Etrasimod for the treatment of ulcerative colitis: up to 4 years of safety data from the global clinical programme

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). The long-term safety, tolerability and efficacy of etrasimod are being evaluated in an ongoing open-label extension (OLE) study. [1]

Objective: To report an updated cumulative safety analysis from the etrasimod UC clinical programme with≤4 years of exposure.

Methodology: Patients who received etrasimod in completed phase 2 (OASIS; OASIS open-label extension [OLE]), phase 3 (ELEVATE UC 52; ELEVATE UC 12) and ongoing ELEVATE UC OLE (data cutoff 30 August 2023) and ES101002 OLE (data snapshot 30 August 2022) studies were included. Treatment-emergent adverse event (TEAE) frequency and exposure-adjusted incidence rates (IRs) per 100 patient-years (PYs) were analysed.

Results: Overall, 1196 patients received≥1 dose of etrasimod once daily ([Table 1]; mean [standard deviation] exposure 70.66 [54.36] weeks; total exposure 1619.5 PYs). Most TEAEs were nonserious and rarely led to discontinuation. TEAEs leading to death were reported in three patients (all deemed unrelated to treatment). IRs of TEAEs of interest were generally low ([Table 2]). Serious infection and herpes zoster infections were infrequent (all IRs<2.0). Three patients experienced four nonserious events of macular oedema (0.3%; IR 0.18), including one leading to discontinuation that resolved. One patient experienced two nonserious events of cystoid macular oedema (<0.1%; IR 0.06) that resolved. Malignancies were uncommon and included five patients with serious events (0.4%), two patients with squamous cell carcinomas and one with basal cell carcinoma. Eleven patients (0.9%) had alanine aminotransferase levels>3 times the upper limit of normal at two consecutive post-baseline visits. No patients met laboratory criteria for Hy’s law. No serious TEAEs of hypertension or bradycardia were reported. No events of second-degree Mobitz type 2 atrioventricular block or higher occurred.

Table 1 Patient demographics and baseline disease characteristics

Characteristic	Etrasimod any dosea (N=1196)
Age, years; mean (SD)b	41.8 (13.37)
Female sex; n (%)	506 (42.3)
Race; n (%)
White	749 (62.6)
Asian	211 (17.6)
Baseline MMS; mean (SD)	5.8 (1.94)
Baseline total Mayo Clinic score; mean (SD)	8.2 (2.27)
Duration of UC, years; mean (SD)	7.3 (6.95)

The cohort comprised the following studies: OASIS (NCT02447302), ELEVATE UC 52 (NCT03945188), ELEVATE UC 12 (NCT03996369), OASIS OLE (NCT02536404), ELEVATE UC OLE (NCT03950232) and the open-label period of ES101002 (NCT04176588). TEAEs were assessed since the first dose of etrasimod (1 mg or 2 mg QD) as Day 1. For patients switching from placebo in randomised studies to OLE studies, their first dose of etrasimod in the OLE was considered as Day 1. Baseline was defined as the last nonmissing measurement taken on or prior to the study treatment group start date. ^aIncludes patients who received any dose of etrasimod 1 mg or 2 mg QD (52 patients received etrasimod 1 mg). ^bAge at treatment start. MMS, modified Mayo score; N, number of patients in the All UC Cohort; n, number of patients with event; OLE, open-label extension; QD, once daily; SD, standard deviation; TEAE, treatment-emergent adverse event; UC, ulcerative colitis.

Table 2 Safety data from the etrasimod UC clinical programme

	Etrasimod any dosea (N=1196)
	n (%)	Exposure-adjusted IR per 100 PYs
Any TEAE	904 (75.6)	163.35
Related TEAEb	382 (31.9)	30.98
Any Grade 3 or higher TEAE	162 (13.5)	10.54
Serious TEAE	126 (10.5)	7.95
Any TEAE leading to study treatment discontinuation	130 (10.9)	7.89
Any TEAE leading to deathc	3 (0.3)	0.18
Infections and infestationsd,e	412 (34.4)	34.13
Serious infections	28 (2.3)	1.71
Herpes zosterf	9 (0.8)	0.54
Posterior reversible encephalopathy syndrome	0	0.00
Macular oedema	3 (0.3)	0.18
Cystoid macular oedemag	1 (<0.1)	0.06
Malignancies (excluding NMSC)h,i	5 (0.4)	0.30
Hypertensionj	40 (3.3)	2.48
Bradycardiak	12 (1.0)	0.72
Sinus bradycardial	9 (0.8)	0.54
AV block, first degree	4 (0.3)	0.24
AV block, second degree (Mobitz type 1)	4 (0.3)	0.24
AV block, second degree (Mobitz type 2) or higher	0	0.00

