Introduction
The time from treatment initiation to symptom relief, including rectal bleeding (RB) and stool frequency (SF), is key for patients (pts) with ulcerative colitis (UC) and can help guide therapy decisions. 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 UC. Data from pt e-diaries can help inform on symptoms in pts with UC.
Aims & Methods
We present a post hoc analysis of daily e-diary data collected on RB and SF from pts enrolled in the ELEVATE UC 52 (NCT03945188) and ELEVATE UC 12 (NCT03996369) phase 3 clinical trials.1 Data were pooled from the ELEVATE UC 52 and ELEVATE UC 12 studies, which randomised pts with moderately to severely active UC and an inadequate response or loss of response or intolerance to ≥1 approved UC therapy 2:1 to receive etrasimod 2 mg once daily or placebo (PBO). Daily Mayo RB and SF subscores (RBS and SFS) and partial modified Mayo score (pMMS; RBS + SFS) were calculated from pt e-diary responses, as well as change from baseline (CFB) during the first 28 days of therapy. Symptomatic responders were pts with ≥30% CFB (decrease) in pMMS. Symptomatic remission was defined as pts with RBS=0 plus SFS=0 or 1 (with ≥1‑point improvement from baseline). RB and SF remission were defined as pts with RBS=0 and SFS=0, respectively. The Mantel–Haenszel weighted test was used to assess the adjusted risk differences in proportions of responders between treatment groups.
Results
At baseline, pts receiving etrasimod and PBO had a mean (SD) RBS of 1.6 (0.69) and 1.6 (0.68), SFS of 2.4 (0.74) and 2.4 (0.74), and pMMS of 4.0 (1.07) and 4.0 (1.07), respectively. Adjusted differences in symptomatic response and symptomatic remission in pts receiving etrasimod vs PBO became significant from Day 2 (5.56 [0.79, 10.33]) and Day 11 (4.69 [0.36, 9.03]), respectively. Adjusted differences (95% confidence interval) in RB remission and SF remission in pts receiving etrasimod vs PBO reached significance from Day 15 (6.33 [0.14, 12.51]) and Day 3 (3.51 [0.87, 6.14]), respectively (all p<0.05; Table).
Table. Responses in pts receiving etrasimod compared with PBO on the first day of a significant adjusted difference in daily symptomatic response, symptomatic remission, RB remission and SF remission
|
|---|
Endpoint
| First day of significanta difference from PBO
| Pooled data from ELEVATE UC 52 and ELEVATE UC 12
| Adjusted difference (95% CI)c
| 2-sided p value at first day of significant difference from PBOd
|
PBO (N=260), n (%)
| N1b
| Etrasimod 2 mg QD (N=527), n (%)
| N1b
|
Daily symptomatic response
| 2
| 27 (11.16)
| 242
| 84 (16.83)
| 499
| 5.56 (0.79, 10.33)
| 0.022
|
Daily symptomatic remission
| 11
| 21 (8.71)
| 241
| 67 (13.59)
| 493
| 4.69 (0.36, 9.03)
| 0.034
|
Daily RB remission
| 15
| 59 (25.21)
| 234
| 153 (31.35)
| 488
| 6.33 (0.14, 12.51)
| 0.045
|
Daily SF remission
| 3
| 6 (2.45)
| 245
| 31 (6.19)
| 501
| 3.51 (0.87, 6.14)
| 0.009
|
aAdjusted differences with nominal p values <0.05 were considered significant
bN1 was the actual number of pts on each day (responders and nonresponders)
cAdjusted differenceswere based on estimated common risk difference using Mantel–Haenszel weights and stratified by actual naïve to biologic/JAKi therapy at study entry (Yes/No), actual baseline corticosteroid use (Yes/No) and actual baseline disease activity (MMS: 4–6 or 7–9)
dThe Mantel–Haenszel weighted test was used to assess the adjusted risk differences in proportions of responders between treatment groups
Data were pooled from NCT03945188 and NCT03996369. Pts missing an assessment at the specified day were considered nonresponders
CI, confidence interval; JAKi, Janus kinase inhibitor; n, number of patients with characteristic; MMS, modified Mayo score; N, number of patients; PBO, placebo; QD, once daily; RB, rectal bleeding; SF, stool frequency; UC, ulcerative colitis |
Conclusion
In this post hoc analysis of the phase 3 ELEVATE trials, we found significant, early improvements in UC symptoms in pts receiving etrasimod vs PBO beginning within 2 days. These findings indicate a potentially rapid onset of symptomatic effect with etrasimod treatment.
