Tofacitinib Effective for Rheumatoid Arthritis Patients with Inadequate Response to Methotrexate

In a post-hoc analysis, researchers found that the clinical efficacy of tofacitinib after 6 months of treatment was greater than placebo, and appeared similar regardless of methotrexate (MTX) dose.

Tofacitinib has understandably been the subject of a number of poster sessions, presentations, and studies at the 2015 Annual Meeting of the American College of Rheumatology this week in San Francisco. The extended coverage for tofacitinib (marketed under the brand name Xeljanz), an oral Janus kinase inhibitor currently approved for the treatment of RA, is due in part because of the medication’s efficacy in treating MTX-resistant patients, and partly due to the fact that it’s a new arrow in the RA treatment quiver. As such, there is a great deal of interest in determining not only how tofacitinib works as monotherapy, but how it works in combination with MTX and other disease-modifying anti-rheumatic drugs‑‑and at different dosages of both tofacitinib and those other medications.

The current analysis, ORAL Scan, was a 2-year, randomized, Phase 3, clinical trial that evaluated tofacitinib therapy with background methotrexate (MTX) in RA patients. MTX-resistant (MTX-IR) patients were randomized 4:4:1:1 to tofacitinib 5 mg twice daily (BID), tofacitinib 10 mg BID, or placebo with advancement to 5 mg BID or to 10 mg BID at Month 3 or Month 6, in combination with background MTX. MTX dose was stable throughout the study and was categorized as Low (≤12.5 mg/week), Medium (>12.5 to <17.5 mg/week), or High (≥17.5 mg/week).

Endpoints evaluated at Month 6 included ACR response rates, proportion of pts achieving low disease activity measured by Clinical Disease Activity Index (CDAI ≤10), CDAI‑defined remission rate (CDAI ≤2.8), proportion of pts achieving an improvement ≥0.5 in Health Assessment Questionnaire-Disability Index (HAQ-DI), and least squares mean change from baseline in HAQ-DI, Disease Activity Score (DAS28-4[ESR]), and CDAI.

Binary variables were evaluated with non-responder imputation, and continuous variables were analyzed using a longitudinal model. Regression analyses were conducted to evaluate efficacy responses by MTX dose group and other covariates.

For the analysis, 797 patients were randomized and treated (tofacitinib 5 mg BID, n=321; tofacitinib 10 mg BID, n=316; placebo, n=160). The Low MTX group included 242 patients; the Medium MTX group included 333 patients, and the High MTX group included 222. Baseline demographics and disease characteristics were similar across MTX dose groups, though weight, BMI, glucocorticoid (GC) use, and CDAI were higher in the High MTX dose group. At Month 6, greater efficacy was seen with tofacitinib compared to placebo for all endpoints across the 3 MTX dose groups.

Efficacy for placebo-treated patients was generally numerically greater in the Medium and High MTX dose groups than in the Low MTX dose group. Efficacy with tofacitinib appeared similar regardless of MTX dose group. Regression analyses demonstrated a lack of effect of BMI, GC use and MTX dose groups on efficacy assessments.

According to the researchers, a randomized clinical trial is needed in which different doses of MTX are added to tofacitinib in MTX-naïve pts in order to examine the effect of MTX dose on tofacitinib efficacy.