Defining Elafibranor’s Role in a New Era of PBC Management, With Cynthia Levy, MD

The treatment landscape for primary biliary cholangitis (PBC) has undergone several notable transformations in recent years, among the most significant being the expansion of the second-line treatment armamentarium with the US Food and Drug Administration approvals of 2 novel peroxisome proliferator-activated receptor delta (PPAR) agonists in 2024.

The first of these approvals was for Ipsen’s elafibranor (Iqirvo) and was based on reduction of alkaline phosphatase (ALP) in the multi-center, randomized, double-blind, placebo-controlled phase 3 ELATIVE trial evaluating the efficacy and safety of elafibranor 80 mg once daily versus placebo for the treatment of patients with PBC with an inadequate response or intolerance to ursodeoxycholic acid.

Since its accelerated approval and the subsequent removal of obeticholic acid from the US market, elafibranor has played a pivotal role in second-line treatment for PBC. Now, new > 3-year data from the ongoing ELATIVE open-label extension presented at the American Association for the Study of Liver Diseases (AASLD) The Liver Meeting 2025 demonstrate continued rapid, sustained, and reproducible responses in clinically relevant biomarkers of cholestasis as well as positive effects on cholestasis, sustained improvement in pruritus and fatigue, stabilization of markers of fibrosis, and a consistent safety profile.

For further insight into this new long-term data, the editorial team of HCPLive Hepatology spoke with Cynthia Levy, MD, a professor of medicine in the division of digestive health and liver diseases and the associate director of the Schiff Center for Liver Diseases at the University of Miami, in the following Q&A:

HCPLive: We saw elafibranor added to the PBC 2LT treatment armamentarium last year – what was the significance of this approval? Why are 2LTs so important in the context of PBC?

Levy: PBC is a rare, autoimmune, progressive, cholestatic liver disease, affecting approximately one woman for every 1000 over the age of 40. A build-up of bile and toxins (cholestasis) and chronic inflammation causes irreversible fibrosis (scarring) of the liver and destruction of the bile ducts. It is a life-long condition that can worsen over time if not effectively treated, leading to liver transplant and in some cases, premature death. PBC impacts patient’s daily lives through debilitating symptoms including most commonly pruritus and fatigue.

Elafibranor is an oral, once-daily, peroxisome proliferator-activated receptor (PPAR) agonist, which exerts an effect on PPARα and PPARδ. Activation of PPARα and PPARδ decreases bile toxicity and improves cholestasis by modulating bile acid synthesis, detoxification and transporters. Activation of PPARα and PPARδ also has anti-inflammatory effects by acting on different pathways.

Up to 40% of patients don’t adequately respond to existing first line treatments, putting them at increased risk of liver failure, liver transplantation or even death. In addition, a high percentage of patients (POISE study demonstrated up to 50%) did not respond to obeticholic acid and in some patients, it exacerbated the symptom of pruritus. So, to have elafibranor, a new 2L treatment option, the first in nearly a decade, is an important development for patients where there remains an unmet clinical need.

HCPLive: With obeticholic acid no longer an option for patients in the United States, what role do you see elafibranor playing in the current PBC treatment landscape?

Levy: PBC is a chronic and progressive disease with no cure. Patients with insufficient response from the first line therapy, ursodeoxycholic acid, should be identified early (after 6-12 months of therapy), and started on second line therapy promptly to mitigate disease progression. Elafibranor is an FDA-approved option to be used as second line therapy in PBC. We know from the pivotal phase 3 trial, ELATIVE, that use of elafibranor leads to a rapid and very significant drop in alkaline phosphatase, the primary marker of disease activity in PBC. In that trial, treatment with elafibranor was associated with an improvement in pruritus (itch) as evidenced by a greater reduction in the worst-itch NRS, albeit not statistically significant, and reductions in PBC-40 itch and 5-D itch total scores compared to placebo. The safety profile was favorable, without any signal of hepatic toxicity.

HCPLive: How does the research being presenting at AASLD add to our understanding of the long-term benefits of treatment with elafibranor? What are some of the key findings?

Levy: These long-term data from the ELATIVE study suggest elafibranor could be a potentially transformative therapy for PBC, offering durable and consistent biochemical response, symptom relief, and fibrosis stabilization, with a favorable safety profile.

Data confirm a durable effect of elafibranor on biomarkers of the disease following over three years of treatment. Patients experienced a reduction in ALP of 47% from baseline, which was sustained out to three years of treatment. The proportion of people with ALP normalization stayed consistent, with one in five patients having normal ALP levels at the end of week 182.

Noninvasive markers of fibrosis, including ELF, LSM and proC3, remained stable over 3 years, suggesting the possibility that elafibranor is slowing the progression of fibrosis in this population.

Improvements in patients with moderate to severe fatigue were significant and sustained, with similar results observed for pruritus. There are no new safety findings with long-term treatment of elafibranor, which demonstrates a favorable safety profile.

HCPLive: Did any new safety concerns emerge?

Levy: No. We have data out to 4.5 years and there are no new safety findings with long-term treatment of elafibranor, which demonstrates a favorable safety profile.

HCPLive: Taken as a whole, how do these data add to our confidence in elafibranor in what has been a rapidly evolving PBC treatment landscape?

Levy: PBC does not impact all patients in the same way. It has a heterogeneous presentation, where patients can be asymptomatic and have high risk of disease progression, or have severe symptoms, including debilitating fatigue or pruritus, with a low risk-stratification.

Due to the multifactorial impact of PBC on a person’s life, to have a treatment that demonstrates improvements in both biomarkers of cholestasis and fibrosis, hallmarks of disease progression in PBC, and symptoms of fatigue and pruritus, provides reassurance in our treatment of patients with this condition.

Therefore, these data on elafibranor that I am presenting at the AASLD congress, with over 3 years of efficacy and 4.5 years of safety data, are very encouraging. They demonstrate elafibranor’s potential as a long-term treatment option that not only manages the markers of cholestasis and disease progression but also show a positive impact on symptoms that have such a detrimental effect on people’s quality of life.

Editors’ Note: Levy reports relevant disclosures with Calliditas, CymaBay, Gilead, GSK, Intercept, Ipsen, Mirum, Zydus, and others.

References

1. Brooks A. FDA Grants Accelerated Approval to Elafibranor (Iqirvo) for PBC. HCPLive. June 10, 2025. Accessed November 13, 2025. https://www.hcplive.com/view/fda-grants-accelerated-approval-to-elafibranor-iqirvo-for-pbc

2. Levy C, Akarca U, Alvares-da-Silva MR, et al. Long-term treatment with elafibranor leads to biochemical and symptomatic improvements for at least 3 years in patients with primary biliary cholangitis. Presented at the American Association for the Study of Liver Diseases (AASLD) The Liver Meeting 2025. Washington, DC. November 7-11, 2025.