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

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.

JAK/STAT pathway: Extracellular signals, diseases, immunity, and therapeutic regimens

“…Although still in Phase 1 trials, their feasibility for treating tumors is being further demonstrated. In addition, several inhibitors targeting the JAK/STAT pathway are being tested in multi-stage clinical trials in a variety of diseases, such as Momelitinib (Mesa et al, 2022), Peficitinib (Tanaka et al, 2021), itacitinib (Naing et al, 2022), AZD1480 (Plimack et al, 2013), Fedratinib (Harrison et al, 2022b), Gandotinib (Berdeja et al, 2018), Filgotinib (Meng et al, 2022), Upadacitinib (Deodhar et al, 2022), Decernotinib (Genovese et al, 2016), lestatitinib (Brown et al, 2021), Decernotinib Frontiers in Bioengineering and Biotechnology frontiersin.org (Fleischmann et al, 2015), lestaurtinib (Mascarenhas et al, 2019), abrocitinib (Reich et al, 2022), ritlecitinib (Winnette et al, 2022), brepocitinib (Peeva et al, 2022), deucravacitinib (Mease et al, 2022), delgocitinib (Worm et al, 2022). The JAK/STAT pathway is activated in a variety of common solid tumors contributing to an aggressive phenotype (Roxburgh and McMillan, 2016).…”