HEPATIC IMPACT OF ETRASIMOD FOR TREATMENT OF MODERATELY TO SEVERELY ACTIVE ULCERATIVE COLITIS: AN INTEGRATED SAFETY SUMMARY FROM THE ETRASIMOD ULCERATIVE COLITIS CLINICAL PROGRAMME

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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

Aims & Methods

Here, we report liver-associated treatment-emergent AEs (TEAEs) from the etrasimod UC clinical programme. 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 31 January 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), per 1 PY, of liver-related TEAEs among pts receiving etrasimod (2 mg once daily, both cohorts) or placebo (PBO; Pivotal UC cohort) were examined. EAIRs 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 similar across etrasimod- (EAIR ≤ 0.04) and PBO-treated (EAIR ≤ 0.03) pts (Table). Similarly, in the All UC cohort (etrasimod, N=942), EAIRs of liver-related TEAEs were ≤ 0.04 (Table). 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 ≤ 0.03) and PBO-treated (EAIR ≤ 0.02) pts was low, and occurred in 1.3% and 0.8% of pts, respectively (Table). 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.

Table. Liver-related TEAEs and treatment-emergent SDEIs reported during the etrasimod UC clinical programme by category (and subcategory) and preferred term
	Pivotal UC cohort		All UC cohort
Category Preferred term	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 n (%) [EAIR per 1 PY] Hepatobiliary disorders Liver disorder Cholestasis Hepatic steatosis Hepatic cytolysis Hepatic function abnormal Hyperbilirubinaemia Primary biliary cholangitis Cholangitis sclerosing Liver injury Biliary dyskinesia Cholecystitis chronic Hepatitis alcoholic Hepatomegaly Hypertransaminasaemia Non-alcoholic steatohepatitis Non-alcoholic fatty liver disease Investigations ALT increased GGT increased AST increased Blood AP increased Hepatic enzyme increased Transaminases increased Blood bilirubin increased Liver function test abnormal Liver function test increased	3 (0.6) [0.01] 2 (0.4) [<0.01] 2 (0.4) [<0.01] 1 (0.2) [<0.01] 1 (0.2) [<0.01] 1 (0.2) [<0.01] 1 (0.2) [<0.01] 0 (0.0) [NC] 0 (0.0) [NC] 0 (0.0) [NC] 0 (0.0) [NC] 0 (0.0) [NC] 0 (0.0) [NC] 0 (0.0) [NC] 0 (0.0) [NC] 0 (0.0) [NC] 11 (2.1) [0.04] 10 (1.9) [0.04] 5 (0.9) [0.02] 4 (0.8) [0.01] 4 (0.8) [0.01] 4 (0.8) [0.01] 2 (0.4) [<0.01] 1^d (0.2) [<0.01] 0 (0.0) [NC]	0 (0.0) [NC] 0 (0.0) [NC] 0 (0.0) [NC] 0 (0.0) [NC] 0 (0.0) [NC] 0 (0.0) [NC] 0 (0.0) [NC] 1 (0.4) [<0.01] 0 (0.0) [NC] 0 (0.0) [NC] 0 (0.0) [NC] 0 (0.0) [NC] 0 (0.0) [NC] 0 (0.0) [NC] 0 (0.0) [NC] 0 (0.0) [NC] 2 (0.8) [0.02] 2 (0.8) [0.02] 3 (1.2) [0.03] 0 (0.0) [NC] 1 (0.4) [<0.01] 