Introduction
A high body mass index (BMI) may negatively impact treatment efficacy in patients with ulcerative colitis (UC) treated with advanced therapies, such as biologics,1 which is relevant due to the prevalence of obesity and UC increasing substantially over the past decades.2,3 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 UC.
Aims & Methods
This post hoc analysis of ELEVATE UC 52 and ELEVATE UC 12 investigated the impact of BMI on the efficacy and safety of etrasimod in patients with UC. ELEVATE UC 52 (NCT03945188) and ELEVATE UC 12 (NCT03996369) were phase 3, randomised, placebo-controlled trials.4 ELEVATE UC 52 had a treat-through design consisting of a 12-week (wk) induction and 40-wk maintenance period; ELEVATE UC 12 comprised a 12-wk induction period. Patients who received ≥1 dose of etrasimod 2 mg QD or placebo were stratified by baseline BMI: <25 kg/m2, 25–30 kg/m2 and >30 kg/m2. Efficacy outcomes (aligned to the predefined outcomes for the ELEVATE UC 52 and ELEVATE UC 12 trials) included the primary endpoint (clinical remission) and selected secondary endpoints at Wk 12 (data pooled for both trials) and Wk 52 (ELEVATE UC 52 only). Safety outcomes assessed the proportions of treatment-emergent adverse events (TEAEs).
Results
Of the 787 patients enrolled in the ELEVATE UC clinical programme, 443 (56.3%) had baseline BMI <25 kg/m2, 217 (27.6%) had baseline BMI 25–30 kg/m2 and 127 (16.1%) had baseline BMI >30 kg/m2. In the BMI <25 kg/m2 and BMI 25–30 kg/m2 subgroups, significantly more patients (p<0.05) receiving etrasimod vs placebo achieved all efficacy endpoints at Wks 12 and 52. In the BMI >30 kg/m2 subgroup, significantly more patients receiving etrasimod vs placebo achieved clinical remission at Wk 52 (p<0.0001; Wk 12: p=0.05), endoscopic improvement and clinical response at Wks 12 and 52, and corticosteroid-free clinical remission at Wk 52 (all p<0.05; Table). The proportions of patients with the most common TEAEs were generally consistent between BMI subgroups receiving etrasimod. Incidence of serious AEs was generally similar across BMI subgroups receiving etrasimod (<25 kg/m2: 17/308 [5.5%]; 25–30 kg/m2: 8/137 [5.8%]; >30 kg/m2: 1/82 [1.2%]).
Table. Primary and select secondary efficacy endpoints at Wk 12 in ELEVATE UC 52 and ELEVATE UC 12 (pooled)a and Wk 52 in ELEVATE UC 52, stratified by baseline BMI
|
|---|
***p<0.001; **p<0.01; *p<0.05.
Population size assessed for each subgroup and time point were: BMI <25 kg/m2: placebo QD, N=135 (Wk 12) and N=70 (Wk 52) and etrasimod 2 mg QD, N=308 (Wk 12) and N=156 (Wk 52); BMI 25–30 kg/m2: placebo QD, N=80 (Wk 12) and N=48 (Wk 52) and etrasimod 2 mg QD, N=137 (Wk 12) and N=81 (Wk 52); BMI >30 kg/m2: placebo QD, N=45 (Wk 12) and N=26 (Wk 52) and etrasimod 2 mg QD, N=82 (Wk 12) and N=52 (Wk 52). Difference (95% CI) and 2-sided p value are based on the Cochran-Mantel-Haenszel method adjusting to reported randomisation stratification of (1) naïve to biologic or Janus kinase inhibitor therapy at study entry, (2) baseline CS use (yes or no), (3) baseline disease activity (MMS: 4–6 or 7–9) and (4) study identifier (ELEVATE UC 52 and ELEVATE UC 12).
aData were pooled at Wk 12 for both trials (ELEVATE UC 52 and ELEVATE UC 12); Wk 52 is ELEVATE UC 52 only.
bClinical remission was defined as SFS=0 (or =1 with a ≥1-point decrease from baseline), RBS=0 and ES ≤1 (excluding friability).
cEndoscopic improvement was defined as ES ≤1.
dClinical response 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.
BMI, body mass index; CI, confidence interval; CS, corticosteroid; ES, endoscopic subscore; MMS, Modified Mayo score; n, number of patients; N, number of patients in the subgroup; N1, number of subjects in each baseline BMI subgroup category, QD, once daily; RBS, rectal bleeding subscore; SFS, stool frequency subscore; UC, ulcerative colitis.
