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

Stanley B Cohen, Yoshiya Tanaka, Xavier Mariette, Jeffrey R Curtis, Eun Bong Lee, Peter Nash, Kevin L Winthrop, Christina Charles-Schoeman, Lisy Wang, Connie Chen, Kenneth Kwok, Pinaki Biswas, Andrea Shapiro, Ann Madsen, Jürgen Wollenhaupt, Stanley B Cohen, Yoshiya Tanaka, Xavier Mariette, Jeffrey R Curtis, Eun Bong Lee, Peter Nash, Kevin L Winthrop, Christina Charles-Schoeman, Lisy Wang, Connie Chen, Kenneth Kwok, Pinaki Biswas, Andrea Shapiro, Ann Madsen, Jürgen Wollenhaupt

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: NCT01262118; NCT01484561; NCT00147498; NCT00413660; NCT00550446; NCT00603512; NCT00687193; NCT01164579; NCT00976599; NCT01059864; NCT01359150; NCT02147587; NCT00960440; NCT00847613; NCT00814307; NCT00856544; NCT00853385; NCT01039688; NCT02187055; NCT00413699; NCT00661661.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.

Keywords: Antirheumatic Agents; Arthritis; Rheumatoid; Therapeutics.

Conflict of interest statement

Competing interests: SBC has received grant/research support from AbbVie, Amgen, Astellas, Bristol-Myers Squibb, Eli Lilly, Genentech, Gilead, Janssen, Novartis, Pfizer Inc, Roche and Sandoz; and consultancy fees from AbbVie, Amgen, Astellas, Bristol-Myers Squibb, Eli Lilly, Genentech, Gilead, Janssen, Novartis, Pfizer Inc, Roche and Sandoz. YT has received grant/research support from AbbVie, Asahi Kasei, Astellas, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Eisai, Eli Lilly, Gilead, GlaxoSmithKline, Janssen, Mitsubishi Tanabe, Novartis, Pfizer Inc, Sanofi and YL Biologics; and speaker fees and/or honoraria from AbbVie, Astellas, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Eisai, Eli Lilly, Janssen, Mitsubishi Tanabe, Novartis, Pfizer Inc, Takeda, Teijin and YL Biologics. XM has received consultancy fees from Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Janssen, Pfizer Inc, Samsung and UCB. JRC has received grant/research support from Amgen, Corrona, Crescendo Bio and Pfizer Inc; and consultancy fees from AbbVie, Amgen, Bristol-Myers Squibb, Corrona, Eli Lilly, Janssen, Myriad, Pfizer Inc, Roche/Genentech and UCB. EBL has received consultancy fees from Pfizer Inc. PN has received grant/research support and consultancy fees from, and is part of the speakers’ bureau for, AbbVie, Bristol-Myers Squibb, Eli Lilly, Janssen, Novartis, Pfizer Inc, Roche, Sanofi and UCB. KLW has received grant/research support and consultancy fees from AbbVie, Bristol-Myers Squibb, Eli Lilly, Gilead, Pfizer Inc, Roche and UCB. CC-S has received grant/research support from AbbVie, Bristol-Myers Squibb and Pfizer Inc; and consultancy fees from Gilead, Pfizer Inc and Regeneron-Sanofi. LW, CC, KK, PB, AS and AM are employees and shareholders of Pfizer Inc. JW has received consultancy fees from, and is on the speaker’s bureau for, Pfizer Inc.

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1
Figure 1
IRs for (A) SIEs, (B) HZ (non-serious and serious) and (C) OIs (excluding TB) over time, for all tofacitinib doses (first events). HZ, herpes zoster; IR, incidence rate; OI, opportunistic infection; SIE, serious infection event; TB, tuberculosis.
Figure 2
Figure 2
HRs of potential risk factors for (A) SIEs (including post-baseline lymphopenia †In Unit=x, ‘x’ is the change in the continuous variable corresponding to which the change in hazards is observed. §Medical history and/or complication of COPD. Aus, Australia; COPD, chronic obstructive pulmonary disease; HAQ-DI, Health Assessment Questionnaire-Disability Index; HR, hazard ratio; HZ, herpes zoster; LTE, long-term extension; NZ, New Zealand; OI, opportunistic infection; ROW, rest of world; SIE, serious infection event; TB, tuberculosis.
Figure 3
Figure 3
IRs for (A) malignancies (excluding NMSC) and (B) NMSC over time, for all tofacitinib doses. IR; incidence rate; NMSC, non-melanoma skin cancer.

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