Tofacitinib for Rheumatoid Arthritis Non-inferior to Combo Therapy


In the phase 3b/4 ORAL Shift study, tofacitinib monotherapy was shown to be comparable to tofacitinib with methotrexate.

Results from the ORAL Shift study in participants with moderately to severely active rheumatoid arthritis indicated that tofacitinib extended release (Xeljanz XR) monotherapy after methotrexate withdrawal is non-inferior to tofacitinib XR with continued methotrexate.

The study results were presented in a late-breaking research session at the Annual European Congress of Rheumatology (EULAR 2019) in Madrid, Spain, by Stanley B. Cohen, MD, Metroplex Clinical Research Center, Dallas, TX.

“The results of ORAL Shift provide important information on the use of Xeljanz XR as monotherapy after methotrexate withdrawal, which is significant as some people living with rheumatoid arthritis are unable or unwilling to use methotrexate,” said Cohen. “From a clinical perspective, these results give physicians data to help inform the decision to take appropriate patients off methotrexate.”

The phase 3b/4 ORAL Shift study included 694 adult patients with moderate to severe rheumatoid arthritis who inadequately responded to methotrexate treatment alone. The 48-week study was split into 2 phases. The first was a 24-week open-label run-in phase during which all participants received tofacitinib XR 11 mg once daily (QD) plus their stabilized dose of methotrexate. The second part was a double-blind, placebo-controlled phase where participants who achieved low disease activity in the run-in (n = 530) were randomized to either continue on tofacitinib XR plus methotrexate (n = 266) or switch to tofacitinib XR monotherapy plus placebo (n = 264) and withdraw from methotrexate.

The study met the primary endpoint, as the change from randomization at week 24 to week 48 in Disease Activity Score (DAS28-4[ESR]) was 0.33 (95% CI 0.20, 0.46) for the tofacitinib XR monotherapy group and 0.03 (95% CI -0.10, 0.16) for the combination treatment group.

“We are extremely pleased with the findings from ORAL Shift, which to date is the only non-inferiority study to evaluate and demonstrate the efficacy of a JAK inhibitor after methotrexate withdrawal in adults with moderately to severely active RA who achieved low disease activity after combination therapy,” said Michael Corbo, Chief Development Officer, Inflammation & Immunology, Pfizer Global Product Development.

The most common adverse events during the double-blind portion of ORAL Shift for the tofacitinib monotherapy and tofacitinib plus methotrexate groups were arthralgia (2.7% vs 0.8%, respectively), increase in alanine aminotransferase (1.9% vs 3.8%), increase in aspartate aminotransferase (1.9% vs 2.3%), nasopharyngitis (1.9% vs 2.6%), upper respiratory tract infection (1.5% vs 2.3%), and bronchitis (1.1% vs 2.6%).

Both the tofacitinib monotherapy and tofacitinib plus methotrexate arms had similar rates of adverse events (40.5% vs 41.0%, respectively), serious adverse events (3.8% vs 1.9%), and study discontinuations due to adverse events (1.9% for both). Two deaths occurred during the study, both in the tofacitinib plus methotrexate arm.

The US Food and Drug Administration (FDA) first approved tofacitinib in 2012 for rheumatoid arthritis. The indication was expanded in 2017 for the treatment of active psoriatic arthritis and in 2018 to include the treatment of adults with moderate to severe ulcerative colitis.

The abstract, “Methotrexate Withdrawal In Patients With Rheumatoid Arthritis Who Achieve Low Disease Activity With Tofacitinib Modified-Release 11 Mg Once Daily + Methotrexate: A Randomised Non-Inferiority Phase 3b/4 Study,” was presented on Saturday, June 15 at EULAR 2019.

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