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.