Background/Purpose: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). Serious infection events (SIEs) have been reported in the tofacitinib RA trials. Limited head-to-head comparator data are available within the tofacitinib RA development program to directly compare rates of events relative to approved biologic therapies. Here we present a meta-analysis of published randomized controlled trials (RCTs) and corresponding long-term extension (LTE) studies to contextualize the risk of SIEs for tofacitinib relative to biologics approved for treatment of moderate to severe RA.

Methods: A systematic literature search (Medline, Embase, PubMed, and regulatory submission documents for approved therapies) was conducted through October 2013. A total of 66 RCTs and 22 LTE trials met the inclusion criteria for the meta-analysis. Incidence rates (per 100 patient-years) of SIEs for each therapy across trials were estimated based on RCT and LTE data using a random effects model. Relative and absolute risk comparisons to placebo were made using RCT data only, based on Mantel-Haenszel methods. Placebo-controlled data ranging between 3-12 months for biologics and 3 months for tofacitinib were assessed. Statistical heterogeneity was assessed using I² statistic.

Results: Incidence rate (per 100 patient-years [95% CI]) estimates from the meta-analysis were 3.04 (2.49, 3.72) for abatacept, 3.72 (2.99, 4.62) for rituximab, 5.45 (4.26, 6.96) for tocilizumab, and 4.90 (4.41, 5.44) across TNF inhibitor (TNFi) therapies. The tofacitinib incidence rates from the five Phase (P) 3 trials only were 3.02 (2.25, 4.05) and 3.00 (2.24, 4.02) for 5 mg twice daily (BID) and 10 mg BID, respectively. The incidence rates in the ongoing LTE studies (as of August 2013) were 2.50 (2.05, 3.04) for 5 mg BID and 3.19 (2.74, 3.72) for 10 mg BID. The risk ratio (RR; [95% CI]) for TNFi relative to placebo in methotrexate inadequate responder (MTX-IR) trials (n=24) was 1.50 (1.00, 2.25). The tofacitinib RRs, relative to placebo, in P3 were 2.21 (0.60, 8.14) for 5 mg BID and 2.02 (0.56, 7.28) for 10 mg BID. Risk differences (expressed as difference in incidence percent; RD; [95% CI]) relative to placebo were 0.94% (0.25%, 1.63%) for TNFi therapies, 0.38% (-0.24%, 0.99%) for tofacitinib 5 mg BID, and 0.40% (-0.22%, 1.02%) for tofacitinib 10 mg BID. Separate analyses of MTX-naïve studies (n=10) showed a RR of 1.24 (0.87, 1.77) for TNFi relative to MTX. RRs from the tofacitinib ORAL Start (A3921069) study vs. MTX were similar to the TNFi estimates for both tofacitinib doses (i.e. 1.10 [0.39, 3.11] for 5 mg BID and 0.75 [0.25, 2.26] for 10 mg BID).

Conclusion: This meta-analysis provided an indirect quantitative assessment of the SIEs for biological therapies to contextualize data from the tofacitinib RA clinical development program. Comparisons of incidence rates, RRs and RDs suggest that risk of SIEs with tofacitinib is comparable to published rates for biologic therapies in the treatment of moderate to severe RA.