Etrasimod for the Treatment of Ulcerative Colitis: Up to 2.5 Years of Pooled Safety Data From Global Clinical Trials

Etrasimod, an investigational oral modulator of the S1P receptor, is in development for the treatment of moderately to severely active UC. The drug selectively activates S1P receptor subtypes 1, 4, and 5. A retrospective analysis was conducted to provide a comprehensive and upto-date safety analysis of results from etrasimod clinical trials in patients with moderately to severely active UC and up to 2.5 years of exposure to etrasimod.¹ Patient data were taken from placebo-controlled and OLE studies, including the phase 2 OASIS study (NCT02447302), the phase 3 ELEVATE UC 52 study (NCT03945188), and the phase 3 ELEVATE UC 12 study (NCT03996369). Etrasimod was administered daily at a dose of 1 or 2 mg. The placebo-controlled UC cohort included patients who had received either placebo or etrasimod in one of the placebo-controlled trials. A larger group included all patients in the placebo-controlled studies as well as all patients in the OLE studies who had received at least 1 dose of etrasimod.

The analysis included 956 patients who had received at least one dose of etrasimod, comprising 769.3 patient-years of exposure. In the placebo-controlled UC cohort, 52 patients had received etrasimod at a dose of 1 mg, daily, and 577 had received etrasimod at a dose of 2 mg, daily; the placebo group included 314 patients. In the all UC cohort, 956 patients had received at least one dose of etrasimod at either 1 or 2 mg, daily. The proportions of patients with AEs of any grade were 51.6% in the placebo group, 59.9% in the placebo-controlled etrasimod group, and 67.9% in the all UC etrasimod group; the proportions of patients with serious AEs were 5.4%, 4.6%, and 7.3% in the 3 groups, respectively; and the proportions of patients with any AE leading to discontinuation of study treatment were 2.5%, 5.1%, and 6.8%, respectively. No deaths occurred in the placebo-controlled UC cohort. One patient in the all UC cohort experienced a serious AE of neuroendocrine tumor that resulted in death, but the investigator considered this AE not likely to be related to the study therapy (Table 2).

ABSTRACT SUMMARY Efficacy of Ustekinumab for Ulcerative Colitis Through 4 Years: Final Clinical and Endoscopy Outcomes From the UNIFI Long-Term Extension.

In final results from the phase 3 UNIFI long-term extension study, the majority of patients with moderately to severely active UC treated with ustekinumab every 8 or 12 weeks achieved clinical remission (58%), endoscopic improvement (67%), clinical response (80%), and a modified Mayo score response (80%) at 4 years (Abstract Tu1722). Among patients who were in clinical remission at baseline or after 1 year of maintenance therapy with ustekinumab, clinical remission was generally maintained with continued ustekinumab therapy in the long-term extension study. No new safety signals were reported.

Table 2.

AEs of Special Interest Among Patients in the Placebo and UC Cohorts

AEs of Special Interest	Placebo-Controlled UC cohort		All UC Cohort
	Etrasimod (n=629) Patients, n (%)	Placebo (n=314) Patients, n (%)	Etrasimod (n=956) Patients, n (%)
Any AEs	377 (59.9)	162 (51.6)	649 (67.9)
Serious AEs	29 (4.6)	17 (5.4)	70 (7.3)
Any AE leading to study treatment discontinuation	32 (5.1)	8 (2.5)	65 (6.8)
Death	0	0	1 (0.1)
Infections and infestations Serious infections Herpes zoster Opportunistic infections	122 (19.4) 4 (0.6) 2 (0.3) 2 (0.3)	52 (16.6) 5 (1.6) 2 (0.6) 1 (0.3)	55 (5.8) 15 (1.6) 7 (0.7) 3 (0.3)
All cardiac disorders Bradycardia AV block, 1st degree AV block, 2nd degree (Mobitz type I)	25 (4.0) 11 (1.8) 2 (0.3) 2 (0.3)	4 (1.3) 0 0 0	36 (3.8) 14 (1.5) 4 (0.4) 3 (0.3)
Hypertension	13 (2.1)	3 (1.0)	21 (2.2)
Macular edema	2 (0.3)	1 (0.3)	1 (0.2)
Malignancies	0	0	1 (0.1)
Increased alanine aminotransferase	11 (1.7)	2 (0.6)	27 (2.8)
Decreased γ-glutamyl transferase	13 (2.1)	2 (0.6)	32 (3.3)
Posterior reversible encephalopathy syndrome	0	0	0

AE, adverse event; AV, atrioventricular; UC, ulcerative colitis. Adapted from Vermiere et al. Abstract 948. Presented at: DDW 2023; May 6-9, 2023; Chicago, Illinois.¹

Across the 3 cohorts, rates of serious infections ranged from 0.6% to 1.6%, and rates of herpes zoster ranged from 0.3% to 0.7%. No bradycardia was observed in any patient in the placebo cohort. Although 11 patients in the placebo-controlled UC cohort who were treated with etrasimod (2 mg, daily) experienced bradycardia, 9 of these events were asymptomatic. Other AEs of special interest were observed at similar rates across the 3 cohorts. In conclusion, the safety profile of etrasimod in patients with UC did not appear to change with a treatment duration of up to 2.5 years.