Introduction
Etrasimod is an oral, once-daily, selective sphingosine 1-phosphate (S1P)1,4,5 receptor modulator for the treatment of moderately to severely active ulcerative colitis (UC), with demonstrated efficacy in patients (pts) with baseline modified Mayo Score (MMS) 4–9.1 No prior clinical trials of advanced therapies in UC have studied efficacy only in pts with baseline MMS ≤6.
Aims & Methods
GLADIATOR (NCT04607837) was a proof-of-concept, global, randomised, double-blind, placebo-controlled trial to evaluate the efficacy and safety of etrasimod in adults with mildly to moderately active UC (MMS 4–6; endoscopic subscore ≥2; rectal bleeding subscore ≥1) and inadequate response, loss of response or intolerance to ≥1 UC therapy. Pts were randomised 2:1 to etrasimod 2 mg or placebo once daily, stratified by previous biologic/Janus kinase inhibitor exposure and baseline corticosteroid use. GLADIATOR used a treat-through design (12-week [wk] induction period followed by a 40‑wk maintenance period). From Wk 12, pts whose disease had worsened or not improved vs baseline may have been eligible to enrol in an open-label extension trial (NCT03950232). The primary efficacy endpoint was the proportion of pts achieving clinical remission at Wk 52; additional endpoints are shown in the Table. Safety was monitored throughout the study.
Results
In the primary analysis set for efficacy, 127 and 60 pts received etrasimod and placebo, respectively. At Wk 52, 26.0% and 18.3% of pts receiving etrasimod and placebo, respectively, were in clinical remission (p=0.2524; Table). At Wk 12, a greater proportion of pts receiving etrasimod achieved clinical remission, endoscopic improvement (EI) and endoscopic improvement-histologic remission (EIHR) vs placebo (p<0.05; Table). Pts receiving etrasimod were more likely to achieve sustained clinical remission vs placebo (p=0.0104; Table). Etrasimod was generally well tolerated and findings were consistent with the known safety profile.
| Table. Proportions of pts (n [%]) achieving endpoints at Wk 12 and Wk 52 in GLADIATOR (nonresponder imputation)a | Endpoint | Placebo (N=60) | Etrasimod 2 mg (N=127) | % difference from placebob (95% CI) | Difference from placebo p valuec |
Wk 12
Wk 12 completers: Placebo: 56 (93.3)d Etrasimod: 122 (96.1)e | Clinical remissionf | 7 (11.7) | 36 (28.3) | 15.6 (4.3, 26.9) | 0.0068 |
| EIg | 12 (20.0) | 56 (44.1) | 23.3 (9.8, 36.9) | 0.0007 |
| EIHRh | 8 (13.3) | 37 (29.1) | 15.0 (3.2, 26.8) | 0.0128 |
Wk 52
Wk 52 completers: Placebo: 28 (46.7)i Etrasimod: 76 (59.8)j | Clinical remissionf | 11 (18.3) | 33 (26.0) | 7.4 (-5.2, 19.9) | 0.2524 |
| EIg | 14 (23.3) | 41 (32.3) | 8.2 (-5.2, 21.7) | 0.2302 |
| EIHRh | 9 (15.0) | 32 (25.2) | 9.6 (-2.1, 21.3) | 0.1089 |
| CS-free clinical remissionk | 10 (16.7) | 32 (25.2) | 8.5 (-3.7, 20.7) | 0.1726 |
| Wk 12 and Wk 52 | Sustained clinical remissionl | 3 (5.0) | 21 (16.5) | 11.2 (2.6, 19.8) | 0.0104 |
aAll randomised pts who received ≥1 dose of study treatment with baseline MMS 4–6, baseline ES ≥2 and baseline RBS ≥1 were included in the primary analysis set for efficacy analysis. All pts with missing data were treated as nonresponders in the primary analysis. bEstimated common risk difference using the Mantel–Haenszel weighted method, stratified by naïve to biologic/JAKi therapy at trial entry (yes/no) and baseline CS use (yes/no). cFrom Mantel–Haenszel test and not adjusted for multiplicity. dIn the placebo group, prior to Wk 12, the following reasons for discontinuation were reported: AE (n=2 [3.3%]); withdrawal by pt (n=2 [3.3%]). eIn the etrasimod group, prior to Wk 12, the following reasons for discontinuation were reported: AE (n=3 [2.4%]); withdrawal by pt (n=1 [0.8%]); disease worsening (n=1 [0.8%]). fClinical remission was defined as SFS=0 or 1 (and no greater than baseline), RBS=0 and ES ≤1 (excluding friability). gEI was defined as ES ≤1. hEIHR was defined as ES ≤1 with histologic remission measured by Geboes Index score <2.0. iIn the placebo group, after Wk 12, the following reasons for discontinuation were reported: disease worsening (n=26 [43.3%]); withdrawal by pt (n=2 [3.3%]). jIn the etrasimod group, after Wk 12, the following reasons for discontinuation were reported: disease worsening (n=33 [26.0%]); withdrawal by pt (n=5 [3.9%]); AE (n=4 [3.1%]); physician decision (n=2 [1.6%]); lack of efficacy (n=1 [0.8%]); study termination by sponsor (n=1 [0.8%]). kCS-free clinical remission was defined as clinical remission at Wk 52 and CS free for ≥12 wks immediately prior to Wk 52. lSustained clinical remission was defined as clinical remission at both Wk 12 and Wk 52. AE, adverse event; CI, confidence interval; CS, corticosteroid; EI, endoscopic improvement; EIHR, endoscopic improvement-histologic remission; ES, endoscopic subscore; JAKi, Janus kinase inhibitor; MMS, modified Mayo score; N, number of pts in cohort; pt, patient; RBS, rectal bleeding subscore; SFS, stool frequency subscore; wk, week. |
Conclusion
In pts with mildly to moderately active UC, etrasimod demonstrated higher rates of clinical remission, EI and EIHR at Wk 12, as well as sustained clinical remission at Wk 52, vs placebo. However, the primary endpoint of clinical remission at Wk 52 was not met. Etrasimod demonstrated efficacy in pts with UC with an MMS 4–9, including those with an MMS 4–6, in the ELEVATE UC clinical programme.1 The proof-of-concept GLADIATOR trial further supports etrasimod’s efficacy in active UC and provides important insights on studying pts with mildly to moderately active UC.
