Background/Purpose: Tofacitinib is an oral Janus kinase inhibitor for the treatment of RA. Here, we report the largest integrated safety analysis of tofacitinib to date using data from Phase (P)1, P2, P3, P3b/4, and open-label long-term extension (LTE) studies in adult patients (pts) with RA.

Methods: Data were pooled for pts who received ≥1 tofacitinib dose, as monotherapy or with background conventional synthetic DMARDs (csDMARDs), integrated across 2 P1, 10 P2, 6 P3, 1 P3b/4, and 2 LTE studies (ORAL Sequel LTE main study database locked at time of analysis: March 2017). Incidence rates (IR; pts with events per 100 patient-years [PY]) and 95% confidence intervals were obtained for safety events of special interest. Additionally, IRs for deep vein thrombosis (DVT) and pulmonary embolism (PE) are reported. IRs were based on the number of pts with incident events during the time between the first and last dose plus 28 days, which was the clinical trial observation period (previous analyses included events outside of the observation period).

Results: This analysis included 7061 pts, representing 22,875 PY of tofacitinib exposure, with a median exposure of 3.1 years, and 30% of pts had >5 years of exposure. A total of 1634 (23.1%) pts discontinued due to adverse events (AEs; IR: 7.1 [6.8, 7.5]). The most common treatment-emergent AEs by MedDRA v20.0 preferred term were viral upper respiratory tract infection (17.3%), upper respiratory tract infection (17.2%), and urinary tract infection (11.8%). The IR for serious AEs was 9.0 (8.6, 9.4), of which infections were the most common. Serious infections occurred in 576 pts (8.2%; IR: 2.5 [2.3, 2.7]), and pneumonia was the most frequently reported serious infection (124 pts [22% of all pts with serious infections]). Overall, 782 pts (11.1%) developed herpes zoster (HZ; IR: 3.6 [3.4, 3.9]); in most pts HZ involved a single dermatome (90.2%). Serious HZ was reported in 57 pts (7.3% of all pts with HZ). Opportunistic infections (excluding tuberculosis [TB]) were reported in 90 pts (1.3%; IR: 0.4 [0.3, 0.5]) and TB was reported in 38 pts (0.5%; IR: 0.2 [0.1, 0.2]). Malignancies (excluding non-melanoma skin cancer [NMSC]) occurred in 177 pts (2.5%; IR: 0.8 [0.7, 0.9]), NMSC in 129 pts (1.8%; IR: 0.6 [0.5, 0.7]) and lymphomas in 12 pts (0.2%; IR: 0.1 [0.0, 0.1]). Gastrointestinal perforations were reported in 28 pts (0.4%; IR: 0.1 [0.1, 0.2]) and major adverse cardiovascular events in 85 pts (1.3%; IR: 0.4 [0.3, 0.5]). DVT was reported in 27 pts (0.4%; IR: 0.12 [0.08, 0.17]) and PE in 28 pts (0.4%; IR: 0.12 [0.08, 0.17]). There were 59 deaths (0.8%; IR: 0.3 [0.2, 0.3]). IRs for AEs of interest were stable across 6-month intervals.

Conclusion: This long-term integrated safety analysis with up to 9.5 years of follow-up and 22,875 PY of tofacitinib exposure represents one of the largest clinical datasets to date for an advanced RA treatment. The safety profile of tofacitinib remained consistent with those of previous randomized controlled trials in the RA clinical development program.