Raj Vuppalanchi, MD, is a Professor of Medicine, Director of Hepatology, and Associate Program Director at the Indiana University School of Medicine.

Raj Vuppalanchi, MD

decision to grant Priority Review to the new drug application (NDA) for saroglitazar in

, HCPLive spoke with Raj Vuppalanchi, MD, Professor of Medicine, Director of Hepatology, and Associate Program Director at the Indiana University School of Medicine, about the growing momentum in the PBC treatment landscape.

In the interview, Vuppalanchi discussed the unmet need that continues to exist for patients who do not achieve an adequate response to ursodeoxycholic acid (UDCA), how saroglitazar's dual peroxisome proliferator-activated receptor (PPAR)-α/γ mechanism may differentiate it from existing therapies, the key findings from the phase 2b/3 EPICS-III trial, and how he expects treatment goals in PBC to evolve as new therapeutic options become available.

HCPLive’s Q&A With Raj Vuppalanchi, MD, Professor of Medicine, Director of Hepatology, and Associate Program Director at the Indiana University School of Medicine

 The FDA's decision to grant Priority Review to saroglitazar highlights growing momentum in the PBC therapeutic pipeline. From your perspective, what has driven the increased focus on innovation in PBC in recent years, and why is this such an important moment for the field?

 Patients with PBC have long suffered due to lack of effective therapies. There's been a first-line treatment option, but many patients do not achieve adequate treatment response, so in recognition of that fact, that this is an unmet need, FDA appropriately granted sponsors the ability to bring in new treatment options to solve this unmet need, and this designation is very much reflective of that.

 Can you tell us a little bit more about saroglitazar's mechanism of action and what differentiates it from currently approved second-line PBC therapies? How might this influence where the therapy could fit into the evolving PBC treatment landscape if approved?

 Saroglitazar has a very unique mechanism of action that is currently not available. It is a PPAR-alpha agonist, which has a very beneficial effect on bile acid homeostasis that is very critical to the pathophysiology of primary biliary cholangitis, and uniquely has PPAR-gamma agonism, which has beneficial effects through the anti-inflammatory and anti-fibrosis pathways.

So combining this unique pathway, we think 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.

 Many patients with PBC continue to have an incomplete biochemical response or intolerance to ursodeoxycholic acid in clinical practice today. Where do you see the greatest unmet need for patients whose disease remains inadequately controlled?

 It's very important that many patients with first-line treatment aim for adequate treatment response. 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 second-line treatment.

"So first of all, there are many eligible patients for second-line treatment, and then comes the option to pick a drug that is effective, safe, tolerable, and affordable. All these aspects are very important to clinicians, and I do think saroglitazar will nicely fit in on the efficacy, safety, and tolerability aspects.

 When evaluating emerging therapies in PBC, how important are endpoints like alkaline phosphatase normalization and biochemical response in shaping clinical decision-making?

 They are very important. As you know, primary biliary cholangitis is an ongoing chronic liver disease where there is progressive destruction of the bile ducts and accumulation of fibrosis, so any marker that is indicative of ongoing disease activity is essentially communicating the fact that there is ongoing damage and loss of bile ducts.

So it is very important that we optimize our treatment strategies to biochemical response, not just to see 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.

 Can you talk a little bit about the key findings from the phase 2b/3 EPICS-III trial that make saroglitazar such a promising option?

 This is a pivotal registrational trial conducted across several centers in the US, as well as centers in Argentina and Turkey. It probably has the most clinical trial participants of Hispanic ethnicity, and we were able to show a treatment response of 56.7% with saroglitazar compared with 9.8% with placebo, giving a treatment difference of 48%. This is statistically significant and a very impressive treatment response.

It also showed alkaline phosphatase normalization of 8.2% compared with zero in the placebo arm. When we look at the treatment response in the US, which may be more relatable to physicians treating patients in the US, we saw a response in the 60% range.

We did not get into the subgroups where, if the alkaline phosphatase is less than three 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 patients and one more choice for treating physicians to personalize the treatment option.

 With multiple emerging therapies entering the PBC pipeline, how do you see the treatment paradigm evolving over the next several years, and what would meaningful progress look like for both clinicians and patients?

 Two parts to this question. First, obviously, more choices are better for the patient and for the treating physician. More choice in picking with regard to efficacy, safety, tolerability, and equally important, access to these treatment options. As a clinician myself seeing patients in the clinic, having a choice is very important. That's fundamental to any practicing physician.

"The second piece is how this helps the treatment paradigm. We would aim for even stricter response rates, complete normalization of alkaline phosphatase, improvement in total bilirubin levels, and associated symptoms like itch and fatigue. We are just at the beginning of this expectation of improving alkaline phosphatase, but very soon I think we will all look beyond ALP levels into other aspects of the disease stat

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.

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

Liu BD, Qureshi K. Secondary Treatment of Primary Biliary Cholangitis: Early Prediction of Inadequate Response to Ursodeoxycholic Acid in Patients with PBC. 

https://doi.org/10.1007/s10620-022-07661-y

Articles

FDA Priority Review for saroglitazar underscores persistent unmet need in primary biliary cholangitis among patients with incomplete biochemical response or intolerance to ursodeoxycholic acid. Dual PPAR-α/γ agonism may provide more comprehensive effects on bile acid homeostasis alongside anti-inflammatory and anti-fibrotic pathways, potentially differentiating it from current second-line options. In EPICS-III, biochemical response and alkaline phosphatase normalization favored saroglitazar versus placebo, including robust responses in US participants. Future goals may shift toward stricter normalization and symptom improvement.

Raj Vuppalanchi, MD, shares insights on saroglitazar, EPICS-III, and the future of personalized treatment for PBC.

Saroglitazar and the Evolving PBC Treatment Landscape, With Raj Vuppalanchi, MD

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.

, 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.

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.

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; 

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 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; 

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.

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

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.

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

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

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

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

Videos

A hepatologist discusses ALP response, fibrosis risk, and treatment optimization in PBC.

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

US Food and Drug Administration’s (FDA)

 Priority Review of the new drug application (NDA) for saroglitazar in 

, 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.

FDA Grants Priority Review to Saroglitazar NDA for Primary Biliary Cholangitis

“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 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.

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.

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.”

An EPICS-III study investigator discusses the mechanism of action of saroglitazar to treat patients with PBC. 