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/m 2 . 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.

Novel therapeutic targets for cholestatic and fatty liver disease

“…167 Of note, in patients with PBC with inadequate response to UDCA 16 weeks of saroglitazar treatment improved the primary endpoint ALP. 168 The dual PPARα/δ agonists elafibranor showed beneficial effects on NASH resolution in a post-hoc analysis (with modified endpoint criteria) of the phase 2b GOLDEN-505 study, 169 but had no significant impact on the main endpoint of NASH resolution without an increase in fibrosis in the phase 3 RESOLVE-IT trial. 170 Elafibranor has also shown first results with improvement of cholestatic liver enzymes in patients with PBC not responding to UDCA 171 (table 1).…”

“…PBC (phase 3, open label) 168 : 16 weeks of saroglitazar (in addition to UDCA) improved serum ALP (primary endpoint) and γGT levels.…”

“… 167 Of note, in patients with PBC with inadequate response to UDCA 16 weeks of saroglitazar treatment improved the primary endpoint ALP. 168 …”

“…► In NASH patients with T2DM 36 months treatment was associated with resolution of NASH and improvement in individual histological scores, including fibrosis; improved hepatic fat content (MR-PDFF) and adipose tissue, hepatic and muscle insulin sensitivity. Side effects: weight gain80 168. : 16 weeks of saroglitazar (in addition to UDCA) improved serum ALP (primary endpoint) and γGT levels.Saroglitazar:► NASH (phase 2)165 : improved ALT, liver fat content (MRI-PDFF), insulin resistance and atherogenic disorders over 16 weeks.…”

Clinical characterization of patients with primary biliary cholangitis: A report from multiple Canadian centres

“…The median age of patients was 61.3 years at last visit: 20.5% of patients were above 70 years of age, 34.9% were between 60-69 years of age, 30.8% were between 50-59 years of age, being investigated (22). Other molecules, including non-steroidal FXR agonists (23)(24)(25) as well as other PPAR agonists (26)(27)(28) are also in development for the treatment of PBC.…”