Seladelpar extends benefit to PBC patients with compensated liver cirrhosis

An interim analysis of the open-label phase III ASSURE study finds benefit in seladelpar, a novel delpar (a potent and selective PPAR*-delta agonist), for individuals with primary biliary cholangitis (PBC) and compensated liver cirrhosis.

“In PBC patients with cirrhosis from the ongoing ASSURE long-term extension study, treatment with seladelpar led to clinically meaningful improvements in markers of cholestasis with a durable effect up to 2 years, and improved markers of liver injury,” said Dr Stuart Gordon from Henry Ford Health, Detroit, Michigan, US, during his presentation at EASL 2024.

Of the patients with cirrhosis (n=35), two-thirds achieved rapid and durable composite** biochemical response by month 6. While this dropped to 56 percent by month 12, Gordon noted that the response was durable for the most part and was maintained among those who made it up until month 24 (65 percent).

About a third of the participants also achieved rapid and durable alkaline phosphatase (ALP) normalization by month 1. By month 6, about half were able to achieve this endpoint, and this effect was generally sustained until month 12. [EASL 2024, abstract OS-019]

Reduction in ALP also occurred quite rapidly (by month 1) and was largely maintained throughout the 24-month period. Total bilirubin percent change from baseline was essentially unchanged, noted Gordon.

Percent changes in gamma-glutamyl transferase (GGT) and alanine aminotransferase (ALT) also dropped by the first month and continued to decrease until month 12. Month 18 saw upticks in the GGT and ALT levels, but these mirrored the levels observed at month 1.

Safety profile

Of the 28 participants who reported adverse events (AEs), seven had serious AEs, but there were no treatment-related serious AEs established, Gordon noted. “All serious AEs were observed in individual patients without a particular pattern.”

Five patients had grade 3 AEs, two discontinued treatment owing to AEs, and eight had liver-related AEs. There were three participants who reported muscle-related AEs that mostly involved stiffness or aches, but these, according to Gordon, were not associated with significant elevations in creatine phosphokinase.

“[Among those who had liver-related AEs,] two developed ascites and one had anorectal varices. There were two patients who had aspartate aminotransferase and ALT elevations, but these were not mutually exclusive; patients could have multiple different liver-related events. Three had bilirubin elevations … Importantly, none had drug-induced [liver-related AEs],” Gordon explained.

Three of the liver-related AEs were grade 3, including a case of haematochezia in a patient who had rectal varices and two serious AEs (hepatorenal syndrome and increase in blood bilirubin).

“[Overall,] seladelpar appeared safe and well tolerated in this patient population,” said Gordon.

Unmet need

“There is an unmet need for patients who progress to cirrhosis,” Gordon said. The retention of bile acids within the liver can result in hepatocellular injury, fibrosis, and cirrhosis, putting patients at risk for adverse clinical outcomes. Also, these patients have limited second-line treatments available.

Seladelpar targets multiple cell types and processes in PBC. It improves cholestasis and lipid metabolism and reduces pruritus and markers of inflammation. In the RESPONSE and ENHANCE trials, more patients achieved the composite biochemical endpoint with seladelpar, and this effect was seen in patients with or without cirrhosis. [N Engl J Med 2024;390:783-794; Hepatology 2023;78:397-415]

Gordon and colleagues evaluated a subgroup of patients with cirrhosis (n=35) from the ASSURE Legacy patient population (n=179), which comprised PBC patients who had insufficient response or intolerance to ursodeoxycholic acid. All but three in the cirrhosis subgroup were women, and the mean age was 60.8 years. Overall, ASSURE Legacy participants received oral seladelpar 10 mg QD.

“[Taken together,] these findings suggest that seladelpar has the potential to be a treatment option for PBC patients with compensated cirrhosis,” Gordon concluded.