Tofacitinib (cp-690,550), an oral Janus kinase inhibitor, in combination with methotrexate, in patients with active rheumatoid arthritis with an inadequate response to tumor necrosis factor-inhibitors: a 6-month phase 3 study

BACKGROUND/PURPOSE:

Tofacitinib (CP-690,550) is a novel, oral Janus kinase inhibitor investigated as a targeted immunomodulator for rheumatoid arthritis (RA). This study was designed to compare efficacy and safety of tofacitinib vs placebo (PBO) in pts with active RA with inadequate response to tumor necrosis factor (TNF)-inhibitors.

METHODS:

In this 6-month (Mo) study (NCT00960440), pts with inadequate response or lack of tolerance to >=1 TNF inhibitor and on concomitant treatment with a stable (>6 weeks) dose of methotrexate (MTX; 7.5–25 mg/week) were randomized 2:2:1:1 to one of four sequences: tofacitinib 5 mg twice daily (BID); tofacitinib 10 mg BID; PBO advanced to 5 mg BID; PBO advanced to 10 mg BID (at Mo 3 all PBO patients were advanced to tofacitinib 5 or 10 mg according to randomization at baseline; for analyses PBO sequences were combined into one group). Primary endpoints included ACR20 responder rate, change from baseline in HAQ-DI, and rate of pts achieving a DAS28-4(ESR) <2.6, all at Mo 3.

RESULTS:

399 pts were randomized and treated: 5 mg BID (n=133); 10 mg BID (n=134); PBO to 5 mg (n=66); PBO to 10 mg (n=66). Mean baseline values were comparable across treatment sequences: age, 54.3–55.4 years; disease duration, 11.3–13 years; HAQ-DI, 1.50–1.66; DAS28-4(ESR), 6.29–6.64; rheumatoid factor (RF) positive, 60.6–70.8%; anti-CCP positive, 68.5–77.8%; >=2 prior anti-TNFs, 32.1–36.6%. Both doses of tofacitinib were statistically superior to PBO for all primary efficacy endpoints at Mo 3 and were maintained to Mo 6 (end of study) (Table). Onset of efficacy as measured by significant ACR20 responses vs PBO was seen by Week 2. Key safety endpoints are summarized in the table. Most AEs were mild; most frequently reported were infections and infestations. There was 1 death due to pulmonary emboli in the 10 mg BID dose group. No serious infectious events were reported in Mo 0–3, and 2 (5 mg BID), 2 (10 mg BID), and 1 (PBO to 5 mg) were reported in Mo 3–6. There were no opportunistic infections. Decreases in neutrophils, increases in LDL and HDL, and small increases in serum creatinine were seen with tofacitinib.

CONCLUSION:

This was the first Phase 3 study of tofacitinib in combination with MTX in pts with active RA with an inadequate response to TNF-inhibitors. In this treatment refractory patient population, tofacitinib demonstrated rapid, significant, and clinically meaningful improvements in the signs and symptoms of RA, physical function, and disease activity over 6 mo of study treatment. No new safety signals were detected.