Session Type: Poster Session (Sunday)
Session Time: 9:00AM-11:00AM
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
To cite this abstract in AMA style:Taylor P, Elboudwarej E, Downie B, Hawtin R, Liu J, Mirza A. 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 [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10). 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/. Accessed January 19, 2020.
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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/