P0907 - Characterization of the Effect of Etrasimod on Peripheral Blood Mononuclear Cells: Data From ELEVATE UC 52 and ELEVATE UC 12 Phase 3 Clinical Trials

Sunday, October 27, 2024

3:30 PM – 7:00 PM ET

Location: Exhibit Hall E

Has Audio

Presenting Author(s)

BS

Britta Siegmund, MD

Med. Klinik für Gastroenterologie, Infektiologie, Rheumatologie, Charité – Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, Campus Benjamin Franklin
Hindenburgdamm, Berlin, Germany

Britta Siegmund, MD¹, Rathi D. Ryan, PhD², Catherine M. Crosby, PhD³, Maria T. Abreu, MD⁴, Séverine Vermeire, MD, PhD⁵, Iris Dotan, MD⁶, Keren M. Rabinowitz, PhD⁷, Xiang Guo, PharmD, MS⁸, H. Kiyomi Komori, PhD⁹, Martina Goetsch, MD¹⁰, John C. Woolcott, PhD⁸, Silvio Danese, MD, PhD¹¹
¹Med. Klinik für Gastroenterologie, Infektiologie, Rheumatologie, Charité – Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, Campus Benjamin Franklin, Hindenburgdamm, Berlin, Germany; ²Pfizer Inc., San Francisco, CA; ³Pfizer Inc., San Diego, CA; ⁴Crohn's and Colitis Center, University of Miami Miller School of Medicine, Miami, FL; ⁵University Hospitals Leuven, Leuven, Vlaams-Brabant, Belgium; ⁶Rabin Medical Center, Tel Aviv University, Petah Tikva, Tel Aviv, Israel; ⁷Rabin Medical Center, Felsentstein Medical Research Centre, Medical and Health Sciences, Tel Aviv, Tel Aviv, Israel; ⁸Pfizer Inc., Collegeville, PA; ⁹Formerly Arena Pharmaceuticals, a wholly-owned subsidiary of Pfizer Inc., New York, NY; ¹⁰Pfizer AG, Zürich, Zurich, Switzerland; ¹¹Humanitas Clinical and Research Center - IRCCS, Rozzano and Humanitas University, Pieve Emanuele, Milan, Lombardia, Italy

Introduction: Etrasimod is an oral, once-daily (QD), selective sphingosine 1-phosphate (S1P)_1,4,5 receptor modulator for the treatment of moderately to severely active ulcerative colitis (UC). S1P receptor modulation reversibly sequesters specific lymphocyte subsets in lymph nodes.¹ This study aimed to better understand immune cell type selectivity of etrasimod using in-depth immunophenotyping of peripheral blood mononuclear cells (PBMCs).

Methods: In ELEVATE UC 52 (NCT03945188) and ELEVATE UC 12 (NCT03996369), patients (pts) aged 16–80 years with moderately to severely active UC were randomized 2:1 to etrasimod 2 mg QD or placebo (PBO). PBMCs were collected and characterized using flow cytometry and epigenetic immune monitoring by Epiontis ID for baseline and Week 12 assessments (both trials). Outputs were expressed as mean percent change from baseline (%CFB) of cell frequencies. Statistical tests were performed with t-tests at a nominal significance level of 0.05.

Results: In ELEVATE UC 52 and ELEVATE UC 12, 185 (64.0%) and 120 (50.4%) pts receiving etrasimod 2 mg QD, and 98 (68.1%) and 68 (58.6%) receiving PBO, respectively, were included in the biomarker analysis set. Baseline demographics and disease characteristics were similar to those in the full analysis set. Using flow cytometry, in both trials, %CFB reductions were observed in total T and B cells with etrasimod (62.24–72.46% decrease) but not PBO. Among CD4+ T-cell subsets, the greatest %CFB reductions with etrasimod were for naïve (Tn) cells. Reductions were also seen in central memory (Tcm), helper (Th)2, regulatory, Th1, Th17, and effector memory (Tem) cells (61.00–87.07% decrease) in both trials. Similarly, CD8+ Tn and Tcm subsets were reduced (69.33–78.48% decrease) with etrasimod; minimal changes were seen in CD8+ Tem cells. For B-cell subsets, memory cells and naïve cells were reduced with etrasimod in both trials (62.45–78.03% decrease). In both trials, minimal changes were observed for natural killer cells. With Epiontis ID, etrasimod induced significant reductions in peripheral CD3+, CD4+, GATA3+, IL17A+, FOXP3+, CCR7+, and LRP5A+ cells vs PBO (both trials; Table).

Discussion: Etrasimod induces selective, pharmacodynamic changes in certain PBMC subsets. Results of cell-type characterization by flow cytometry and Epiontis ID were complementary.

Reference:
1. Scott FL et al. Br J Pharmacol 2016; 173: 1778–1792.

Note: The table for this abstract can be viewed in the ePoster Gallery section of the ACG 2024 ePoster Site or in The American Journal of Gastroenterology's abstract supplement issue, both of which will be available starting October 27, 2024.

Disclosures:

Britta Siegmund: AbbVie – Consultant, Speakers Bureau. Arena Pharmaceuticals – Consultant, Speakers Bureau. Boehringer Ingelheim – Consultant, Speakers Bureau. Bristol Myers Squibb – Consultant, Speakers Bureau. CED Service GmbH – Consultant, Speakers Bureau. Celgene – Consultant, Speakers Bureau. Dr. Falk Pharma – Consultant, Speakers Bureau. Eli Lilly and Company – Consultant, Grant/Research Support, Speakers Bureau. Ferring Pharmaceuticals – Consultant, Speakers Bureau. Galapagos NV – Consultant, Speakers Bureau. Janssen – Consultant, Speakers Bureau. Novartis – Consultant, Speakers Bureau. Pfizer – Consultant, Speakers Bureau. Prometheus Therapeutics – Consultant, Speakers Bureau. Takeda – Consultant, Speakers Bureau.

Rathi Ryan: Pfizer Inc – Employee, Stock Options.

Catherine Crosby: Pfizer Inc – Employee, Stock Options.

Maria Abreu: AbbVie – Advisory Committee/Board Member, Consultant. Alimentiv – Lecturing Fee. Arena Pharmaceuticals Inc. – Advisory Committee/Board Member, Consultant. Bristol Myers Squibb – Advisory Committee/Board Member, Consultant. Celsius Therapeutics – Advisory Committee/Board Member, Consultant. Gilead – Advisory Committee/Board Member, Consultant. Janssen – Advisory Committee/Board Member, Consultant, Lecturing Fee. Lilly – Advisory Committee/Board Member, Consultant. Pfizer – Advisory Committee/Board Member, Consultant. Prime – Lecturing Fee. Prometheus Biosciences – Advisory Committee/Board Member, Consultant. UCB – Advisory Committee/Board Member, Consultant. WedMD Global LLC – Lecturing Fee.

Séverine Vermeire: AbbVie – Consultant, Grant/Research Support. Abivax – Consultant. AbolerlsPharma – Consultant. AgomAb – Consultant. Alimentiv – Consultant. Arena Pharmaceuticals – Consultant. AstraZeneca – Consultant. BioraTherapeutics – Consultant. Boehringer Ingelheim – Consultant. Bristol Myers Squibb – Consultant. Celgene – Consultant. Cytoki Pharma – Consultant. Dr Falk Pharma – Consultant. Eli Lilly – Consultant. Ferring – Consultant. Galapagos – Consultant, Grant/Research Support. Genentech Roche – Consultant. Gilead – Consultant. GSK – Consultant. Hospira – Consultant. J&J – Consultant, Grant/Research Support. Janssen – Consultant. lmidomics – Consultant. Materia Prima – Consultant. Mestag Therapeutics – Consultant. Microbiotica – Consultant. MiroBio – Consultant. Morphic – Consultant. MrMHealth – Consultant. MSD – Consultant. Mundipharma – Consultant. Pfizer Inc – Consultant, Grant/Research Support. Prodigest – Consultant. Progenity – Consultant. Prometheus – Consultant. Robarts Clinical Trials – Consultant. Surrozen – Consultant. Takeda – Consultant, Grant/Research Support. Theravance – Consultant. Tillots Pharma AG – Consultant. VectivBio – Consultant. Ventyx – Consultant. Zealand Pharma – Consultant.

