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Clinical Trial
. 2024 Aug 14;18(8):1270-1282.
doi: 10.1093/ecco-jcc/jjae038.

Efficacy and Safety of Etrasimod in Patients with Moderately to Severely Active Isolated Proctitis: Results From the Phase 3 ELEVATE UC Clinical Programme

Laurent Peyrin-Biroulet  1   2   3   4   5   6 , Marla C Dubinsky  7 , Bruce E Sands  8 , Julian Panés  9 , Stefan Schreiber  10 , Walter Reinisch  11 , Brian G Feagan  12   13 , Silvio Danese  14 , Andres J Yarur  15 , Geert R D'Haens  16 , Martina Goetsch  17 , Karolina Wosik  18 , Michael Keating  19 , Krisztina Lazin  17 , Joseph Wu  20 , Irene Modesto  19 , Aoibhinn McDonnell  21 , Lauren Bartolome  19 , Séverine Vermeire  22
Affiliations
Clinical Trial

Efficacy and Safety of Etrasimod in Patients with Moderately to Severely Active Isolated Proctitis: Results From the Phase 3 ELEVATE UC Clinical Programme

Laurent Peyrin-Biroulet et al. J Crohns Colitis. .

Erratum in

Abstract

Background and aims: Pivotal trials in ulcerative colitis have historically excluded patients with isolated proctitis. Etrasimod is an oral, once-daily, selective sphingosine 1-phosphate1,4,5 receptor modulator for the treatment of moderately to severely active ulcerative colitis. This post hoc analysis assessed efficacy and safety of etrasimod 2 mg once daily in patients with isolated proctitis (centrally read) from the phase 3 ELEVATE UC 52 and ELEVATE UC 12 trials.

Methods: Patients, including those with isolated proctitis (<10 cm rectal involvement) who met all other inclusion criteria in ELEVATE UC 52 and ELEVATE UC 12, were randomised 2:1 to receive etrasimod or placebo. Primary, secondary and other identified efficacy endpoints and safety were assessed.

Results: We analysed data from 64 and 723 patients at Week 12 (both trials pooled), and 36 and 397 patients at Week 52 (ELEVATE UC 52 only) with isolated proctitis and more extensive colitis (≥10 cm rectal involvement), respectively. Patients with isolated proctitis receiving etrasimod demonstrated significant improvements versus placebo, including clinical remission rates at Weeks 12 (42.9% vs 13.6%) and 52 (44.4% vs 11.1%), endoscopic improvement (52.4% vs 22.7%) at Week 12 and bowel urgency numerical rating scale score at Week 12 (all p < 0.01). Generally similar trends were observed in patients with more extensive colitis. Safety was consistent across subgroups, with no new findings.

Conclusions: Etrasimod demonstrated significant improvements versus placebo in patients with isolated proctitis, and those with more extensive disease, in most efficacy endpoints at Week 12 and 52. Clinicaltrials.gov: NCT03945188; NCT03996369.

Keywords: S1P receptor modulator; etrasimod; proctitis.

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Conflict of interest statement

LPB reports fees from AbbVie, Abivax, Adacyte, Alimentiv, Alma Bio Therapeutics, Amgen, Applied Molecular Transport, Arena, Biogen, Bristol-Myers Squibb, Celltrion, CONNECT Biopharm, Cytoki Pharma, Enthera, Ferring, Fresenius Kabi, Galapagos, Genentech, Gilead Sciences, Gossamer Bio, GlaxoSmithKline, HAC-Pharma, IAG Image Analysis, Index Pharmaceuticals, Inotrem, Janssen, Lilly, Medac, Mopac, Morphic Therapeutics, MSD, Nordic Pharma, Norgine, Novartis, OM Pharma, ONO Pharma, OSE Immunotherapeutics, Pandion Therapeutics, Par’Immune, Pfizer, Prometheus, Protagonist, Roche, Roivant, Samsung, Sandoz, Sanofi, Takeda, Theravance, Thermo Fisher, Tigenix, Tillots, Vectivbio, Ventyx, Viatris, Vifor and Ysopia.

MCD reports consulting fees from AbbVie, Abivax, Arena Pharmaceuticals, AstraZeneca, Bristol-Myers Squibb, Celgene, Eli Lilly, Galapagos, Genentech, Gilead Sciences, Janssen Pharmaceuticals, Pfizer Inc, Prometheus Biosciences, Prometheus Laboratories, Takeda and UCB; grants and research support from Janssen; shareholder/royalties from Trellus Health; and directorship/ownership interest in Treullus Health.

BES reports consulting fees from AbbVie, Alimentiv, Amgen, Arena Pharmaceuticals, Artugen Therapeutics, AstraZeneca, Boehringer Ingelheim, Boston Pharmaceuticals, Calibr, Celgene, Celltrion, ClostraBio, Enthera, Equillium, Evommune, Fresenius Kabi, Galapagos, Genentech (Roche), Gilead Sciences, GlaxoSmithKline, Gossamer Bio, Index Pharmaceuticals, Innovation Pharmaceuticals, Inotrem, Kaleido, Kallyope, Merck, Morphic Therapeutics, MRM Health, Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonist Therapeutics, Q32 Bio, Sun Pharma, Surrozen, Target RWE, Teva, TLL Pharmaceutical, Ventyx Biosciences; speaker fees from Abivax and Lilly; research grants and consulting fees from Bristol-Myers Squibb, Janssen, Pfizer, Takeda, and Theravance Biopharma; and holds stock in Ventyx Biopharma.

