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
Aims & Methods
This study aimed to better understand immune cell type selectivity of etrasimod using in-depth immunophenotyping of peripheral blood mononuclear cells (PBMC). In ELEVATE UC 52 (NCT03945188) and ELEVATE UC 12 (NCT03996369), patients (pts) aged 16–80 years with moderately to severely active UC were randomised 2:1 to etrasimod 2 mg QD or placebo (PBO). PBMCs were collected and characterised 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 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).
Table. Epiontis ID PBMC %CFB at Week 12 (biomarker analysis set)
|
|---|
| ELEVATE UC 52
| ELEVATE UC 12
|
n, mean CFB, % (SD)
| PBO
(N = 98)
| Etrasimod 2 mg QD
(N = 185)
| PBO
(N = 68)
| Etrasimod 2 mg QD
(N = 120)
|
CD3+ (T cells)
CD4+ (CD4 T cells)
GATA3+ (Th2 cells)
IL17A+ (Th17 cells)
FOXP3+ (Treg cells)
CD8B+ (CD8 T cells)
CCR7+ (LN homing cells)
CXCR3+ (Th1, activated T cells)
LRP5A+ (B cells)
MVD+ (NK cells)
| 28, -1.61 (62.62)
28, -1.63 (67.21)
27, 0.91 (74.49)
28, -4.61 (69.25)
27, -2.01 (52.99)
28, -6.53 (52.03)
27, -7.18 (48.44)
28, 5.16 (63.25)
28, -9.45 (54.26)
28, 13.72 (50.83)
| 64, -45.05 (52.48)*
62, -65.29 (31.33)***
58, -62.56 (33.11)***
60, -59.85 (35.28)***
59, -52.40 (37.59)***
60, -28.65 (70.59)
61, -56.64 (24.04)***
56, 1.92 (105.60)
62, -59.22 (33.40)***
62, 39.96 (91.54)
| 25, 7.07 (41.22)
25, 11.20 (45.41)
25, -3.60 (44.35)
25, 3.96 (42.72)
24, 3.36 (56.09)
25, 10.96 (50.60)
25, 8.35 (46.89)
25, 2.16 (41.96)
25, 13.94 (64.45)
25, 17.79 (31.80)
| 47, -32.57 (50.77)***
47, -49.51 (41.10)***
45, -43.15 (39.43)***
46, -34.43 (48.66)**
44, -41.86 (38.78)**
47, -11.67 (65.27)46, -47.71 (25.33)*** 46, 28.54 (93.48)
47, -44.60 (55.28)***
46, 71.31 (89.23)***
|
*p < 0.05, **p < 0.01 and ***p < 0.001. Significant differences for etrasimod vs placebo are denoted with asterisks. The p-values were determined with a 2-sided t-test of the null hypothesis that the etrasimod-treated population parameter mean is equal to the PBO-treated population parameter mean.
Values shown are for Epiontis ID parameters in PBMC by visit.
%CFB, percent change from baseline; CD, cluster of differentiation; CCR, C-C chemokine receptor; CXCR, C-X-C motif chemokine receptor; GATA, GATA binding protein; FOXP, forkhead box protein; IL, interleukin; LN, lymph node; LRP, low-density lipoprotein receptor-related protein; MVD, mevalonate diphosphate decarboxylase; N, number of patients in cohort; n, number of patients in group; NK, natural killer; PBMC, peripheral blood mononuclear cell; PBO, placebo; QD, once daily; SD, standard deviation; Th, helper T cell; Treg, regulatory T cell; UC, ulcerative colitis. |
Conclusion
Etrasimod induces selective, pharmacodynamic changes in certain PBMC subsets. Results of cell-type characterisation by flow cytometry and Epiontis ID were complementary.
References
1. Scott FL et al. Br J Pharmacol 2016; 173: 1778–1792
Disclosure
BS has received lecture fees from AbbVie, CED Service GmbH, Chiesi, Falk, Forga Software, Galapagos, IBD Passport, Janssen, Materia Prima, Pfizer Inc and Lilly; consultancy fees from AbbVie, Arena Pharma, Boehringer Ingelheim, BMS, Celgene, CT-Scout, Endpoint Health, Galpagos, Gilead Sciences, Janssen, Landos, Lilly, Pfizer Inc, PredictImmune and PsiCro. CMC, XG and JCW are employees and shareholders of Pfizer Inc. RDR is an employee of and holds stock options with Pfizer Inc. MTA has received consultancy fees from AbbVie Inc, Amgen, Arena Pharmaceuticals, Bristol Myers Squibb, Celsius, Eli Lilly, Gilead, Janssen, Janssen Biotech Inc, Microba Life Sciences, Pfizer, Prometheus, Prometheus Bioscience, Takeda, and UCB Biopharma. SV has received lecture/speaker fees from AbbVie, Dr. Falk Pharma, Ferring, Galapagos, Hospira, Janssen, MSD, Takeda and Tillotts; consultancy/advisory fees from AbbVie, AbolerIS Pharma, Alimentiv, Arena, AstraZeneca, Avaxia, BMS, Boehringer Ingelheim, Celgene, CVasThera, Dr Falk Pharma, Ferring, Galapagos, Genentech/Roche, Gilead, Hospira, Imidomics, Janssen, Johnson and Johnson, Lilly, Materia Prima, MiroBio, Morphic, MrMHealth, MSD, Mundipharma, Pfizer Inc, Prodigest, Progenity, Prometheus, Robarts Clinical Trials, Second Genome, Shire, Surrozen, Takeda, Theravance Biopharma, Tillots Pharma AG and Zealand Pharma; grant/research support from AbbVie, MSD, Pfizer Inc, Galapagos, Janssen and Takeda. ID has received consultancy fees, research grants or honoraria from Abbott, AbbVie, Altman, Arena, Athos, Cambridge Healthcare, Celgene/BMS, Celltrion, Falk Pharma, DSM, Ferring, Food Industries Organisation, Galapagos, Genentech/Roche, Gilead, GSK, Hospital for Sick Children, Integra Holdings, Iterative Scopes, Janssen, Mediahuset, Medscape, Neopharm, Nestle, Peer voice, Pfizer, Rafa Laboratories, Sangamo, Sublimity, Takeda and Wilbio. KMR has received grant/research support from Bristol Myers Squibb. HKK has received consultancy fees from Kinevant Sciences and is an employee/shareholder for Uniquity Bio. MG is an employee and shareholder of Pfizer AG. SD has received lecture/speaker fees from AbbVie, Amgen, Ferring Pharmaceuticals Inc., Gilead, Janssen, Mylan, Pfizer and Takeda; consultancy/advisory fees from AbbVie, Allergan, Amgen, AstraZeneca, Biogen, Boehringer Ingelheim, Celgene, Celltrion, Ferring, Gilead Sciences, Hospira, Janssen, Johnson & Johnson, MSD, Mundipharma, Pfizer Inc, Roche, Sandoz, Takeda, TiGenix, UCB, and Vifor; holds directorship/ownership for Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele.