Saroglitazar Targets Bile Acid Dysregulation, Inflammation in PBC, With Raj Vuppalanchi, MD

Following the US Food and Drug Administration’s (FDA) Priority Review of the new drug application (NDA) for saroglitazar in primary biliary cholangitis (PBC), with a Prescription Drug User Fee Act (PDUFA) target action date of November 27, 2026, Raj Vuppalanchi, MD, discusses the therapy’s mechanism of action and the Phase 2b/3 EPICS-III data supporting the application.

“Patients with PBC have long suffered due to lack of effective therapies; there has been a first-line treatment option, but many patients do not achieve adequate treatment response,” Vuppalanchi, a Professor of Medicine, Director of Hepatology, and Associate Program Director at the Indiana University School of Medicine, said in an interview with HCPLive’s content team.

PBC is characterized by impaired bile flow, accumulation of toxic bile acids, and chronic inflammation, resulting in elevations in bilirubin, alkaline phosphatase (ALP), and other markers of liver injury. This process, if left untreated or unresponsive to existing therapies, can lead to progressive hepatic fibrosis and cirrhosis, ultimately resulting in hepatic decompensation and death unless liver transplantation is performed.

Approved therapies for PBC include the first-line agent ursodeoxycholic acid (UDCA) and the second-line agent obeticholic acid (OCA) for patients who are intolerant of or inadequately responsive to UDCA. However, a substantial proportion of patients do not achieve adequate biochemical response, highlighting the ongoing unmet need in this population.

Saroglitazar’s Mechanism of Action

Saroglitazar is a dual peroxisome proliferator-activated receptor (PPAR) agonist that targets both bile acid dysregulation and inflammation in PBC. According to investigators, the therapy reduces the overproduction of toxic bile acids through PPAR-alpha activation while also decreasing inflammatory signaling through PPAR-gamma activity. These combined effects may help reduce liver injury, as reflected by decreases in alkaline phosphatase (ALP) and other liver enzymes.

“We think combining this unique pathway addresses the pathophysiology much more comprehensively, and possibly differentiates itself among the options that are available for patients with primary biliary cholangitis who do not respond to first-line treatment,” Vuppalanchi said.

EPICS-III Methodology and Results

The randomized, double-blind, placebo-controlled EPICS-III trial evaluated saroglitazar in adult patients with PBC who had an inadequate response to or intolerance of UDCA. Results were presented as a late-breaking session at the European Association for the Study of the Liver (EASL) Congress in Barcelona, Spain, on May 30, 2026.

A composite biochemical response was defined as achieving ALP < 1.67 × upper limit of normal (ULN), ≥ 15% decrease in ALP from baseline, and total bilirubin ≤ ULN or direct bilirubin ≤ ULN in patients with known Gilbert’s syndrome at 12 months.

At week 52, saroglitazar met its primary endpoint in 148 patients, demonstrating a treatment difference of -124.1 U/L (-40.1%) in least-squares mean change from baseline in ALP. Patients receiving saroglitazar achieved a -115.4 U/L (-33.5%) reduction from baseline compared with a +8.8 U/L (+6.5%) increase among those receiving placebo.

In total, 56.7% of patients treated with saroglitazar achieved biochemical response compared with 9.8% of patients receiving placebo, a treatment difference of 48% (95% CI, 35.3-60.8; P <.001).

For patients with a baseline ALP ≤ 3 × ULN, biochemical response rates were 83.1% in the saroglitazar group versus 14.7% in the placebo group.

As a secondary endpoint, at week 24, patients treated with saroglitazar experienced a statistically significant reduction in pruritus compared with placebo, with a change from baseline in 5-D Itch Total score of -5.9 versus -2.7, a treatment difference of -3.2 (95% CI, -5.66 to -0.82; P = .009). At week 52, saroglitazar-treated patients experienced a change of -4.6 compared with -4.4 in the placebo group, which was not statistically significant.

Saroglitazar was generally well tolerated in the EPICS-III trial. Most treatment-emergent adverse events were mild to moderate in nature. Serious adverse events were reported in 6.3% of patients in the saroglitazar group versus 11.1% in the placebo group.

Looking Ahead

Discussing the potential impact of a future FDA approval, Vuppalanchi emphasized the importance of identifying which patients may derive the greatest benefit.

“We did not get into the subgroups where if the ALP is < 3 times the upper limit of normal, the treatment response is even higher in the 70% range, but we are hoping that when this treatment is approved and available, it gives one more choice for the patients and one more choice for the treating physicians to personalize the treatment option.”

Editor’s Note: Vuppalanchi reports relevant disclosures with Eli Lilly and Company, Galectin Therapeutics, Takeda, AstraZeneca, Zydus Therapeutics Inc, Gilead Sciences, Kowa Pharmaceuticals, and GlaxoSmithKline.

References:

1. Zydus Therapeutics, Inc. Zydus Therapeutics New Drug Application (NDA) for Saroglitazar to Treat Primary Biliary Cholangitis (PBC) Granted Priority Review by the US FDA. Prnewswire.com. Published May 28, 2026. Accessed June 10, 2026. https://www.prnewswire.com/news-releases/zydus-therapeutics-new-drug-application-nda-for-saroglitazar-to-treat-primary-biliary-cholangitis-pbc-granted-priority-review-by-the-us-fda-302784488.html

2. Liu BD, Qureshi K. Secondary Treatment of Primary Biliary Cholangitis: Early Prediction of Inadequate Response to Ursodeoxycholic Acid in Patients with PBC. Digestive Diseases and Sciences. 2022;68(2):346-348. doi:https://doi.org/10.1007/s10620-022-07661-y