THU0014 TARGETING ACTIVATED ASK1 IN SYNOVIAL FIBROBLASTS IN COMBINATION WITH JAK1 INHIBITION ENHANCES EFFICACY IN RAT CIA
Authors: Paqui Gonzalez-Traves, Christian Franci, Julie A. DI Paolo
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> Despite improved therapy, rheumatoid arthritis (RA) remains an area of unmet medical need. Current therapies have improved disease control by targeting inflammatory pathways. However, treatments rarely induce remission, highlighting the need for new therapies. Filgotinib (FIL) is an oral selective JAK1 inhibitor that has demonstrated clinical efficacy in RA trials.<sup>1-3</sup> Apoptosis signal-regulating kinase 1 (ASK1) is a member of the MAP3K family that activates p38 and c-jun and has recently been shown to modulate human RA fibroblast-like synoviocyte (FLS) invasion, proliferation, and migration in vitro.<sup>4</sup> We hypothesize that by dual targeting of JAK-dependent inflammatory pathways with FIL, and ASK1 signaling in FLS with an ASK1 inhibitor, we can demonstrate an increase in efficacy in a rat collagen-induced arthritis (CIA) model. <h3>Objectives:</h3> To evaluate the individual and combination activity of JAK1 and ASK1 inhibition in the rat CIA model by oral dosing with FIL and an ASK1 inhibitor. <h3>Methods:</h3> The in vivo efficacy of FIL and an ASK1 inhibitor were tested individually or in combination in a therapeutic rat CIA model. Dosing was initiated at the onset of disease (day 11) and continued until day 18. Efficacy evaluations were based on animal body weights, daily ankle caliper measurements, ankle diameter (expressed as area under the curve), terminal hind paw weights, and histopathology of the ankles and knees. <h3>Results:</h3> Administration of FIL individually significantly reduced ankle diameter and final paw weights by 51% and 52%, respectively (p&lt;0.05). There was no change in body weight loss or in histological measurements with treatment. Conversely, ASK1 inhibition did not reduce inflammation as measured by ankle diameter or paw swelling, but resulted in a 48% reduction in ankle histopathological score (p&lt;0.05). The combination of FIL and the ASK1 inhibitor showed significantly greater effects on all measured parameters including paw weight (81% reduction), ankle diameter (78% reduction), and ankle and knee histopathology scores (69% and 87% reduction, respectively) than either agent alone. Body weight loss was also significantly reduced with the combination, and increased toward normal weight gain compared to the monotherapy arms. <h3>Conclusion:</h3> Combining FIL with ASK1 inhibition significantly improved clinical and histopathology scores, and reduced body weight loss in this model. These data suggest that simultaneously targeting JAK and ASK1 pathways can provide orthogonal activities that can enhance overall disease control. <h3>References:</h3> [1] Kavanaugh A, et al. Ann Rheum Dis. 2017;76:1009-1019. [2] Westhovens R, et al. Ann Rheum Dis. 2017;76:998-1008. [3] MC Genovese, et al. ACR 2018, Abstract L06. [4] Nygaard G, et al. Biochem Pharm. 2018;151:282-290. <h3>Disclosure of Interests:</h3> Paqui Gonzalez-Traves Grant/research support from: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Christian Franci Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Julie A. Di Paolo Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc.