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 To evaluate the efficacy and safety of zimlovisertib (interleukin‐1 receptor‐associated kinase 4 inhibitor) in combination with ritlecitinib (a Janus kinase [JAK] 3 and tyrosine kinase expressed in hepatocellular carcinoma [TEC] kinase family inhibitors) or tofacitinib (a JAK inhibitor) vs tofacitinib alone. Methods This phase 2 study randomized patients with moderate to severe active RA 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% CI, −2.84, −2.46]) vs tofacitinib (−2.30 [90% CI, −2.49, −2.11]; P value = 0.032); mean CFB with zimlovisertib+ritlecitinib (−2.35 [90% CI, −2.54, −2.15]) was similar to tofacitinib. TEAEs were reported in 246 (53.5%) patients, with the highest aggregate incidence of TEAEs in the tofacitinib group (n = 60 [58.8%]). Most TEAEs were mild; severe TEAEs were reported by nine (2.0%) patients and 10 patients reported serious AEs. One patient receiving tofacitinib died due to 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, while the efficacy of zimlovisertib+ritlecitinib did not achieve statistical significance vs tofacitinib. All treatments were well tolerated.