Introduction
Etrasimod is an oral, once-daily, selective sphingosine 1‑phosphate (S1P)1,4,5 receptor modulator for the treatment of moderately to severely active ulcerative colitis (UC). In patients with moderately to severely active UC, treatment guidelines recommend early use of advanced therapies rather than gradual step up after failure of 5-aminosalicylate (5-ASA).1
Aims & Methods
This prespecified subgroup analysis assessed the efficacy of etrasimod vs placebo in patients in ELEVATE UC 52 (NCT03945188) with, and without, prior oral 5-ASA failure only (defined as inadequate response, loss of response or intolerance to previous treatment with oral 5-ASA but not to any other previous UC medication). Efficacy endpoints assessed at Weeks 12 and 52 included clinical remission, endoscopic improvement, symptomatic remission and composite histological endpoints.
Results
In total, 45 and 29 patients receiving etrasimod and placebo, respectively, had prior 5-ASA failure only and 244 and 115 patients did not. At Weeks 12 and 52, among those who had failed prior 5-ASA only, significantly more patients receiving etrasimod vs placebo achieved clinical remission (Week 12, % difference [Δ]: 38.3%, p < 0.001; Week 52, Δ: 45.0%, p < 0.001), endoscopic improvement (Week 12, Δ: 54.7%, p < 0.001; Week 52, Δ: 47.8%, p < 0.001), symptomatic remission (Week 12, Δ: 38.6%, p < 0.001; Week 52, Δ: 45.0%, p < 0.001) and endoscopic improvement-histologic remission (Week 12, Δ: 35.6%, p < 0.001; Week 52, Δ: 31.1%, p < 0.001; Table). Significantly more patients receiving etrasimod vs placebo in this subgroup achieved endoscopic normalisation-histologic remission (Week 12, Δ: 19.9%, p = 0.002; Week 52, Δ: 24.3%, p < 0.001) and disease clearance (Week 12, Δ: 15.6%, p = 0.008; Week 52, Δ: 27.8%, p < 0.001). Among those who had failed other therapies, significantly more patients receiving etrasimod vs placebo also achieved all endpoints at Weeks 12 and 52 (p < 0.01).
Table. Key efficacy endpoints achieved by patients with prior oral 5-ASA treatment failure only in ELEVATE UC 52
|
|---|
aClinical remission: SFS = 0 (or = 1 with a ≥ 1-point decrease from baseline), RBS = 0 and ES ≤ 1 (excluding friability).
bDifference (95% CI) and 2-sided p value are based on the Cochran–Mantel–Haenszel method adjusting to reported randomisation stratification of (1) naïve to biologic or JAK inhibitor therapy at study entry, (2) baseline corticosteroid use and (3) baseline disease activity (MMS 4–6 or 7–9).
cEndoscopic improvement: ES ≤ 1.
dSymptomatic remission: SFS = 0 (or = 1 with a ≥ 1-point decrease from baseline) and RBS = 0.
eEIHR: ES ≤ 1 with histologic remission (Geboes Index score < 2.0).
fEndoscopic normalisation-histologic remission: Geboes Index score < 2.0 and ES = 0.
gDisease clearance: NHI = 0 and ES = 0 and RBS = 0 and SFS = 0 or 1 (if 1, must have ≥ 1-point decrease from baseline).
5-ASA, 5-aminosalicylate; CI, confidence interval; EIHR, endoscopic improvement-histologic remission; ES, endoscopic subscore; JAK, Janus kinase; MMS, modified Mayo score; n, number of patients achieving each endpoint; N, number of patients in each treatment group; NHI, Nancy Histological Index; QD, once daily; RBS, rectal bleeding subscore; SFS, stool frequency subscore; UC, ulcerative colitis.
