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

Document Type

Conference Proceeding

Publication Date

5-1-2025

Publication Title

J Hepatol

Abstract

Background and aims: Primary biliary cholangitis (PBC) is a chronic, progressive, autoimmune, cholestatic liver disease that can cause cirrhosis and portal hypertension (PHT). Seladelpar is a first-in-class delpar (selective PPAR-delta agonist) approved for the treatment of PBC in combination with ursodeoxycholic acid (UDCA) in adults who have an inadequate response to UDCA, or as monotherapy in patients (pts) unable to tolerate UDCA. In two Phase 3, placebo-controlled studies (ENHANCE [NCT03602560] and RESPONSE [NCT04620733]), seladelpar significantly reduced cholestatic markers of disease and pruritus with a safety profile similar to placebo (primary analyses at month 3 in ENHANCE and month 12 in RESPONSE). Here, we present pooled safety data from these studies in a subgroup of patients with cirrhosis and clinical signs of PHT. Method: Pts 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 placebo, seladelpar 5 mg, or seladelpar 10 mg for up to 52 weeks in ENHANCE and 2:1 to daily 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. Pts with cirrhosis were identified as having signs of PHT at baseline (BL) if they had thrombocytopenia (platelet count < 140 × 103 μL), low albumin, elevated TB, or medical history of varices or ascites. Data are reported for the seladelpar (5 mg and 10 mg) and placebo groups. Results: Among 56 pts with a diagnosis of cirrhosis at BL across the two studies, 27 had signs of PHT at BL (21 pts on seladelpar [15 21 on 10 mg] and 6 placebo). The majority of pts were female (85%) and White (89%), with a mean (range) age of 55.6 (33–74) years, and BL 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%) pts on placebo and 15 21 (71%) pts on seladelpar experienced an adverse event (AE); 2 6 (33%) pts on placebo and 1 21 (5%) pts on seladelpar discontinued treatment due to AEs. Serious AEs occurred in 1 6 (17%) pts on placebo and 1 21 (5%) pts on seladelpar and deemed unrelated to study drug. Liver-related AEs by a predefined search strategy were similar across pts 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 pts and 1 21 (5%) seladelpar treated pts. Conclusion: In this pooled analysis of pts 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.

Volume

82

First Page

S230

Last Page

S231

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