0 (0.0) [NC] 0 (0.0) [NC] 0 (0.0) [NC] 1 (0.4) [<0.01]	5 (0.5) [<0.01] 3 (0.3) [<0.01] 3 (0.3) [<0.01] 1 (0.1) [<0.01] 3 (0.3) [<0.01] 1 (0.1) [<0.01] 1 (0.1) [<0.01] 0 (0.0) [NC] 2 (0.2) [<0.01] 1 (0.1) [<0.01] 1 (0.1) [<0.01] 1 (0.1) [<0.01] 1 (0.1) [<0.01] 1 (0.1) [<0.01] 1 (0.1) [<0.01] 1 (0.1) [<0.01] 27 (2.9) [0.04] 31 (3.3) [0.04] 17 (1.8) [0.02] 9 (1.0) [0.01] 8^b (0.8) [ 0.01] 5^c(0.5) [<0.01] 3 (0.3) [<0.01] 1 (0.1) [<0.01] 0 (0.0) [NC]
	Pivotal UC cohort
Category Subcategory Preferred term	Etrasimod 2 mg QD (N=527)		Placebo QD (N=260)
Liver-related SDEI,^e,fn (%) [EAIR per 1 PY] Liver injury^g,h,i Liver transaminases elevation^j ALT increased AST increased Transaminases increased Bilirubin elevation/liver transaminases elevation^j Liver function test abnormal	7 (1.3) [0.03] 6 (1.1) [0.02] 5 (0.9) [0.02] 4 (0.8) [0.01] 1 (0.2) [<0.01] 1 (0.2) [<0.01] 1 (0.2) [<0.01]		2 (0.8) [0.02] 2 (0.8) [0.02] 2 (0.8) [0.02] 1 (0.4) [<0.01] 0 (0.0) [NC] 0 (0.0) [NC] 0 (0.0) [NC]
^aTEAEs were defined as adverse events 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 ^bOne female pt (34 years of age) in ELEVATE UC 52 experienced SAEs of hepatic enzyme increased (mild, Grade 1) and abdominal pain (severe, Grade 3) on Day 196 (ALT 3.5 x ULN, AST 7.8 x ULN, GGT 1.9 x ULN, bilirubin 1.8 x ULN). Abdominal pain resolved on Day 202. Hepatic enzyme increased resolved on Day 224 and was assessed by the investigator as unlikely related to study treatment ^cOne 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 a 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 a 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 ^dThis 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 ^eSDEIs 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 ^fAn AE that continued from the previous study treatment was not counted as a TEAE in subsequent study treatment ^gThe 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]. 28 July 2009) https://www.fda.gov/regulatory-information/search-fda-guidance-documents/drug-induced-liver-injury-premarketing-clinical-evaluation [Accessed 31 March 2023] ^hSponsor-designated category ⁱPts were counted only once per summarisation level per treatment group. Percentages are based on the number of pts in the cohort. PTs were coded using MedDRA version 24.1 ^jSponsor-designated subcategory ALT, alanine aminotransferase; AP, alkaline phosphatase; AST, aspartate aminotransferase; EAIR, exposure-adjusted incidence rate; GGT, gamma-glutamyl transferase; MedDRA; Medical Dictionary for Regulatory Activities; NC, not calculated (when n=0); 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