JP reports personal fees from AbbVie, Arena, Athos, Atomwise, Boehringer Ingelheim, Celgene, Celsius, Celltrion, Ferring, Galapagos, Genentech/Roche, GlaxoSmithKline, Immunic, Janssen, Mirum, Morphic Therapeutics, Pandion, Pfizer Inc, Progenity, Prometheus, Revolo, Sanofi, Takeda, Theravance Biopharma and Wassermann; and grant support from AbbVie and Pfizer Inc.

SS reports lecture/speaker fees from AbbVie, Arena, Biogen, Bristol-Myers Squibb, Celgene, Celltrion, Falk, Fresenius, Janssen, MSD, Pfizer Inc and Takeda; and consultancy fees from AbbVie, Arena, Biogen, Bristol-Myers Squibb, Celgene, Celltrion, Falk, Fresenius, Gilead Sciences, IMAB, Janssen, MSD, Mylan, Pfizer Inc, Protagonist, Provention Bio, Takeda and Theravance.

WR reports speaker fees from AbbVie, Celltrion, Falk Pharma GmbH, Ferring, Galapagos Medice, Janssen, MSD, Pfizer, Pharmacosmos, Roche, Shire, Takeda and Therakos; consultancy fees from AbbVie, Amgen, AOP Orphan, Arena Pharmaceuticals, Astellas, AstraZeneca, Bioclinica, Boehringer Ingelheim, Bristol-Myers Squibb, Calyx, Celgene, Celltrion, Eli Lilly, Falk Pharma GmbH, Ferring, Galapagos, Gatehouse Bio Inc., Genentech, Gilead Sciences, Grünenthal, ICON, Index Pharma, Inova, Janssen, Landos Biopharma, Medahead, MedImmune, Microbiotica, Mitsubishi Tanabe Pharma Corporation, MSD, Novartis, OMass, Otsuka, Parexel, Periconsulting, Pharmacosmos, Pfizer, Protagonist, Provention, Quell Therapeutics, Sandoz, Seres Therapeutics, Setpointmedical, Sigmoid, Sublimity, Takeda, Teva Pharma, Therakos, Theravance and Zealand; is an advisory board member for AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Celltrion, Galapagos, Janssen, Mitsubishi Tanabe Pharma Corporation, MSD, Pharmacosmos, Pfizer, Sandoz and Takeda; and receives research funding from AbbVie, Janssen, MSD, Sandoz, Sanofi and Takeda.

BGF is a senior scientific director for Alimentiv Inc, which provides central reading services. He is not a company employee and has no equity stake in the organisation which is owned by a medical trust. He also reports speaker fees for AbbVie, Janssen, and Takeda; is a consultant/advisory board member for AbbVie, AbolerIS, AgomAB Therapeutics, Allianthera, Amgen, AnaptysBio, Applied Molecular Transport Inc, Arena Pharma, Avoro Capital Advisors, Atomwise, BioJamp, Biora Therapeutics, Boehringer Ingelheim, Boxer, Celsius Therapeutics, Celgene/Bristol-Myers Squibb, Connect BioPharma, Cytoki, Disc Medicine, Duality, EcoR1, Eli Lilly, Equillium, Ermium, First Wave, First Word Group, Galapagos, Galen Atlantica, Genentech/Roche, Gilead, Gossamer Pharma, GlaxoSmithKline, Hinge Bio, Hot Spot Therapeutics, Index Pharma, Imhotex, Immunic Therapeutics, JAKAcademy, Janssen, Japan Tobacco Inc., Kaleido Biosciences, Landos Biopharma, Leadiant and L.E.K, Lenczner Slaght, LifeSci Capital, Lument AB, Millennium, MiroBio, Morgan Lewis, Morphic Therapeutics, Mylan, OM Pharma, Origo BioPharma, Orphagen, Pandion Therapeutics, Pendopharm, Pfizer, Play to Know AG, Progenity, Prometheus Therapeutics and Diagnostics, Protagonist, PTM Therapeutics, Q32 Bio, Rebiotix, REDX, Roche, Sandoz, Sanofi, Seres Therapeutics, Silverback Therapeutics, Surrozen Inc., Takeda, Teva, Thelium, Tigenix, Tillotts, Ventyx Biosciences, VHSquared Ltd., Viatris, Ysios, Ysopia and Zealand Pharma; and is a shareholder of Gossamer Pharma.

