Exposure-efficacy Analysis
The exposure-efficacy analysis was conducted using SAS version 9.4. The
analysis dataset for filgotinib and its active metabolite GS-829845
included all subjects from the three Phase 3 and two Phase 2 studies who
were (1) randomized/enrolled and had received at least one dose of
filgotinib at randomized/enrolled phase; (2), who had at least one
nonmissing PK parameter of interest estimated from a PopPK model
(described above) for the analyte of interest. ER analyses for efficacy
were performed following completion of Phase 3 and Phase 2 studies
(FINCH 1, FINCH 2, FINCH 3, DARWIN 1, and DARWIN 2,) to support the dose
for commercialization.
The primary objective of the included studies was to evaluate the effect
of filgotinib for the treatment of RA as measured by the proportion of
subjects achieving ACR20 (primary endpoint) at Week 12 (DARWIN 1, DARWIN
2, FINCH 1, and FINCH 3) or Week 24 (FINCH 2). Secondary efficacy
endpoints included the proportion of subjects who achieved ACR50, ACR70,
and Disease Activity Score (DAS) 28(CRP) ≤ 3.2, or DAS28(CRP)
< 2.6 at Week 12 or Week 24, as applicable. Exposure-efficacy
analyses were conducted to assess the relationship between filgotinib
exposures and the various efficacy endpoints based on pooled Phase 2 and
Phase 3 data regardless of the RA population.
As both filgotinib and its metabolite, GS-829845, contribute to efficacy
via JAK1 inhibition, their exposures were combined by accounting for
relative inhibition potency in the analyses for efficacy.
AUC0-24 of filgotinib and AUC0-24 of its
active metabolite GS-829845 were combined into AUCeff.
AUCeff was calculated by using this equation:
AUCeff = AUCFIL + AUCmet* 1/10 * (425.51/357.43) where AUCFIL and
AUCmet was the AUC0-24 of filgotinib and
GS-829845, respectively, 1/10 is the difference in potency between
parent and metabolite [8], and 425.51 and 357.43 are the molecular
weights of filgotinib and GS-829845, respectively.
Subjects were grouped into octile subgroups based on the
AUCeff in the filgotinib and GS-829845 analysis set. For
each subject, the determination of octile subgroup was based on the
rankings of AUCeff values from all the subjects in the
filgotinib and GS-829845 analysis set with the number of observations
approximately equally distributed within the eight octile subgroups. The
relationship between exposure (AUCeff) and binary
efficacy endpoints [ACR20, ACR50, ACR70, DAS28 (CRP) ≤ 3.2, and
DAS28(CRP) < 2.6 at Week 12 and Week 24] were explored.
Exposure-efficacy relationships were also evaluated by examining
AUCeff in subjects who achieved and who did not achieve
ACR20/50/70 or DAS28 responses in Phase 2 and Phase 3 studies across all
the doses.