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EFFICACY AND SAFETY OF ETRASIMOD IN PATIENTS WITH AND WITHOUT CONCOMITANT CORTICOSTEROID TREATMENT IN THE PHASE 3 ELEVATE UC 52 AND ELEVATE UC 12 TRIALS

Bruce E. Sands 1, Krisztina Barbara Gecse 2, David T. Rubin 3, Yvette Leung 4, Julian Panés 5, Martina Goetsch 6, Wenjin Wang 7, Kevin Shan 8, John C. Woolcott 7, Christina Smith 7, Karolina Wosik 9, Stefan Schreiber 10

Affiliations

1 Icahn School of Medicine at Mount Sinai, New York, United States

2 Amsterdam University Medical Center, Amsterdam, Netherlands

3 University of Chicago Medicine Inflammatory Bowel Disease Center, Chicago, United States

4 University of British Columbia, Vancouver, Canada

5 Formerly of Hospital Clínic Barcelona, IDIBAPS, CIBRehd, Barcelona, Spain

6 Pfizer AG, Zürich, Switzerland

7 Pfizer Inc, Collegeville, United States

8 Pfizer Inc, New York, United States

9 Pfizer Inc, Kirkland, Canada

10 University Hospital Schleswig-Holstein, Kiel University, Kiel, Germany

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Abstract

Introduction

Etrasimod is an investigational, oral, once-daily, selective sphingosine 1-phosphate (S1P)_1,4,5 receptor modulator in development for the treatment of moderately to severely active ulcerative colitis (UC).

Aims & Methods

We report efficacy and safety of etrasimod in patients (pts) with/without concomitant corticosteroid (CS) use at baseline (BL) of the ELEVATE UC phase 3 trials. In ELEVATE UC 52 (NCT03945188) and ELEVATE UC 12 (NCT03996369), pts with moderately to severely active UC were randomised 2:1 to once‑daily etrasimod 2 mg or placebo (PBO). ELEVATE UC 52 used a treat-through design with a 12-week (wk) induction period followed by a 40-wk maintenance period. ELEVATE UC 12 had a 12‑wk induction period. At entry, pts were permitted to receive oral concomitant CS (prednisone [≤ 20 mg/day], budesonide [≤ 9 mg/day], or equivalent]) if on a stable dose for ≥ 4 wks prior to screening endoscopy; from Wk 12 CS tapering was recommended. Primary and secondary efficacy endpoints (defined in Table) and safety were assessed by BL concomitant CS status.

Results

In ELEVATE UC 52, 32.2% (93/289) and 29.2% (42/144) of etrasimod- and PBO-treated pts, respectively, were receiving CS at BL. In ELEVATE UC 12, 27.3% (65/238) and 29.3% (34/116) of etrasimod- and PBO-treated pts were receiving CS at BL. Among pts receiving CS at BL in ELEVATE UC 52, a higher proportion of etrasimod- vs PBO-treated pts achieved the endpoint of clinical remission (CR) at Wk 12 (p<0.05) and Wk 52 (p<0.001); this was also observed in pts not receiving CS at BL (p<0.001 at Wks 12 and 52; Table). In ELEVATE UC 12, a higher observed proportion of etrasimod- vs PBO-treated pts receiving CS at BL achieved CR at Wk 12 (p>0.05); a significant difference was observed in pts not receiving CS at BL (p<0.01). In both studies, similar results were observed across all secondary endpoints, with greater differences between etrasimod and PBO seen in pts not receiving CS at BL (Table). Across both ELEVATE trials, there were fewer serious adverse events and serious infections in the etrasimod arm in pts with CS at BL, than in those without CS at BL. In the PBO arms, the opposite was true.

