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). Etrasimod 2 mg QD improved bowel urgency (BU) at Weeks (Wks) 12 and 52 in the ELEVATE UC clinical programme.1
Aims & Methods
We assessed associations between BU and efficacy endpoints, health-related quality of life (HRQoL) and biomarkers in patients receiving etrasimod in ELEVATE UC 52 (NCT03945188). BU was assessed at baseline (BL), Wk 12 and Wk 52 via a patient-reported, 11-point Urgency Numerical Rating Scale (NRS; 0–10; none to worst possible BU). We defined patient subgroups as with/without BU remission (NRS ≤ 1) or clinically meaningful improvement (CMI) in BU (NRS ≥ 3-point decrease from BL) at Wks 12 and 52. Associations were assessed between BU remission or CMI in BU (yes/no) and binary efficacy endpoints (multivariable logistic regression), change from BL in HRQoL using the inflammatory bowel diseases questionnaire total score and 36-item short form survey physical and mental component scores (multivariable linear regression) and faecal calprotectin (fCAL; Wilcoxon Rank test) at Wks 12 and 52.
Results
A larger proportion of patients with BU remission (73.6%) and CMI in BU (78.9%) at Wk 12 were naïve to biologic/Janus kinase inhibitors vs experienced. At Wk 12, significantly more patients with vs without BU remission met efficacy endpoints (odds ratio, OR [95% confidence interval, CI]: clinical remission 4.0 [2.3, 7.1]; endoscopic improvement 3.6 [2.1, 6.2]; both p < 0.0001) and had significantly greater improvement in HRQoL scores and lower fCAL (all p < 0.05; Table). A similar association was seen for CMI in BU at Wk 12 (OR [95% CI]: clinical remission 3.7 [2.1, 6.4]; endoscopic improvement 2.6 [1.6, 4.3]; both p < 0.001; Table) and for patients meeting BU outcomes at Wk 52.
| Table. Association of bowel urgency remissiona and clinically meaningful improvement in bowel urgencyb at Wk 12 with clinical and endoscopic endpoints, HRQoL and fCAL at Wk 12 in ELEVATE UC 52 |
|---|
Data are presented for the full analysis set (baseline MMS 4–9).
aDefined as NRS ≤ 1.
bDefined as NRS ≥ 3-point decrease from BL.
cDefined as SF subscore = 0 (or = 1 with a ≥ 1-point decrease from BL), RB subscore = 0 and ES ≤ 1 (excluding friability).
dOR (95% CI) and p values were obtained from a multivariable logistic regression with a covariate for bowel urgency status (yes/no) at Wk 12, naïve to biologic/Janus kinase inhibitor therapy at BL (yes/no), BL corticosteroid use (yes/no) and BL disease activity (MMS 4–6 or MMS 7–9). Missing responses are considered as nonresponse.
eDefined as a ≥ 2-point and ≥ 30% decrease from BL in MMS and a ≥ 1-point decrease from BL in RB subscore or an absolute RB subscore ≤ 1.
fDefined as ES of ≤ 1.
gEach response to a total of 32 questions is graded 1–7, with an overall possible score range of 32–224 (very poor to perfect HRQoL).
hBL is the last measurement taken prior to the first dose of study treatment. LS mean difference (95% CI) estimates are obtained from a multivariable linear regression model, adjusting for bowel urgency subgroup (yes/no) at Wk 12, BL score of respective endpoint, SF at Wk 12 and RB at Wk 12.
iSF-36 comprises eight multi-question domains, each scored 0–100 (worst to best HRQoL) then aggregated into the physical and mental component summary scores.
jWilcoxon test p value is calculated based on normal approximation. Missing values are imputed using the last observation carried forward method.
