Background: Final data are presented for the ORAL Sequel long-term extension (LTE) study evaluating the safety and efficacy of tofacitinib 5 mg and 10 mg twice daily (BID) for up to 9.5 years in patients with rheumatoid arthritis (RA).
Methods: Eligible patients had previously completed a phase 1, 2, or 3 qualifying index study of tofacitinib and received open-label tofacitinib 5 mg or 10 mg BID. Stable background therapy, including csDMARDs, was continued; adjustments to tofacitinib or background therapy were permitted at investigators' discretion. Assignment to dose groups (5 mg or 10 mg BID) was based on patients' average total daily dose. The primary objective was to determine the long-term safety and tolerability of tofacitinib 5 mg and 10 mg BID; the key secondary objective was to evaluate the long-term persistence of efficacy.
Results: Between February 5, 2007, and November 30, 2016, 4481 patients were enrolled. Total tofacitinib exposure was 16,291 patient-years. Safety data are reported up to month 114 for all tofacitinib; efficacy data are reported up to month 96 for tofacitinib 5 mg BID and month 72 for 10 mg BID (with low patient numbers limiting interpretation beyond these time points). Overall, 52% of patients discontinued (24% due to adverse events [AEs] and 4% due to insufficient clinical response); the safety profile remained consistent with that observed in prior phase 1, 2, 3, or LTE studies. The incidence rate (IR; number of patients with events per 100 patient-years) for AEs leading to discontinuation was 6.8. For all-cause AEs of special interest, IRs were 3.4 for herpes zoster, 2.4 for serious infections, 0.8 for malignancies excluding non-melanoma skin cancer, 0.4 for major adverse cardiovascular events, and 0.3 for all-cause mortality. Clinically meaningful improvements in the signs and symptoms of RA and physical functioning, which were observed in the index studies, were maintained.
Conclusions: Tofacitinib 5 mg and 10 mg BID demonstrated a consistent safety profile (as monotherapy or combination therapy) and sustained efficacy in this open-label LTE study of patients with RA. Safety data are reported up to 9.5 years, and efficacy data up to 8 years, based on adequate patient numbers to support conclusions.
Trial registration: NCT00413699 , funded by Pfizer Inc (date of trial registration: December 20, 2006).
Keywords: Long-term extension; Rheumatoid arthritis; Tofacitinib.