Discussion
In the PopPK analysis, plasma concentrations were adequately described by the final models of filgotinib and GS-829845 separately and thus the predicted individual PK exposures were further used in the ER analyses. The final filgotinib model was able to adequately predict AUCtau with geometric mean ratio (GMR) = 0.98, but it still had a tendency to modestly underpredict Cmax (GMRs of 0.76-0.79 based on different populations). Various efforts were made to address this issue both on the structural (e.g., different absorption models, 2 vs 3-compartment models) and the stochastic model (e.g., separate IIV by sampling density or phase, skewed ETA distributions, IOV on absorption parameters and volume of distribution, full omega blocks, etc.). However, none of these additional modifications to the PopPK model resulted in further improvement of the Cmaxunderprediction. Overall, the bias is acknowledged and taken into consideration when using model-derived exposures in the context of exposure-response analyses with particular attention to the use of Cmax. In all, estimated filgotinib AUCtau is adequate for the intended purpose to support exposure-response analyses in subjects with RA.
The pharmacokinetic-pharmacodynamic relationship of filgotinib was studied previously. Dose-dependent inhibition of the JAK1-related IL-6-induced pSTAT1 by filgotinib was demonstrated at doses of 50 mg of filgotinib and higher with maximum inhibition of pSTAT1 (~78%) plateaued at or above 200 mg total daily dose and intermediate inhibition (~47%) observed at a total daily dose of 100 mg [19].
Exposure-response analyses based on Phase 2 and Phase 3 clinical studies were further conducted to confirm the dose. Exposure‑efficacy analyses consistently revealed high response rates (approximately 70%-80% for ACR20 at Week 12) across the exposure range for the filgotinib 200 mg doses. A trend of increasing response with increasing exposure was observed over the exposure range for multiple secondary efficacy endpoints including ACR50, ACR70, DAS28 (CRP) ≤ 3.2, and DAS28 (CRP) < 2.6, with a plateau in response corresponding to filgotinib 200 mg exposures (5th to 95thAUCeff percentiles approximately 10,000 – 20,000 h∙ng/mL). An analysis of those who achieved and those who did not achieve responses across dose groups demonstrated that subjects who achieved responses had numerically higher exposures, consistent with numerically higher response rates at the 200 mg dose versus the 100 mg dose observed in Phase 2 and Phase 3 studies. Exposure‑safety relationships established that filgotinib and GS-829845 exposures (AUC0‑24) were similar regardless of the presence or absence of the most frequent TEAEs, the most frequent Grade 3/4 laboratory abnormalities, serious TEAEs, or serious infections, indicating no exposure-safety relationship.
This exposure-response analysis based on pooled data from Phase 2 and Phase 3 studies 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 RI). Filgotinib and its metabolite were shown to be moderately higher (1.45‐ and 1.33‐fold, respectively) in the elderly subjects (≥75 years) compared with younger subjects; in subjects with severe RI, filgotinib was 1.54 fold higher and 2.74 fold higher for the metabolite [15]. It is also suggested that modest changes in filgotinib and GS-829845 exposures due to the influence of other intrinsic/extrinsic factors, such as moderate hepatic impairment and food intake, are not clinically meaningful [20],[21].
Collectively, the ER analyses indicate robust therapeutic effects across the exposure range observed at 200 mg once daily in subjects with moderately to severely active RA. The trend towards greater efficacy with higher exposures observed for the primary and secondary endpoints [ACR20, ACR50, ACR70, DAS28 (CRP) ≤ 3.2, and DAS28 (CRP) < 2.6] and a lack of exposure-safety relationship based on the evaluated TEAEs and common laboratory abnormalities indicates an advantage to the 200 mg filgotinib dose relative to the 100 mg filgotinib dose for most adult patients.