Proof-of-concept study to evaluate the safety and efficacy of saroglitazar in patients with primary biliary cholangitis
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.
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In a placebo-controlled phase 2 RCT, 37 patients with primary biliary cholangitis receiving ursodeoxycholic acid were randomly assigned to receive 4 mg or 2 mg saroglitazar, or placebo.
“In a placebo-controlled phase 2 RCT, 37 patients with primary biliary cholangitis receiving ursodeoxycholic acid were randomly assigned to receive 4 mg or 2 mg saroglitazar, or placebo.”
From Primary biliary cholangitis. (2024) · cites this paper as [101]
Alkaline phosphatase was significantly reduced after 4 weeks of saroglitazar treatment compared with placebo, and this therapeutic effect was sustained during the 16-week treatment period.
“Alkaline phosphatase was significantly reduced after 4 weeks of saroglitazar treatment compared with placebo, and this therapeutic effect was sustained during the 16-week treatment period.”
From Primary biliary cholangitis. (2024) · cites this paper as [101]
Adverse events including liver injury occurred more frequently in the 4 mg saroglitazar group than in the 2 mg group.
“Adverse events including liver injury occurred more frequently in the 4 mg group than in the 2 mg group.101”
From Primary biliary cholangitis. (2024) · cites this paper as [101]
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- Authors
- Vuppalanchi, R., Caldwell, S. H., Pyrsopoulos, N., deLemos, A. S., Rossi, S., Levy, C., Goldberg, D. S., Mena, E. A., Sheikh, A., Ravinuthala, R., Shaikh, F., Bainbridge, J. D., Parmar, D. V., & Chalasani, N. P.
- Affiliations
- Indiana University School of Medicine (US)
- University of Virginia (US)
- Rutgers, The State University of New Jersey (US)
- Einstein Healthcare Network (US)
- University of Miami (US)
- California Liver Research Institute (US)
- Ohio Gastroenterology and Liver Institute (US)
- Indiana University Hospital (US)
- Corresponding author
- Vuppalanchi, Raj
- Chalasani, Naga P.
- ORCID
- Venue
- Journal of Hepatology
- Publisher
- Elsevier BV
- Published
- 2022-01
- Volume
- 76
- Issue
- 1
- Pages
- 75-85
- ISSN
- 0168-8278 (ISSN-L)
- OpenAlex
- W3196850442
- Cited by
- 79
- References
- 13
- Citations by year
- 2026: 13 · 2025: 27 · 2024: 19 · 2023: 12 · 2022: 8
- FWCI
- 5.43
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Hepatology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Keywords
- saroglitazar, primary biliary cirrhosis, alkaline phosphatase, liver enzymes, aminotransferase elevation, drug safety, dose comparison, treatment-emergent adverse events, cholestatic liver disease, drug repurposing
- MeSH terms
- Double-Blind Method, Female, Humans, Liver Cirrhosis, Biliary, Male, Middle Aged, Phenylpropionates, Placebos, Pyrroles, Treatment Outcome
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