Iris Dotan: AbbVie – Advisory Committee/Board Member, Consultant, Speakers Bureau. Altman – Advisory Committee/Board Member, Consultant, Speakers Bureau. Athos – Advisory Committee/Board Member, Consultant, Speakers Bureau. Celgene/Bristol Myers Squibb – Advisory Committee/Board Member, Consultant, Speakers Bureau. Celltrion – Advisory Committee/Board Member, Consultant, Speakers Bureau. Eli Lilly – Advisory Committee/Board Member, Consultant, Speakers Bureau. Ferring – Advisory Committee/Board Member, Consultant, Speakers Bureau. Galapagos – Advisory Committee/Board Member, Consultant, Speakers Bureau. Gilead – Advisory Committee/Board Member, Consultant, Speakers Bureau. Gutreat and Harp Diagnostics – shareholder. Iterative Scopes – Advisory Committee/Board Member, Consultant, Speakers Bureau. Janssen – Advisory Committee/Board Member, Consultant, Speakers Bureau. Pfizer – Advisory Committee/Board Member, Consultant, Speakers Bureau. Prometheus – Advisory Committee/Board Member, Consultant, Speakers Bureau. Roche/Genentech – Advisory Committee/Board Member, Consultant, Speakers Bureau. Sandoz – Advisory Committee/Board Member, Consultant, Speakers Bureau. Sangamo – Advisory Committee/Board Member, Consultant, Speakers Bureau. Sublimity – Advisory Committee/Board Member, Consultant, Speakers Bureau. Takeda – Advisory Committee/Board Member, Consultant, Speakers Bureau.

Keren Rabinowitz: Bristol-Myers Squibb – Grant/Research Support.

Xiang Guo: Pfizer Inc – Employee, Stock Options.

H. Kiyomi Komori: Kinevant Sciences – Consultant. Uniquity Bio – Employee, Stock Options.

Martina Goetsch: Pfizer AG – Employee, Stock Options.

John Woolcott: Pfizer Inc – Employee, Stock Options.

Silvio Danese: AbbVie – Consultant, Speakers Bureau. Alimentiv – Consultant. Allergan – Consultant. Amgen – Consultant, Speakers Bureau. Applied Molecular Transport – Consultant. AstraZeneca – Consultant. Athos Therapeutics – Consultant. Biogen – Consultant. Boehringer Ingelheim – Consultant. Bristol Myers Squibb – Consultant. Celgene – Consultant. Celltrion Healthcare – Consultant. Dr Falk Pharma – Consultant. Eli Lilly and Company – Consultant. Enthera – Consultant. Ferring – Consultant, Speakers Bureau. Gilead – Consultant, Speakers Bureau. Hospira – Consultant. Inotrem – Consultant. Janssen – Consultant, Speakers Bureau. Johnson & Johnson – Consultant. Morphic – Consultant. MSD – Consultant. Mundipharma – Consultant. Mylan – Consultant, Speakers Bureau. Pfizer Inc – Consultant, Speakers Bureau. Roche – Consultant. Sandoz – Consultant. Sublimity Therapeutics – Consultant. Takeda – Consultant, Speakers Bureau. Teladoc Health – Consultant. TiGenix – Consultant. UCB Inc. – Consultant. Vial – Consultant. Vifor – Consultant.