Placebo-Controlled Trial of Tofacitinib Monotherapy in Rheumatoid Arthritis

Abstract

BackgroundTofacitinib (CP-690,550) is a novel oral Janus kinase inhibitor that is being investigated as a targeted immunomodulator and disease-modifying therapy for rheumatoid arthritis. MethodsIn this phase 3, double-blind, placebo-controlled, parallel-group, 6-month study, 611 patients were randomly assigned, in a 4:4:1:1 ratio, to 5 mg of tofacitinib twice daily, 10 mg of tofacitinib twice daily, placebo for 3 months followed by 5 mg of tofacitinib twice daily, or placebo for 3 months followed by 10 mg of tofacitinib twice daily. The primary end points, assessed at month 3, were the percentage of patients with at least a 20% improvement in the American College of Rheumatology scale (ACR 20), the change from baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) scores (which range from 0 to 3, with higher scores indicating greater disability), and the percentage of patients with a Disease Activity Score for 28-joint counts based on the erythrocyte sedimentation rate (DAS28-4[ESR]) of less than 2.6 (with scores ranging from 0 to 9.4 and higher scores indicating more disease activity). ResultsAt month 3, a higher percentage of patients in the tofacitinib groups than in the placebo groups met the criteria for an ACR 20 response (59.8% in the 5-mg tofacitinib group and 65.7% in the 10-mg tofacitinib group vs. 26.7% in the combined placebo groups, P<0.001 for both comparisons). The reductions from baseline in HAQ-DI scores were greater in the 5-mg and 10-mg tofacitinib groups than in the placebo groups (−0.50 and −0.57 points, respectively, vs. −0.19 points; P<0.001). The percentage of patients with a DAS28-4(ESR) of less than 2.6 was not significantly higher with tofacitinib than with placebo (5.6% and 8.7% in the 5-mg and 10-mg tofacitinib groups, respectively, and 4.4% with placebo; P = 0.62 and P = 0.10 for the two comparisons). Serious infections developed in six patients who were receiving tofacitinib. Common adverse events were headache and upper respiratory tract infection. Tofacitinib treatment was associated with elevations in low-density lipoprotein cholesterol levels and reductions in neutrophil counts. ConclusionsIn patients with active rheumatoid arthritis, tofacitinib monotherapy was associated with reductions in signs and symptoms of rheumatoid arthritis and improvement in physical function. (Funded by Pfizer; ORAL Solo ClinicalTrials.gov number, NCT00814307.)The New England Journal of Medicine Downloaded from nejm.org at UNIV STUDI PIEMONTE ORIENTALE on August 9, 2012. For personal use only. No other uses without permission.

Evaluation of the Effect of Tofacitinib Exposure on Outcomes in Kidney Transplant Patients

“…meaningfully between the two tofacitinib treatment armsmost likely reflecting the overlapping pharmacokinetic exposures within the dose range studied. The high event frequencies of PTLD and serious infections reported in the fixed-dose tofacitinib treatment groups in this Phase 2b transplant study were contrary to the findings in patients with rheumatoid arthritis (3)(4)(5)(6)(7)(8), which is likely attributable to differences in patient populations and the more intense and complex combination immunosuppressive regimens received by transplant patients.…”

“…Cytokine signaling through the JAK pathway is integral to lymphocyte activation, proliferation and function; thus, inhibition of JAK3 and/or JAK1 results in suppression of multiple aspects of the immune response (1,2). The efficacy of tofacitinib for the treatment of moderate to severe rheumatoid arthritis has been demonstrated in many studies (3)(4)(5)(6)(7)(8). Tofacitinib is also being developed for the treatment of other autoimmune disorders such as psoriasis (9) and inflammatory bowel disease (10).…”

Tofacitinib With Methotrexate in Third‐Line Treatment of Patients With Active Rheumatoid Arthritis: Patient‐Reported Outcomes From a Phase III Trial

“…Six phase III RCTs have demonstrated significant improvements in signs and symptoms of active RA compared with placebo (17)(18)(19)(20)(21) or MTX (22). PROs have been reported from all 6 phase III trials, and they have demonstrated significant improvements with tofacitinib treatment versus placebo, with and without background MTX, across a range of patient populations (23)(24)(25)(26)(27)(28).…”

Tofacitinib: a janus kinase inhibitor for rheumatoid arthritis

“…12 In the ORAL Solo trial, in patients with an inadequate response to DMARDs (most frequently methotrexate but including other nonbiological DMARDS, TNF inhibitors and other biological agents), the three-month ACR20 response rate with tofacitinib monotherapy (5mg twice daily) was 60% (vs 27% with placebo; p<0.001); this improvement was maintained after six months. 6 There was a corresponding reduction in disability score but disease activity was not significantly different from placebo at three months.…”