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). Prior analyses demonstrated etrasimod efficacy in UC1 and greater improvement from baseline in Inflammatory Bowel Disease Questionnaire (IBDQ) total score and domains vs placebo (PBO).2
Aims & Methods
This post hoc subgroup analysis examined the effect of prior and concomitant therapies on IBDQ scores in the phase 3 ELEVATE UC clinical programme. In ELEVATE UC 52 (NCT03945188) and ELEVATE UC 12 (NCT03996369), eligible patients (pts) with modified Mayo scores of 4–9 completed the 32‑item IBDQ at Weeks (Wks)12 (both trials) and 52 (ELEVATE UC 52). In this analysis, pts were stratified by prior biologic/Janus kinase inhibitor (bio/JAKi) and baseline corticosteroid (CS) use. Least squares (LS) mean change from baseline in IBDQ total and domain scores were compared for etrasimod vs PBO (data as observed). Proportions of pts with IBDQ remission (total score ≥ 170) were analysed (nonresponder imputation).
Results
Among all randomised patients, there were 304/433 and 236/354 pts without prior bio/JAKi use and 298/433 and 255/354 pts without baseline CS use in ELEVATE UC 52 and ELEVATE UC 12, respectively. Overall, mean baseline IBDQ total scores were similar in pts with and without prior bio/JAKi or baseline CS use. At Wks12 (both trials) and 52 (ELEVATE UC 52), LS mean change from baseline in IBDQ total and domain scores was higher (p<0.05) for etrasimod vs PBO in pts without prior bio/JAKi and pts without baseline CS use (Table). IBDQ remission was generally achieved by significantly higher proportions of pts receiving etrasimod vs PBO regardless of prior bio/JAKi or baseline CS use at Wk52 (prior bio/JAKi use: No, 46.8% vs 21.2% [p<0.001] and Yes, 25.0% vs 11.1% [p=0.043]; baseline CS use: No, 41.3% vs 15.7% [p<0.001] and Yes, 38.7% vs 23.8% [p=0.087]).
Table. LS mean change from baseline in IBDQ total score and domains by prior bio/JAKi and baseline CS use (full analysis set)
|
|---|
| [n], LS mean change from baselinea (SE) | Without prior bio/JAKi use | With prior bio/JAKi use | Without baseline CS use | With baseline CS use |
Etrasimod
2 mg QD | PBO | Etrasimod
2 mg QD | PBO | Etrasimod
2 mg QD | PBO | Etrasimod
2 mg QD | PBO |
| ELEVATE UC 52 | N=205 | N=99 | N=84 | N=45 | N=196 | N=102 | N=93 | N=42 |
Wk12
IBDQ total score
Bowel symptoms
Systemic symptoms
Emotional health
Social function | [n=168]
47.44 (2.888)***
17.10 (0.941)***
6.52 (0.467)***
15.77 (1.090)***
8.01 (0.548)** | [n=79]
27.74 (4.144)
9.55 (1.350)
3.58 (0.670)
9.14 (1.563)
5.56 (0.785) | [n=64]
33.98 (5.183)
12.79 (1.645)
4.77 (0.843)
11.34 (1.970)
5.06 (0.989) | [n=35]
34.27 (7.099)
12.62 (2.262)
5.21 (1.161)
10.83 (2.697)
5.47 (1.354) | [n=151]
41.48 (3.035)**
15.39 (0.999)***
5.98 (0.475)**
13.76 (1.149)**
6.38 (0.589)* | [n=77]
24.97 (4.185)
8.69 (1.380)
3.52 (0.656)
8.59 (1.583)
4.28 (0.811) | [n=81]
44.45 (4.537)
15.60 (1.459)
5.75 (0.773)
15.15 (1.683)
7.87 (0.842) | [n=37]
35.51 (6.576)
12.51 (2.113)
4.66 (1.120)
11.10 (2.437)
7.16 (1.217) |
Wk52
IBDQ total score
Bowel symptoms
Systemic symptoms
Emotional health
Social function | [n=116]
58.66 (3.209)**
20.70 (1.057)**
7.86 (0.520)*
20.25 (1.218)*
10.22 (0.612)** | [n=31]
39.75 (5.611)
14.17 (1.877)
5.63 (0.912)
14.28 (2.146)
6.47 (1.074) | [n=27]
47.11 (6.797)
17.55 (2.217)
5.96 (1.080)
16.03 (2.618)
7.90 (1.312) | [n=10]
29.54 (10.705)
11.88 (3.526)
4.24 (1.687)
9.28 (4.144)
4.85 (2.074) | [n=97]
55.75 (3.544)***
19.79 (1.177)***
7.67 (0.550)**
19.83 (1.354)**
8.70 (0.683)** | [n=24]
30.64 (6.563)
11.48 (2.203)
4.13 (1.009)
11.58 (2.530)
4.12 (1.253) | [n=46]
51.84 (5.113)
18.70 (1.690)
6.46 (0.891)
16.88 (1.903)
10.38 (0.974) | [n=17]
46.70 (7.772)
16.44 (2.591)
6.94 (1.365)
15.46 (2.891)
8.49 (1.495) |
| ELEVATE UC 12 | N=159 | N=77 | N=79 | N=39 | N=173 | N=82 | N=65 | N=34 |
Wk12
IBDQ total score
Bowel symptoms
Systemic symptoms
Emotional health
Social function | [n=129]
42.17 (3.321)***
16.21 (1.134)***
5.55 (0.545)**
13.66 (1.265)**
6.81 (0.591)** | [n=64]
22.29 (4.598)
8.46 (1.565)
2.75 (0.756)
7.24 (1.747)
3.78 (0.820) | [n=60]
51.13 (4.408)*
18.26 (1.456)
6.89 (0.761)
17.25 (1.653)*
8.66 (0.848) | [n=31]
35.64 (6.038)
13.45 (1.996)
4.51 (1.043)
11.11 (2.264)
6.63 (1.161) | [n=145]
44.85 (2.929)***
16.85 (1.003)***
6.02 (0.492)**
14.69 (1.102)***
7.33 (0.526)*** | [n=67]
24.79 (4.268)
9.37 (1.462)
3.29 (0.718)
7.72 (1.605)
4.30 (0.767) | [n=44]
50.71 (5.343)
18.37 (1.781)
6.94 (0.910)
16.98 (2.002)