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

Harbord M et al. J Crohns Colitis 2016; 10: 239–254.
Sandborn WJ et al. N Engl J Med 2021; 285: 1280–1291.

Disclosure

MR: Unrestricted Educational Grants from Abbvie, BMS, Janssen, UCB, Pfizer, Takeda, Celgene, Genentech, Gilead; Advisory Boards and Consultant for Abbvie, Janssen, UCB, Takeda, Pfizer, Miraca Labs, Amgen, Celgene, Seres, Allergan, Genentech, Gilead, Salix, Prometheus, Lilly, TARGET Pharma Solutions, ALFASIGMA, S.p.A., Bristol Meyer Squibb (BMS); CME Companies: CME Outfitters, Imedex, GI Health Foundation (GiHF), Cornerstones, Remedy, MJH life sciences; Royalties: Wolters Kluwer Health as Author/Editor of UpToDate
SV: grant/research support: AbbVie, MSD, Pfizer, Galapagos, Takeda; consultancy/advisory: AbbVie, AbolerIS, Alimentiv, Arena, AstraZeneca, Avaxia, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, CVasThera, Dr. Falk, Eli Lilly, Ferring, Galapagos, Genentech/Roche, Gilead, Hospira, Imidomics, Janssen, Johnson & Johnson, Materia Prima, MiroBio, Morphic, MrMHealth, MSD, Mundipharma, Pfizer, Prodigest, Progenity, Prometheus, Robarts Clinical Trials, Second Genome, Shire, Surrozen, Takeda, Theravance, Tillotts, Zealand; lecture/speaker: AbbVie, Dr. Falk, Ferring, Hospira, MSD, Takeda, Tillotts.
DTR: grant support: Takeda, Helmsley Charitable Trust, GastroIntestinal Research Foundation; consultancy fees/is a member of advisory boards: AbbVie, AltruBio, ASLAN Pharmaceuticals, Athos Therapeutics, Bellatrix Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Chronicles, ClostraBio, Connect Biopharma, EcoR1, Genentech/Roche, Gilead Sciences, Iterative Health, Janssen Pharmaceuticals, Kaleido Biosciences, Eli Lilly, Pfizer Inc, Prometheus, Reistone, Seres Therapeutics, Syneos, Takeda, Target RWE, Trellus Health; is on the Board of Trustees for Crohn’s & Colitis Foundation and Cornerstones Health, Inc; holds stock options in Alike Health, AltruBio, Datos Health and Iterative Health.
MCD: grant/research support: Janssen; consultancy: AbbVie, Arena, Bristol-Myers Squibb, Celgene, Eli Lilly, Galapagos, Genentech, Gilead, Janssen, Pfizer, Prometheus, Takeda, Trellus Health, UCB; shares/royalties: Trellus; directorship/ownership interests: Trellus.
AH: consultancy fees: AbbVie, Allergan, Atlantic, Bristol-Myers Squibb, Celltrion, Dr. Falk Pharma, Ferring Pharmaceuticals, Janssen, MSD, Napp, Pfizer Inc, Pharmacosmos, Shire, Takeda; lecture fees: AbbVie, Atlantic, Bristol-Myers Squibb, Celltrion, Falk, Ferring Pharmaceuticals, Janssen, MSD, Napp, Pfizer Inc, Pharmacosmos, Shire, Takeda; is an advisory board member of AbbVie, Atlantic, Bristol-Myers Squibb, Celltrion, Falk, Ferring Pharmaceuticals, Janssen, MSD, Napp, Pfizer Inc, Pharmacosmos, Shire, Takeda; is a member of the Global Steering Committee of Genentech.
JCW, JG, JCW: employees & shareholders of Pfizer.
KJG: consultancy fees: Pfizer Inc and Arena Pharmaceuticals; is an independent contractor.
AMcD: employee of Pfizer Ltd & shareholder of Pfizer.
KL: employee of Pfizer Inc & shareholder of Pfizer Inc.
LPB: grant/research support: Takeda, Fresenius Kabi and Celltrion; consultancy fees: AbbVie, Alimentiv, Alma Bio Therapeutics, Amgen, Applied Molecular Transport, Arena Pharmaceuticals, Biogen, Bristol-Myers Squibb, Celltrion, CONNECT Biopharm, Cytoki Pharma, Enthera, Ferring Pharmaceuticals, Fresenius Kabi, Galapagos, Genentech, Gilead Sciences, Gossamer Bio, GSK, HAC-Pharma, IAG Image Analysis, Index Pharmaceuticals, Inotrem, Janssen, Eli Lilly, Medac, Mopac, Morphic, MSD, Norgine, Novartis, OM Pharma, ONO Pharma, OSE Immunotherapeutics, Pandion Therapeutics, Par'Immune, Pfizer Inc, Prometheus, Protagonist, Roche, Sandoz, Takeda, Theravance, Thermo Fisher, TiGenix, Tillotts, Viatris, Vifor, Ysopia and Abivax; lecture/speaker fees: Galapagos, AbbVie, Janssen, Genentech, Ferring Pharmaceuticals, Tillotts, Celltrion, Takeda, Pfizer, Sandoz, Biogen, MSD, Amgen, Vifor, Arena Pharmaceuticals, Eli Lilly, Gilead Sciences, Viatris, Medac, Sanofi; holds stock in CTMA.