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).

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.

Introduction

Sphingosine 1-phosphate (S1P) receptor modulators have been associated with an increased risk of macular oedema.¹ Etrasimod is an oral, once-daily, selective S1P_1,4,5 receptor modulator for the treatment of moderately to severely active ulcerative colitis (UC) and in development for the treatment of other immune-mediated inflammatory diseases.

Aims & Methods

We assessed the proportions and incidence rates (IRs; patients with events per 100 patient-years [PY] of exposure) of Macular oedema and Cystoid macular oedema in a comprehensive analysis of safety data from the etrasimod clinical programme. UC data were analysed in two cohorts: Placebo-controlled UC (completed phase [ph] 2 OASIS, ph 3 ELEVATE UC 52 and ELEVATE UC 12) and All UC (patients treated with etrasimod in the Placebo-controlled UC plus open‑label extension [OLE] studies; completed ph 2 OASIS OLE and ongoing ph 3 ELEVATE UC and ES101002 OLE studies, both datacut at 31 Jan 2022). Data from completed ph 2 studies in Crohn’s disease (CULTIVATE substudy A), and Placebo‑controlled studies in eosinophilic oesophagitis (VOYAGE), alopecia areata and atopic dermatitis (ADVISE) were also analysed.

Results

Across the etrasimod UC clinical programme, 942 patients received ≥1 dose of etrasimod 2 mg once daily (QD), with 757.9 PY of exposure. In the Placebo-controlled UC cohort, Macular oedema was reported in two patients (0.3%; IR 0.70) receiving etrasimod 2 mg QD (one patient with long-term corticosteroid use in ELEVATE UC 52 and one patient with prior uveitis in ELEVATE UC 12, which was not considered clinically significant by the investigator) and one patient (0.3%; IR 0.84) receiving placebo (ELEVATE UC 12). In the All UC cohort, one patient (0.1%; IR 0.13) receiving etrasimod 2 mg QD during the ELEVATE UC OLE reported two events of Cystoid macular oedema (Table). Four of five Macular oedema events began at Days 74–94, all were non-serious and only one event led to treatment discontinuation. No events of Macular oedema were reported in studies of etrasimod in other indications (Table).

Conclusion

The incidence of Macular oedema in patients treated with etrasimod in the clinical programme was low and generally comparable with placebo. These results are consistent with other S1P receptor modulators¹ and provide clinically relevant information on events of Macular oedema.

References

1. Bencardino S et al. J Clin Med 2023; 12: 5014.

Disclosure

MCD is a consultant for AbbVie, Abivax, AstraZeneca, Bristol Myers Squibb, Janssen, Lilly, Merck, Pfizer Inc, Prometheus Labs, Spyre and Takeda. JW, DB and IM are employees and shareholders of Pfizer Inc. AM is an employee of Pfizer Ltd and shareholder of Pfizer Inc. KL is an employee of Pfizer AG and a shareholder of Pfizer Inc. MG is an employee and shareholder of Pfizer AG. AA is a consultant for AbbVie, Allergan, Amgen, Arena, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, Ferring Pharmaceuticals, Galapagos, Gilead Sciences, Janssen, Lilly, Lionhealth, MSD, Mylan, Nestlé, Pfizer Inc, Roche, Samsung Bioepis, Sandoz, Takeda and Tillots Pharma; has received grant/research support from Biogen, MSD, Takeda and Pfizer Inc; and lecture/speaker fees from AbbVie, Amgen, Biogen, Bristol Myers Squibb, Ferring Pharmaceuticals, Galapagos, Gilead Sciences, Janssen, Lilly, Lionhealth, MSD, Novartis, Pfizer Inc, Roche, Samsung Bioepis, Sandoz, Takeda and TiGenix.

Introduction

Anti-TNF agents play a significant role in the induction and maintenance therapy of moderate to severe ulcerative colitis. However, at least 30% of patients experience loss of response within the first year of treatment.

Aims & Methods

This study aims to compare Tofacitinib versus Vedolizumab in patients with ulcerative colitis in the setting of previous anti-TNF failure. We performed a systematic review in PubMed, Embase and Cochrane databases, searching for randomized and non-randomized studies comparing Tofacetinib versus Vedolizumab in this population. The primary outcome was colectomy rate. The secondary outcomes were thromboembolic event rate and infectious incidence. The odds ratio (OR) was used for binary outcomes with their respective 95% confidence interval (CI). Heterogeneity was assessed using the Cochran Q test and I² statistics.

Results

The meta-analyses included 6 studies and 2,241 patients. There was a significant difference favoring Vedolizumab in colectomy rate (OR 2.03; 95% CI 1.30 to 3.16, p=0.002; I2=0%). There were no difference in thromboembolic event rate (OR 0.90; 95% CI 0.39 to 2.06; p=0.798; I2=0%) and infection incidence (OR 0.83; 95% CI 0.56 to 1.25; p=0.378; I2=0%).

Conclusion

In patients with ulcerative colitis with prior anti-TNF failure, tofacitinib showed higher colectomy rate compared to vedolizumab, with no difference in thromboembolic and infectious events between both groups. Considering this, vedolizumab seems to be a reasonable option in this population.

References

1. Straatmijer T, Biemans V, Visschedijk MC, Hoentjen F, De Vries A, Van Bodegraven AA, et al. SUPERIOR EFFECTIVENESS OF TOFACITINIB COMPARED TO VEDOLIZUMAB IN ANTI-TNF EXPERIENCED ULCERATIVE COLITIS PATIENTS: A NATIONWIDE DUTCH REGISTRY STUDY. United Eur Gastroenterol J. 2022;10((Straatmijer T., t.straatmijer@amsterdamumc.nl; De Boer K.H.N.) Amsterdam UMC, Amsterdam, Netherlands):390–1.
2. Buisson A, Serrero M, Altwegg R, Guilmoteau T, Bouguen G, Nachury M, et al. Real-world comparison of effectiveness between tofacitinib and ustekinumab in patients with ulcerative colitis exposed to at least one anti-TNF agent: Results from the TORUS study. J Crohns Colitis. 2023;17((Buisson A.; Guilmoteau T.) CHU Clermont-Ferrand, IBD Unit, Clermont-Ferrand, France):i707.
3. Adimadhyam S, Lewis JD, Simon AL, Wolfe AE, Smith S, Hou L, et al. Real-world Evidence Comparing Tofacitinib and Vedolizumab in Anti-TNF-experienced Patients With Ulcerative Colitis. Inflamm Bowel Dis. 2024 Apr 3;30(4):554–62.
4. Hyun HK, Zhang HS, Yu J, Kang EA, Park J, Park SJ, et al. Comparative effectiveness of second-line biological therapies for ulcerative colitis and Crohn’s disease in patients with prior failure of anti-tumour necrosis factor treatment. BMC Gastroenterol. 2022 Mar 27;22(1):143.