Seladelpar improves cholestatic, liver injury markers in patients with PBC, cirrhosis

Treatment with seladelpar led to improvements in markers of cholestasis and liver injury in patients with primary biliary cholangitis (PBC) and compensated cirrhosis, according to an additional analysis of the RESPONSE trial presented at DDW 2025.

This phase III trial analysed 193 patients with PBC who were inadequately responsive or intolerant to ursodeoxycholic acid. Of these, 27 patients had cirrhosis at baseline, whereas the remaining 166 patients were not cirrhotic. Participants were randomized to receive either seladelpar 10 mg (18 cirrhotic and 110 noncirrhotic) or placebo (nine and 56, respectively) for 12 months. [DDW 2025, abstract 532]

Among patients with cirrhosis, baseline mean ALP* was 344 U/L, GGT** was 241.2 U/L, and ALT*** was 45.6 U/L in the seladelpar group, while these values were 349.3, 461.9, and 52.6 U/L, respectively, in the placebo group. Baseline mean total bilirubin (TB) was 1 mg/dL in both treatment groups.

At 12 months, seladelpar-treated patients experienced rapid and sustained reductions in ALP levels, irrespective of whether they had cirrhosis (least squares [LS] mean change from baseline, -121.4 vs 23.2 U/L) or not (LS mean change from baseline, -134.8 vs -18.0 U/L) than placebo-treated patients.

Both the cirrhotic and noncirrhotic cohorts treated with seladelpar also had a greater reduction in GGT levels than those treated with placebo at 12 months (LS mean change from baseline, -76.1 vs 10.3 U/L [cirrhotic] and -112.4 vs -23.4 U/L [noncirrhotic]).

There was also a reduction in ALT levels in patients with and without cirrhosis who received seladelpar (LS mean change from baseline, -5.1 vs 1.9 U/L and -12.9 vs -4.7 U/L, respectively) compared with those who received placebo.

In both cohorts, TB levels remained stable at month 12 in the seladelpar group compared with the placebo group (0.17 vs 0.43 mg/dL [cirrhotic] and -0.05 vs -0.02 mg/dL [noncirrhotic]).

Liver stiffness also remained stable over 12 months, regardless of whether the patients had cirrhosis or not, in both treatment groups, said Dr Ziad Younes from Gastro One, Germantown in Tennessee, US.

Of note, only one patient with cirrhosis in the seladelpar group had elevated ALT or AST⁺ (≥3 x ULN) and TB, while two patients in the placebo group did, he added.

“Overall, in patients with PBC and cirrhosis, seladelpar decreased cholestatic and liver injury markers compared with placebo, similar to the effects seen in patients without cirrhosis in the RESPONSE trial,” noted Younes.

Safety

In terms of safety, the rate of adverse events (AEs) was similar between the seladelpar and placebo groups, regardless of the presence (89 percent for both groups) or absence (86 percent vs 84 percent) of cirrhosis.

However, two patients with cirrhosis experienced serious AEs (SAEs) in the seladelpar group, with one patient having a femur fracture and another having coronary artery disease, dyspnoea exertional, and oesophageal varices haemorrhage.

No treatment-related SAEs and AEs leading to treatment discontinuation and death were noted among cirrhotic patients treated with seladelpar.

“Seladelpar appeared safe and well tolerated in patients with PBC and compensated cirrhosis. The AE profile and liver enzyme elevations with seladelpar were similar to those of placebo,” Younes said.