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)].