THU0181 TREATMENT WITH UPADACITINIB RESULTS IN THE NORMALIZATION OF KEY PATHOBIOLOGIC PATHWAYS IN PATIENTS WITH RHEUMATOID ARTHRITIS: BIOMARKER RESULTS FROM THE PHASE 3 SELECT-NEXT AND SELECT-BEYOND STUDIES
Authors: Thierry Sornasse, Jeremy Sokolove, Iain McInnes
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Upadacitinib (UPA), an oral JAK inhibitor selective for JAK1, demonstrated efficacy in patients with moderate-to-severe rheumatoid arthritis (RA) with an inadequate response (IR) to conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) or biologic DMARDs (bDMARDs) in the SELECT-NEXT<sup>1</sup> and SELECT-BEYOND<sup>2</sup> trials, respectively. The pivotal immune regulatory pathway targets served by JAK1 in patients have not been comprehensively explored. <h3>Objectives</h3> To investigate the mode of action (MoA) of UPA in patients with RA via a proteomic approach that evaluates a set of plasma proteins associated with inflammation. <h3>Methods</h3> Patients from the SELECT-NEXT and SELECT-BEYOND (PBO, n=167; UPA 15 mg QD, n=200) studies were randomly selected from the pool of patients with plasma samples available at baseline, Week 2, and Week 12. Samples from 24 age- and sex-matched healthy controls were included. The levels of 92 proteins were analyzed using the Olink® Inflammation Panel. Results from both studies were combined. Data were clustered using the Ward (unsupervised) method; correlations were calculated using the Pearson method; and multiple comparisons were corrected using the Benjamini–Hochberg method; all statistical analyses were performed in JMP 13.10 (SAS Institute). Pathway analysis was performed with Ingenuity® Pathway Analysis (Qiagen Inc.) version 45868156. <h3>Results</h3> At baseline, levels of IL-6, CXCL9, CXCL10, and CCL7 correlated significantly with baseline DAS28-ESR, consistent with effector roles for IL-6 and interferon (IFN) in intercurrent disease activity. Clustering of the differential protein fold change at Weeks 2 and 12 for UPA and PBO groups revealed four clusters enriched for proteins related to: 1) IL-6, IFN, leukocyte trafficking, and macrophage activation (↓↓↓); 2) T helper cell differentiation (↓); 3) T and B cell signaling (↓↓); and 4) hematopoiesis and myeloid cell differentiation (↑). Pathway analysis based on the differential expression of 37 significantly modulated proteins suggests that treatment with UPA results in the normalization of key pathways associated with the pathobiology of RA including: 1) pathways associated with IL-1, IL-6, IL-12, IL-15, IL-18, IFNα, IFNβ, IFNγ, CSF2, and TNF; and 2) pathways associated with behaviors of leukocytes (lymphocytes, myeloid cells, and granulocytes), including leukocyte migration, T cell response, and inflammatory response. In keeping with the latter, the changes in IL-6, CCL23, CCL7, MMP1, and S100A12 levels at Week 12 correlated significantly with the relative change in DAS28-ESR, suggesting a link between UPA MoA and macrophage activation. <h3>Conclusion</h3> In keeping with its selectivity for JAK1, UPA operates via inhibition of multiple JAK1-dependent upstream pathways that result in the normalization of key functional downstream effects associated with the pathobiology of RA, including T cell and myeloid cell-related pathways. Notably, non-JAK signaling pathways also normalize, suggesting functional integration of JAK1 with parallel pathogenic signaling in RA effector cells. <h3>References</h3> [1] Burmester GR, et al. Lancet2018;391:2503–12; [2] Genovese MC, et al. Lancet2018;391:2513–24 <h3>Acknowledgement</h3> AbbVie, Inc was the study sponsor, contributed to the study design, data collection, analysis &amp; interpretation, and to writing, reviewing, and approval of the final version. Medical writing support was provided by John Ewbank, PhD, of 2 the Nth. <h3>Disclosure of Interests</h3> Thierry Sornasse Shareholder of: AbbVie, Employee of: AbbVie, Jeremy Sokolove Shareholder of: AbbVie, Employee of: AbbVie, Iain McInnes Grant/research support from: AstraZeneca, Celgene, Compugen, Novartis, Roche, UCB Pharma, Consultant for: AbbVie, Celgene, Galvani, Lilly, Novartis, Pfizer, UCB Pharma