An oral Janus kinase inhibitor, in combination with methotrexate, led to significant improvements in a treatment-refractory rheumatoid arthritis (RA) population with no significant safety concerns.

In the Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of the Safety and Efficacy of 2 Doses of CP-690,550 In Patients With Active Rheumatoid Arthritis On Background Methotrexate With Inadequate Response to TNF Inhibitors study [ORAL Sync; NCT00960440], 399 participants with active RA, age 54.3 to 55.4 years, and a disease duration of 11 to 13 years, were randomized 2:2:1:1.

• Tofacitinib 5 mg twice daily

• Tofacitinib 10 mg twice daily

• Placebo, advanced to tofacitinib 5 mg twice daily

• Placebo, advanced to tofacitinib 10 mg twice daily

All patients were receiving methotrexate and had failed at least one tumor necrosis factor (TNF) inhibitor, reported lead investigator Gerd-Rüdiger Burmester, MD, Charité-University Medicine, Berlin, Germany. Approximately one-third of subjects (27%) had failed two TNF inhibitors, and 8% had failed three or more. Fourteen percent of patients had discontinued anti-TNF treatment due to intolerance.

Primary study endpoints were ACR20 responder rate, Health Assessment Questionnaire-Disability Index (HAQ-DI) change from baseline, and the rate of patients who achieved a Disease Activity Score 28 (DAS28) erythrocyte sedimentation rate (ESR) <2.6 at Month 3.

At 3 months, the ACR20 rate increased 41.7% in the 5-mg group and 48.1% in the 10-mg group compared with 24.4% in the placebo groups (p<0.05 and p<0.0001, respectively; Table 1). Statistically significant improvements also occurred in ACR 50 and 70 rates at Month 3 and in all indicators at 6 months. The mean change in the HAQ at 3 months was −0.43% in (p<0.0001; Table 1). Approximately 10% of patients in the 10-mg group achieved remission.

There were also statistically significant improvements in the DAS28–4 (ESR) at 3 months, with a mean change of −1.9% and −2.1% in the 5-mg and 10-mg groups, respectively, and −2.4% and −2.7% at 6 months.

Adverse events (AE) were generally mild—primarily infections—with no significant differences between groups. At 3 months, 1.5% of the study drug group experienced serious AEs compared with 4.5% in the placebo group. One patient who was taking the 10-mg BID dose of tofacitinib, a 51-year-old woman with a prior history of obesity and hypertension who was also taking hormone replacement therapy, died during the study from a pulmonary embolism. The death was judged by the study investigator to be unrelated to the study medication.

Less than 1% of participants were lost to follow up, while 9% and 10% of the study drug groups discontinued the trial because of adverse effects versus 5% of the placebo group.

This was the first Phase 3 study of tofacitinib in combination with methotrexate in patients with active RA who responded inadequately to TNF inhibitors. In this patient population, tofacitinib demonstrated rapid, significant, and clinically meaningful improvements in the signs and symptoms of RA, physical function, and disease activity.