8.44 (1.008) | [n=28]
39.72 (6.596)
14.38 (2.197)
4.96 (1.123)
13.08 (2.478)
7.29 (1.243) |
The IBDQ evaluates disease-related quality of life using 32 items examined with 4 domains: bowel symptoms (score range, 10–70), systemic symptoms (score range, 5–35), emotional health (score range, 12–84) and social function (score range, 5–35). For the total score (range, 32–224) and each domain, a higher score indicates a better quality of life
Responses after intercurrent events and missing responses were considered as nonresponses
*p<0.05; **p<0.01; ***p<0.001. Presented p values are for etrasimod 2 mg once daily vs PBO. P values are presented without adjustment for multiplicity
aFor ELEVATE UC 52, estimates are from a mixed-effect model with repeated measures model for change from baseline with a covariate for baseline score, and factors for naive to bio/JAKi therapy (Yes or No, for with or without baseline CS use subgroups only) or baseline CS use (Yes or No, for with or without prior bio/JAKi use subgroups only), baseline disease activity (MMS: 4–6 or 7–9), treatment, visit and treatment by visit interaction. For ELEVATE UC 12, estimates are from an analysis of covariance model for change from baseline, with a covariate for baseline score, and factors for naive to bio/JAKi therapy (Yes or No, for with or without baseline CS use subgroups only) or baseline CS use (Yes or No, for with or without prior bio/JAKi use subgroups only), baseline disease activity (MMS: 4–6 or 7–9) and treatment
Bio/JAKi, biologic/Janus kinase inhibitor; CS, corticosteroid; IBDQ, Inflammatory Bowel Disease Questionnaire; LS mean, least squares mean; MMS, modified Mayo score; N, total number of pts in the full analysis set; n, number of pts with available IBDQ data at the specified time point; PBO, placebo; pt; patient; QD, once daily; SE, standard error; UC, ulcerative colitis; Wk, week |
Conclusion
Pts receiving etrasimod had improvements in IBDQ total score and in all 4 domains at Wk12, maintained at Wk52. Significant differences were shown in these outcomes with etrasimod vs PBO in pts without prior bio/JAKi and without baseline CS use. IBDQ remission was generally achieved by higher proportions of pts without vs with prior bio/JAKi or without vs with baseline CS use.
References
- Sandborn W et al. Lancet 2023: Epub ahead of print
- Armuzzi A et al. J Crohns Colitis 2023: 17; i593–i594
Disclosure
AA: research support: Biogen, MSD, Takeda, Pfizer Inc; lecture fees: AbbVie, Amgen, Biogen, Bristol-Myers Squibb, Ferring Pharmaceuticals, Galapagos, Gilead Sciences, Janssen, MSD, Novartis, Pfizer Inc, Roche, Samsung Bioepis, Sandoz, Takeda, TiGenix; consultancy fees: AbbVie, Allergan, Amgen, Arena Pharmaceuticals, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Celltrion, Eli Lilly, Ferring Pharmaceuticals, Galapagos, Gilead Sciences, Janssen, MSD, Mylan, Pfizer Inc, Roche, Samsung, Bioepis, Sandoz, Takeda.
DTR: grant support: Takeda, Helmsley Charitable Trust and GastroIntestinal Research Foundation; consultancy fees/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, Prometheus, Reistone, Seres Therapeutics, Takeda, Target RWE, Trellus Health; Board of Trustees: Crohn’s & Colitis Foundation and Cornerstones Health, Inc; stock options: Alike Health, AltruBio, Datos Health, Iterative Health.
SS: lecture/speaker fees: AbbVie, Arena Pharmaceuticals, Biogen, Bristol-Myers Squibb, Celgene, Celltrion, Dr. Falk Pharma, Fresenius, Janssen, MSD, Pfizer Inc, Takeda; consultancy/advisory fees: 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.
JP: personal fees: AbbVie, Arena Pharmaceuticals, 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, Wassermann; grant support: AbbVie and Pfizer Inc.
MF, LB, JW: employees and shareholders of Pfizer Inc.
MG: employee & shareholder of Pfizer AG.
AB: employee of Pfizer Healthcare India & shareholder of Pfizer.
MC: grant support: Pfizer, Galapagos, Janssen; consultancy fees: Takeda, Janssen, Gilead Sciences, Pfizer Inc, Lily, Tillotts; investigator: Takeda, Janssen Cilag International NV, AbbVie, Shire, Janssen Cilag International LV, Genentech, Celgene, F Hoffmann La Roche, Shield, Boehringer Ingelheim, Hospira, Millenium Pharmaceuticals; principal investigator: Janssen, AbbVie, Takeda, MSD, Ferring Pharmaceuticals.
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; grant/research support: Janssen; shares/royalties in Trellus Health; directorship/ownership interests: Trellus Health.