Table. Efficacy at Wk 12 and Wk 52 in patients with and without CS use at baseline in the ELEVATE UC 52 and UC 12 phase 3 trials
	ELEVATE UC 52 Week 12		ELEVATE UC 52 Week 52		ELEVATE UC 12 Week 12
	CS at BL	no-CS at BL	CS at BL	no-CS at BL	CS at BL	no-CS at BL
Clinical remission,^a n/N (%)^b PBO Etrasimod Diff. % (95% CI)^c p^c	7/42 (16.7) 30/93 (32.3) 16.03 (1.08, 30.98) 0.036	5/102 (4.9) 51/196 (26.0) 22.70 (15.27, 30.13) <0.001	4/42 (9.5) 29/93 (31.2) 21.72 (8.82, 34.62) <0.001	7/102 (6.9) 65/196 (33.2) 26.72 (18.53, 34.92) <0.001	7/34 (20.6) 19/65 (29.2) 8.53 (-8.64, 25.71) 0.330	10/82 (12.2) 43/173 (24.9) 13.19 (3.78, 22.60) 0.006
Endoscopic improvement,^d n/N (%)^b PBO Etrasimod Diff. % (95% CI)^c p^c	12/42 (28.6) 38/93 (40.9) 12.25 (-4.73, 29.23) 0.157	12/102 (11.8) 70/196 (35.7) 25.52 (16.25, 34.80) <0.001	9/42 (21.4) 36/93 (38.7) 17.15 (1.55, 32.74) 0.031	10/102 (9.8) 77/196 (39.3) 29.96 (21.04, 38.88) <0.001	11/34 (32.4) 22/65 (33.8) 1.40 (-17.69, 20.49) 0.886	11/82 (13.4) 56/173 (32.4) 19.43 (9.41, 29.46) <0.001
Symptomatic remission,^en/N (%)^b PBO Etrasimod Diff. % (95% CI)^c p^c	13/42 (31.0) 42/93 (45.2) 14.47 (-2.68, 31.62) 0.098	19/102 (18.6) 92/196 (46.9) 28.68 (18.22, 39.14) <0.001	9/42 (21.4) 37/93 (39.8) 18.01 (2.28, 33.74) 0.025	19/102 (18.6) 90/196 (45.9) 28.15 (17.92, 38.38) <0.001	14/34 (41.2) 29/65 (44.6) 3.23 (-16.61, 23.08) 0.750	20/82 (24.4) 85/173 (49.1) 25.58 (13.73, 37.42) <0.001
Endoscopic improvement, histological remission,^fn/N (%)^b PBO Etrasimod Diff. % (95% CI)^c p^c	5/42 (11.9) 20/93 (21.5) 10.28 (-2.99, 23.55) 0.129	4/102 (3.9) 46/196 (23.5) 20.11 (12.77, 27.45) <0.001	7/42 (16.7) 24/93 (25.8) 8.15 (-6.32, 22.61) 0.270	8/102 (7.8) 55/196 (28.1) 21.10 (12.97, 29.23) <0.001	5/34 (14.7) 10/65 (15.4) 0.68 (-13.53, 14.89) 0.926	5/82 (6.1) 31/173 (17.9) 12.17 (4.48, 19.86) 0.002
Clinical response,^g n/N (%)^b PBO Etrasimod Diff. % (95% CI)^c p^c	19/42 (45.2) 63/93 (67.7) 22.86 (5.21, 40.51) 0.011	33/102 (32.4) 119/196 (60.7) 28.56 (17.03, 40.10) <0.001	13/42 (31.0) 43/93 (46.2) 15.25 (-1.74, 32.23) 0.079	22/102 (21.6) 100/196 (51.0) 30.17 (19.62, 40.71) <0.001	18/34 (52.9) 38/65 (58.5) 5.32 (-15.06, 25.70) 0.609	30/82 (36.6) 113/173 (65.3) 29.85 (17.40, 42.29) <0.001
Data in bold indicate significant p values. All data shown refer to the full analysis set (MMS 4–9) with CS at baseline (CS at BL) or no CS at baseline (no-CS at BL) ^aClinical remission, the primary efficacy endpoint, was defined as SFS=0 (or =1 with a ≥ 1-point decrease from baseline), RBS=0, and ES ≤ 1 (excluding friability) ^bPercentages are based on N, the number of patients in the subgroup in the analysis set by treatment, patients missing an assessment at the specified analysis visit are considered non-responders ^cDifference is for etrasimod minus placebo and is based on estimated common risk difference using the Mantel-Haenszel weights; p-value is 2-sided to test the hypothesis of the risk difference being 0 ^dEndoscopic improvement (key secondary efficacy endpoint) was defined as an ES ≤ 1 (excluding friability) ^eSymptomatic remission (key secondary efficacy endpoint) was defined as SFS=0 (or =1 with a ≥ 1-point decrease from baseline) and RBS=0 ^fEndoscopic improvement , histological remission (key secondary efficacy endpoint) was defined as ES ≤ 1 (excluding friability) with histologic remission measured by a Geboes Index score < 2.0 ^gClinical response (other secondary efficacy endpoint) was defined as a ≥ 2-point and ≥ 30% decrease from baseline in MMS, and a ≥ 1-point decrease from baseline in RBS or an absolute RBS ≤ 1 BL, baseline; CI, confidence interval; CS, corticosteroid; ES, endoscopic subscore; Etra, etrasimod; MMS, modified Mayo score; N, the number of patients in the subgroup in the analysis set by treatment; n, number of responding patients; PBO, placebo; RBS, rectal-bleeding subscore; SFS, stool-frequency subscore; UC ulcerative colitis

Conclusion

Regardless of concomitant CS use at BL, etrasimod generally demonstrated efficacy at Wks 12 and 52, with greater treatment effect seen in pts without CS use at BL. No additional safety signal was apparent when etrasimod was initiated in combination with CS compared to without CS.