References
1. Sandborn WJ et al. Lancet 2023; 401: 1159–1171.
Disclosure
SD: Lecture fees: AbbVie, Amgen, Ferring Pharmaceuticals Inc, Gilead, Janssen, Mylan, Pfizer Inc, Takeda; Consultancy fees: AbbVie, Allergan, Amgen, AstraZeneca, Biogen, Boehringer Ingelheim, Celgene, Celltrion, Ferring, Gilead Sciences, Hospira, Janssen, Johnson&Johnson, MSD, Mundipharma, Pfizer Inc, Roche, Sandoz, Takeda, TiGenix, UCB, Vifor; Directorship: Gastroenterology and Endoscopy.
MG, KL: Employees of Pfizer AG; shareholders of Pfizer Inc.
LPB: Consultancy fees: AbbVie, Abivax, Alimentiv, Alma Bio Therapeutics, Amgen, Applied Molecular Transport, Arena, Biogen, BMS, Celltrion, CONNECT Biopharm, Cytoki Pharma, Enthera, Ferring, Fresenius Kabi, Galapagos, Genentech, Gilead, Gossamer Bio, GlaxoSmithKline, HAC-Pharma, IAG Image Analysis, Index Pharmaceuticals, Inotrem, Janssen, Lilly, Medac, Mopac, Morphic, MSD, Norgine, Novartis, OM Pharma, ONO Pharma, OSE Immunotherapeutics, Pandion Therapeutics, Par’Immune, Pfizer Inc, Prometheus, Protagonist, Roche, Roivant, Samsung, Sandoz, Sanofi, Takeda, Theravance, Thermo Fisher, Tigenix, Tillotts, Viatris, Vifor, Vectivbio, Ventyx, Ysopia; Grants: Takeda, Fresenius Kabi, Celltrion; Lectures: AbbVie, Amgen, Arena, Biogen, Celltrion, Ferring, Galapagos, Genetech, Gilead, Janssen, Lilly, Medac, MSD, Pfizer Inc, Sandoz, Takeda, Tillotts, Viatris, Vifor.
AJY: Consultancy fees: AbbVie, Arena, BMS, Celltrion, Pfizer Inc, Takeda; Lectures: AbbVie, BMS.
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BGF: Senior Scientific Director of Alimentiv Inc, which provides central reading services. He is not a company employee and has no equity stake in the organisation, which is owned by a medical trust; Speaker fees: AbbVie, Janssen, Takeda; Consultancy fees: AbbVie, AbolerIS, AgomAB Therapeutics, Allianthera, Amgen, AnaptysBio, Applied Molecular Transport Inc, Arena Pharma, Avoro Capital Advisors, Atomwise, BioJamp, Biora Therapeutics, Boehringer Ingelheim, Boxer, Celsius Therapeutics,Celgene/BMS, Connect BioPharma, Cytoki, Disc Medicine, Duality, EcoR1, Eli Lilly, Equillium, Ermium, First Wave, First Word Group, Galapagos, Galen Atlantica, Genentech, Gilead, Gossamer Pharma, GSK, Hinge Bio, Hot Spot Therapeutics, Index Pharma, Imhotex, Immunic Therapeutics, JAKAcademy, Janssen, Japan Tobacco Inc, Kaleido Biosciences, Landos Biopharma, Leadiant, L.E.K. Consulting, Lenczner Slaght, LifeSci Capital, Lument AB, Millennium, MiroBio, Morgan Lewis, Morphic Therapeutics, Mylan, OM Pharma, Origo BioPharma, Orphagen, Pandion Therapeutics, Pendopharm, Pfizer Inc, Prometheus Therapeutics and Diagnostics, Play to Know AG, Progenity, Protagonist, PTM Therapeutics, Q32 Bio, Rebiotix, REDX, Roche, Sandoz, Sanofi, Seres Therapeutics, Silverback Therapeutics, Surrozen Inc, Takeda, Teva, Thelium, Tigenix, Tillotts, Ventyx Biosciences, VHSquared Ltd, Viatris, Ysios, Ysopia, Zealand Pharma; Shareholder: Gossamer Pharma.
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GG, JY, NL, CZ, WW, SM, EHL, IM, SS, WN: Employees/shareholders of Pfizer Inc.
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