Cynthia Levy, MD, is a professor of clinical medicine and hepatology at the University of Miami Miller School of Medicine.

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:

: 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?

: 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.

 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?

: 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.

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?

: 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.

: 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.

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

: 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.

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

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.

Articles

The treatment landscape for primary biliary cholangitis (PBC) has evolved with the FDA approval of two novel PPAR agonists, including elafibranor, which has become a pivotal second-line treatment. Elafibranor has shown sustained efficacy in reducing alkaline phosphatase and improving symptoms like pruritus and fatigue, with a favorable safety profile over more than three years. The long-term data suggest it may slow fibrosis progression, offering a transformative therapy for PBC patients, especially those with inadequate response to first-line treatments like ursodeoxycholic acid.

Levy explains elafibranor’s role in the PBC 2LT treatment landscape and new long-term ELATIVE open-label extension data presented at AASLD 2025.

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

Credit: University of Miami Miller School of Medicine

New data from the phase 2 ELMWOOD study of elafibranor in patients with 

 are shedding light on the peroxisome proliferator-activated receptor (PPAR) agonist’s safety and tolerability in this patient population.

Study findings were presented at the European Association for the Study of the Liver (EASL) congress and suggest elafibranor may be a potential treatment option for PSC, a chronic liver disease for which none currently exist.

In 2024, elafibranor was granted accelerated US Food and Drug Administration approval for the treatment of of 

 in combination with ursodeoxycholic acid (UDCA) in adults who have an inadequate response to UDCA, or as monotherapy in patients unable to tolerate UDCA.

 Now, the PPAR agonist is being explored in PSC in the randomized, double-blind, placebo-controlled, phase 2 ELMWOOD trial.

The 12 week study enrolled 68 patients with PSC who were randomly assigned to receive either elafibranor 80 mg, elafibranor 120 mg, or placebo. The primary endpoint was the safety and tolerability of elafibranor.

Efficacy results showed patients on elafibranor had significant dose-dependent reductions in alkaline phosphatase, with patients on elafibranor 80 mg and 120 mg experiencing significant reductions at week 12 versus placebo (−103.2 U/L and −171.1 U/L vs +32.1 U/L; 

 <.0001), and improvements observed as early as week 4. Similar findings were observed in other biochemical liver parameters, including alanine aminotransferase and gamma-glutamyl transferase.

Patients on elafibranor also experienced stabilization in Enhanced Liver Fibrosis versus patients on placebo at week 12, and patients on elafibranor 120 mg experienced improvements in pruritus compared with patients on placebo according to the Worst Itch Numeric Rating Scale score (-0.96 vs -0.28; 

Treatment-emergent adverse events were experienced by 68.2%, 78.3% and 69.6% of patients on elafibranor 80 mg, 120 mg, and placebo, respectively. Adverse events leading to treatment discontinuation occurred more commonly in patients on placebo (8.7%) than elafibranor 80 mg (4.5%) or 120 mg (4.3%), and serious adverse events occurred in 4.3% of patients on placebo versus none on elafibranor.

For additional insight into elafibranor’s potential in PSC and the ELMWOOD data, the editorial team of 

 spoke with Cynthia Levy, MD, a professor of clinical medicine and hepatology at the University of Miami Miller School of Medicine, in the following Q&A:

: What unmet need currently exists for effective treatment options in PSC?

: PSC is a rare, progressive liver disease with no approved therapeutic options. Liver transplant remains the only intervention that can meaningfully impact long-term outcomes. Therefore, patients remain at risk for progression to biliary cirrhosis and other complications. This creates a significant unmet need for patients particularly for safe and effective treatments that could simultaneously delay or prevent the need for transplantation and improve quality of life.

: Can you explain elafibranor’s mechanism of action and why we think this might hold value for the treatment of PSC?

