Tofacitinib 5 mg Twice Daily in Patients with Rheumatoid Arthritis and Inadequate Response to Disease-Modifying Antirheumatic Drugs: A Comprehensive Review of Phase 3 Efficacy and Safety

Abstract

Background: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). We performed a comprehensive review of phase 3 studies of tofacitinib 5 mg twice daily (BID) (approved dose in many countries) in patients with moderate to severe RA and inadequate response to prior disease-modifying antirheumatic drugs.

Methods: A search of PubMed and ClinicalTrials.gov identified 5 studies: ORAL Solo (NCT00814307), ORAL Sync (NCT00856544), ORAL Standard (included adalimumab 40 mg once every 2 weeks; NCT00853385), ORAL Scan (NCT00847613), and ORAL Step (NCT00960440). Efficacy and safety data for tofacitinib 5 mg BID, placebo, and adalimumab were analyzed.

Results: Across the 5 studies, 1216 patients received tofacitinib 5 mg BID, 681 received placebo, and 204 received adalimumab. At month 3, tofacitinib demonstrated significantly higher 20%, 50%, and 70% improvement in American College of Rheumatology response criteria (ACR20, ACR50, and ACR70, respectively) response rates, greater improvement in Health Assessment Questionnaire-Disability Index, and a higher proportion of Disease Activity Score-defined remission than placebo. Frequencies of adverse events (AEs), serious AEs, and discontinuations due to AEs were similar for tofacitinib and placebo at month 3; serious infection events were more frequent for tofacitinib. In ORAL Standard, although not powered for formal comparisons, tofacitinib and adalimumab had numerically similar efficacy and AEs; serious AEs and serious infection events were more frequent with tofacitinib.

Conclusions: Tofacitinib 5 mg BID reduced RA signs and symptoms and improved physical function versus placebo in patients with inadequate response to prior disease-modifying antirheumatic drugs. Tofacitinib 5 mg BID had a consistent, manageable safety profile across studies, with no new safety signals identified.

FIGURE 1

The ACR20 response rates (% [SE]) over time in the phase 3 studies (FAS, NRI). *p < 0.05, **p < 0.001, ***p < 0.0001 versus placebo. The ACR20 response rate at month 3 was a primary end point in the ORAL Solo and ORAL Step studies, and the ACR20 response rate at month 6 was a primary end point in the ORAL Sync, ORAL Scan, and ORAL Standard studies. ACR20 indicates ≥20% improvement in American College of Rheumatology criteria; FAS, full analysis set; N, number of patients included in analysis; NRI, non-responder imputation; SE, standard error. Color online-figure is available at http://www.jclinrheum.com.

FIGURE 2

Least-squares mean (SE) change from baseline in HAQ-DI over time in the phase 3 studies (FAS, longitudinal model). *p < 0.05, **p < 0.001, ***p < 0.0001 versus placebo. Least-squares mean change from baseline at month 3 was the primary end point across studies. Because of the step-down method, significance was not declared in ORAL Scan. FAS indicates full analysis set; HAQ-DI, Health Assessment Questionnaire‑Disability Index; LS, least squares; N, number of patients included in analysis; SE, standard error. Color online-figure is available at http://www.jclinrheum.com.

FIGURE 3

Safety outcomes at month 3 across the phase 3 studies. n, number of patients with event; N, number of patients included in analysis; SAE, serious adverse event. Color online-figure is available at http://www.jclinrheum.com.