Looking Beyond ALP Response in PBC With Saroglitazar, With Raj Vuppalanchi, MD

As saroglitazar moves closer to a potential approval decision from the US Food and Drug Administration (FDA) for primary biliary cholangitis (PBC), hepatology expert Raj Vuppalanchi, MD, is encouraging clinicians to look beyond alkaline phosphatase (ALP) reduction alone when assessing treatment success.

In an interview with HCPLive, Vuppalanchi, professor of medicine, director of hepatology, and associate program director at Indiana University School of Medicine, suggested that biochemical improvement should be considered alongside broader measures of disease control.

"It is very important that we optimize our treatment strategies to biochemical response, not just to see the improvement in alkaline phosphatase, but also to make sure that there is no ongoing damage to the bile ducts, and there is no ongoing fibrosis," Vuppalanchi told us.

For more from Vuppalanchi, check out part 1 of our interview, where he discusses the mechanism of action behind saroglitazar and the clinical rationale supporting its development in PBC.

The comments come following the FDA's acceptance of the new drug application (NDA) for saroglitazar, a dual peroxisome proliferator-activated receptor (PPAR)-alpha and PPAR-gamma agonist being evaluated in patients with PBC who have an inadequate response to or intolerance of ursodeoxycholic acid (UDCA). The agency granted Priority Review and assigned a Prescription Drug User Fee Act (PDUFA) target action date of November 27, 2026.

Looking Beyond ALP in PBC Management

PBC is a chronic autoimmune cholestatic liver disease characterized by progressive destruction of the intrahepatic bile ducts. Without adequate disease control, ongoing cholestatic injury can lead to fibrosis, cirrhosis, liver failure, and the need for transplantation. Although UDCA remains the standard first-line therapy, approximately 30-40% of patients fail to achieve an adequate biochemical response, leaving them at increased risk for disease progression.³⁻⁴

For decades, ALP has served as the principal surrogate marker of treatment response in both clinical trials and routine practice. Lower ALP levels have been consistently associated with improved transplant-free survival and reduced risk of liver-related complications. However, Vuppalanchi suggested clinicians should view biochemical improvement within the broader context of disease control.

Notably, EPICS-III employed a composite biochemical response endpoint rather than ALP normalization alone. Response was defined as ALP <1.67 times the upper limit of normal (ULN), at least a 15% reduction from baseline ALP, and total bilirubin ≤ULN at week 52.²

The trial met its primary endpoint, with 56.7% of patients receiving saroglitazar achieving composite biochemical response compared with 9.8% of patients receiving placebo, representing a treatment difference of 48.0% (95% Confidence Interval [CI], 35.3 to 60.8; P <.001).²

Among patients with baseline ALP ≤3× ULN, response rates were 83.1% with saroglitazar versus 14.7% with placebo, suggesting particularly robust activity in this subgroup.²

Addressing the Gap Between Monitoring and Treatment Escalation

Beyond defining treatment success, Vuppalanchi highlighted a challenge frequently encountered in clinical practice: patients who experience some improvement with UDCA but fail to achieve accepted biochemical targets may not consistently receive additional therapy.

"There are many patients where liver tests seem to improve, but do not achieve the thresholds that we would like to achieve, but may not be offered the second line treatment," he said.

The issue has become increasingly important as evidence continues to demonstrate that incomplete biochemical response is associated with poorer long-term outcomes. Multiple risk prediction models, including the GLOBE and UK-PBC scores, incorporate biochemical parameters to estimate the likelihood of liver transplantation or liver-related death, underscoring the prognostic significance of achieving treatment targets.⁴⁻⁵

Current second-line treatment options remain limited. Obeticholic acid is approved for patients with an inadequate response to or intolerance of UDCA, although its use has been restricted in patients with advanced cirrhosis due to safety concerns. Additional agents are under investigation as the field seeks therapies capable of improving biochemical response while maintaining tolerability.

If approved, saroglitazar would provide another second-line option with a distinct mechanism of action through dual activation of PPAR-alpha and PPAR-gamma pathways, which are involved in bile acid metabolism, inflammation, and lipid regulation.²

Safety Findings and Remaining Questions

Safety findings from EPICS-III were generally consistent with prior experience with saroglitazar. Most treatment-emergent adverse events were mild to moderate in severity. Serious adverse events occurred in 6.3% of patients receiving saroglitazar and 11.1% of patients receiving placebo, although the study was not powered to detect differences in serious event rates between treatment groups.²

The trial also demonstrated a statistically significant improvement in pruritus at week 24, measured by the 5-D Itch Total score. Mean change from baseline was -5.9 with saroglitazar compared with -2.7 with placebo, yielding a treatment difference of -3.2 (95% CI, -5.66 to -0.82; P = .009).²

However, this difference was not maintained through week 52, when changes from baseline were -4.6 and -4.4, respectively. As a result, the long-term clinical significance of the early antipruritic signal remains uncertain.

"We need to ensure that patients are not only improving their liver tests, but that we are truly controlling the disease process and preventing long-term complications," Vuppalanchi said.

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. PR Newswire. Published May 28, 2026. Accessed June 10, 2026.

2. Vuppalanchi R. EPICS-III: phase 2b/3 trial of saroglitazar in primary biliary cholangitis. Presented at: EASL Congress; May 30, 2026; Barcelona, Spain.

3. Liu BD, Qureshi K. Secondary treatment of primary biliary cholangitis: early prediction of inadequate response to ursodeoxycholic acid in patients with PBC. Dig Dis Sci. 2023;68(2):346-348. doi:10.1007/s10620-022-07661-y

4. Lammers WJ, Hirschfield GM, Corpechot C, et al. Development and validation of a scoring system to predict outcomes of patients with primary biliary cirrhosis receiving ursodeoxycholic acid therapy. Gastroenterology. 2015;149(7):1804-1812.e4. doi:10.1053/j.gastro.2015.07.061

5. Carbone M, Sharp SJ, Flack S, et al. The UK-PBC risk scores: derivation and validation of a scoring system for long-term prediction of end-stage liver disease in primary biliary cholangitis. Hepatology. 2016;63(3):930-950. doi:10.1002/hep.28017