Session Type: ACR Poster Session A
Session Time: 9:00AM-11:00AM
Background/Purpose: Bruton’s Tyrosine Kinase (BTK) mediates signaling in hematopoietic cells important for the initiation and progression of rheumatoid arthritis (RA). GS-4059 is an oral, selective, irreversible BTK inhibitor being developed in RA. 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-4059 is efficacious in two different rat models of collagen-induced arthritis (CIA); 2) the combination of GS-4059 with a JAK inhibitor increases efficacy in a chronic CIA model; and 3) the activities of targeting BTK or JAK as single agents can be functionally differentiated.
Methods: The in vivo efficacy of GS-4059 and a JAK inhibitor were tested alone or in combination in rat CIA model. In the chronic model, dosing was initiated at the peak of disease and continued into the chronic phase; 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 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 histopathologic evaluation 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-4059 demonstrated dose-responsive efficacy in two rat CIA models. In the chronic model, administration of either GS-4059 or a JAK inhibitor showed efficacy on the clinical and histopathologic parameters. Combination therapy with GS-4059 and a JAK inhibitor showed significantly greater effects on paw weights, ankle swelling, and ankle histopathology scores than the single agents. Body weight loss was significantly inhibited in the combination therapy group, and weight was increased compared to the monotherapy arms, suggesting the combination treatment was more effective. Serum anti-type II collagen antibody (IgG) levels were significantly reduced in rats treated with the combination of GS-4059 and a JAK inhibitor. Knee ED-1 immunopositive osteoclast counts were significantly reduced in the animals treated with GS-4059 or the combination, but not in the single agent JAK inhibitor group, highlighting functionally distinct effects of BTK or JAK inhibition. PK analysis of GS-4059 and the JAK inhibitor showed serum exposure levels similar to those achieved in human studies.
Conclusion: GS-4059 is a novel BTK inhibitor that displayed in vivo therapeutic efficacy in the acute and chronic rat CIA models. Combining GS-4059 with a JAK inhibitor significantly improved clinical and histopathology scores, and reduced body weight loss in the rat CIA model, at exposures achieved in humans. These data suggest that simultaneously targeting BTK and JAK can provide an efficacious therapy for inflammatory diseases.
To cite this abstract in AMA style:Di Paolo J, Franci C, Gentzler T, Murray B, Li L. Targeting the BTK-JAK Axis in Preclinical Models of Rat Collagen-Induced Arthritis with GS-4059 in Combination with a JAK Inhibitor [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/targeting-the-btk-jak-axis-in-preclinical-models-of-rat-collagen-induced-arthritis-with-gs-4059-in-combination-with-a-jak-inhibitor/. Accessed September 17, 2019.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/targeting-the-btk-jak-axis-in-preclinical-models-of-rat-collagen-induced-arthritis-with-gs-4059-in-combination-with-a-jak-inhibitor/