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). Early patient (pt)-reported response is often seen as an indicator of continued improvement through Week (Wk) 12.1
Aims & Methods
This post hoc analysis investigated relationships between pt-reported symptoms by Day 7 and clinical endpoints at Wk 12 in pts receiving etrasimod 2 mg QD or placebo in the ELEVATE UC clinical programme (NCT03945188, NCT03996369) using rectal bleeding (RB) and stool frequency (SF) subscores reported via daily e-diary records. For pts reporting symptomatic, RB and SF response by Day 7 (yes/no), the proportion achieving clinical endpoints (clinical remission [CR], endoscopic improvement [EI] and EI-histologic remission [EIHR]) at Wk 12 was measured. Adjusted risk differences in proportions of responders between treatment groups were estimated and tested using the Mantel-Haenszel weighted method.
Results
Among pts reporting symptomatic response by Day 7 (etrasimod 2 mg, N1 = 151; placebo, N1 = 60), pts treated with etrasimod vs placebo demonstrated significantly greater CR (47.7% vs 15.0%, adjusted difference [Δ] 33.9, p < 0.001), EI (54.3% vs 20.0%, Δ 35.7, p < 0.001) and EIHR (31.1% vs 6.7%, Δ 24.8, p < 0.001) rates at Wk 12 (Table). In pts who did not demonstrate symptomatic response by Day 7 (etrasimod 2 mg, N1 = 376; placebo, N1 = 200), those treated with etrasimod vs placebo achieved significantly greater rates of CR (18.9% vs 10.0%, Δ 8.7, p = 0.002), EI (27.7% vs 17.0%, Δ 10.5, p = 0.002) and EIHR (16.0% vs 7.5%, Δ 8.3, p = 0.002) at Wk 12 (Table). Similarly, Day 7 RB and SF responders and nonresponders treated with etrasimod vs placebo also demonstrated significantly greater rates of CR, EI and EIHR at Wk 12 (all p < 0.001; Table).
| Table. Wk 12 clinical endpoint in Day 7 symptomatic, RB and SF responders and nonresponders (FAS with baseline MMS 4–9) |
|---|
Data are pooled from ELEVATE UC 52 and ELEVATE UC 12.
aDefined as SF subscore = 0 (or = 1 with a ≥ 1-point decrease from baseline), RB subscore = 0 and endoscopic subscore ≤ 1 (excluding friability). SF and RB subscores are derived from pt daily e-diary records using the scores from the three most recent consecutive days within the seven days prior to the day of bowel preparation, averaged and rounded to the nearest integer.
bDefined as endoscopic subscore ≤ 1.
cDefined as endoscopic subscore ≤ 1 with histologic remission measured by a Geboes Index score < 2.0.
dDefined as pts achieving ≥ 30% decrease from baseline in partial MMS by Day 7.
eDifference (%) is based on estimated common risk difference using the Mantel–Haenszel weights and is stratified by actual naïve to biologic/Janus kinase inhibitor therapy at study entry (yes/no), actual baseline corticosteroid use (yes/no) and actual baseline disease activity (MMS: 4–6 or 7–9).
fThe 2-sided p value is to test the hypothesis of the common risk difference being 0 using Mantel–Haenszel weighted test.
gDefined as pts achieving RB subscore ≥ 1-point decrease from baseline by Day 7, based on collected daily scores.
hDefined as pts achieving SF subscore = 0 or ≥ 1-point decrease from baseline by Day 7, based on collected daily scores.
Δ, adjusted difference; CI, confidence interval; CR, clinical remission; EI, endoscopic improvement; EIHR, EI-histologic remission; FAS, full analysis set; MMS, modified Mayo score; N, number of pts in treatment group; n, number of pts achieving Day 7 and Wk 12 endpoint; N1, number of pts achieving Day 7 endpoint; pt, patient; QD, once daily; RB, rectal bleeding; SF, stool frequency; UC, ulcerative colitis; Wk, Week.
|
| Clinical responsea at Wk 12, yes
| Endoscopic improvementb at Wk 12, yes
| Endoscopic improvement histologic remissionc at Wk 12, yes
|
| Placebo QD
(N = 260)
| Etrasimod 2 mg QD
(N = 527)
| Placebo QD
(N = 260)
| Etrasimod 2 mg QD
(N = 527)
| Placebo QD
(N = 260)
| Etrasimod 2 mg QD
(N = 527)
|
Day 7 symptomatic responder,d n/N1 (%)
Δ (95% CI)e
p valuef
| 9/60 (15.0)
| 72/151 (47.7)
33.9 (22.1, 45.7)
< 0.001
| 12/60 (20.0)
| 82/151 (54.3)
35.7 (23.2, 48.3)
< 0.001
| 4/60 (6.7)
| 47/151 (31.1)
24.8 (14.9, 34.7)
< 0.001
|
Day 7 symptomatic nonresponder, n/N1 (%)
Δ (95% CI)e
p valuef
| 20/200 (10.0)
| 71/376 (18.9)
8.7 (3.1, 14.3)
0.002
| 34/200 (17.0)
| 104/376 (27.7)
10.5 (3.8, 17.2)
0.002
| 15/200 (7.5)
| 60/376 (16.0)
8.3 (3.2, 13.4)
0.002
|
Day 7 RB responder,g
n/N1 (%)
Δ (95% CI)e
p valuef
| 8/78 (10.3)
| 64/168 (38.1)
28.1 (18.0, 38.2)
< 0.001
| 15/78 (19.2)
| 75/168 (44.6)
27.2 (15.9, 38.4)
< 0.001
| 8/78 (10.3)
| 44/168 (26.2)
16.5 (6.9, 26.1)
< 0.001
|
Day 7 RB nonresponder,
n/N1 (%)
Δ (95% CI)e
p valuef
| 21/182 (11.5)
| 79/359 (22.0)
10.7 (4.5, 16.9)
< 0.001
| 31/182 (17.0)
| 111/359 (30.9)
14.1 (7.0, 21.2)
< 0.001
| 11/182 (6.0)
| 63/359 (17.5)
11.7 (6.5, 17.0)
< 0.001
|
Day 7 SF responder,h
n/N1 (%)
Δ (95% CI)e
p valuef
| 6/46 (13.0)
| 55/114 (48.2)
34.7 (21.9, 47.6)
< 0.001
| 10/46 (21.7)
| 65/114 (57.0)
34.2 (19.7, 48.8)
< 0.001
| 3/46 (6.5)
| 34/114 (29.8)
22.5 (11.5, 33.6)
< 0.001
|
Day 7 SF nonresponder,
n/N1 (%)
Δ (95% CI)e
p valuef
| 23/214 (10.7)
| 88/413 (21.3)
10.5 (4.9, 16.2)
< 0.001
| 36/214 (16.8)
| 121/413 (29.3)
12.8 (6.3, 19.4)
< 0.001
| 16/214 (7.5)
| 73/413 (17.7)
10.6 (5.5, 15.6)
< 0.001
|
Conclusion
Pts treated with etrasimod may experience rapid symptomatic improvements. In ELEVATE UC, pts treated with etrasimod who both did and did not demonstrate rapid symptomatic improvements had higher rates of clinical endpoint achievement at Wk 12 vs placebo. Pts treated with etrasimod who demonstrated an early, Day 7 response had the greatest likelihood of meeting clinical endpoints at Wk 12.
