PURPOSE: Fenebrutinib (GDC-0853), a Bruton's tyrosine kinase (BTK) inhibitor was 
investigated in a Phase 2 clinical trial in patients with rheumatoid arthritis 
(RA). Our aim was to apply a model-informed drug development (MIDD) approach to 
examine the totality of available clinical efficacy data.
METHODS: Population pharmacokinetics (popPK) modeling, exposure-response (E-R) 
analysis, and model-based meta-analysis (MBMA) of fenebrutinib were performed 
based on the Phase 2 data.
RESULTS: PopPK of fenebrutinib after oral administration was described using a 
3-compartment model with linear elimination and a flexible absorption transit 
compartment model. Healthy subjects had a 52% higher apparent clearance than 
patients. E-R analyses based on longitudinal ACR20, ACR50, and ACR70 and DAS28 
(CRP) data modeled fenebrutinib effect with an Emax function, and an efficacy 
plateau was achieved within the exposure range obtained in the Phase 2 clinical 
trial. Based on literature data, a summary-level clinical efficacy database was 
constructed, and MBMA determined ACR20, ACR50, and ACR70 responder rates in the 
placebo and adalimumab arms of the Phase 2 clinical trial were found to be 
consistent with historical data for these treatments.
CONCLUSIONS: Our multi-pronged approach applied MIDD to maximize knowledge 
extraction of efficacy data and enabled robust interpretation from a Phase 2 
clinical trial.