Arthritis Rheumatol. 2020 Sep; 72(9): 1435–1446.In this randomised phase II trial with MTX treatment-refractory RA patients, greater efficacy was observed with fenebrutinib 150 mg once daily or 200 mg twice daily compared to placebo, while response rates were numerically similar to those observed with adalimumab. BTK inhibitors have demonstrated clinical efficacy in B cell malignancies and multiple sclerosis, although there is limited clinical evidence of its efficacy in RA. Fenebrutinib (FEN) an orally active and selective non-covalent inhibitor of BTK, has demonstrated dose-dependent activity in vivo in rats, and Phase 1 trials have shown it to be well tolerated with no safety elements precluding further investigation. This study aimed to evaluate FEN, in patients with active RA. Cohort 1 comprised patients with an inadequate response to MTX, and patients were randomized to receive placebo, FEN 50 mg once daily, FEN 150 mg once daily, FEN 200 mg twice daily, or adalimumab (ADA) 40 mg Q2W. Cohort 2 comprised patients with an inadequate response to TNF, and patients were randomized to receive placebo or FEN 200 mg twice daily.FEN demonstrated efficacy comparable to ADA in patients with inadequate response to MTX, and safety consistent with existing immunomodulatory therapies for RA. FEN was also efficacious in patients who had failed prior therapies. Longitudinal evaluation showed greater efficacy at earlier time points with ADA compared to FEN 200 mg twice daily, but responses were comparable by week 12. This slower onset of response may be due to delayed effect of BTK inhibition on systemic inflammation. The most common AEs were nausea, headache and upper respiratory tract infection, and rates of AEs for all FEN doses (38–51%) were comparable to ADA (45%). FEN had significant effects on myeloid and B cell biomarkers (CCL4 and rheumatoid factor). It is unknown whether longer exposure to FEN would lead to greater reduction in IgM, IgG or higher incidence of HGG, or whether this would increase the risk of infection. This was the first study to demonstrate treatment benefits of inhibiting BTK, a novel therapeutic target for RA.