Exposure-Response Relationships for Efficacy and Safety of Filgotinib
and its metabolite GS-829845 in Subjects with Rheumatoid Arthritis Based
on Phase 2 and Phase 3 Studies
Abstract
Aims:Filgotinib is a potent, oral, JAK1-preferential inhibitor for the
treatment of rheumatoid arthritis (RA). This report describes
exposure-response (ER) analyses of filgotinib for dose confirmation
based on three Phase 3 and two Phase 2 studies in moderate to severe RA
patients. Methods:The PK exposures used in ER analyses were derived from
population pharmacokinetic analysis. The relationship between filgotinib
exposures and various efficacy endpoints (ACR20/50/70 and DAS28) was
assessed over octile groups of exposures by using combined exposures of
filgotinib and GS-829845 (major, active metabolite). For the ER analyses
of safety, exposures were examined between subjects who experienced and
who did not experience the evaluated safety events, which was conducted
separately for filgotinib and GS-829845. Results:Exposure efficacy
relationships consistently revealed high response rates across the
exposure range for filgotinib 200 mg once daily dose. A trend of
increasing response with increasing exposure was observed over the
exposure range for the primary and multiple secondary efficacy
endpoints, with exposures associated with the 200 mg dose primarily
residing on the curve plateau. For exposure-safety analyses, filgotinib
and GS-829845 exposures were similar irrespective of presence/absence of
the evaluated safety endpoints, indicating no exposure-safety
relationship for common TEAEs, common laboratory abnormalities, serious
TEAEs, or serious infections. Conclusions:ER analyses confirmed that
filgotinib produced more robust therapeutic effects across the exposure
range observed at 200 mg once daily compared to lower doses. The
positive exposure-efficacy relationship and a lack of exposure-safety
relationship on the evaluated safety endpoints supported the 200 mg once
daily dose for commercialization.