References
1. Sandborn WJ et al. Lancet 2023: Epub ahead of print
Disclosure
MCD: consultancy fees: AbbVie, Arena Pharmaceuticals, Bristol-Myers Squibb, Celgene, Eli Lilly, Galapagos, Genentech, Gilead Sciences, Janssen Pharmaceuticals, Pfizer Inc, Prometheus Laboratories, Takeda, Trellus Health, UCB; received grant/research support: Janssen; shares/royalties in Trellus Health; directorship/ownership interests in Trellus Health.
SV: lecture/speaker fees: AbbVie, Dr. Falk Pharma, Ferring Pharmaceuticals, Hospira, MSD, Takeda, Tillotts; consultancy/advisory fees: AbbVie, AbolerIS, Alimentiv, Arena Pharmaceuticals, AstraZeneca, Avaxia, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, CVasThera, Dr. Falk Pharma, Eli Lilly, Ferring Pharmaceuticals, Galapagos, Genentech/Roche, Gilead Sciences, Hospira, Imidomics, Janssen, Johnson & Johnson, Materia Prima, MiroBio, Morphic, MrMHealth, MSD, Mundipharma, Pfizer Inc, Prodigest, Progenity, Prometheus, Robarts Clinical Trials, Second Genome, Shire, Surrozen, Takeda, Theravance Biopharma, Tillotts, Zealand Pharma; grant/research support: AbbVie, MSD, Pfizer Inc, Galapagos, Takeda.
MC: grant support: Galapagos, Janssen, Pfizer Inc; consultancy fees: Eli Lilly, Gilead Sciences, Janssen, Pfizer Inc, Takeda, Tillotts; investigator: AbbVie, Boehringer Ingelheim, Celgene, F Hoffmann La Roche, Genentech, Hospira, Janssen Cilag International LV, Janssen Cilag International NV, Millenium Pharmaceuticals, Shield, Shire, Takeda; Principal Investigator: AbbVie, Ferring Pharmaceuticals, Janssen, MSD, Takeda.
PMI: grant support: Celltrion, Janssen, MSD, Takeda; lecture fees: AbbVie, Bristol-Myers Squibb, Celgene, Celltrion, Dr. Falk Pharma, Ferring Pharmaceuticals, Galapagos, Gilead Sciences, Janssen, MSD, Pfizer, Sapphire Medical, Sandoz, Shire, Takeda, Tillotts, Warner Chilcott; advisory fees: AbbVie, Arena Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Celltrion, Eli Lilly, Genentech, Gilead Sciences, Hospira, Janssen, MSD, Pfizer, Pharmacosmos, Prometheus, Roche, Sandoz, Samsung Bioepis, Takeda, Topivert, VH2, Vifor, Warner Chilcott.
LB, JCW, CJR, WW: employees and shareholders of Pfizer Inc.
MG: employee and shareholder of Pfizer AG.
JT: advisory board fees: AbbVie, Arena Pharmaceuticals, Bristol-Myers Squibb, Galapagos, Janssen and Pfizer Inc; research grants: AbbVie and Janssen; speaker fees: AbbVie, Galapagos, Janssen, Pfizer Inc.
RP: consultancy fees: Abbott, AbbVie, Abivax, Alimentiv (formerly Robarts), Amgen, Arena Pharmaceuticals, AstraZeneca, Biogen, BIOJAMP, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Celltrion, Cosmos Pharmaceuticals, Eisai, Elan, Eli Lilly, Ferring Pharmaceuticals, Fresenius Kabi, Galapagos, Genentech, Gilead Sciences, GSK, Janssen, Merck, Mylan, Novartis, Oppilan Pharma, Organon, Pandion Pharma, Pendopharm, Pfizer, Progenity, Prometheus Biosciences, Protagonist Therapeutics, Roche, Sandoz, Satisfai Health, Shire, Sublimity Therapeutics, Takeda, Theravance Biopharma, Trellus, Viatris, Ventyx Biosciences, UCB; speaker fees: AbbVie, Amgen, Arena Pharmaceuticals, Bristol-Myers Squibb, Celgene, Eli Lilly, Ferring Pharmaceuticals, Fresenius Kabi, Gilead Sciences, Janssen, Merck, Organon, Pfizer, Roche, Sandoz, Shire, Takeda; advisory boards: AbbVie, Alimentiv (formerly Robarts), Amgen, Arena Pharmaceuticals, AstraZeneca, Biogen, BIOJAMP, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Ferring Pharmaceuticals, Fresenius Kabi, Genentech, Gilead Sciences, GSK, Janssen, Merck, Mylan, Novartis, Oppilan Pharma, Organon, Pandion Pharma, Pfizer, Progenity, Protagonist Therapeutics, Roche, Sandoz, Shire, Sublimity Therapeutics, Takeda, Ventyx Biosciences; research support: AbbVie, Janssen, Takeda, Pfizer.
