Proof-of-concept study to evaluate the safety and efficacy of saroglitazar in patients with primary biliary cholangitis

Raj Vuppalanchi, Stephen H. Caldwell, Nikolaos Pyrsopoulos, Andrew S. deLemos, Simona Rossi, Cynthia Levy, David S. Goldberg, Edward A. Mena, Aasim Sheikh, Ravi Ravinuthala, Farheen Shaikh, James D. Bainbridge, Deven V. Parmar, Naga P. Chalasani

Research output: Contribution to journalArticlepeer-review

Abstract

Background & Aim: Saroglitazar is a novel peroxisome proliferator-activated receptor (PPAR) agonist with dual agonistic properties (α/γ). Due to a strong mechanistic rationale, we aimed to test the safety and efficacy of saroglitazar in patients with primary biliary cholangitis (PBC) who were either ursodeoxycholic acid (UDCA) resistant or intolerant. Methods: In this double-blind, phase II proof-of-concept trial, 37 patients with PBC were randomized to saroglitazar 4 mg (n = 13), saroglitazar 2 mg (n = 14), or placebo (n = 10) daily for 16 weeks. The primary efficacy endpoint was the reduction in alkaline phosphatase (ALP) level at Week 16. Results: A significant reduction of mean ALP levels was observed at Week 16 relative to baseline in both the saroglitazar 4 mg (least-squares [LS] mean =-163.3 U/L, SE = 25.1, p <0.001) and 2 mg (LS mean =-155.8 U/L, SE = 24.4, p <0.001) groups, compared with placebo (LS mean =-21.1 U/L, SE = 28.9). Treatment with saroglitazar resulted in a rapid reduction of ALP concentration at Week 4 that was sustained through the study duration. At least 1 treatment-emergent adverse event occurred in 11 (84.6%) patients in the saroglitazar 4 mg group, in 12 (85.7%) patients in the 2 mg group and in 8 (80%) patients in the placebo group. Study drug was discontinued in 4 patients (3 patients in the 4 mg group and 1 patient in the 2 mg group) due to aminotransferase increases that promptly returned to baseline values after drug discontinuation. Conclusions: Saroglitazar at 2 mg and 4 mg daily was tolerated and resulted in rapid and sustained improvements in ALP. Further studies are underway at a daily dose of 2 mg and 1 mg due to the higher incidence of elevated liver enzymes observed with the 4 mg dose. ClinicalTrials.gov Identifier: NCT03112681 Lay summary: Saroglitazar resulted in a rapid and sustained improvement in alkaline phosphatase levels in patients with primary biliary cholangitis. The mean percentage reductions in alkaline phosphatase levels were 49% and 51% in the saroglitazar 4 mg and 2 mg groups compared to 3% in the placebo group.

Original languageEnglish (US)
Pages (from-to)75-85
Number of pages11
JournalJournal of Hepatology
Volume76
Issue number1
DOIs
StatePublished - Jan 2022

Keywords

  • biochemical response
  • dyslipidemia
  • Peroxisome proliferator-activated receptor
  • pruritus
  • ursodeoxycholic acid

ASJC Scopus subject areas

  • Hepatology

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