Exposure-efficacy Analysis
Exposure-Response for Efficacy
Supporting Dose
Confirmation
The Analysis Set for exposure-efficacy included pooled Phase 2 and Phase
3 subjects with RA who received filgotinib and had evaluable PopPK-based
exposure estimates (AUC0-24) for both filgotinib and
GS-829845 (N = 2678).
Exposure-efficacy analysis across the Phase 2 and Phase 3 program
confirmed that filgotinib produced robust therapeutic effects across the
exposure range observed at 200 mg once daily at both Week 12 and Week 24
(Figure 1 and Figure 2). In this ER analysis over a wide dose/exposure
range, high response rates (approximately 70% to 80% for ACR20, the
primary endpoint) were demonstrated across octile groups associated with
200 mg in subjects with RA receiving filgotinib at Week 12 (Figure 1).
ACR20 responses in the filgotinib 200 mg group appeared to be on the
plateau of the ER curve in the analysis, with the filgotinib 100 mg
group being slightly lower than the curve plateau. For multiple
secondary efficacy endpoints including ACR50, ACR70, DAS28 (CRP) ≤ 3.2,
and DAS28 (CRP) < 2.6, a trend of increasing response with
increasing exposure was observed over the first 4 octiles (corresponding
to 100 mg and lower doses) and a plateau was observed over the last 4
octiles (corresponding to 200 mg exposures). The analysis on Week 24
data showed similar findings to the Week 12 analysis (Figure 2).
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. In Figure 3, AUCeff overlapped between those
who achieved (black) and those who did not achieve (gray) ACR20/50/70 or
DAS28 responses, however, those who achieved responses had numerically
higher median AUCeff compared with those who did not
achieve responses at both Week 12 and Week 24.
Overall, filgotinib exposure-efficacy analysis across the Phase 2 and
Phase 3 program confirmed that filgotinib produced more robust
therapeutic effects across the exposure range observed at 200 mg once
daily compared to lower doses. This analysis supported 200 mg for most
adult patients and 100 mg for special populations who may have elevated
PK exposures [e.g. elder patients aged 75 years and older and patients
with moderate to severe renal impairment (RI)].