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

Following the US Food and Drug Administration's (FDA) decision to grant Priority Review to the new drug application (NDA) for saroglitazar in primary biliary cholangitis (PBC), 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

HCPLive: 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?

Raj Vuppalanchi, MD: 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.

HCPLive: 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?

Vuppalanchi: 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.

HCPLive: 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?

Vuppalanchi: 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.

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

Vuppalanchi: 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.

HCPLive: 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?

Vuppalanchi: 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.

HCPLive: 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?

Vuppalanchi: 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.

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. 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

2. Liu BD, Qureshi K. Secondary Treatment of Primary Biliary Cholangitis: Early Prediction of Inadequate Response to Ursodeoxycholic Acid in Patients with PBC. Digestive Diseases and Sciences. 2022;68(2):346-348. doi:https://doi.org/10.1007/s10620-022-07661-y