|
| Week 12 | Week 52 |
| Placebo QD
(N = 29) | Etrasimod 2 mg QD
(N = 45) | Placebo QD
(N = 29) | Etrasimod 2 mg QD
(N = 45)
|
Clinical remission,a n (%)
Difference,b (95% CI)
p value
| 1 (3.4)
| 19 (42.2)
38.3 (19.7, 56.9)
< 0.001
| 1 (3.4)
| 21 (46.7)
45.0 (27.9, 62.1)
< 0.001
|
Endoscopic improvement,c n (%)
Difference,b % (95% CI)
p value
| 1 (3.4)
| 27 (60.0)
54.7 (35.4, 74.0)
< 0.001
| 2 (6.9)
| 24 (53.3)
47.8 (29.3, 66.2)
< 0.001
|
Symptomatic remission,d n (%)
Difference,b % (95% CI)
p value
| 6 (20.7)
| 27 (60.0)
38.6 (16.0, 61.2)
< 0.001
| 4 (13.8)
| 26 (57.8)
45.0 (25.1, 64.9)
< 0.001
|
EIHR,e n (%)
Difference,b % (95% CI)
p value
| 1 (3.4)
| 17 (37.8)
35.6 (16.4, 54.9)
< 0.001
| 0
| 14 (31.1)
31.1 (16.0, 46.1)
< 0.001
|
Endoscopic normalisation-histologic remission,f n (%)
Difference,b % (95% CI)
p value
| 0
| 8 (17.8)
19.9 (7.3, 32.5)
0.002
| 0
| 11 (24.4)
24.3 (10.5, 38.2)
< 0.001
|
Disease clearance,g n (%)
Difference,b % (95% CI)
p value
| 0
| 6 (13.3)
15.6 (4.2, 27.0)
0.008
| 0
| 13 (28.9)
27.8 (13.3, 42.4)
< 0.001
|
Conclusion
Etrasimod demonstrated robust efficacy as first-line advanced therapy in patients who had failed oral 5-ASA only, across all evaluated endpoints including stringent composite histological endpoints, consistent with the overall ELEVATE UC population. Etrasimod shows efficacy when used early in the UC treatment algorithm.
References
1. Singh S et al. Gastroenterology 2024; 167: 1307–1343.
Pfizer’s generative artificial intelligence tool MAIA was used to assist production of the abstract first draft. Authors reviewed/edited and take responsibility for the content.
Disclosure
DTR received grant support from Takeda; consultancy fees from AbbVie, Abivax SA, Altrubio, Avalo Therapeutics, Bausch Health, Bristol Myers Squibb, Buhlmann Diagnostics Corp, Celltrion, ClostraBio, Connect BioPharma, Douglas Pharmaceuticals, Eli Lilly & Co., Foresee, Genentech (Roche) Inc., Image Analysis Group, InDex Pharmaceuticals, Iterative Health, Janssen Pharmaceuticals, Odyssey Therapeutics, Pfizer Inc, Sanofi, Takeda Pharmaceuticals, Throne and Vedanta.
CWL received speaker fees from AbbVie, Dr Falk, Ferring, Hospira, Janssen, MSD, Pfizer Inc, Shire, Takeda and Warner-Chilcott; consultancy fees from AbbVie, Dr Falk, Gilead, GSK, Hospira, Iterative Scopes, Janssen, MSD, Oshi Health, Pfizer Inc, Pharmacosmos, Takeda, Topivert, Trellus Health and Vifor Pharma; research funding from AbbVie and Gilead.
FB received research/grant support from AbbVie, Amgen, Eurogenerics, Janssen and Takeda; lecture fees/speaker’s bureau from AbbVie, Arena Pharmaceuticals, Celltrion, Ferring, Galapagos, Janssen, Merck Sharp & Dohme, Pfizer Inc and Takeda; consultancy fees from AbbVie, Abivax, Amgen, Arena Pharmaceuticals, Celgene, Celltrion, Ferring, Fresenius Kabi, Janssen, Merck Sharp & Dohme, Pfizer Inc and Sandoz.
MK is an employee and shareholder of Pfizer Inc.
AB is an employee of Pfizer Healthcare India Private Ltd and shareholder of Pfizer Inc.
KL is an employee of Pfizer AG and shareholder of Pfizer Inc.
MG is an employee of Pfizer AG and shareholder of Pfizer Inc.
AMM is an employee and shareholder of Pfizer Inc.
KW is an employee of Pfizer Canada Inc and shareholder of Pfizer Inc.
JKM is an advisory committee/board member on AbbVie, Alimentiv, Amgen, AstraZeneca, Bausch Health, Bristol Myers Squibb, Celltrion, Ferring, Fresenius Kabi, Janssen, Lilly, Lupin, Organon, Paladin, Pfizer Inc, Pharmascience, Qu Biologics, Roche, Sandoz, SCOPE, Takeda, Teva and Viatris; receives lecture/speaker fees from AbbVie, Amgen, Bausch Health, Ferring, Fresenius Kabi, Janssen, Organon, Pfizer Inc, Pharmascience, Roche, Takeda and Viatris.
