Exploratory EPICS-III Trial Analysis Shows Biochemical Responses in U.S. and Non-U.S. Patients With Primary Biliary Cholangitis
Zydus Therapeutics Inc., a wholly owned subsidiary of Zydus Lifesciences Limited, has announced that new analyses from the pivotal EPICS-III Phase 2(b)/3 clinical trial of saroglitazar in adults with primary biliary cholangitis (PBC) will be presented as a late-breaking oral presentation at the American College of Gastroenterology (ACG) 2026 Annual Meeting.
The presentation will feature a post hoc exploratory analysis examining whether treatment responses to saroglitazar were consistent across geographic regions, with a particular focus on patients in the United States compared with those outside the U.S.
Saroglitazar is an investigational therapy currently under review by the U.S. Food and Drug Administration (FDA). Its safety and effectiveness for PBC have not been established by the FDA.
Key Highlights
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Conference presentation: Geographic subgroup findings from the EPICS-III trial will be presented at ACG 2026.
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Higher biochemical response rates: Composite biochemical response rates were 60.7% with saroglitazar versus 0% with placebo in the U.S. subgroup, compared with 55.1% versus 13.5% in the non-U.S. subgroup.
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ALP improvements: Alkaline phosphatase (ALP) levels decreased numerically more with saroglitazar than placebo in both geographic subgroups at Week 52.
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Safety profile: Saroglitazar was generally well tolerated, with adverse events generally balanced between treatment and placebo groups.
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Regulatory status: Saroglitazar is under FDA review for PBC, with a U.S. launch targeted by March 2027 if approved.
EPICS-III: Geographic Subgroup Analysis
The analysis evaluated biochemical responses among participants enrolled in different geographic regions in the EPICS-III trial. The U.S. subgroup included 28 patients treated with saroglitazar and 14 receiving placebo. The composite non-U.S. subgroup included patients from Argentina, Iceland, and Turkey, with 69 receiving saroglitazar and 37 receiving placebo.
Composite Biochemical Response at Week 52
| Outcome | U.S. Subgroup | Non-U.S. Subgroup |
|---|---|---|
| Saroglitazar response rate | 60.7% | 55.1% |
| Placebo response rate | 0% | 13.5% |
| Treatment difference | 60.7 percentage points | 41.6 percentage points |
Composite biochemical response was defined as meeting all of the following criteria at Week 52:
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ALP below 1.67 times the upper limit of normal (ULN).
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At least a 15% reduction in ALP from baseline.
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Total bilirubin at or below ULN, or direct bilirubin at or below ULN in participants with known Gilbert's syndrome.
The analysis found higher composite biochemical response rates with saroglitazar than placebo in both geographic subgroups. The treatment difference was numerically larger in the U.S. subgroup.
Important limitation: This was a post hoc exploratory analysis. The findings should be interpreted cautiously and do not establish that treatment effects differ significantly between geographic regions.
ALP Normalization and Changes From Baseline
The analysis also evaluated ALP normalization and changes in ALP levels at Week 52.
ALP Normalization
The treatment difference in ALP normalization rates was broadly similar between the U.S. and non-U.S. subgroups:
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U.S. subgroup: 7.7 percentage points.
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Non-U.S. subgroup: 9.6 percentage points.
ALP normalization was defined as an ALP level below 116 U/L. One additional U.S. participant receiving saroglitazar had an ALP level of 117 U/L at Week 52 and therefore did not meet the normalization threshold. Three additional participants in the non-U.S. saroglitazar group had ALP levels of 118, 119, and 120 U/L, respectively.
Change in ALP From Baseline at Week 52
| Group | Saroglitazar | Placebo | Treatment Difference |
|---|---|---|---|
| U.S. subgroup | −104 U/L | +62.2 U/L | −166.2 U/L |
| Non-U.S. subgroup | −110.9 U/L | −6.2 U/L | −104.7 U/L |
ALP reductions were numerically greater with saroglitazar than placebo in both subgroups. The treatment difference was larger in the U.S. subgroup.
