OBJECTIVE: To evaluate fenebrutinib, an oral and highly selective non-covalent 
inhibitor of Bruton's tyrosine kinase (BTK), in patients with active rheumatoid 
arthritis (RA).
METHODS: Patients with RA and inadequate response to methotrexate (cohort 1, 
n=480) were randomized to fenebrutinib (50 mg once daily, 150 mg once daily, 200 
mg twice daily), 40 mg adalimumab every other week, or placebo. Patients with RA 
and inadequate response to tumor necrosis factor inhibitors (cohort 2, n=98) 
received fenebrutinib (200 mg twice daily) or placebo. Both cohorts continued 
methotrexate therapy.
RESULTS: In cohort 1, American College of Rheumatology scores (ACR50) at week 12 
were similar for fenebrutinib 50 mg once daily and placebo, and higher for 
fenebrutinib 150 mg once daily (28%) and 200 mg twice daily (35%) than placebo 
(15%) (p=0.017; p=0.0003). Fenebrutinib 200 mg twice daily and adalimumab (36%) 
were comparable (p=0.81). In cohort 2, more patients achieved ACR50 with 
fenebrutinib 200 mg twice daily (25%) than placebo (12%) (p=0.072). The most 
common adverse events for fenebrutinib included nausea, headache, anemia, and 
upper respiratory tract infections. Fenebrutinib had significant effects on 
myeloid and B cell biomarkers (CCL4 and rheumatoid factor). Fenebrutinib and 
adalimumab caused overlapping as well as distinct changes in B cell and myeloid 
biomarkers.
CONCLUSION: Fenebrutinib demonstrated efficacy comparable to adalimumab in 
patients with an inadequate response to methotrexate, and safety consistent with 
existing immunomodulatory therapies for RA. These data support targeting both B 
and myeloid cells via this novel mechanism for potential efficacy in the 
treatment of RA.