S145 Safety of Seladelpar in Primary Biliary Cholangitis Patients With Cirrhosis and Clinical Signs of Portal Hypertension: Data From the ENHANCE and RESPONSE Studies

Introduction: Primary biliary cholangitis (PBC) is a cholestatic liver disease that can cause cirrhosis and portal hypertension (PHT). Seladelpar (SEL) is a first-in-class delpar (selective PPAR-delta agonist) approved for the treatment of PBC in combination with ursodeoxycholic acid (UDCA) in adults with an inadequate response to UDCA, or as monotherapy in patients (pts) unable to tolerate UDCA. In 2 Phase 3, placebo (PBO)-controlled studies (ENHANCE [NCT03602560] and RESPONSE [NCT04620733]), SEL significantly reduced cholestatic markers of disease and pruritus with safety similar to PBO. Here, we present pooled safety data from these studies in a subgroup of pts with cirrhosis and clinical signs of PHT. Methods: Pts with PBC who received UDCA for ≥12 months or were UDCA intolerant with alkaline phosphatase ≥1.67 × upper limit of normal and total bilirubin (TB) ≤2 × upper limit of normal were randomized 1:1:1 to daily PBO, SEL 5 mg, or SEL 10 mg for up to 52 weeks in ENHANCE and 2:1 to daily SEL 10 mg or PBO for 52 weeks in RESPONSE. Cirrhosis was defined by medical history, liver biopsy, transient elastography, laboratory findings, radiological features, or clinical determination by the investigator. Signs of PHT at baseline (BL) included thrombocytopenia (platelet count <140 × 103/µL), low albumin, elevated TB, or medical history of varices or ascites. Results: In 56 pts with cirrhosis at BL across both studies, 27 had signs of PHT at BL (SEL: 21 pts [15/21 on 10 mg]; PBO: 6 pts). Most pts were women (85%) and White (89%), with a mean (range) age of 55.6 (33–74) years and BL mean alkaline phosphatase and TB levels of 319.9 U/L and 1.2 mg/dL. Mean liver stiffness was 17.4 (3.5) kPa with PBO and 21.0 (11.8) kPa with SEL. In total, 5/6 (83%) pts on PBO and 15/21 (71%) pts on SEL had an adverse event (AE); 2/6 (33%) pts on PBO and 1/21 (5%) pts on SEL discontinued treatment due to AEs. Serious AEs occurred in 1/6 (17%) pts on PBO and 1/21 (5%) pts on SEL and deemed unrelated to study drug. Liver-related AEs by a predefined search strategy were similar across pts on PBO (2/6, 33%) or SEL (3/21, 14%) and included hepatomegaly, ascites, hyperbilirubinemia, and portal hypertensive gastropathy. Liver-related laboratory abnormalities by predefined categories occurred in 2/6 (33%) PBO pts and 1/21 (5%) SEL pts. Conclusion: In this pooled analysis of pts with PBC and cirrhosis with clinical signs of PHT from ENHANCE and RESPONSE, safety outcomes were overall similar between SEL and PBO, with no new safety signals.