Pfizer Inc. announced the publication of two-year results from the ORAL Start study in the The New England Journal of Medicine. ORAL Start is a 24-month Phase 3 study in patients with moderately to severely active rheumatoid arthritis who had not previously received methotrexate. The study showed that Xeljanz (tofacitinib citrate) 5 mg and 10 mg twice daily, as monotherapy (e.g., taken without methotrexate), inhibited the progression of structural damage and reduced the signs and symptoms of rheumatoid arthritis, and was statistically significantly superior to methotrexate on these measures at Month 6 (primary endpoint) and at all measured time points up to 24 months. Xeljanz is not indicated in patients who had not previously received methotrexate. The safety profile of Xeljanz in the ORAL Start study was consistent with that seen previously in the clinical development program.
In the United States, Xeljanz 5 mg tablets are indicated for the treatment of adults with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to methotrexate. Xeljanz may be used alone or in combination with methotrexate or other non-biologic, disease-modifying antirheumatic drugs (DMARDs). Use of Xeljanz in combination with biologic DMARDs or potent immunosuppressants, such as azathioprine and cyclosporine, is not recommended. The recommended dose is a 5 mg pill taken twice daily.
“This study showed that Xeljanz taken by itself was statistically significantly superior to methotrexate in measures of clinical, radiographic and functional efficacy rheumatoid arthritis outcomes, and these results were sustained over two years,” said lead investigator Roy Fleischmann, professor, Metroplex Clinical Research Center, Dallas, Texas. “These results also add to the information on the efficacy and safety of Xeljanz as monotherapy.”
The ORAL Start study was a 24-month Phase 3 randomized, double-blind, controlled trial in which 956 patients with moderately to severely active rheumatoid arthritis who had not previously received methotrexate were randomized to receive Xeljanz 5 mg or 10 mg twice daily or to methotrexate dose-titrated over eight weeks to 20 mg weekly. As previously announced, both doses of Xeljanz met the study’s co-primary efficacy endpoints: reduction of progression of radiographic measures of disease as measured by average change from baseline in van der Heijde modified Total Sharp Score (mTSS) [0.18 and 0.04 (both P<0.001) for Xeljanz 5 mg and 10 mg twice daily, respectively, versus 0.84 for methotrexate], and clinical response as measured by ACR70 response rates, a measure of at least 70% reduction in signs and symptoms of rheumatoid arthritis [25.5% and 37.7% for Xeljanz 5 mg and 10 mg twice daily, respectively (both P<0.001), versus 12.0% for methotrexate], at Month 6. ORAL Start also evaluated improvement in physical function as measured by mean change from baseline in the Health Assessment Questionnaire Disability Index (HAQ-DI) [-0.83 and -0.94 (both P<0.001) for Xeljanz 5 mg and 10 mg twice-daily, respectively, versus -0.58 for methotrexate], at Month 6. These results were sustained at all measured time points up to 24 months.
The six- and 12-month radiographic data from this study were recently added to the Xeljanz U.S. label as part of an FDA approved label update.
“The publication of the ORAL Start data in The New England Journal of Medicine marks the sixth Phase 3 study in the Xeljanz clinical program to be published in a major medical journal,” said Dr. Steven Romano, Global Medicines development lead for the Pfizer Global Innovative Pharmaceutical business. “The publication of all of the completed Xeljanz Phase 3 rheumatoid arthritis clinical studies in such respected publications speaks to the significance and clinical relevance of the data for Xeljanz.”
The safety profile of Xeljanz in the ORAL Start study was consistent with that seen previously in the clinical development program. The incidence of adverse events, serious adverse events and discontinuations due to adverse events were similar across groups. Most adverse events were mild or moderate and the most frequently reported adverse events in all groups were infections. Herpes zoster (shingles) occurred in 4.0% of patients on Xeljanz and 1.1% of patients on methotrexate. Confirmed malignancies developed in five patients treated with Xeljanz and one patient treated with methotrexate. Xeljanz was associated with increases in average serum creatinine and lipid levels.
Date: June 18, 2014