These results provide additional information about biochemical responses but should be considered within the limitations of the exploratory analysis.
Safety and Tolerability
In the overall EPICS-III trial, saroglitazar was generally well tolerated. Adverse events were generally balanced between participants receiving saroglitazar and those receiving placebo.
The most common adverse reactions reported among saroglitazar-treated participants were:
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Pruritus (itching)
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Headache
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Urinary tract infection
Further interpretation of safety outcomes should be based on the complete clinical trial results and regulatory review.
Investigator Perspective
Raj Vuppalanchi, MD, Professor of Medicine at Indiana University School of Medicine and Global Principal Investigator for EPICS-III, said the findings offer additional insight into biochemical responses observed among patients enrolled in different geographic regions.
He emphasized that the analysis was post hoc and that its findings should be interpreted accordingly, while noting the importance of continuing to evaluate the EPICS-III data to better understand the results across the study population.
Saroglitazar Development Program for PBC
Zydus Therapeutics is developing saroglitazar for adults with PBC who have an inadequate response to ursodeoxycholic acid (UDCA), or as a monotherapy option for patients who cannot tolerate UDCA.
Saroglitazar is a dual peroxisome proliferator-activated receptor (PPAR) alpha/gamma agonist being investigated for its potential effects on bile acid toxicity and liver inflammation.
The therapy has received the following FDA designations for PBC:
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Orphan Drug Designation
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Fast Track Designation
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Priority Review
The company has stated that saroglitazar is under FDA review and that it plans to launch the treatment in the United States by March 2027 if it receives approval.
About Primary Biliary Cholangitis (PBC)
Primary biliary cholangitis is a rare, progressive autoimmune disease that damages the small bile ducts in the liver. This can lead to bile accumulation, liver inflammation, fibrosis, cirrhosis, and, in severe cases, liver transplantation or death.
Common clinical features include:
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Elevated ALP and bilirubin levels.
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Pruritus, or persistent itching.
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Fatigue, which can significantly affect quality of life.
Treatment aims to manage the disease, improve biochemical markers, and reduce the risk of disease progression.
About the EPICS-III Trial
EPICS-III is a multicenter, randomized, double-blind, placebo-controlled, seamless Phase 2(b)/3 trial evaluating the efficacy and safety of saroglitazar in adults with PBC who had an inadequate response to or intolerance of UDCA.
Following dose selection, the Phase 3 portion randomized 148 participants in a 2:1 ratio to receive saroglitazar magnesium 1 mg or placebo. The saroglitazar magnesium formulation contains 0.97 mg of saroglitazar and 0.03 mg of magnesium.
The main trial findings were previously announced and presented at the European Association for the Study of the Liver (EASL) Congress 2026.
About Zydus Therapeutics Inc.
Zydus Therapeutics, a wholly owned subsidiary of Zydus Lifesciences Limited, is a clinical-stage biopharmaceutical company focused on developing treatments for rare and serious liver diseases, including PBC and metabolic dysfunction-associated steatohepatitis (MASH).
The company is headquartered in Pennington, New Jersey. For more information, visit www.zydustx.com.
About Zydus Lifesciences Limited
Zydus Lifesciences Limited is a global healthcare company that discovers, develops, manufactures, and markets a broad range of healthcare therapies.
The group employs more than 30,000 people worldwide, including approximately 1,500 scientists engaged in research and development. Its portfolio spans pharmaceuticals, vaccines, therapeutics, biological products, and new chemical entities.
For more information, visit www.zyduslife.com.
Regulatory disclaimer: Saroglitazar remains investigational for PBC in the United States. The FDA has not approved it for this indication, and its safety and effectiveness have not been established. The geographic subgroup findings are exploratory and should not be interpreted as definitive evidence of differences in treatment effects between regions.