The All UC cohort comprised the following studies: OASIS (NCT02447302), ELEVATE UC 52 (NCT03945188), ELEVATE UC 12 (NCT03996369), OASIS OLE (NCT02536404), ELEVATE UC OLE (data cutoff 30 August 2023; NCT03950232) and the open-label period of ES101002 (data snapshot 30 August 30 2022; NCT04176588). For patients switching from placebo in randomised studies to OLE studies, their first dose of etrasimod in the OLE was considered as Day 1. TEAE is defined as an AE that started after the first dose of etrasimod (1 mg or 2 mg QD). Terms are coded using MedDRA version 25.1. Exposure-adjusted IR is defined as the number of patients with AE divided by the total PYs at risk for AE (sum of individual time to first episode of AE, or time in the study if patient was event free). Exposure-adjusted IR is presented per 100 PYs. ^aIncludes patients who received any dose of etrasimod 1 mg or 2 mg QD (52 patients received etrasimod 1 mg). ^bAs determined by the physician. ^cOne event of neuroendocrine tumour of unknown primary site that resulted in death in a patient who received etrasimod 2 mg QD for approximately 24.3 weeks; one event of acute monocytic leukaemia that resulted in death due to cardiac arrest in a patient who received etrasimod 2 mg QD for approximately 43.4 weeks; one event of cardiac arrest during a scheduled colectomy procedure resulting in death in a patient who received etrasimod 2 mg QD in ELEVATE UC 12 and subsequently for 70.4 weeks during ELEVATE OLE. All deaths were deemed unrelated to study treatment as assessed by investigators. ^dInfections of interest included nonserious events of cytomegalovirus (three patients) and tuberculosis (one patient). One patient experienced a herpes simplex meningitis event that led to discontinuation and resolved. eSevere infections and infestations of CTCAE Grade 3–5 were experienced by 19 (1.6%) patients (Grade 3, n=18 [1.5%]; Grade 4, n=1 [<0.1%]; Grade 5, n=0). ^fAll events were nonserious and did not lead to discontinuation. ^gTwo nonserious events were reported in one patient that led to treatment discontinuation; both events were moderate and resolved. ^hDefined as Serious TEAE under System Organ Class of Neoplasm benign, malignant and unspecified (including cysts and polyps). ⁱFive patients experienced serious TEAEs: neuroendocrine tumour of unknown primary site, acute monocytic leukaemia, neuroendocrine carcinoma metastatic, colon cancer and intraductal proliferative breast lesion; all were deemed unrelated to study treatment as assessed by investigators. ^jNo serious TEAEs of hypertension or confirmed cases of hypertensive crisis have been reported to date. ^kThree events led to treatment discontinuation; all were nonserious and resolved. ^lTwo events led to treatment discontinuation; both were nonserious and resolved. AE, adverse event; AV, atrioventricular; CTCAE, common terminology criteria for adverse events; IR, incidence rate; MedDRA, Medical Dictionary for Regulatory Activities; N, number of patients in the All UC cohort; n, number of patients with event; NMSC, non-melanoma skin cancer; OLE, open-label extension; PY, patient-year; QD, once daily; TEAE, treatment-emergent adverse event; UC, ulcerative colitis.

Conclusion: Etrasimod remains well tolerated in patients with moderately to severely active UC, with a favourable safety profile that has not changed with longer-term treatment exposure for up to 4 years.

Informationen zum Einsatz von KI: Pfizer&apos;s genAI tool MAIA assisted with 1st draft development; authors assume content responsibility.

 

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• References

• 1 Vermeire S. et al. J Crohns Colitis 2023; 17: i619-i620

Publication History

Article published online:
04 September 2025