Safety and efficacy of tofacitinib up to 48 months in patients with active psoriatic arthritis: final analysis of the OPAL Balance long-term extension study

Background Tofacitinib is an oral Janus kinase inhibitor for the treatment of psoriatic arthritis. Here we report the final analysis of Oral Psoriatic Arthritis Trial (OPAL) Balance, a 36-month long-term extension study, with a 12-month methotrexate withdrawal substudy, that assessed tofacitinib safety, tolerability, and efficacy in patients with active psoriatic arthritis. Methods For this open-label, long-term extension study, which was run at 124 centres in 16 countries, eligible patients had participated in the OPAL Broaden or OPAL Beyond phase 3 studies. Patients could enter OPAL Balance up to 3 months after completing one of the qualifying studies or discontinuing for reasons other than an adverse event related to study drug. In OPAL Balance, patients received open-label tofacitinib 5 mg twice daily, with increases to 10 mg twice daily for inadequate symptom control allowed from month 1, and reductions to 5 mg twice daily allowed thereafter for safety. Specific conventional synthetic disease-modifying antirheumatic drugs could be continued concomitantly. The primary endpoints were incidence and severity of adverse events, the incidence of laboratory abnormalities, and changes from baseline in laboratory parameters. Participants who were eligible could enter the randomised, double-blind, methotrexate withdrawal substudy (open-label tofacitinib 5 mg twice daily plus either masked placebo or masked methotrexate); safety data from which are included here (up to month 48). Efficacy was reported up to month 36 (substudy data excluded). The risk period for safety outcomes was the time from treatment exposure to the last dose plus 28 days or date of last observation. OPAL Balance is registered with ClinicalTrials.gov (NCT01976364) and is now complete. Findings Between Feb 17, 2014, and March 28, 2016, 686 patients were enrolled and given tofacitinib 5 mg or 10 mg twice daily (179 patients were treated in the substudy and 453 [66%] of 686 completed the long-term extension study or substudy; mean treatment duration 794.6 days [SD 329.2] in long-term extension study, 879.0 days [396.6] in long-term extension study plus substudy). The mean age of participants in the all tofacitinib group was 48.8 years (SD 11.8) and 370 (54%) of 686 participants were female. Up to month 48, 574 (84%) of 686 participants reported all-cause adverse events, 115 (17%) reported serious adverse events, and 78 (11%) discontinued due to an adverse event. Six patients died, one within the risk period (incidence of 0.1 patients with events [95% CI 0.0-0.3] per 100 person-years). The incidences of adverse events of special interest, reported as number of patients with events per 100 person-years, included: 1.7 (1.2-2.5) for herpes zoster (non-serious and serious); 1.0 (0.6-1.6) for serious infections; 0.4 (0.1-0.8) for opportunistic infections; 0.7 (0.4-1.2) for malignancies (excluding non-melanoma skin cancer [NMSC]); 0.9 (0.5-1.5) for NMSC; 0.2 (0.1-0.6) for major adverse cardiovascular events; 0.1 (0.0-0.3) for pulmonary embolism; and 0.4 (0.1-0.8) for arterial thromboembolism. No deep vein thromboses occurred. Laboratory parameter changes were as expected with treatment. Efficacy was sustained up to month 36. Interpretation This analysis supports the long-term safety (up to 48 months) and efficacy (up to 36 months) of tofacitinib in patients with psoriatic arthritis, which were consistent with previous phase 3 studies. F unding Pfizer. Copyright (C) 2021 Elsevier Ltd. All rights reserved.