: Elafibranor is an oral peroxisome proliferator-activated receptor (PPAR) agonist, which exerts an effect on PPARα and PPARδ. Activation of PPARα and PPARδ can help to downregulate and/or modulate several pathways involved in the disease pathogenesis, including inflammation, fibrosis and bile acid toxicity. These results are encouraging and reinforce elafibranor’s action as a PPARα/δ agonist in potentially treating multiple liver diseases, like PSC, where effective and safe therapies do not currently exist and are much needed.

: How was elafibranor’s potential in PSC explored in the phase 2 ELMWOOD study?

: The ELMWOOD study was a 12-week, double-blind, Phase 2 trial that enrolled patients with large duct PSC and elevated ALP. Patients were randomized 1:1:1 to receive daily oral elafibranor 80 mg, 120 mg, or placebo, stratified by baseline UDCA use. The primary objective was to assess the safety and tolerability of elafibranor, with secondary endpoints evaluating changes in liver biomarkers and pruritus.

: What were some of the key safety and efficacy findings presented at EASL?

: Elafibranor demonstrated a favorable safety profile and dose-dependent efficacy. Both the 80 mg and 120 mg doses significantly reduced key markers of cholestasis and liver injury—including ALP, ALT, and GGT—as early as Week 4. The 120 mg dose also led to a statistically significant reduction in pruritus. Notably, no serious treatment-emergent adverse events (TEAEs) occurred in patients on elafibranor, compared to 4.3% in the placebo group.

In addition, the data showed patients on elafibranor also had stabilization in Enhanced Liver Fibrosis (ELF), a non-invasive marker of liver fibrosis, versus patients on placebo at week 12. This treatment difference was most notable in the subgroup of patients with moderate to severe disease at baseline.

: Did any of these findings stand out to you as particularly surprising or significant?

: Yes, the rapid onset of efficacy was particularly encouraging. Improvements in liver enzymes were evident as early as Week 4, and pruritus relief was observed by Week 12. The overall safety profile was also notable—particularly the absence of serious TEAEs with elafibranor, which supports its continued exploration in this population.

: What are the next steps for continuing to explore elafibranor’s use in PSC?

: Following these promising Phase 2 results, an open-label extension study is underway to evaluate the effects of elafibranor 120 mg over 96 weeks, including its potential impact on liver fibrosis, a very relevant endpoint in PSC.

Editors’ note: Levy has relevant disclosures with Calliditas Therapeutics, Cara Therapeutics, CymaBay Therapeutics, GENFIT, Gilead Sciences, GlaxoSmithKline, HighTide Therapeutics, Intercept Pharmaceuticals, Ipsen, Mirum Pharmaceuticals, Novartis, Target RWE, and Zydus Lifesciences.

Ipsen. Late-breaking elafibranor primary sclerosing cholangitis (PSC) data demonstrates favorable safety profile and significant efficacy in second potential rare liver disease indication. April 24, 2025. Accessed May 14, 2025. 

https://www.ipsen.com/press-releases/late-breaking-elafibranor-primary-sclerosing-cholangitis-psc-data-demonstrates-favorable-safety-profile-and-significant-efficacy-in-second-potential-rare-liver-disease-indication-3067100/

Brooks A. FDA Grants Accelerated Approval to Elafibranor (Iqirvo) for PBC. 

Elafibranor, a PPAR agonist, shows promise as a treatment for primary sclerosing cholangitis (PSC), a chronic liver disease lacking approved therapies. The phase 2 ELMWOOD study demonstrated its safety and efficacy, with significant dose-dependent reductions in alkaline phosphatase and improvements in liver biomarkers and pruritus. The study reported no serious treatment-emergent adverse events with elafibranor, contrasting with the placebo group. An open-label extension study is underway to further explore elafibranor's long-term effects, particularly on liver fibrosis, a critical endpoint in PSC management.

Levy explains the unmet need for effective PSC treatment options and reviews new data from the phase 2 ELMWOOD trial of elafibranor in PSC.