Two-year results from the ORAL Start study were published in The New England Journal of Medicine ( NEJM ). 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 Tofacitinib citrate ( Xeljanz ) 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.
Tofacitinib is not indicated in patients who had not previously received Methotrexate. The safety profile of Tofacitinib in the ORAL Start study was consistent with that seen previously in the clinical development program.
In the United States, Tofacitinib 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.
Tofacitinib may be used alone or in combination with Methotrexate or other non-biologic, disease-modifying antirheumatic drugs ( DMARDs ).
Use of Tofacitinib 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.
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 Tofacitinib 5 mg or 10 mg twice daily or to Methotrexate dose-titrated over 8 weeks to 20 mg weekly.
Both doses of Tofacitinib 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 less than 0.001 ) for Tofacitinib 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 Tofacitinib 5 mg and 10 mg twice daily, respectively ( both P less than 0.001 ), versus 12.0% for Methotrexate ], at month 6.
ORAL Start has 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 less than 0.001 ) for Tofacitinib 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 safety profile of Tofacitinib 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 occurred in 4.0% of patients on Tofacitinib and 1.1% of patients on Methotrexate.
Confirmed malignancies developed in five patients treated with Tofacitinib and one patient treated with Methotrexate.
Tofacitinib was associated with increases in average serum creatinine and lipid levels. ( Xagena )
Source: Pfizer, 2014