P574 Characterization of plasma inflammatory protein abundance in patients with ulcerative colitis treated with etrasimod: an exploratory analysis of the phase 3 ELEVATE UC 52 and ELEVATE UC 12 trials
Siegmund, B.(1)*;Ryan, R.(2);Abreu, M.T.(3);Vermeire, S.(4);Dotan, I.(5,6);Goetsch, M.(7);Crosby, C.(8);Woolcott, J.(9);Komori, H.K.(10);Danese, S.(11);
(1)Charité - Universitätsmedizin Berlin, Medizinische Klinik für Gastroenterologie, Berlin, Germany;(2)Pfizer Inc, Biomarker Statistics, New York- New York, United States;(3)University of Miami Miller School of Medicine, Gastroenterology, Miami- Florida, United States;(4)University Hospitals Leuven, Gastroenterology, Leuven, Belgium;(5)Division of Gastroenterology- Rabin Medical Center, Gastroenterology, Petah Tikva, Israel;(6)Sackler Faculty of Medicine- Tel Aviv University, Gastroenterology, Tel Aviv, Israel;(7)Pfizer AG, Global Clinical Development, Zurich, Switzerland;(8)Pfizer Inc, Translational Medicine, New York- New York, United States;(9)Pfizer Inc, Global Medical Affairs- Gastroenterology, Collegeville- Pennsylvania, United States;(10)Kinevant Sciences, Translational Research, San Diego- California, United States;(11)Gastroenterology and Endoscopy- IRCCS Ospedale San Raffaele and University Vita-Salute San Raffaele, Gastroenterology, Milan, Italy;
Background
Etrasimod is an investigational, once-daily, oral, selective sphingosine 1-phosphate receptor 1,4,5 modulator (S1P1,4,5) in development for the treatment of moderately to severely active ulcerative colitis (UC). To better understand how etrasimod reduces inflammation and induces clinical remission, the phase 3 ELEVATE UC 52 and ELEVATE UC 12 trials included a per protocol exploratory analysis of peripheral blood inflammatory proteomics, the results of which are presented here.
Methods
In ELEVATE UC 52 (NCT03945188) and ELEVATE UC 12 (NCT03996369), patients (16-80 years) with moderately to severely active UC were randomised 2:1 to once-daily etrasimod 2 mg or placebo (PBO). Plasma was collected at baseline and week 12 for both trials and week 52 for ELEVATE UC 52. Characterization of plasma inflammatory protein abundance and changes in abundance over time were assessed by proximity extension assay using the Olink Target 96 Inflammation panel. Normalized protein expression and change from baseline by visit were summarized by descriptive statistics; fold changes in Olink measurements were expressed as log2.
Results
Plasma samples were collected and analysed from 238 patients in ELEVATE UC 52 (162 etrasimod, 76 PBO) and 163 patients in ELEVATE UC 12 (108 etrasimod, 55 PBO). While no meaningful changes in protein biomarkers were observed over time in PBO-treated patients, factors modulated by etrasimod included those associated with tissue remodelling (MMP-1, MMP-10), T-cell response (CD5, CD6, CD8A, TNFRSF9), chemotaxis (CCL11, CCL19, CCL28, CX3CL1), and pleiotropic cytokine response (IL-7, IL-17A, IL-10, OSM), with a high degree of overlap and consistency in trends between the two trials (Figure 1). Etrasimod induced statistically significant reductions in circulating inflammatory proteins including IL-17A and OSM at week 12, and these remained decreased at week 52. Decreases in IL-17A and OSM at weeks 12 and 52 correlated with efficacy outcome measures across various clinical subgroups in responders vs nonresponders (Table 1).
Conclusion
In this per protocol exploratory analysis of two independent phase 3 randomised controlled trials, etrasimod induced consistent, statistically significant changes in circulating inflammatory proteins involved in tissue remodelling, T-cell response, chemotaxis, and cytokine response, including IL-17A and OSM. The reduction in activated immune cells in the peripheral blood of responders suggests etrasimod induces a reduction in inflammation that could contribute to remission.