Background/Purpose:   Spleen Tyrosine Kinase (SYK) mediates signaling in hematopoietic cells important for the initiation and progression of rheumatoid arthritis (RA). GS-9876 is an oral, selective SYK inhibitor being developed in RA. Janus kinase (JAK) inhibitors, have demonstrated clinical efficacy in RA and exert their biological activity principally by blockade of proinflammatory cytokine signaling. Here we demonstrate that 1) the single agent activity of GS-9876 is efficacious in a late stage rat model of collagen-induced arthritis (CIA); 2) the combination of GS-9876 with a JAK inhibitor increases efficacy in this model; and 3) the effects of targeting SYK or JAK as single agents can be functionally differentiated.

Methods:   The in vivo efficacy of GS-9876 and a JAK inhibitor were tested alone or in combination in a therapeutic rat CIA model. Dosing was initiated at the peak of disease (day 17-20) and continued into the chronic phase until day 34; making the test more indicative of late treatment effects in the highly destructive macrophage-mediated phase, rather than in the acute, early neutrophil mediated phase of t this model. 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 ankles and knees. Anti-type II collagen antibody levels in terminal serum were analyzed, and PK was collected to evaluate the relationship to efficacy. Joint tissue RNA and protein were analyzed for transcriptional and protein modulation.

Results:  GS-9876 demonstrated dose-responsive efficacy in the rat CIA model. GS-9876 or a JAK inhibitor alone showed efficacy on clinical and histopathology parameters. Administration of the SYK or JAK inhibitor in combination showed significantly alleviated increases in terminal paw weights, ankle swelling, and ankle histopathology scores than either agent alone. Body weight loss was also significantly reduced in the combination therapy group, and weight was increased compared to the monotherapy arms. Knee ED-1 immunopositive osteoclast counts were significantly reduced in the animals treated with GS-9876, but not a JAK inhibitor, highlighting functionally distinct effects of SYK and JAK inhibition. PK analysis of GS-9876 showed serum exposure levels similar to those achieved in human studies.

Conclusion:   GS-9876 is a novel SYK inhibitor which displays in vivo therapeutic efficacy in a chronic rat CIA model. Combining GS-9876 with JAK inhibition significantly improved clinical and histopathology scores, and reduced body weight loss in this model, at exposures similar to those achieved in healthy human volunteers. These data suggest that simultaneously targeting SYK and JAK can provide an efficacious therapy for inflammatory diseases.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/combination-of-the-syk-inhibitor-gs-9876-with-a-jak-inhibitor-increases-efficacy-in-a-chronic-rat-model-of-collagen-induced-arthritis/