Background/Purpose: Tofacitinib (CP-690,550) is a novel, oral Janus kinase inhibitor being investigated as a targeted immunomodulator in rheumatoid arthtitis (RA). This 24-mo study compared efficacy, including reduction of structural damage progression, and safety of tofacitinib vs placebo (PBO) in pts with active RA with inadequate response to methotrexate (MTX).
Methods: Pts on stable dose MTX were randomized 4:4:1:1 to 1 of 4 sequences in this Phase 3 study (NCT00847613): tofacitinib 5 mg twice daily (BID); 10 mg BID; PBO advanced to 5 mg BID; PBO to 10 mg BID. Pts on PBO advanced at Mo 6, or at Mo 3 if non-responsive (<20% reduction from baseline [BL] in swollen/tender joint counts). Reported data are from planned 12‑mo analyses, which combined PBO into 1 group.
Results: 797 pts were randomized and treated. Pt groups were comparable for HAQ-DI, DAS28-4(ESR), disease duration, estimated structural progression, erosion score (ES), and positive RF/anti-CCP at BL. Tofacitinib 10 mg BID was efficacious compared with PBO in structure preservation measured by mean change from BL in modified Total Sharp Score (mTSS) at Mo 6 and demonstrated superior differences vs PBO for all 4 primary efficacy endpoints (Table). The 5 mg BID dose was superior to PBO for ACR20 response rates at Mo 6 but not for mTSS. Due to a step-down statistical procedure, significance was not declared for HAQ‑DI and DAS28-4(ESR) <2.6 for 5 mg BID. Secondary analyses showed that the proportion of pts with no radiographic progression (mTTS change from BL ≤0.5) or no new erosions (ES change from BL ≤0.5) was superior to PBO for both doses, and evaluation of subgroups with predictors of poor prognosis showed a consistent pattern of structure preservation. Adverse events (AEs), serious AEs and serious infection events (SIEs) were distributed across groups (Table). Most frequently-reported AEs in the tofacitinib groups were infections; most were mild with similar incidence in both groups. There were 6 deaths (5 mg BID, 4; 10 mg BID, 1; PBO, 1). Decreases in neutrophils, increases in LDL and HDL, and small increases in serum creatinine were seen with tofacitinib.
Conclusions: In this P3 study, tofacitinib significantly reduced progression of structural damage vs PBO in pts with active RA on MTX. Consistent with other studies, tofacitinib demonstrated significant and clinically meaningful reductions in signs and symptoms of RA and physical function. No new safety signals were detected.
Disclosure: D. van der Heijde, Abbott, Amgen, AstraZeneca, BMS, Centocor, Chugai, Eli-Lilly, GSK, Merck, Novartis, Otsuka, Pfizer, Roche, Sanofi-Aventis, Schering-Plough, UCB, Wyeth, 5 ; Y. Tanaka, Pfizer Inc, 5 ; R. Fleischmann, Pfizer Inc, 2, Pfizer Inc, 5 ; E. C. Keystone, Pfizer Inc, 2, Pfizer Inc, 5 ; J. M. Kremer, Pfizer Inc, 2, Pfizer Inc, 5 ; C. A. F. Zerbini, None; M. Cardiel, None; S. B. Cohen, Genentech and Biogen IDEC Inc., 5, Merck Pharmaceuticals, 5, Sanofi-Aventis Pharmaceutical, 5, Proctor & Gamble Pharmaceuticals, 5, Pfizer Inc, 5, Centocor, Inc., 3, Amgen, 5, Scios, Inc., 5, Bristol-Myers Squibb, 5, Wyeth Pharmaceuticals, 5 ; P. T. Nash, Pfizer Inc, Wyeth, 5, Pfizer Inc, Wyeth, 5 ; Y. W. Song, Pfizer Inc, 2 ; D. Tegzova, None; B. Wyman, Pfizer Inc, 3 ; D. Gruben, Pfizer Inc, 3 ; B. Benda, Pfizer Inc, 3 ; G. Wallenstein, Pfizer Inc, 1, Pfizer Inc, 3 ; S. H. Zwillich, Pfizer Inc, 3, Pfizer Inc, 1 ; J. D. Bradley, Pfizer Inc, 3 ; C. A. Connell, Pfizer Inc, 3 .