwok 10, Pinaki Biswas 10, Andrea Shapiro 11, Ann Madsen 10, Jürgen Wollenhaupt 12

Author Information

1 Metroplex Clinical Research Center and University of Texas Southwestern Medical Center, Dallas, Texas, USA.

2 University of Occupational and Environmental Health, Kitakyushu, Japan.

3 Paris-Saclay University, AP-HP, INSERM, Le Kremlin Bicêtre, France.

4 University of Alabama at Birmingham, Birmingham, Alabama, USA.

5 Seoul National University, Seoul, Korea (the Democratic People's Republic of).

6 Department of Medicine, Griffith University, Brisbane, Australia.

7 Oregon Health and Science University, Portland, Oregon, USA.

8 University of California, Los Angeles, California, USA.

9 Pfizer Inc, Groton, Connecticut, USA Lisy.Wang@Pfizer.com.

10 Pfizer Inc, New York, New York, USA.

11 Pfizer Inc, Peapack, New Jersey, USA.

12 Struenseehaus Centre for Rheumatology and Clinical Immunology, Hamburg, Germany.

Abstract

Objective: Tofacitinib is an oral Janus kinase (JAK) inhibitor for the treatment of rheumatoid arthritis (RA). We report the largest integrated safety analysis of tofacitinib, as of March 2017, using data from phase I, II, III, IIIb/IV and long-term extension studies in adult patients with RA.

Methods: Data were pooled for patients with RA who received ≥1 tofacitinib dose. Incidence rates (IRs; patients with events/100 patient-years [PY]; 95% CIs) of first-time occurrences were obtained for adverse events (AEs) of interest.

Results: 7061 patients received tofacitinib (total exposure: 22 875 PY; median [range] exposure: 3.1 [0 to 9.6] years). IRs (95% CI) for serious AEs, serious infections, herpes zoster (all), opportunistic infections (excluding tuberculosis [TB]) and TB were 9.0 (8.6 to 9.4), 2.5 (2.3 to 2.7), 3.6 (3.4 to 3.9), 0.4 (0.3 to 0.5) and 0.2 (0.1 to 0.2), respectively. IRs (95% CI) for malignancies (excluding non-melanoma skin cancer [NMSC]), NMSC and lymphomas were 0.8 (0.7 to 0.9), 0.6 (0.5 to 0.7) and 0.1 (0.0 to 0.1), respectively. IRs (95% CI) for gastrointestinal perforations, deep vein thrombosis, pulmonary embolism, venous thromboembolism, arterial thromboembolism and major adverse cardiovascular events were 0.1 (0.1 to 0.2), 0.2 (0.1 to 0.2), 0.1 (0.1 to 0.2), 0.3 (0.2 to 0.3), 0.4 (0.3 to 0.5) and 0.4 (0.3 to 0.5), respectively. IR (95% CI) for mortality was 0.3 (0.2 to 0.3). IRs generally remained consistent across 6-month intervals to >78 months.

Conclusion: This represents the largest clinical dataset for a JAK inhibitor in RA to date. IRs remained consistent with previous reports from the tofacitinib RA clinical development programme, and stable over time.

Trial registration numbers: NCT01262118NCT01484561NCT00147498NCT00413660NCT00550446NCT00603512NCT00687193NCT01164579NCT00976599NCT01059864NCT01359150NCT02147587NCT00960440NCT00847613NCT00814307NCT00856544NCT00853385NCT01039688NCT02187055NCT00413699NCT00661661.For summary of phase I, phase II, phase III, phase IIIb/IV and LTE studies included in the integrated safety analysis, see online supplemental table 1.