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). In ELEVATE UC 52 (NCT03945188), etrasimod was superior to placebo (PBO) in achieving Week (Wk) 52 corticosteroid (CS)-free clinical remission (CR).1
Aims & Methods
This post hoc analysis reports CS-free efficacy and safety in patients (pts) on baseline (BL) CS. Pts were randomised 2:1 to once-daily etrasimod 2 mg or PBO using a treat-through design (12-wk induction and 40-wk maintenance period). At entry, pts could receive concomitant CS (prednisone [≤ 20 mg/day], budesonide [≤ 9 mg/day] or equivalent) if on a stable dose ≥ 4 wks immediately before screening endoscopy; from Wk 12, CS tapering was recommended. CS-free was defined as withdrawal of CS ≥ 12 wks prior to assessment timepoint. CS-free outcomes assessed were CS-free CR at Wk 52, CS-free endoscopic improvement (EI) at Wk 52, and CR at Wk 12 + CS-free CR at Wk 52. From Wk 12, 4-wk CS‑free symptomatic remission (SR; 4 wk in contrast to ≥ 12-wks CS free) was analysed at each visit. Logistic regressions examined associations with CS-free efficacy at Wk 52. Safety was assessed.
Results
At BL, 32.2% (93/289) and 29.2% (42/144) of etrasimod and PBO pts received CS; of these, significantly more etrasimod vs PBO pts achieved CS-free CR at Wk 52, CS-free EI at Wk 52 and CR at Wk 12 + CS-free CR at Wk 52 (all p<0.05; Table). At Wks 40–52, there were significant differences (16.6–26.6%; p<0.05) in 4-wk CS-free SR between etrasimod and PBO. In this subpopulation, being biologic/Janus kinase inhibitor-naïve was not a significant predictor of 12-wk CS-free CR at Wk 52 (odds ratio [OR]: 3.61; 95% confidence interval [CI] 0.91, 14.39; p=0.07); age, per 10-year increase, was significantly associated (OR: 1.51; 95% CI 1.03, 2.22; p=0.04). Etrasimod vs PBO pts with concomitant CS at BL experienced slightly more adverse events (AEs; not exposure adjusted) (71.0% [66/93] vs 61.9% [26/42]) but fewer serious AEs (6.5% [6/93] vs 14.3% [6/42]), including serious infections (0% [0/93] vs 7.1% [3/42]).
| Table. CS-free efficacy in pts receiving concomitant CS at BL of ELEVATE UC 52 (FAS) |
|---|
| Etrasimod
2 mg QD,
n/N (%)
| PBO
QD,
n/N (%)
| Adjusted difference %
(95% CI)
pa
|
12-wk CS-free clinical remission at Wk 52
| 29/93 (31.2)
| 3/42 (7.1)
| 23.2
(10.6, 35.7)
0.0003
|
12-wk CS-free endoscopic improvement at Wk 52
| 35/93 (37.6)
| 8/42 (19.0)
| 17.5
(2.5, 32.5)
0.0226
|
CR at Wk 12 + CS-free CR at Wk 52
| 18/93 (19.4)
| 2/42 (4.8)
| 14.3
(3.5, 25.1)
0.0092
|
All pts in the FAS had a modified Mayo score from 4 to 9 at BL. Clinical remission was defined as SFS=0 (or 1 with a ≥ 1-point decrease from BL), RBS=0 and ES ≤ 1 (excluding friability). Endoscopic improvement was defined as ES ≤ 1 (excluding friability)
aAdjusted difference (%) is based on estimated common risk difference using Mantel-Haenszel weights; p is 2-sided to test the hypothesis of the adjusted risk difference being 0
BL, baseline; CR, clinical remission; CS, corticosteroid; ES, endoscopic subscore; FAS, full analysis set; n, number of unique pts achieving each endpoint; N, total number of pts in the analysis; pt, patient; PBO, placebo; QD, once daily; RBS, rectal bleeding subscore; SFS, stool frequency subscore; Wk, week
|
Conclusion
More etrasimod vs PBO pts who received CS at BL met CS‑free efficacy endpoints. Four-wk CS-free SR with etrasimod was superior to PBO from Wk 40. Concomitant CS use at BL had no notable negative effect on the safety of etrasimod, consistent with the overall ELEVATE UC 52 population.1
References
1. Sandborn W et al. Lancet 2023: Epub ahead of print.
Disclosure
BES: grants/research: Arena, Janssen; speaker: BMS, Janssen, Lilly, Pfizer, Takeda; consultancy/advisory board: 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; stock: Ventyx Biosciences; non-financial support: Janssen, Lilly, Pfizer, Takeda.
YL: speaker: Pfizer Inc, Takeda, Abbvie, Jannsen; Consultancy, Advisory Committee/Board Member: Pfizer Inc, BMS, Takeda, Abbvie, Amgen BioJamp, Lilly.
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.
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.
JP: personal: AbbVie, Arena, Athos, Atomwise, Boehringer Ingelheim, Celgene, Celltrion, Ferring Pharmaceuticals, Galapagos, Genentech/Roche, GSK, Immunic, Janssen, Mirum, Morphic, Nestlé, Origo, Pandion, Pfizer Inc, Progenity, Revolo, Takeda, Theravance Biopharma and Wassermann; grant support: AbbVie, Pfizer Inc.
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 Pharma, Fresenius, Janssen, MSD, Pfizer Inc, Takeda; consultancy/advisory: AbbVie, Arena, Biogen, Bristol-Myers Squibb, Celgene, Celltrion, Dr. Falk Pharma, Fresenius, Gilead Sciences, IMAB, Janssen, MSD, Mylan, Pfizer Inc, Protagonist, Provention Bio, Takeda, Theravance.