Open‐label, clinical trial extension: Two‐year safety and efficacy results of seladelpar in patients with primary biliary cholangitis

Abstract

SummaryBackgroundSeladelpar is a potent and selective peroxisome proliferator‐activated receptor‐δ agonist that targets multiple cell types involved in primary biliary cholangitis (PBC), leading to anti‐cholestatic, anti‐inflammatory and anti‐pruritic effects.AimsTo evaluate the long‐term safety and efficacy of seladelpar in patients with PBC.MethodsIn an open‐label, international, long‐term extension study, patients with PBC completing seladelpar lead‐in studies continued treatment. Seladelpar was taken orally once daily at doses of 5 or 10 mg with dose adjustment permitted for safety or tolerability. The primary analysis was for safety and the secondary efficacy analysis examined biochemical markers of cholestasis and liver injury. The study was terminated early due to the unexpected histological findings in a concurrent study for non‐alcoholic steatohepatitis, which were subsequently found to predate treatment. Safety and efficacy data were analysed through 2 years.ResultsThere were no serious treatment‐related adverse events observed among 106 patients treated with seladelpar for up to 2 years. There were four discontinuations for safety, one possibly related to seladelpar. Among 53 patients who completed 2 years of seladelpar, response rates increased from years 1 to 2 for the composite endpoint (alkaline phosphatase [ALP] <1.67 × ULN, ≥15% decrease in ALP, and total bilirubin ≤ULN) and ALP normalisation from 66% to 79% and from 26% to 42%, respectively. In those with elevated bilirubin at baseline, 43% achieved normalisation at year 2.ConclusionsSeladelpar was safe, and markedly improved biochemical markers of cholestasis and liver injury in patients with PBC. These effects were maintained or improved throughout the second year. Clinicaltrials.gov: NCT03301506; Clinicaltrialsregister.eu: 2017‐003910‐16.

Editorial: The evolving paradigms and treatments for primary biliary cholangitis

“…Mayo et al 7 have reported the 2‐year safety and efficacy results of an open‐label LTSE study with seladelpar in subjects with PBC who completed 1 year in phase 2 ( n = 104) and phase 3, ENHANCE study ( n = 2) 8,9 . Although 106 subjects were enrolled, only 53 completed 2 years in the study: 79% achieved the composite endpoint (ALP < 1.67 × ULN, >/=15% ALP decrease and normal total bilirubin) with 40% achieving ALP normalisation.…”

Exploring Advanced Therapies for Primary Biliary Cholangitis: Insights from the Gut Microbiota–Bile Acid–Immunity Network

“…Other PPAR ligands such as seladelpar (MBX-8025), elafibranor (GFT-505), and saroglitazar are also currently undergoing investigation. Seladelpar is a selective PPARδ agonist, with reported safety and efficacy in improving liver biochemical response and alleviating pruritus in PBC patients [81][82][83][84]. In a recently published phase 3 clinical trial, seladelpar demonstrated significant improvements compared to placebo in terms of biochemical response, normalization of alkaline phosphatase, and alleviation of itching [111].…”

The treatment of primary biliary cholangitis: from shadow to light

“… 99 After 24 months of treatment, the number of patients responding to seladelpar increased from 66% to 79% and the number of patients with normalization of ALP levels increased from 26% to 42%. 100 Seladelpar relieves itching and lowers bile acid and IL-31 levels. 101 Seladelpar at a dose of 5/10 mg also improves sleep and fatigue in patients with PBC.…”