FRI0285 FILGOTINIB TREATMENT RESULTS IN REDUCTION OF BIOMARKERS ASSOCIATED WITH DISEASE IN PATIENTS WITH ANKYLOSING SPONDYLITIS. (2nd June 2020) - Maksymowych, W. P.
Abstract : Background: Ankylosing spondylitis (AS) is a chronic, immune-mediated disease characterized by inflammation of the sacroiliac joints and spine, and a young age of onset of 20–40 years. In the recent TORTUGA study, filgotinib (FIL), an oral, selective Janus kinase 1 (JAK1) inhibitor, significantly reduced AS disease activity compared with placebo (PBO). 1 Selective JAK1 inhibition by FIL has the potential to simultaneously block multiple inflammatory pathways, thus we analyzed biomarker concentrations in serum samples from TORTUGA. Objectives: To evaluate the impact of selective JAK1 inhibition with FIL on circulating disease associated biomarkers in adult patients with active AS enrolled in the TORTUGA study. Methods: TORTUGA (Clinicaltrials.gov identifier NCT03117270 ) was a 12-week, randomized, double-blind, placebo-controlled, phase 2 study. Patients were randomized 1:1 to FIL 200 mg (n=58) or PBO (n=58) once-daily. Serum samples (FIL n=56, PBO n=53) were collected at baseline (BL) and weeks 1, 4 and 12, and analyzed using the Meso Scale Discovery immunoassay platform (Meso Scale Diagnostics, Rockville, MD, USA) to evaluate 135 biomarkers. Biomarker concentration changes from BL were analyzed on paired patient data and reported for weeks 1, 4 and 12, and clustering analysis was performed. Correlation between the 135 biomarkers and selected clinical scores at BL was assessed by Spearman rank correlation analysis. Results: FIL treatment produced significant reductions in serum concentrations of multiple biomarkers associated with AS disease activity. Five clusters of biomarker response were identified based on the kinetics and magnitude of percent changes from BL. These clusters also represented discrete biological functions: cluster 1 (rapid, strong >50% decrease in all three time points) included systemic inflammation biomarkers eg, CRP, SAA; cluster 2 (>20% decrease in at least one time point) included immune cell biomarkers eg, MIP3B, IL12p40; cluster 3 (<20% decrease in all three time points) included cellular adhesion biomarkers eg, ICAM-1, VCAM-1; cluster 4 (delayed decrease) included matrix remodelling biomarkers eg, MMP1, TIMP1; and cluster 5 included biomarkers that exhibited a gradual increase in serum concentration with FIL treatment. Spearman rank correlation analyses showed that at BL, the systemic inflammation biomarkers CRP and SAA, as well as a number of biomarkers including ICAM-1 and MMP3, were positively correlated with BL AS disease activity score (ASDAS); conversely, only a few biomarkers showed a negative correlation with BL ASDAS, the cytokine receptor FLT3 and the chemotactic cytokine fractalkine (FRACTAL). Conclusion: In patients with active AS, FIL treatment significantly decreased levels of circulating biomarkers associated with active AS disease, including proinflammatory cytokines and chemokines, cell adhesion molecules, and markers of matrix remodelling. Clustering analysis revealed early and late biomarker changes associated with disease. These data are consistent with reduced AS disease activity in TORTUGA and suggest that FIL treatment leads to a rapid and sustained reduction of inflammation in AS. References: [1]van der Heijde D et al. Lancet 2018;392:2378–87 Acknowledgments: This study was funded by Gilead Sciences, Inc. Editorial support was provided by Fishawack Communications Inc and funded by Gilead Sciences, Inc. Disclosure of Interests: Walter P. Maksymowych Grant/research support from: AbbVie, Novartis, Pfizer, and UCB, Consultant of: AbbVie, Boehringer Ingelheim, Celgene, Eli Lilly, Galapagos, Janssen, Novartis, Pfizer, and UCB, Employee of: Chief Medical Officer of CARE Arthritis Limited, Speakers bureau: AbbVie, Janssen, Novartis, Pfizer, and UCB, Yuan Tian Employee of: Gilead Sciences Inc., Oh Kyu Yoon Shareholder of: Gilead Sciences Inc., Employee of: Gilead Sciences Inc., William Barchuk Shareholder of: Gilead Sciences Inc and Eli Lilly, Employee of: Current employee of Gilead Sciences Inc and a former employee of AbbVie, Eli Lilly, and Johnson & Johnson, René Galien Shareholder of: Galapagos, Employee of: Galapagos, Robin Besuyen Shareholder of: Galapagos, Employee of: Galapagos, Yihua Liu Shareholder of: Gilead Sciences Inc., Employee of: Gilead Sciences Inc., Amer M. Mirza Shareholder of: Gilead Sciences Inc., Employee of: Gilead Sciences Inc., Vlad Malkov Shareholder of: Gilead Sciences Inc., Employee of: Gilead Sciences Inc., Angie Hertz Shareholder of: Gilead Sciences Inc, Employee of: Gilead Sciences Inc