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Exposure-Response Relationships for Efficacy and Safety of Filgotinib and its metabolite GS-829845 in Subjects with Rheumatoid Arthritis Based on Phase 2 and Phase 3 Studies
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  • Amy Meng,
  • Kacey Anderson,
  • Cara Nelson,
  • Liyun Ni,
  • Shu-Min Chuang,
  • Francesco Bellanti,
  • Peter Chang,
  • Craig Comisar,
  • Brian Kearney,
  • Beatrix Bartok,
  • Anita Mathias
Amy Meng
Gilead Sciences Inc
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Kacey Anderson
Gilead Sciences Inc
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Cara Nelson
Gilead Sciences Inc
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Liyun Ni
Gilead Sciences Inc
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Shu-Min Chuang
Gilead Sciences Inc
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Francesco Bellanti
Certara LP
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Peter Chang
Certara LP
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Craig Comisar
Certara LP
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Brian Kearney
Gilead Sciences Inc
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Beatrix Bartok
Gilead Sciences Inc
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Anita Mathias
Gilead Sciences Inc
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Abstract

Aims:Filgotinib is a potent, oral, JAK1-preferential inhibitor for the treatment of rheumatoid arthritis (RA). This report describes exposure-response (ER) analyses of filgotinib for dose confirmation based on three Phase 3 and two Phase 2 studies in moderate to severe RA patients. Methods:The PK exposures used in ER analyses were derived from population pharmacokinetic analysis. The relationship between filgotinib exposures and various efficacy endpoints (ACR20/50/70 and DAS28) was assessed over octile groups of exposures by using combined exposures of filgotinib and GS-829845 (major, active metabolite). For the ER analyses of safety, exposures were examined between subjects who experienced and who did not experience the evaluated safety events, which was conducted separately for filgotinib and GS-829845. Results:Exposure efficacy relationships consistently revealed high response rates across the exposure range for filgotinib 200 mg once daily dose. A trend of increasing response with increasing exposure was observed over the exposure range for the primary and multiple secondary efficacy endpoints, with exposures associated with the 200 mg dose primarily residing on the curve plateau. For exposure-safety analyses, filgotinib and GS-829845 exposures were similar irrespective of presence/absence of the evaluated safety endpoints, indicating no exposure-safety relationship for common TEAEs, common laboratory abnormalities, serious TEAEs, or serious infections. Conclusions:ER analyses confirmed that filgotinib produced more robust therapeutic effects across the exposure range observed at 200 mg once daily compared to lower doses. The positive exposure-efficacy relationship and a lack of exposure-safety relationship on the evaluated safety endpoints supported the 200 mg once daily dose for commercialization.

Peer review status:IN REVISION

27 May 2021Submitted to British Journal of Clinical Pharmacology
03 Jun 2021Assigned to Editor
03 Jun 2021Submission Checks Completed
20 Jun 2021Reviewer(s) Assigned
22 Jul 2021Review(s) Completed, Editorial Evaluation Pending
23 Aug 2021Editorial Decision: Revise Major