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.