Background/Purpose: Filgotinib (FIL), an oral, selective, Janus Kinase 1 (JAK1) inhibitor was effective in Phase 3 studies of active RA in patients (pts) with inadequate response or intolerance to biologic DMARDs (bDMARD-IR; FINCH-2 ClinicalTrials.gov Identifier: NCT02873936). We evaluated blood and urine biomarkers from FINCH-2 pts to better understand the relationship between molecular drivers of RA and identify any association between biomarkers at baseline and therapeutic response.

Methods: Forty-two cytokines known to be associated with RA pathobiology were quantified by single and multiplexed ELISA at baseline and week 12. The multiplicative interaction between each baseline biomarker (low [≤ median] or high [ > median]) and q.d. FIL 100mg (n = 153) or FIL 200 mg (n = 148), relative to placebo (PBO; n = 148), was tested for an effect on week 12 response (ACR-N, ACR20, ACR50, ACR70, DAS28-CRP). The relative concentrations of soluble intercellular adhesion molecule 1 (sICAM1) and serum chemokine (C-X-C motif) ligand (CXCL13) was previously associated with clinical outcomes in pts with RA treated with bDMARDs.¹ We similarly evaluated the therapeutic effect of FIL with sICAM1/CXCL13 ratio (low vs. high) on week 12 clinical responses. Odds ratios (OR) from logistic regression and effect estimates from linear regression models (Wald Chi-Square Test) were reported to assess whether the interaction between biomarker and treatment was associated with clinical response (FDR < 0.20).

Results: Comparing FIL 100 mg pts to PBO, high baseline levels of 8 serum cytokines (Chemokine (C-C motif) ligand 3[CCL3], CXCL10, IL-5, IL-6, IL-18, MMP3, serum amyloid A [SAA] and vascular cell adhesion molecule 1 [VCAM1]) were individually associated with improved ACR response or reduction in RA disease activity (DAS28-CRP) by week 12 (Δ ACRN range [27.5, 79.4]; Δ DAS28-CRP range [-0.70, -0.93]). High baseline serum CRP, CXCL13, and vascular endothelial growth factor A [VEGFA] levels were also associated with improved response to FIL 200 mg (Δ ACRN range [15.4, 32.9]; Δ DAS28-CRP range [-0.79, -1.39]; ACR50 OR range [6.13, 7.10]). Additionally, PBO-treated pts with a low sICAM1/CXCL13 ratio had lower ACR50 response rate compared to pts with high sICAM1/CXCL13 ratio (low vs high ratio Δ = -15.2%). In contrast, FIL treated pts exhibited the opposite effect, where a low sICAM1/CXCL13 ratio led to an increased ACR50 response (FIL 100 mg: low vs high ratio Δ = + 10.7%; FIL 200 mg: low vs high ratio Δ = + 19.9%). Relative to PBO with high sICAM1/CXCL13 ratio, a low sICAM1/CXCL13 ratio was significantly associated with an improved likelihood of ACR50 response to FIL 100 mg and 200 mg respectively at week 12 (OR = 7.40, P = 0.001; OR = 5.23, P = 0.007). Notably, these significant interactions held for ACR20 and ACR70 in FIL 200 mg (Table).

Conclusion: Individually, high baseline levels of key inflammatory serum cytokines, as well as the presence of a low sICAM1/CXCL13 ratio were each indicative of positive outcomes in these bDMARD-IR RA pts treated with FIL. Further evaluation of these biomarkers alone or in combination may suggest a cytokine profile in RA pts that enriches for the probability of high-end responses to therapy.
1. Dennis G et al. Arthritis Res Ther. 2014;16(2):R90

Biomarkers at Baseline Table

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/key-inflammatory-biomarkers-at-baseline-are-associated-with-filgotinib-response-at-week-12-in-rheumatoid-arthritis-patients-with-inadequate-response-or-intolerance-to-biologic-dmards/