Regional Differences in Saroglitazar Response in PBC, With Raj Vuppalanchi, MD

US patients with primary biliary cholangitis (PBC) showed a numerically larger treatment response to saroglitazar than non-US patients in an exploratory subgroup analysis of the phase 3 EPICS-III trial. The analysis was presented as a late-breaking abstract at the American College of Gastroenterology (ACG) 2026 Annual Scientific Meeting in Nashville, Tennessee.1

For the primary composite biochemical end point, the treatment difference versus placebo was 60.7 percentage points in the US and 41.6 percentage points outside the US.1

Saroglitazar is a dual peroxisome proliferator-activated receptor (PPAR)-α/γ agonist in development as a second-line therapy for patients with PBC and an inadequate response or intolerance to ursodeoxycholic acid (UDCA).1 In the overall trial, presented at the European Association for the Study of the Liver (EASL) Congress 2026, 56.7% of patients receiving saroglitazar magnesium 1 mg achieved biochemical response at week 52, compared with 9.8% receiving placebo (P <.001).2

Raj Vuppalanchi, MD, of Indiana University School of Medicine, told HCPLive the regional analysis was designed to help clinicians weigh which trial data best reflect their own patients. “As clinicians, when we are sitting in front of the patient, we have to look at the need of the patient,” said Vuppalanchi. “We’ll have to look at the data that best represents the patient sitting in front of me.”

How Did Saroglitazar Perform in US vs Non-US Patients?

EPICS-III randomly assigned participants in a 2:1 ratio to saroglitazar magnesium 1 mg or placebo for 52 weeks.1,3 The US subgroup included 28 patients receiving saroglitazar and 14 receiving placebo, and the non-US subgroup included 69 and 37, respectively, enrolled in Argentina, Iceland, and Turkey. Biochemical response was defined as alkaline phosphatase (ALP) < 1.67 times the upper limit of normal (ULN), an ALP decrease of ≥ 15%, and total bilirubin at or below the ULN.1

In the US subgroup, 60.7% (17/28) of saroglitazar recipients achieved biochemical response at week 52, compared with 0% (0/14) of placebo recipients. Outside the US, response rates were 55.1% (38/69) and 13.5% (5/37), respectively.1 Response rates with saroglitazar were similar across regions, and the larger US treatment difference largely reflected the absence of placebo responders in the US subgroup.

The treatment difference in mean ALP change from baseline to week 52 was −166 U/L in the US subgroup vs −105 U/L outside the US.¹ ALP normalization occurred in 7.1% (2/28) of US and 8.7% (6/69) of non-US saroglitazar recipients, compared with 0% of placebo recipients in both regions.1

How Did Baseline Characteristics and Pruritus Differ by Region?

Baseline demographic and disease characteristics were generally comparable between subgroups. Median baseline ALP was modestly higher in the US subgroup (302 vs 287 U/L), and Hispanic or Latino ethnicity was more common outside the US (44.9% and 43.2% vs 10.7% and 28.6% across arms).¹ All non-US participants were White.1

Among participants with moderate to severe pruritus at baseline, the 5-D itch score treatment difference at week 24 was −4.4 points in the US subgroup vs −2.8 points outside the US.¹ At week 52, the difference was −1.7 points outside the US, while the US difference shifted to +2.5 points, favoring placebo.1

Vuppalanchi described pruritus as a key extrahepatic target in PBC, alongside fatigue and sleep. He said itch can disrupt sleep, which in turn affects fatigue and quality of life for patients and caregivers.

What Did Safety Data Show, and What Comes Next?

Saroglitazar was well tolerated across regions.¹ No patients met Hy’s law criteria, and there were no cases of drug-induced liver injury or rhabdomyolysis. A total of 5 potential hepatic events occurred (4 with saroglitazar 1 mg, 1 with placebo), and none was considered related to the study drug.1

Vuppalanchi acknowledged post hoc analyses are not tested for statistical significance, so numerical differences can inform clinical judgment or prompt prospective trials.

“I think this brings into the question that disease biology may be different between different patient populations, and it is important for the physician to pick the right drug for their patient to get the best treatment response,” said Vuppalanchi.

Editors’ note: Vuppalanchi reports relevant disclosures with Zydus Therapeutics, Takeda Pharmaceuticals, and Eli Lilly and Company.

References:

1. Vuppalanchi R, deLemos A, Chalasani N, Kumar S, Parmar D. Greater treatment response to saroglitazar in US versus non-US patients with primary biliary cholangitis: a geographic subgroup analysis of the phase 3 EPICS-III trial. Presented at: American College of Gastroenterology 2026 Annual Scientific Meeting; October 9-14, 2026; Nashville, TN.

2. Vuppalanchi R, Villamil A, Yilmaz Y, et al. A phase 2b/3 trial of saroglitazar magnesium in primary biliary cholangitis (EPICS III). Abstract LB265134. Presented at: EASL Congress; May 30, 2026; Barcelona, Spain.

3. ClinicalTrials.gov identifier: NCT05133336. Accessed October 13, 2026. https://clinicaltrials.gov/study/NCT05133336