Efficacy and Safety of Zimlovisertib, Ritlecitinib, and Tofacitinib, Alone and in Combination, in Patients With Moderate to Severe Rheumatoid Arthritis and an Inadequate Response to Methotrexate

OBJECTIVE: We aimed to evaluate the efficacy and safety of zimlovisertib (interleukin-1 receptor-associated kinase 4 inhibitor) in combination with ritlecitinib (a JAK3 and tyrosine kinase expressed in hepatocellular carcinoma TEC kinase family inhibitors) or tofacitinib (a JAK inhibitor) versus tofacitinib alone. METHODS: This phase 2 study randomized patients with moderate to severe active rheumatoid arthritis to zimlovisertib 400 mg + tofacitinib 11 mg, zimlovisertib 400 mg + ritlecitinib 100 mg, zimlovisertib 400 mg, ritlecitinib 100 mg, or tofacitinib 11 mg (4:4:3:3:4) for 24 weeks. The primary endpoint was change from baseline (CFB) in Disease Activity Score in 28 joints, C-reactive protein (DAS28-CRP) at week 12. Treatment-emergent adverse events (TEAEs) were monitored. RESULTS: Overall, 460 patients were randomized. At week 12, zimlovisertib + tofacitinib demonstrated a greater magnitude of mean CFB in DAS28-CRP (-2.65; 90% confidence interval CI, -2.84 to -2.46) versus tofacitinib (-2.30; 90% CI, -2.49 to -2.11; P = 0.032); mean CFB with zimlovisertib + ritlecitinib (-2.35; 90% CI, -2.54 to -2.15) was similar to tofacitinib. TEAEs were reported in 246 patients (53.5%), with the highest aggregate incidence of TEAEs in the tofacitinib group (n = 60 58.8%). Most TEAEs were mild; severe TEAEs were reported by 9 patients (2.0%) and 10 patients reported serious AEs. One patient receiving tofacitinib died because of severe COVID-19 infection. Safety profiles were similar across all treatment groups, with no evidence of additive/synergistic issues. CONCLUSION: Zimlovisertib + tofacitinib was more effective than tofacitinib for the primary endpoint, whereas the efficacy of zimlovisertib + ritlecitinib did not achieve statistical significance versus tofacitinib. All treatments were well tolerated.