Primary biliary cholangitis (PBC) is a chronic liver disease that causes inflammation in the bile ducts, which can eventually lead to cirrhosis if left untreated. While therapies like ursodeoxycholic acid (UDCA) and obeticholic acid (OCA) are available, many patients, especially those with cirrhosis, do not respond effectively to these treatments.
That’s why the phase 3 placebo-controlled RESPONSE trial investigated the efficacy and safety of seladelpar, a new PPAR-delta agonist, in PBC patients who had not responded sufficiently to standard therapies.
Background and Study Design
This study enrolled 193 patients with PBC, 27 had compensated cirrhosis at the start. Cirrhosis was identified based on medical history, liver stiffness measurements (>16.9 kPa), lab results, and imaging. Participants were randomly assigned (2:1 ratio) to receive either 10 mg of seladelpar or a placebo daily for 12 months.
The primary goal was to measure changes in alkaline phosphatase (ALP), which is a marker of liver bile duct function, alongside other indicators like gamma-glutamyl transferase (GGT), alanine aminotransferase (ALT), and total bilirubin (TB). Researchers also monitored safety and adverse events throughout the study.
Results in Patients with Cirrhosis
At baseline, patients with cirrhosis had more severe liver function issues, with higher levels of ALP (345.8 U/L), TB (0.97 mg/dL) and liver stiffness (18.8 kPa) compared to those without cirrhosis. After 12 months of treatment, seladelpar significantly improved liver function in cirrhotic patients, with ALP levels dropping by an average of -121.4 U/L compared to -23.2 U/L in the placebo group.
GGT and ALT levels also showed noticeable declines in the seladelpar group. Importantly, no cirrhotic patients discontinued seladelpar due to adverse events, and there were no concerning elevations in ALT or aspartate aminotransferase (AST) beyond three times the upper limit of normal (ULN).
Results in Patients Without Cirrhosis
In patients without cirrhosis, seladelpar similarly produced significant improvements in ALP, with an average reduction of -134.8 U/L compared to -18.0 U/L in the placebo group. As in the cirrhotic group, seladelpar was well-tolerated, with a safety profile comparable to placebo.
Across the entire trial population, elevated ALT or AST levels exceeding three times the ULN were observed in just 5.6 percent of seladelpar-treated patients, compared to 22.2 percent in the placebo group.
Conclusion
The RESPONSE trial demonstrated that seladelpar effectively and safely reduces biomarkers of cholestasis and liver damage in patients with PBC, regardless of whether they have cirrhosis. This is particularly encouraging for patients with cirrhosis, who often have more severe disease and fewer effective treatment options.
By lowering ALP and improving other liver markers, seladelpar shows promise as a therapeutic option for PBC patients who do not respond well to current therapies. These findings underscore seladelpar’s potential as a second-line treatment for PBC, addressing an important unmet need.
Reference:
Villamil A, Younes Z, Bowlus C, et al. Efficacy and safety of seladelpar in patients with primary biliary cholangitis and compensated cirrhosis in the phase 3 placebo-controlled RESPONSE trial. The Liver Meeting 2024 Abstracts. Abstract 0164; 2024.
The RESPONSE trial assessed the efficacy and safety of seladelpar in patients with primary biliary cholangitis (PBC), including those with compensated cirrhosis who had suboptimal responses to existing therapies. Here’s an essential recap of the findings.