BL, baseline; CI, confidence interval; ES, endoscopic subscore; fCAL, faecal calprotectin; HRQoL, health-related quality of life; IBDQ, inflammatory bowel disease questionnaire; LS, least squares; max, maximum; min, minimum; MMS, modified Mayo score; N, total number of patients; n, number of responders or patients with observations; NRS, Numerical Rating Scale; OR, odds ratio; RB, rectal bleeding; SD, standard deviation; SE, standard error; SF-36, 36-item short form survey; SF, stool frequency; UC, ulcerative colitis; Wk, Week.
|
| Bowel urgency remission – yes
(N = 87)
| Bowel urgency remission – no
(N = 202)
| Clinically meaningful improvement in bowel urgency – yes
(N = 128)
| Clinically meaningful improvement in bowel urgency – no
(N = 161)
|
Clinical remission,c n (%)
OR (95% CI)d
p value
| 41 (47.1)
4.0 (2.3, 7.1)
< 0.0001
| 40 (19.8)
| 53 (41.4)
3.7 (2.1, 6.4)
< 0.0001
| 28 (17.4)
|
Clinical response,e n (%)
OR (95% CI)d
p value
| 81 (93.1)
14.4 (5.9, 34.9)
< 0.0001
| 101 (50.0)
| 109 (85.2)
6.8 (3.8, 12.3)
< 0.0001
| 73 (45.3)
|
Endoscopic improvement,f n (%)
OR (95% CI)d
p value
| 49 (56.3)
3.6 (2.1, 6.2)
< 0.0001
| 59 (29.2)
| 62 (48.4)
2.6 (1.6, 4.3)
0.0003
| 46 (28.6)
|
IBDQ change from BL,g LS mean (SE)
LS mean difference (95% CI)h
p value
| 59.9 (3.3)
21.8 (13.5, 30.1)
< 0.0001
| 38.2 (2.3)
| 57.3 (2.5)
25.5 (17.7, 33.2)
< 0.0001
| 31.8 (2.7)
|
SF-36 physical component change from BL,i LS mean (SE)
LS mean difference (95% CI)h
p value
| 8.4 (0.7)
4.0 (2.2, 5.8)
< 0.0001
| 4.4 (0.5)
| 7.5 (0.5)
4.0 (2.3, 5.8)
< 0.0001
| 3.5 (0.6)
|
SF-36 mental component change from BL,i LS mean (SE)
LS mean difference (95% CI)h
p value
| 9.0 (1.0)
3.0 (0.5, 5.4)
< 0.05
| 6.1 (0.7)
| 10.0 (0.7)
6.5 (4.3, 8.7)
< 0.0001
| 3.5 (0.8)
|
fCAL, µg/g, mean (SD);
median (min, max)
p valuej
| 744.5 (1758.0);
119.9 (4.9, 11763.2)
< 0.0001
| 2314.2 (5182.2);
554.8 (3.8, 30075.4)
| 876.8 (1846.1)
134.3 (3.8, 11763.2)
< 0.0001
| 2608.8 (5682.6)
532.9 (3.8, 30075.4)
|
Conclusion
Bowel urgency outcomes were associated with improvements in clinical and endoscopic endpoints, HRQoL scores and reduced fCAL at Wks 12 and 52. With etrasimod, BU outcomes may be surrogate markers of disease activity and HRQoL improvement.
References
1. Dubinsky MC et al. Am J Gastroenterol 2023; 118: S890–S891.
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; Shareholder/ Royalties from Trellus Health, and has Directorship/Ownership interest in Trellus Health.
ERC reports speaker's bureau fees from AbbVie, Janssen, Eli Lilly, Takeda and Celltrion; and consulting fees from AbbVie, Janssen, Pfizer Inc, Takeda, Bristol Myers Squibb and Eli Lilly.
PMI reports grant fees 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.
MG and KL are employees of Pfizer AG and shareholders of Pfizer Inc.
AB is an employee of Pfizer Healthcare India Private Ltd and shareholder of Pfizer Inc.
GP is an employee of Pfizer Healthcare India Private Ltd
PH is an employee of Pfizer Inc; shareholder of Clene Nanomedicine, Haleon, Idorsia, Liquidia, Longboard Pharmaceuticals, Pfizer Inc, Proctor & Gamble; holds IP/Patents for US 2022/0257594 A1; and recieves grant/research support from AbbVie, Bristol Myers Squibb, Buhlmann, Janssen, Lilly, Pfizer Inc and Takeda.
CC is an employee and shareholder of Pfizer Inc.
KW is an employee of Pfizer Canada Inc and shareholder of Pfizer Inc.
RP receives consultancy 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; is on the advisory boards for 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 receives research support from AbbVie, Janssen, Takeda and Pfizer Inc.