Background/Purpose: Tofacitinib is a novel, oral Janus kinase inhibitor being investigated as a targeted immunomodulator and disease-modifying therapy in RA. Here we report the safety and tolerability of tofacitinib and the durability of response up to 48 months (mo) in long-term extension (LTE) studies.

Methods: Data were pooled from two open-label studies (NCT00413699, NCT00661661) involving patients (pts) who had participated in randomized Phase (P)2 or P3 studies of tofacitinib. Treatment was initiated with tofacitinib 5 or 10 mg twice-daily (BID); data from doses are pooled. Baseline was that of the P2 or P3 study for pts enrolling within 14 days of participation; if enrollment was >14 days after participation, baseline was the start of the LTE study. Primary endpoints were adverse events (AE) and confirmed laboratory safety data. Secondary endpoints included ACR responses, DAS28‑4(ESR), and HAQ-DI. Safety data were included over 60 mo of observation but efficacy data were only available up to Mo 48 (limited pt numbers [n=58] post-Mo 48).

Results: 4102 pts were treated for a total duration of 6034 patient-years (pt‑y); mean (maximum) treatment duration was 531 (1844) days. 852 pts (20.8%) discontinued (AEs: 440 [10.7%]; lack of efficacy: 83 [2.0%]; other: 329 [8.1%]). The most commonly reported classes of AEs were infections and infestations (50.8%), gastrointestinal disorders (23.6%), musculoskeletal/connective tissue disorders (23.4%), and investigations (16.1%). The most frequent investigator-reported AEs (%) were nasopharyngitis (12.7%), upper respiratory tract infection (10.5%), and urinary tract infection (6.6%). Serious AEs (SAEs) were reported in 15.4% of pts with an incidence rate (IR) of 11.11 per 100 pt-y (95% CI 10.28, 12.02). Serious infection events (SIEs) were reported in 4.5% of pts with an IR of 3.07 per 100 pt-y (95% CI 2.66, 3.55). IRs for SAEs and SIEs did not increase between 36-¹and 48-mo observations.

Decreased hemoglobin (Hgb; ≥2 g/dL from baseline, or Hgb <8 g/dL) was observed in 3.5% of pts. Raised aminotransferases (>3 x upper limit of normal) were observed in 3.2% (ALT) and 1.5% (AST) of pts. Moderate-to-severe neutropenia (absolute neutrophil count [ANC] 0.5–1.5 x 10³/mm³) was reported in 0.7% of pts; there were no cases of confirmed ANC <0.5 x 10³/mm³. Increases (>50% from baseline) in creatinine were noted in 3.2% of pts. Mean values for laboratory safety measures were consistent with observations in P2 and P3 studies, and were stable over time.

Efficacy was maintained through Mo 48. ACR20, ACR50, and ACR70 responses in pts treated with tofacitinib 5 and 10 mg BID (results pooled) at Mo 1 and Mo 48 were 67% and 69%, 44% and 47%, and 25% and 31%, respectively. Mean DAS28-4(ESR) was 6.2 at baseline, and was reduced to 3.8 at Mo 1, and 3.6 at Mo 48.  Mean HAQ-DI score was 1.4 at baseline and improved to 0.85 at Mo 1, and 0.81 at Mo 48.

Safety and efficacy were similar for pts receiving tofacitinib as monotherapy or with background DMARDs.

Conclusion: Tofacitinib dosed at 5 or 10 mg BID in pts with RA demonstrated a consistent safety profile and sustained efficacy over 48 mo in open-label LTE studies.

References

   1.   Wollenhaupt J et al. Arthritis and Rheumatism 2011; 63: S153.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/tofacitinib-an-oral-janus-kinase-inhibitor-in-the-treatment-of-rheumatoid-arthritis-open-label-long-term-extension-safety-and-efficacy-up-to-48-months/