A Multicenter, Open-Label, Single-Arm Study to Evaluate the Efficacy and Safety of Saroglitazar in Patients With Primary Biliary Cholangitis

Abstract

Introduction: Patients with primary biliary cholangitis (PBC) without biochemical response to ursodeoxycholic acid (UDCA) are at increased risk of liver-related mortality. Saroglitazar is a novel peroxisome proliferator-activated receptor (PPAR) agonist with dual PPAR agonistic properties (α/γ). There is a strong mechanistic rationale for studying saroglitazar in PBC because PPARα is a molecular target of fibrates that showed improvements in liver tests in patients with PBC.

Methods: In this 16-week, open-label, phase 3 study, 37 patients were screened across 3 clinical centers to enroll 7 patients. All patients received daily dose of saroglitazar 4 mg for 16 weeks in addition to their ongoing treatment with UDCA. The primary efficacy endpoint was the reduction in alkaline phosphatase (ALP) level at week 16 as compared to baseline.

Results: Mean age of the study population was 51.1 ± 10.0 years, all patients were female of Mexican descent, and mean body mass index was 25.5± = 4.8 kg/m2. Six (85.7%) patients reported taking ursodiol at baseline and continued throughout the study with a mean daily dosage of 417 mg. Among these, the daily dosage of UDCA 500 mg in 4 and 250 mg in 2 subjects, respectively. The mean baseline ALP level was 230 ± 103 U/L. The primary efficacy endpoint, mean change (reduction) from baseline in ALP concentration at week 16 based on the modified intent-to-treat population was -94 ± 53 U/L (P = 0.003), corresponding to a reduction of 48 ± 23%. Treatment with saroglitazar 4 mg resulted in a rapid and sustained decrease of ALP levels at week 4 (-84 ± 47 U/L, P = 0.003). Six patients who completed the study achieved mean ALP reduction of at least 40% at week 4 and all subsequent visits.

Discussion: Although the study was terminated because of lack of enrollment, saroglitazar daily for 16 weeks resulted in rapid and sustained improvements in ALP with an acceptable safety profile in patients with PBC.

Trial registration: ClinicalTrials.gov NCT03112681.

Conflict of interest statement

Guarantor of the article: Raj Vuppalanchi, MD.

Specific author contribution: The authors of the study were responsible for data analysis, data interpretation, and manuscript preparation. All authors had full access to the study data and approved the manuscript before submission.

Financial support: Zydus Discovery DMCC funded the study.

Potential competing interests: None to report.

Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.

Figures

Figure 1.

Trends of select liver biochemistries and lipid profile parameters during the study period. (a) Mean changes in ALP and GGT levels from BL at various study visits. Treatment with saroglitazar 4 mg resulted in rapid reduction of ALP concentration at week 4 (mean = −83.9 IU/L, SD = 46.9, P = 0.003) and sustained throughout the duration of treatment. The mean changes in GGT concentration was −69.2 IU/L (SD = 65.7, P = 0.032) and −77.7 IU/L (SD = 28.1, P = 0.001) for week 8 and week 16 which corresponds to a reduction of 49.6% and 60.8% at week 8 and week 12, respectively. (b) Change in ALP and gamma-glutamyl transferase levels compared with baseline at various study visits expressed as percent change from BL. Six patients who completed the study achieved mean ALP reduction of at least 40% at week 4 and all subsequent visits. For 1 patient who discontinued the study after the week 8 assessment, no clinically meaningful changes in ALP concentration were observed at week 8 (mean = 445 IU/L) compared with baseline (mean = 436 IU/L). At week 16, 5 (71.4%) patients were within the ULN in ALP concentration and 6 (85.7%) patients were within 1.67 × ULN. (c) Mean total bilirubin levels (mg/dL) at various study visits. (d) Mean changes in lipid panel parameters at week 16 as compared to baseline. At week 16, the mean reduction in total cholesterol was −22 ± 30 mg/dL (P = 0.10), triglycerides was −26 ± 34 mg/dL (P = 0.096), and low-density lipoprotein was −19 ± 28 mg/dL (P = 0.122) which corresponds to a reduction of 10.3%, 21.5%, and 14.0%, respectively. No clinically relevant changes were observed for high-density lipoprotein concentration. ALP, alkaline phosphatase; BL, baseline; GGT, gamma-glutamyl transferase; HDL, high-density lipoprotein; LDL, low-density lipoprotein; ULN, upper limit of the normal.