Disclosure

BES: financial support for research/grants, e.g. Grant/Research Support: Arena, Janssen. Lecture fees/Speakers Bureau: BMS, Janssen, Lilly, Pfizer, Takeda. Consultancy, Advisory Committee/Board Member: AbbVie, Alimentiv, Amgen, Arena, AstraZeneca, Boehringer-Ingelheim, BMS, Celltrion, Fresenius Kabi, Genentech, GSK, Janssen, Lilly, Merck, Pfizer, Prometheus Biosciences, Sun Pharma Global, Takeda Pharmaceuticals International, Teva Branded Pharmaceutical Products R&D. Shareholder/Stock Options: Ventyx Biosciences. Other non-financial support: Janssen, Lilly, Pfizer, Takeda.
KBG: research support: Celltrion, Galapagos, Pfizer Inc; speaker honoraria and/or consulting fees: AbbVie, Celltrion, Ferring Pharmaceuticals, Immunic Therapeutics, Janssen, Novartis, Pfizer Inc, Samsung Bioepis, Takeda, Tillotts.
DTR: grant support: Takeda, Helmsley Charitable Trust, GastroIntestinal Research Foundation; consultancy fees/is a member of advisory boards: AbbVie, AltruBio, ASLAN Pharmaceuticals, Athos Therapeutics, Bellatrix Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Chronicles, Syneos, ClostraBio, Connect Biopharma, EcoR1, Genentech/Roche, Gilead Sciences, Iterative Health, Janssen Pharmaceuticals, Kaleido Biosciences, Eli Lilly, Pfizer Inc, Prometheus, Reistone, Seres Therapeutics, Takeda, Target RWE, Trellus Health; is on the Board of Trustees for Crohn’s & Colitis Foundation and Cornerstones Health, Inc; holds stock options in Alike Health, AltruBio, Datos Health and Iterative Health.
YL: speaker: Pfizer, Takeda, Abbvie, Jannsen; Consultancy, Advisory Committee/Board Member: Pfizer, BMS, Takeda, Abbvie, Amgen BioJamp, Lilly
JP: personal: AbbVie, Arena Pharmaceuticals, Athos, Atomwise, Boehringer Ingelheim, Celgene, Celltrion, Ferring, Galapagos, Genentech/Roche, GSK, Immunic, Janssen, Mirum, Morphic, Nestlé, Origo, Pandion, Pfizer, Progenity, Revolo, Takeda, Theravance and Wassermann; grant support: AbbVie, Pfizer.
MG: employee & shareholder of Pfizer AG.
WW, KS, JCW, CCS: employees & shareholders of Pfizer Inc.
KW: employee & shareholder of Pfizer Canada Inc.
SS: speaker: AbbVie, Arena, Biogen, Bristol-Myers Squibb, Celgene, Celltrion, Dr. Falk, Fresenius, Janssen, MSD, Pfizer, Takeda; consultancy/advisory: AbbVie, Arena, Biogen, Bristol-Myers Squibb, Celgene, Celltrion, Dr. Falk, Fresenius, Gilead, IMAB, Janssen, MSD, Mylan, Pfizer Inc, Protagonist, Provention, Takeda, Theravance.

Conference

UEG Week Copenhagen 2023

Topics

IBD

Submission format

Abstract

Session

PP 05 IBD (Posters)

Citation

United European Gastroenterology Journal 2023; 11 (Supplement 8)

