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

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. 

https://www.hcplive.com/view/fda-grants-accelerated-approval-to-elafibranor-iqirvo-for-pbc

Articles

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.