|
| BMI <25 kg/m2
| BMI 25–30 kg/m2
| BMI >30 kg/m2
|
| Placebo QD
| Etrasimod 2 mg QD
| % Difference (95% CI)
| Placebo QD
| Etrasimod 2 mg QD
| % Difference (95% CI)
| Placebo QD
| Etrasimod 2 mg QD
| % Difference (95% CI) |
Clinical remission,b
Wk 12, n (%)
Clinical remission,b
Wk 52, n (%)
| 18 (13.3)
7 (10.0)
| 86 (27.9)
48 (30.8)
| 15.0 (7.4, 22.7)***
22.7 (12.6, 32.9)***
| 8 (10.0)
3 (6.3)
| 39 (28.5)
27 (33.3)
| 18.6 (8.2, 29.0)***
26.3 (13.7, 38.9)***
| 3 (6.7)
1 (3.9)
| 18 (22.0)
19 (36.5)
| 12.7 (0.0, 25.4)
33.3 (17.3, 49.4)***
|
Endoscopic
improvement,c
Wk 12, n (%)
Endoscopic improvement,c
Wk 52, n (%)
| 28 (20.7)
11 (15.7)
| 111 (36.0)
56 (35.9)
| 15.2 (6.7, 23.8)***
23.2 (12.3, 34.0)***
| 14 (17.5)
6 (12.5)
| 49 (35.8)
32 (39.5)
| 18.5 (6.8, 30.1)**
25.4 (11.2, 39.6)***
| 4 (8.9)
2 (7.7)
| 26 (31.7)
25 (48.1)
| 19.7 (6.0, 33.5)**
43.2 (25.5, 60.8)***
|
Clinical response,d
Wk 12, n (%)
Clinical response,d
Wk 52, n (%)
| 55 (40.7)
15 (21.4)
| 195 (63.3)
72 (46.2)
| 22.2 (12.3, 32.1)***
26.8 (14.6, 38.9)***
| 28 (35.0)
13 (27.1)
| 88 (64.2)
44 (54.3)
| 28.5 (15.2, 41.9)***
26.4 (10.1, 42.8)**
| 17 (37.8)
7 (26.9)
| 50 (61.0)
27 (51.9)
| 25.4 (7.3, 43.6)**
24.7 (1.9, 47.5)*
|
CS-free clinical
remissione with CS use at baseline, Wk 52, n/N1 (%)
| 3/24 (12.5)
| 19/64 (29.7)
| 19.9 (2.1, 37.6)*
| 0/9 (0.0)
| 7/18 (38.9)
| 40.5 (16.6, 64.4)***
| 0/9 (0.0)
| 3/11 (27.3)
| 38.8 (4.8, 72.9)*
|
Conclusion
In the ELEVATE UC clinical programme, significant improvements in efficacy were observed for patients receiving etrasimod 2 mg QD vs placebo, regardless of baseline BMI. The safety profile of etrasimod was consistent between BMI subgroups and with the overall ELEVATE UC population.
References
1. Kurnool S et al. Aliment Pharmacol Ther 2018; 47: 1472–1479.
2. Molodecky NA et al. Gastroenterology 2012; 142: 46-54 e42; quiz e30.
3. Ng M et al. Lancet 2014; 384: 766–781.
4. Sandborn WJ et al. J Crohns Colitis 2023; 17: 338–351.
Disclosure
AJY has received consultancy fees from AbbVie, Pfizer Inc, Arena, Takeda and Bristol Myers Squibb; and lecture/speaker fees from Bristol Myers Squibb. MDL is a consultant for AbbVie, Janssen, Pfizer Inc, Takeda, Bristol Myers Squibb, Target PharmaSolutions, Prometheus, Lilly, Salix, Valeant, Genentech, Roche, Calibr and Theravance; and has received research support from Pfizer Inc and Takeda. JT has received advisory board fees from AbbVie, Arena, Bristol Myers Squibb, Galapagos, Janssen and Pfizer Inc; research grants from AbbVie and Janssen; and speaker fees from AbbVie, Galapagos, Janssen and Pfizer Inc. NN is a consultant and advisory board member for AbbVie, Bristol Myers Squibb, Janssen, Lilly and Pfizer Inc; and has received research support from Ferring, Janssen, Pfizer Inc and Seres. RKC has received consultancy and advisory board fees from AbbVie, Adiso, Bristol Myers Squibb, CorEvitas, Fresenius Kabi, Fzata, IBD Education Group, Janssen, Magellan Health, Option Care, Pfizer Inc, Sandoz, Samsung Bioepis, Sebela and Takeda; and research grant/support from Janssen. AMA is an employee and shareholder of Pfizer Inc. DB and WN are employees of Pfizer Inc. CMC and JW are employees and shareholders of Pfizer Inc. GP is an employee of Pfizer Healthcare India Private Ltd. MG is an employee and shareholder of Pfizer AG. RP is a consultant for Abbott, AbbVie, Abbivax, Alimentiv (formerly Robarts), Amgen, Arena Pharmaceuticals, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, Cosmos Pharmaceuticals, Eisai, Elan, Ferring, Galapagos, Fresenius Kabi, Genentech, Gilead Sciences, Glaxo-Smith Kline, JAMP Bio, Janssen, Lilly, 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 and UCB; has received speaker fees for AbbVie, Amgen, Arena Pharmaceuticals, Bristol-Myers Squibb, Celgene, Ferring, Fresenius Kabi, Gilead Sciences, Janssen, Lilly, Merck, Organon, Pfizer, Roche, Sandoz, Shire and Takeda; is an advisory board member for AbbVie, Alimentiv (formerly Robarts), Amgen, Arena Pharmaceuticals, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Ferring, Fresenius Kabi, Genentech, Gilead Sciences, Glaxo-Smith Kline, JAMP Bio, Janssen, Lilly, Merck, Mylan, Novartis, Oppilan Pharma, Organon, Pandion Pharma, Pfizer, Progenity, Protagonist Therapeutics, Roche, Sandoz, Shire, Sublimity Therapeutics, Takeda and Ventyx; and has received research support from AbbVie, Janssen, Takeda and Pfizer.
