S812 Hepatic Safety of Ozanimod in Ulcerative Colitis and Relapsing Multiple Sclerosis Phase 3 Trials

Abstract

Introduction: Ozanimod (OZA) is a sphingosine 1-phosphate (S1P) receptor modulator approved for the treatment of moderately to severely active ulcerative colitis (UC) and relapsing forms of multiple sclerosis (MS) in the United States and European Union. Other S1P receptor modulators have shown substantial elevations in hepatic enzymes. Methods: The impact of OZA on liver function tests was assessed in this safety analysis from phase 3 UC and MS trials. In the 52-week (10-week induction period and 42-week maintenance period), randomized True North (TN) trial, patients (pts) with moderately to severely active UC were treated with placebo (n=216) or OZA 0.92 mg (equivalent to OZA HCl 1 mg) (n=796). In the randomized MS trials (SUNBEAM and RADIANCE), MS pts were treated with interferon beta-1a 30 µg (n=885) or OZA (n=882) for 12 and 24 months, respectively. Hepatic enzymes were assessed at baseline and Weeks 5, 10, 18, 28, 40, and 52 in TN, and at baseline and every 3 months for the MS trials. In the UC and MS trials, enzyme elevations were confirmed with a repeated test within 14 days. Results: Percentages of pts on OZA 0.92 mg with elevations in alanine transaminase (ALT), aspartate aminotransferase (AST), and bilirubin are shown in the Table; < 6% and < 2% of pts had ALT and AST elevations ≥3 x upper limit of normal (ULN), respectively, and < 2% had bilirubin elevations >2 x ULN. Of those with ALT ≥3 x ULN, 86.4% (19/22) of UC pts and 85.4% (41/48) of MS pts recovered to ALT < 3 x ULN within 3 months. Most hepatic treatment-emergent adverse events (TEAEs) were mild to moderate in UC and MS pts. In TN, 3 (0.4%) pts on OZA reported a hepatobiliary disorder TEAE, 1 (0.1%) of whom had hyperbilirubinemia. In the MS trials, 15 (1.7%) pts on OZA 0.92 mg reported a hepatobiliary disorder TEAE, 3 (0.3%) of whom had hyperbilirubinemia. Hepatic-related events leading to discontinuation, which were generally asymptomatic laboratory abnormalities, were reported in 4 (0.5%) UC pts and in 11 (1.2%) MS pts on OZA 0.92 mg. No serious hepatic TEAEs, Hy’s law cases, or severe drug-induced hepatocellular injuries occurred with OZA 0.92 mg in any of the trials. Conclusion: In this analysis of phase 3 UC and MS trials with OZA, elevations of aminotransferases and bilirubin occurring with OZA were infrequent, generally asymptomatic, and transient. These elevations, which generally resolved without study drug discontinuation, did not meet the criteria for Hy’s law or protocol-defined serious AEs. Table 1. - Maximum postbaseline ALT, AST, and bilirubin levels with OZA 0.92 mg Parameter TN (UC)(n=783) Sunbeam/Radiance (MS) (n=878) ALT >1 × ULN 215 (27.5) 373 (42.5) ≥3 × ULN 22 (2.8) 48 (5.5) ≥5 × ULN 8 (1.0) 14 (1.6) AST >1 × ULN 136 (17.4) 185 (21.1) ≥3 × ULN 14 (1.8) 9 (1.0) ≥5 × ULN 5 (0.6) 5 (0.6) Bilirubin >1 × ULN 32 (4.1) 122 (13.9) >2 × ULN 3 (0.4) 14 (1.6) >3 × ULN 1 (0.1) 3 (0.3)