P181 Safety of seladelpar in patients with primary biliary cholangitis with cirrhosis and clinical signs of portal hypertension: data from the ENHANCE and RESPONSE studies

Seladelpar is a first-in-class delpar (selective PPAR-delta agonist) indicated in the UK for the treatment of primary biliary cholangitis (PBC) including pruritus in combination with ursodeoxycholic acid (UDCA). In two Phase 3, placebo-controlled studies (ENHANCE [NCT03602560], RESPONSE [NCT04620733]), seladelpar significantly reduced cholestatic markers and pruritus with a safety profile similar to placebo. Here, we present pooled safety data from these studies in a subgroup of patients with cirrhosis and portal hypertension (PHT). Patients with PBC who received UDCA for ≥12 months or were UDCA intolerant, with alkaline phosphatase (ALP) ≥1.67 × upper limit of normal (ULN) and total bilirubin (TB) ≤2 × ULN, were randomised 1:1:1 to daily, oral placebo, seladelpar 5 mg, or seladelpar 10 mg for up to 52 weeks in ENHANCE and 2:1 to seladelpar 10 mg or placebo 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. Patients with cirrhosis were identified as having signs of PHT at baseline if they had thrombocytopenia (platelet count <140 × 103/µL), low albumin, elevated TB, or history of varices or ascites. Among 56 patients with cirrhosis at baseline across the two studies, 27 had signs of PHT at baseline (21 on seladelpar [15/21 on 10 mg], 6 on placebo). Most patients were female (85%) and White (89%), with a mean (range) age of 55.6 (33–74) years, and baseline mean ALP and TB levels of 319.9 U/L and 1.2 mg/dL. Mean (SD) liver stiffness was 17.4 (3.5) kPa with placebo and 21.0 (11.8) kPa with seladelpar. In total, 5/6 (83%) patients on placebo and 15/21 (71%) patients on seladelpar experienced an adverse event (AE); 2/6 (33%) patients on placebo and 1/21 (5%) patients on seladelpar discontinued treatment due to AEs. Serious AEs occurred in 1/6 (17%) patients on placebo and 1/21 (5%) patients on seladelpar and were deemed unrelated to study drug. Liver-related AEs by a predefined search strategy were similar across patients on placebo (2/6, 33%) or seladelpar (3/21, 14%) and included hepatomegaly, ascites, hyperbilirubinaemia, and portal hypertensive gastropathy. Liver-related laboratory abnormalities by predefined categories occurred in 2/6 (33%) placebo-treated patients and 1/21 (5%) seladelpar-treated patients. In this pooled analysis of patients with PBC and cirrhosis with clinical signs of PHT from the ENHANCE and RESPONSE studies, safety outcomes were overall similar between seladelpar and placebo, with no new safety signals.

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