Seladelpar Efficacious for Patients with PBC and Compensated Cirrhosis

Selective PPAR-delta agonist seladelpar (Livdelzi) was associated with significantly improved measures of cholestasis and liver injury among patients with primary biliary cholangitis (PBC) compensated cirrhosis, according to interim, long-term data from the phase 3 ASSURE trial.¹

In research presented at the American College of Gastroenterology (ACG) 2024 Scientific Sessions in Philadelphia, PA, this week, a team of US investigators supported by Gilead reported that seladelpar may be an effective, safe, and tolerable treatment for patients with PBC and compensated cirrhosis.

The US Food and Drug Adminsitration (FDA) approved seladelpar for the treatment of patients with PBC on an accelerated regulatory pathway this August; the approval was supported by topline findings from the RESPONSE trial that which showed about two-thirds (62%) of patients treated with the agent achieved composite biochemical response at 12 months—a tripled rate versus the placebo arm (20%). At the time of the indication, Gilead stated seladelpar was the only marketed US treatment for PBC that has shown statically significantly improved measures in key biomarkers, alkaline phosphatase (ALP) normalization and pruritus symptoms versus placebo.²

In the phase 3, international, open-label ASSURE data presented at ACG, investigators led by Stuart C. Gordon, MD, of the Creighton University School of Medicine, presented interim efficacy and safety results in patients with both PBC and compensated cirrhosis receiving the newly regulated therapy.¹

Eligible patients in the trial had been selected from prior seladelpar clinical research if they had an inadequate response or intolerance to ursodeoxycholic acid (UDCA) and had no history of hepatic decompensation. The participants in RESPONSE received daily oral 10 mg seladelpar for open-label assessment.

At the time of data cutoff on June 29, 2023, the team had enrolled 174 patients from 4 prior seladelpar studies, including the ENHANCE trial. Among them, 33 (18.9%) had compensated cirrhosis at the time of study entry.

Gordon and colleagues sought efficacy endpoints including composite response to ALP <1.67 times the upper limit of normal (ULN); ALP decreases of ≥15%; total bilirubin ≤ULN; ALP normalization; and change from baseline in ALP, total bilirubin, gamma-glutamyl transferase (GGT), alanine aminotransferase (ALT), and asparate aminotransferase (AST) at 12 months.

Among the patients with PBC and compensated cirrhosis, 30 (91%) were female; mean age was 60.4 years old. Another 8 (24.2%) patients had portal hypertension, 93.9% were Child-Pugh (CP) class A, and 6.1% were CP-B. At baseline, mean liver stiffness was 19.3 kPa, mean ALP was 241.9 U/L, total bilirubin was 0.92 mg/dL—27.3% greater than ULN.

Through the data cutoff date, 23 patients with compensated cirrhosis had completed 12 months of treatment. More than half (n = 12 [52.2%]) met the composite biochemical endpoint at 12 months. Another 9 (39.1%) patients achieved ALP normalization, and mean percent change in ALP was -38.1% from baseline.

The team additionally reported reductions in GGT and ALT (-35.1% and -19.6%, respectively) from baseline to 12 months. However, no significant changes in AST nor total bilirubin were observed.

Overall, the treatment was safe and tolerable, with no liver- nor drug-related serious adverse events nor discontinuations reported in patients. The team concluded their findings are supportive of perhaps expanded indications for seladelpar in the spectrum of cholestatic liver disease patients.

“In this interim analysis, PBC patients with compensated cirrhosis treated with seladelpar 10 mg for 12 months achieved meaningful improvements in cholestasis and markers of liver injury; seladelpar was safe and well tolerated,” investigators wrote. “These findings suggest that seladelpar may offer a safe and effective therapy for PBC patients with compensated cirrhosis.”

References

1. ^{Gordon SC, Jacobsen I, Younes ZH, Silveira M, et al. Efficacy and Safety of Seladelpar in Patients With Primary Biliary Cholangitis and Compensated Liver Cirrhosis in the Open-Label, Long-Term ASSURE Safety Study: Interim Results. Abstract presented at: American College of Gastroenterology (ACG) 2024 Scientific Sessions. Philadelphia, PA. October 25 – 30, 2024.}
2. ^{Brooks A. FDA Grants Accelerated Approval to Seladelpar (Livdelzi) for Primary Biliary Cholangitis. HCPLive. Published August 14, 2024. https://www.hcplive.com/view/fda-grants-accelerated-approval-to-seladelpar-livdelzi-for-primary-biliary-cholangitis}