SD reports lecture fees from AbbVie, Amgen, Ferring Pharmaceuticals Inc., Gilead Sciences, Janssen, Mylan, Pfizer and Takeda; consultancy fees from AbbVie, Allergan, Amgen, AstraZeneca, Biogen, Boehringer Ingelheim, Celgene, Celltrion, Ferring, Gilead Sciences, Hospira, Janssen, Johnson and Johnson, MSD, Mundipharma, Pfizer Inc, Roche, Sandoz, Takeda, TiGenix, UCB and Vifor; and directorship/ownership for Gastroenterology and Endoscopy.

AJY reports consultancy fees from Arena, Bristol-Myers Squibb, Pfizer and Takeda; and lecture fees from Bristol-Myers Squibb.

GRDH is an advisor for AbbVie, Alimentiv, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celltrion, Cosmo, Eli Lilly, Galapagos, GlaxoSmithKline, Johnson and Johnson, Pfizer Inc, Polpharma, Prometheus Biosciences, Takeda, Tillotts and Ventyx; and reports speaker fees for AbbVie, Boehringer Ingelheim, Celltrion, Eli Lilly, Johnson and Johnson, Pfizer Inc, Takeda and Tillotts.

MG is an employee and shareholder of Pfizer AG.

KW is an employee and shareholder of Pfizer Canada Inc.

MK, JW, IM, and LB are employees and shareholders of Pfizer Inc.

AM is an employee of Pfizer Ltd, and a shareholder of Pfizer.

SV reports lecture fees from AbbVie, Dr. Falk Pharma, Ferring, Hospira, MSD, Takeda and Tillotts; consultancy fees from AbbVie, AbolerIS Pharma, Alimentiv, Arena, AstraZeneca, Avaxia, BMS, Boehringer Ingelheim, Celgene, CVasThera, Dr Falk Pharma, Eli Lilly, Ferring, Galapagos, Genentech/Roche, Gilead, Hospira, Imidomics, Janssen, Johnson and Johnson, 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; and grant/research support from AbbVie, Galapagos, MSD, Pfizer Inc and Takeda.

Figures

Graphical Abstract
Graphical Abstract
Figure 1.
Figure 1.
Clinical remission in (A) patients with isolated proctitis and (B) those with more extensive colitis. Nominal p values are reported without adjustment for multiple comparisons. Treatment comparisons and 2-sided p values were obtained using the Cochran–Mantel–Haenszel method assuming common proportion difference within each subgroup, adjusting for naïvety to prior biologic/Janus kinase inhibitor therapy, baseline corticosteroid use and baseline disease activity (MMS 4–6 or 7–9) and, for pooled study data (Week 12), additionally adjusting for study stratification. Patients with missing responses were considered nonresponders. Δ, adjusted percentage difference for etrasimod minus placebo; QD, once daily.
Figure 2.
Figure 2.
(A) Endoscopic improvement, (B) symptomatic remission, (C) EIHR and (D) clinical response in patients with isolated proctitis. Nominal p values are reported without adjustment for multiple comparisons. Treatment comparisons and 2-sided p values were obtained using the Cochran–Mantel–Haenszel method assuming common proportion difference within each subgroup, adjusting for naïvety to prior biologic/Janus kinase inhibitor therapy, baseline corticosteroid use and baseline disease activity (MMS 4–6 or 7–9) and, for pooled study data (Week 12), additionally adjusting for study stratification. Patients with missing responses were considered nonresponders. Δ, adjusted percentage difference for etrasimod minus placebo; QD, once daily.
Figure 3.
Figure 3.
(A) CS-free clinical remission and (B) sustained clinical remission in patients with isolated proctitis. Nominal p values are reported without adjustment for multiple comparisons. Treatment comparisons and 2-sided p values were obtained using the Cochran–Mantel–Haenszel method assuming common proportion difference within each subgroup, adjusting for naïvety to prior biologic/Janus kinase inhibitor therapy, baseline corticosteroid use and baseline disease activity (MMS 4–6 or 7–9). Patients with missing responses were considered nonresponders. Δ, adjusted percentage difference for etrasimod minus placebo; QD, once daily.
Figure 4.
Figure 4.
Proportion of patients with isolated proctitis with (A) cessation of rectal bleeding (RBS = 0) over time and (B) achievement of symptomatic remission over time. *p < 0.05 for etrasimod versus placebo. Missing responses were considered as nonresponse. N, total number of patients; n, number of patients with evaluable data at a visit; QD, once daily.
Figure 5.
Figure 5.
Improvement in bowel urgency NRS in patients with isolated proctitis. Data are reported as observed. aEstimates at Week 12 are from ANCOVA for change from baseline with a covariate for baseline score, and stratification factors for naive to biologic/Janus kinase inhibitor therapy at study entry, baseline CS use, baseline disease activity (MMS: 4–6 or 7–9), study stratification and treatment. Estimates at Week 52 are from a mixed model for repeated measures for change from baseline with a covariate for baseline score, same three stratification factors, treatment, visit, and treatment by visit interaction, including data from ELEVATE UC 52 only. Δ, least-squares mean difference; ANCOVA, analysis of covariance; LSM, least-squares mean; QD, once daily.
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