Hepatic Impact of Etrasimod for Treatment of Moderately to Severely Active Ulcerative Colitis: An Integrated Safety Summary From the Etrasimod Ulcerative Colitis Clinical Program

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). Patients (pts) with inflammatory bowel disease may experience changes in liver function tests,1 with liver adverse events (AEs) reported in previous S1P receptor modulator trials.2 Methods: Here, we report liver-associated treatment-emergent AEs (TEAEs) from the etrasimod UC clinical program. Pts in the phase (p)2 (OASIS, NCT02447302), p3 (ELEVATE UC 52, NCT03945188; ELEVATE UC 12, NCT03996369), and p2 and p3 open-label extension (OLE) studies (NCT02536404; NCT03950232; NCT04176588 [data snapshot January 31, 2022]) were evaluated in two data cohorts: Pivotal UC (ELEVATE UC 52 and ELEVATE 12) and All UC (all p2, p3, and OLE studies). Exposure-adjusted incidence rates (EAIRs; number of pts with AEs divided by total pt-years [PY] at risk for AEs), of liver-related TEAEs, per 1 PY for hepatobiliary disorders and per 100 PY for investigations among pts receiving etrasimod (2 mg once daily, both cohorts) or placebo (PBO; Pivotal UC cohort) were examined. EAIRs, per 100 PY, of liver-related sponsor-designated events of interest (SDEIs) in the Pivotal UC cohort, and discontinuations due to liver-related TEAEs in the All UC cohort, were assessed. Results: In the Pivotal UC cohort (etrasimod, N=527; PBO, N=260), incidence of liver-related TEAEs was higher in etrasimod- (EAIR ≤ 4.04) vs PBO-treated (EAIRs ≤ 2.86) pts (Table 1). Similarly, in the All UC cohort (etrasimod, N=942), EAIRs of liver-related TEAEs were ≤ 4.06 (Table 1). Proportions of pts with liver-related TEAEs across both cohorts were ≤ 3.3% and ≤ 1.2% for etrasimod- and PBO-treated pts, respectively. In the Pivotal UC cohort, incidence of SDEIs in etrasimod- (EAIR ≤ 2.55) and PBO-treated (EAIR ≤ 1.89) pts was low, and occurred in 1.3% and 0.8% of pts, respectively (Table 1). In the All UC cohort, three etrasimod-treated pts discontinued due to liver-related TEAEs: abnormal liver function test, increased blood alkaline phosphatase, and increased alanine aminotransferase, respectively. Conclusion: Incidence of liver-related TEAEs and SDEIs was generally low among pts treated with etrasimod and PBO with infrequent etrasimod discontinuations due to liver-related TEAEs. References: 1. Harbord M et al. J Crohns Colitis 2016; 10: 239–254. 2. Sandborn WJ et al. N Engl J Med 2021; 285: 1280–1291. Table 1. - Liver-Related TEAEs and Treatment-Emergent SDEIs Reported During the Etrasimod UC Clinical Program by Category (and Subcategory) and Preferred Term Category Preferred term Pivotal UC cohort All UC cohort Etrasimod 2 mg QD (N=527) Placebo QD (N=260) Etrasimod 2 mg QD (N=942) Total exposure PY 265.6 103.0 757.9 Liver-related TEAE [a] Hepatobiliary disorders, n (%) [EAIR per 1 PY] Liver disorder 3 (0.6) [0.01] 0 5 (0.5) [< 0.01] Cholestasis 2 (0.4) [< 0.01] 0 3 (0.3) [< 0.01] Hepatic steatosis 2 (0.4) [< 0.01] 0 3 (0.3) [< 0.01] Hepatic cytolysis 1 (0.2) [< 0.01] 0 1 (0.1) [< 0.01] Hepatic function abnormal 1 (0.2) [< 0.01] 0 3 (0.3) [< 0.01] Hyperbilirubinemia 1 (0.2) [< 0.01] 0 1 (0.1) [< 0.01] Primary biliary cholangitis 1 (0.2) [< 0.01] 0 1 (0.1) [< 0.01] Cholangitis sclerosing 0 1 (0.4) [< 0.0] 0 Liver injury 0 0 2 (0.2) [< 0.01] Biliary dyskinesia 0 0 1 (0.1) [< 0.01] Cholecystitis chronic 0 0 1 (0.1) [< 0.01] Hepatitis alcoholic 0 0 1 (0.1) [< 0.01] Hepatomegaly 0 0 1 (0.1) [< 0.01] Hypertransaminasemia 0 0 1 (0.1) [< 0.01] Non-alcoholic steatohepatitis 0 0 1 (0.1) [< 0.01] Non-alcoholic fatty liver disease 0 0 1 (0.1) [< 0.01] Investigations n (%) [EAIR per 100 PY] ALT increased 11 (2.1) [4.04] 2 (0.8) [1.89] 27 (2.9) [3.53] GGT increased 10 (1.9) [3.68] 2 (0.8) [1.90] 31 (3.3) [4.06] AST increased 5 (0.9) [1.82] 3 (1.2) [2.86] 17 (1.8) [2.20] Blood AP increased 4 (0.8) [1.45] 0 9 (1.0) [1.16] Transaminases increased 4 (0.8) [1.46] 0 5 [b] (0.5) [0.64] Blood bilirubin increased 2 (0.4) [0.72] 0 3 (0.3) [0.38] Liver function test abnormal 1 [c] (0.2) [0.36] 0 1 (0.1) [0.13] Liver function test increased 0 1 (0.4) [0.95] 0 Category Subcategory Preferred term Pivotal UC Cohort Etrasimod 2 mg QD (N=527) Placebo QD (N=260) Liver-related SDEI [d][e], n (%) [EAIR per 100 PY] Liver injury [f][g][h] 7 (1.3) [2.55] 2 (0.8) [1.89] Liver transaminases elevation [i] 6 (1.1) [2.19] 2 (0.8) [1.89] ALT increased 5 (0.9) [1.82] 2 (0.8) [1.89] AST increased 4 (0.8) [1.46] 1 (0.4) [0.94] Transaminases increased 1 (0.2) [0.36] 0 Bilirubin elevation/liver transaminases elevation [i] 1 (0.2) [0.36] 0 Liver function test abnormal 1 (0.2) [0.36] 0.1 [a] TEAEs were defined as AEs that started after the first dose of study treatment and were associated with the treatment most recently received by the pt at the time of onset;[b] One female pt (38 years of age) in ELEVATE UC 12 had a Grade 1 event unrelated to the study treatment. No action was taken with respect to the study treatment, and the pt recovered/event resolved. One male pt (57 years of age) in a p3 OLE study had a Grade 1 event related to the study treatment. The study treatment dose was not changed, and the event was ongoing at the time of the data snapshot for this analysis (January 2022). One male pt (50 years of age) in ELEVATE UC 52 had a Grade 1 event unrelated to the study treatment. The study treatment dose was not changed, and the pt recovered/event resolved. The same pt had a second event recorded with the same characteristics; this event was ongoing at the time of the data snapshot (January 2022) for this analysis. One male pt (39 years of age) had a Grade 2 event (ALT 3.5 x ULN, AST 3 x ULN), unrelated to study treatment, in ELEVATE UC 52 (onset was from Day 355 from trial baseline) and the event was classed as an SDEI. When the patient completed ELEVATE UC 52, he enrolled in the OLE study. The event was ongoing but was downgraded to Grade 1 during the OLE and was not classed as an SDEI. The event resolved on Day 395. One male pt (51 years of age) in ELEVATE UC 52 had a Grade 2 event related to the study treatment. The study treatment dose was not changed, and the event was ongoing at the time of the data snapshot (January 2022) for this analysis.[c] This Grade 2 event (onset Day 15, AST and ALT elevated to 3.1 and 5.8 x ULN, respectively, and GGT 5.7 x ULN; nausea and vomiting Day 23; all values returned to normal by Day 36) occurred in a female pt (34 years of age) in ELEVATE UC 12. The study treatment was withdrawn on Day 19, and the pt recovered/event was resolved. The event was assessed by the investigator as probably related to study treatment.[d] SDEIs were a subset of all reported liver-related TEAEs that were prospectively reviewed and medically confirmed by data such as laboratory data, and were defined as events for which onset was after the first dose of study drug and must not have been part of a pre-existing condition that had not changed significantly.[e] An AE that continued from the previous study treatment was not counted as a TEAE in subsequent study treatment.[f] The PTs of ‘ALT increased’ and ‘AST increased’ were considered SDEIs if confirmed by an elevation of the corresponding transaminase to ≥ 5 × ULN, sustained elevations of the respective transaminase to > 3 × ULN, or, if lower, accompanied by non-specific symptoms consistent with liver damage, eg anorexia, nausea, fatigue, right upper abdominal discomfort, and vomiting (US Food and Drug Administration. Guidance for industry drug-induced liver injury: premarketing clinical evaluation. Drug Safety [Online]. July 28, 2009) https://www.fda.gov/regulatory-information/search-fda-guidance-documents/drug-induced-liver-injury-premarketing-clinical-evaluation [Accessed March 31, 2023].[g] Sponsor-designated category.[h] Pts were counted only once per summarization level per treatment group. Percentages are based on the number of pts in the cohort. PTs were coded using MedDRA version 24.1.[i] Sponsor-designated subcategory.For AEs with 0 pts with events, % and EAIR are also 0, so not displayed.AE, adverse event; ALT, alanine aminotransferase; AP, alkaline phosphatase; AST, aspartate aminotransferase; EAIR, exposure-adjusted incidence rate; GGT, gamma-glutamyl transferase; MedDRA, Medical Dictionary for Regulatory Activities; N, total number of patients in the cohort; n, number of patients with an event; OLE, open-label, long-term extension; p, phase; PT, preferred term; pt, patient; PY, pt-years; QD, once daily; SAE, serious adverse event; SDEI, sponsor-designated events of interest; TEAE, treatment-emergent AE; UC, ulcerative colitis; ULN, upper limit of normal.