Zydus reports higher Week 52 biochemical response rates with saroglitazar versus placebo across U.S. and non-U.S. PBC subgroups in EPICS-III.
Written By: Sravani Pamanji, PharmD
Reviewed By: Pharmacally Editorial Team
Zydus Therapeutics announced new findings from a post hoc analysis of its EPICS-III Phase 2b/3 trial on October 12, 2026. The analysis evaluated biochemical responses to investigational saroglitazar magnesium in adults with primary biliary cholangitis (PBC), comparing patients enrolled in the United States with those from other participating countries.
The findings were announced ahead of a late-breaking oral presentation at the American College of Gastroenterology (ACG) 2026 Annual Meeting. They extend the clinical evidence for saroglitazar in patients who respond inadequately to, or cannot tolerate, ursodeoxycholic acid (UDCA).
EPICS-III Trial Design and Analysis
EPICS-III is a randomized, double-blind, placebo-controlled, seamless Phase 2b/3 study. Following dose selection, 148 patients entered the randomized Phase 3 portion and received saroglitazar magnesium 1 mg or placebo in a 2:1 allocation. The 1 mg dose corresponds to 0.97 mg saroglitazar and 0.03 mg magnesium.
The U.S. subgroup included 28 patients receiving saroglitazar and 14 receiving placebo. The non-U.S. subgroup comprised 69 and 37 patients, respectively, from Argentina, Iceland and Turkey.
The analysis assessed composite biochemical response at Week 52, defined by ALP below 1.67 times the upper limit of normal (ULN), a reduction of at least 15% from baseline, and total bilirubin at or below ULN, with a specified exception for patients with Gilbert’s syndrome.
Biochemical Response Favored Saroglitazar
In the U.S. subgroup, 60.7% of patients receiving saroglitazar achieved the composite biochemical response, compared with none receiving placebo. In the non-U.S. subgroup, response rates were 55.1% and 13.5%, respectively.
The absolute treatment differences were 60.7 percentage points in the U.S. subgroup and 41.6 percentage points in the non-U.S. subgroup.
Both populations showed a favorable response pattern. However, the numerically larger difference in U.S. patients does not establish greater efficacy in that region. The analysis was exploratory, involved relatively small subgroups and does not demonstrate a statistically meaningful difference in treatment effect between regions.
In the overall Phase 3 population, Zydus previously reported Week 52 biochemical response rates of 56.7% with saroglitazar and 9.8% with placebo (p less than 0.001). The subgroup findings are consistent with this overall efficacy signal but should not be interpreted as independent confirmation of efficacy.
ALP Normalization and Changes in ALP
The analysis also assessed ALP normalization, defined as an ALP concentration below 116 U/L at Week 52. The reported treatment differences were 7.7 percentage points in the U.S. subgroup and 9.6 percentage points in the non-U.S. subgroup.
Some saroglitazar-treated patients had ALP values close to the normalization threshold. One additional U.S. patient had a level of 117 U/L, while three non-U.S. patients had levels of 118, 119 and 120 U/L. These observations should be distinguished from the composite response endpoint, which does not require complete ALP normalization.
ALP changes from baseline also favored saroglitazar. In U.S. patients, ALP decreased by 104 U/L with saroglitazar but increased by 62.2 U/L with placebo, producing a treatment difference of −166.2 U/L. In non-U.S. patients, ALP decreased by 110.9 U/L with saroglitazar and 6.2 U/L with placebo, a treatment difference of −104.7 U/L.
These numerical differences do not establish regional variation in treatment effectiveness.
Clinical Significance and Safety
PBC is a chronic, progressive autoimmune disease that damages small bile ducts in the liver. Impaired bile flow can cause bile accumulation, contributing to liver injury, fibrosis and cirrhosis, and potentially leading to liver transplantation or death. Fatigue and pruritus are common symptoms, while ALP and bilirubin are important biochemical markers of disease activity.
Saroglitazar is a dual peroxisome proliferator-activated receptor (PPAR) α/γ agonist being investigated for its potential to target bile acid toxicity and liver inflammation. These proposed mechanisms provide a therapeutic rationale but do not establish clinical benefit.
In the overall EPICS-III trial, saroglitazar was generally well tolerated, with adverse events broadly balanced between treatment groups. Pruritus, headache and urinary tract infection were among the commonly reported adverse reactions. The subgroup announcement did not provide separate comparative safety results by geographic region.
Regulatory Status and Next Steps
Saroglitazar remains investigational for PBC and is not FDA-approved for this indication. The FDA has granted Orphan Drug and Fast Track designations, as well as Priority Review for the New Drug Application (NDA). The FDA assigned a Prescription Drug User Fee Act (PDUFA) target action date of November 27, 2026.
Zydus has indicated plans for a potential U.S. launch by March 2027, subject to regulatory approval. The target action date is not a guarantee of approval.
Overall, the subgroup analysis supports a consistent biochemical response signal across geographic populations. However, its exploratory design and limited subgroup sizes constrain interpretation. Further evidence is needed to clarify saroglitazar’s long-term clinical benefits and safety in PBC.
References
Zydus Therapeutics Presents New Post Hoc Analysis of Phase 3 EPICS-III Trial at ACG 2026 Showing Greater Biochemical Response with Investigational Saroglitazar Compared to Placebo Across Geographic Subgroups in PBC, Zydus Therapeutics, 12 October 2026
Saroglitazar Magnesium for Treatment of Primary Biliary Cholangitis (EPICS-III), ClinicalTrials.gov ID NCT05133336
About the Writer
Sravani Pamanji is a PharmD (LinkedIn) professional with experience in scientific writing, medical literature review, drug profile preparation, and clinical case documentation. She has contributed to scientific publication and presented at the 74th Indian Pharmaceutical Congress. Her training includes ICH GCP E6(R3), scientific research, and medication safety. She is passionate about evidence-based medical communication and accurate dissemination of clinical and pharmaceutical information.