Background/Purpose: Tofacitinib is a novel, oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). This analysis provides comparative safety data on the incidence of safety events for patients (pts) with an inadequate response (IR) to a nonbiologic disease-modifying antirheumatic drug (DMARD-IR) versus pts with an IR to a biologic DMARD (bDMARD-IR). These data were presented previously.¹

Methods: The primary comparison was performed on pooled data from 5 randomized, controlled Phase 3 (P3) studies in RA pts treated with tofacitinib 5 mg or 10 mg BID for 6 to 12 months. Supportive analyses were conducted on 2 pooled open-label long-term extension (LTE) studies. All pts enrolled were nonbiologic or biologic DMARD-IR.

Results: In the pooled P3 studies, 2389 tofacitinib-treated pts with 1783 pt-years (pt‑yrs) of exposure were analyzed in the DMARD-IR population and 641 pts with 315 pt-yrs of exposure in the bDMARD-IR group. Baseline demographics were generally similar, albeit the bDMARD-IR group was generally older, heavier and had fewer Asian pts. Compared with the DMARD-IR, the bDMARD-IR population exhibited increases in the rate (events/100 pt-yrs) of serious adverse events (SAEs) (12.3 [95% confidence interval (CI) 9.0, 16.9] vs 9.9 [8.6, 11.5]) and discontinuations due to adverse events (AE DC) (15.0 [95% CI 11.3, 20.0] vs 9.6 [7.7, 12.1]) in both tofacitinib treatment arms and in placebo. There were four adalimumab pts (and 0 events) that were bDMARD-IR. The rates of deaths, serious infections (SI), malignancies and major adverse cardiovascular events were similar across the populations (Table). LTE studies included 2715 pts with 3588 pt-yrs of exposure in the DMARD-IR population and 566 pts with 514 pt-yrs of exposure in the bDMARD‑IR group. As compared with the DMARD-IR, the bDMARD-IR population showed increases in rates (events/100 pt-yrs) of SAEs (14.6 [95% CI 11.6, 18.4] vs 10.2 [9.2, 11.3]), AE DC (10.0 [95% CI 7.6, 13.1] vs 6.8 [6.0, 7.7]) and SIs (4.7 [95% CI 3.1, 7.0] vs 2.7 [2.2, 3.3]). The rates of the other safety events were similar.

Conclusion: Event rates for important safety events for both DMARD-IR and bDMARD-IR pts are within the ranges observed with biologic therapies approved for treatment of RA with some differences noted in SI (LTE only), SAE and AE DC favoring the DMARD-IR population.

Reference:   1. Burmester G et al.  Ann Rheum Dis 2013; 72: 245-245.

Table  Incidence Rates (Events/100 Pt-Yrs) for Safety Events in DMARD-IR and bDMARD-IR Populations in the Pooled Phase 3 Studies

	DMARD-IR Incidence Rate (95% CI) [number of pts with event]					bDMARD-IR Incidence Rate (95% CI) [number of pts with event]
Parameter	Tofacitinib			Placebo n=500	Adalimumab n=200	Tofacitinib			Placebo n=181
	5 mg BID n=969	10 mg BID n=973	All* n=2389			5 mg BID n=247	10 mg BID n=241	All* n=641
Mortality (deaths within 30 days of last dose)	0.52 (0.20, 1.40) [4]	0.51 (0.19, 1.37) [4]	0.45 (0.22, 0.90) [8]	0.63 (0.09, 4.44) [1]	0.57 (0.08, 4.04) [1]	0.71 (0.10, 5.05) [1]	0	0.64 (0.16, 2.54) [2]	0
Serious Infections	3.29 (2.22, 4.86) [25]	3.08 (2.07, 4.60) [24]	2.92 (2.23, 3.84) [52]	1.88 (0.61, 5.82) [3]	1.71 (0.55, 5.31) [3]	2.85 (1.07, 7.58) [4]	2.30 (0.74, 7.13) [3]	2.86 (1.49, 5.49) [9]	0
Malignancies (excl. NMSC†)	0.52 (0.20, 1.40) [4]	0.77 (0.35, 1.71) [6]	0.56 (0.30, 1.04) [10]	0	0.57 (0.08, 4.05) [1]	0.71 (0.10, 5.05) [1]	1.53 (0.38, 6.13) [2]	0.95 (0.31, 2.95) [3]	0
Composite MACEΨ (adjudicated)	0.39 (0.13, 1.22) [3]	0.64 (0.27, 1.54) [5]	0.45 (0.22, 0.90) [8]	1.25 (0.31, 5.00) [2]	1.71 (0.55, 5.30) [3]	0.71 (0.10, 5.06) [1]	0.77 (0.11, 5.45) [1]	1.27 (0.48, 3.39) [4]	0
*Tofacitinib All group comprises pts randomized to tofacitinib 5 or 10 mg BID at study start plus placebo pts advanced to tofacitinib treatment per protocol design. Placebo pts advanced to tofacitinib are counted in placebo until advancement and in the “Tofacitinib All” group after advancement. †NMSC, nonmelanoma skin cancer. ΨMACE, major adverse cardiovascular events. All data as of 29 Sep 2011

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