References
1. Chaparro M et al. J Crohns Colitis 2023; 17: i107–i110.
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
MCD reports consulting fees from AbbVie, Abivax, Arena Pharmaceuticals, AstraZeneca, Bristol Myers Squibb, Eli Lilly, Galapagos, Genentech, Gilead Sciences, Janssen Pharmaceuticals, Johnson & Johnson, Merck, Pfizer Inc, Prometheus Laboratories, Prometheus Biosciences, Sanofi, Sphyre, Takeda and UCB; is a shareholder/receives royalties from Trellus Health, and has a directorship/ownership interest in Trellus Health.
MC receives speaker/consulting fees and research/education funding from AbbVie, Biogen, Dr. Falk Pharma, Ferring, Gilead, Hospira, Janssen, Lilly, MSD, Pfizer Inc, Shire Pharmaceuticals, Takeda and Tillotts Pharma.
PMI receives grants from Celltrion, Janssen, MSD and Takeda; lecture fees from AbbVie, Bristol Myers Squibb, Celgene, Celltrion, Falk Pharma, Ferring, Galapagos, Gilead, MSD, Janssen, Pfizer Inc, Takeda, Tillotts, Sapphire Medical, Sandoz, Shire and Warner Chilcott; and advisory fees from AbbVie, Arena, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, Genentech, Gilead, Hospira, Janssen, Lilly, MSD, Pfizer Inc, Pharmacosmos, Prometheus, Roche, Sandoz, Samsung Bioepis, Takeda, Topivert, VH2, Vifor Pharma and Warner Chilcott.
PH is an employee of Pfizer Inc, a shareholder of Clene Nanomedicine, Haleon, Idorsia, Liquidia, Longboard Pharmaceuticals, Pfizer Inc and Proctor & Gamble; holds IP/patents for US 2022/0257594 A1; and receives grant/research support from AbbVie, Bristol Myers Squibb, Buhlmann, Janssen, Lilly, Pfizer Inc and Takeda.
SS, JCW, and WW are employees and shareholders of Pfizer Inc.
MG is an employee of Pfizer AG and shareholder of Pfizer Inc.
JT receives advisory board fees from AbbVie, Lilly, Janssen and Pfizer Inc; research grants from AbbVie and Janssen; and speaker fees from AbbVie, Janssen, Lilly, Takeda and Pfizer Inc.
RP receives consulting fees from Abbott, AbbVie, Abbivax, Alimentiv (formerly Robarts), Amgen, Arena Pharmaceuticals, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, Cosmos Pharmaceuticals, Eisai, Elan, Eli Lilly, Ferring, Galapagos, Fresenius Kabi, Genentech, Gilead Sciences, GlaxoSmithKline, JAMP Bio, Janssen, Merck, Mylan, Novartis, Oppilan Pharma, Organon, Pandion Pharma, Pendopharm, Pfizer Inc, Progenity, Prometheus Biosciences, Protagonist Therapeutics, Roche, Sandoz, Satisfai Health, Shire, Sublimity Therapeutics, Takeda Pharmaceuticals, Theravance Biopharma, Trellus, Viatris, Ventyx and UCB; speaker's fees from AbbVie, Amgen, Arena Pharmaceuticals, Bristol Myers Squibb, Celgene, Eli Lilly, Ferring, Fresenius Kabi, Gilead Sciences, Janssen, Merck, Organon, Pfizer Inc, Roche, Sandoz, Shire and Takeda Pharmaceuticals; advisory board fees from AbbVie, Alimentiv (formerly Robarts), Amgen, Arena Pharmaceuticals, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly, Ferring, Fresenius Kabi, Genentech, Gilead Sciences, GlaxoSmithKline, JAMP Bio, Janssen, Merck, Mylan, Novartis, Oppilan Pharma, Organon, Pandion Pharma, Pfizer Inc, Progenity, Protagonist Therapeutics, Roche, Sandoz, Shire, Sublimity Therapeutics, Takeda Pharmaceuticals and Ventyx; and grant/research support from AbbVie, Janssen, Takeda and Pfizer Inc.