Published

2023

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Parameter	Overall (n = 264)	Steroid non-responders (n = 117)	Steroid responders (n =147)	P-value
Extent, n/N (%) Proctitis Left sided colitis Extensive colitis	9 (3.8) 59 (24.9) 169 (71.3)	5 (4.9) 26 (25.5) 71 (69.6)	4 (3.0) 33 (24.4) 98 (72.6)	0.71
Day 1 Stool frequency (median [IQR]) CRP (mg/L) (median [IQR]) Albumin (g/L) (mean [SD]) CRP/Albumin ratio (median [IQR]) Seo index (mean [SD]) Lindgren index (mean [SD])	10.0 (7.0 – 15.0) 60.1 (20.2 – 122.6) 31.2 (6.0) 2.0 (0.7 – 3.9) 222.1 (28.6) 23.3 (11.9)	10.0 (7.0 – 15.0) 61.5 (22.4 – 119.9) 31.2 (5.5) 2.1 (0.8 – 3.9) 220.1 (26.7) 22.8 (10.3)	10.0 (7.0 – 15.0) 56.2 (16.1 – 132.1) 31.2 (6.4) 1.9 (0.6 – 4.4) 223.3 (29.9) 23.7 (13.1)	0.71 0.54 0.94 0.25 0.64 0.59
Day 3 Stool frequency (median [IQR]) CRP (mg/L) (median [IQR]) Albumin (g/L) (mean [SD]) CRP/Albumin ratio (median [IQR]) Lindgren index (mean [SD])	6.0 (3.0 – 8.0) 32.9 (15.7 – 75.2) 29.9 (10.2) 1.3 (0.5 – 2.3) 13.7 (8.5)	7.0 (5.0 – 10.0) 43.4 (19.1 – 86.9) 29.2 (7.6) 1.6 (0.6 – 3.2) 16.3 (9.0)	4.0 (3.0 – 7.0) 25.4 (9.9 – 62.2) 30.6 (12.2) 0.8 (0.2 – 1.3) 11.4 (7.5)	<0.01 0.05 0.56 0.25 <0.01
Fulfilling Oxford criteria on day 3 (stool frequency >8 or 3-8/day with CRP>45mg/L)	53/123 (43.1)	34/58 (58.6)	19/65 (29.2)	<0.01
Medical rescue therapy, n/N (%)	102/260 (39.2)	102/117 (87.2)	0/143 (0.0)	<0.01
Colectomy in index admission, n/N (%)	21/259 (8.1)	21/116 (18.1)	0/143 (0.0)	<0.01
Hospital admission with exacerbation between 3-12 months of discharge n/N (%)	38/223 (17.0)	13/94 (13.8)	25/129 (19.4)	0.28
Colectomy between 3-12 months of discharge n/N (%)	12/223 (5.4)	6/94 (6.4)	6/129 (4.7)	0.57
Overall colectomy within 12 months of discharge n/N (%)	32/243 (13.0)	14/96 (14.6)	18/147 (12.2)	0.59

	Placebo IV	GUS 200 mg IV	Adjusted treatment difference (95% CI)
Full Analysis set, N	280	421	-
Clinical remission at Wk12, n (%)^a	22 (7.9%)	95 (22.6%)	14.9% (9.9%, 19.9%) p<0.001
Symptomatic remission at Wk4, n (%)^b	36 (12.9%)	95 (22.6%)	9.9% (4.4%, 15.4%) p<0.001
Symptomatic remission at Wk12, n (%)^b	58 (20.7%)	210 (49.9%)	29.4% (22.8%, 36.0%) p<0.001
Clinical response at Wk12, n (%)^c	78 (27.9%)	259 (61.5%)	33.8% (26.9%, 40.7%) p<0.001
Endoscopic improvement at Wk12, n (%)^d	31 (11.1%)	113 (26.8%)	16.0% (10.5%, 21.4%) p<0.001
Histo-endoscopic mucosal improvement at Wk12, n (%)^e	21 (7.5%)	99 (23.5%)	16.2% (11.1%, 21.2%) p<0.001
Endoscopic normalization at Wk12, n (%)^f	14 (5.0%)	63 (15.0%)	10.1% (5.9%, 14.3%)***
***Nominal p-value <0.001. ^aClinical remission was defined as a Mayo stool frequency subscore of 0 or 1 and not increased from baseline, a Mayo rectal bleeding subscore of 0, and a Mayo endoscopy subscore of 0 or 1 with no friability present on the endoscopy. ^bSymptomatic remission was defined as a stool frequency subscore of 0 or 1 and not increased from baseline, and a rectal bleeding subscore of 0. ^cClinical response was defined as a decrease from baseline in the modified Mayo score by ≥30% and ≥2 points, with either a ≥1-point decrease from baseline in the rectal bleeding subscore or a rectal bleeding subscore of 0 or 1. ^dEndoscopic improvement was defined as an endoscopy subscore of 0 or 1 with no friability present on the endoscopy. ^eHisto-endoscopic mucosal improvement was defined as achieving a combination of histologic improvement (neutrophil infiltration in <5% of crypts, no crypt destruction, and no erosions, ulcerations or granulation tissue according to the Geboes grading system, i.e., Geboes score ≤ 3.1) and endoscopic improvement. ^fEndoscopic normalization was defined as an endoscopy subscore of 0. Note: Patients who had a prohibited change in UC medication, an ostomy or colectomy, or discontinued study agent due to lack of therapeutic effect or due to an AE of worsening of UC prior to the designated analysis timepoint were considered not to have achieved the endpoint. Data after discontinuation of study agent due to COVID-19 related reasons (excluding COVID-19 infection) were considered to be missing. Patients who were missing one or more components pertaining to a specified endpoint at Week 12 were considered not to have achieved the endpoint. The p-values were based on the Cochran-Mantel-Haenszel (CMH) chi-square test.

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