Safety and efficacy of elafibranor in primary sclerosing cholangitis: The ELMWOOD phase II randomized-controlled trial

Cynthia Levy¹, George F Abouda², Bahri M Bilir³, Alan Bonder⁴, Christopher L Bowlus⁵, Isabel Campos-Varela⁶, Nora Cazzagon⁷, Natasha Chandok⁸, Kuldeep Cheent⁹, Helena Cortez-Pinto¹⁰, Münevver Demir¹¹, Michael T Dill¹², Bertus Eksteen¹³, Jonathan M Fenkel¹⁴, Richard Gilroy¹⁵, Hin Hin Ko¹⁶, Ira M Jacobson¹⁷, Yiannis Kallis¹⁸, Marcelo Kugelmas¹⁹, Velimir Luketic²⁰, Alessandra Mangia²¹, Aldo J Montano-Loza²², Ashis Mukhopadhya²³, Antonio Olveira²⁴, Bhaktasharan C Patel²⁵, Antonello Pietrangelo²⁶, Faruq Pradhan²⁷, Magdalena Salcedo²⁸, Mitchell L Shiffman²⁹, Kathrin Sprinzl³⁰, Rachael Swann³¹, Douglas Thorburn³², Paul J Thuluvath³³, Palak J Trivedi³⁴, Juan Turnes³⁵, Claudia O Zein³⁶, Hugo Gomes da Silva³⁷, Seema Jaitly³⁸, Benjamin Miller³⁶, Claire Milligan³⁸, Aude Tavenard³⁹, Kris V Kowdley⁴⁰

Affiliations

¹ Schiff Center for Liver Diseases, University of Miami, Miami, Florida, USA; Division of Digestive Health and Liver Diseases, University of Miami School of Medicine, Miami, Florida, USA. Electronic address: clevy@med.miami.edu.
² NHS Humber Health Partnership, Hull University Teaching Hospitals NHS Trust, Hull, UK.
³ Advent Health Transplant Institute, Denver, Colorado, USA; Rocky Mountain Gastroenterology, Denver, Colorado, USA.
⁴ Liver Center, Department of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
⁵ Division of Gastroenterology and Hepatology, UC Davis School of Medicine, Sacramento, California, USA.
⁶ Liver Unit, Hospital University Vall d'Hebron, Barcelona, Spain.
⁷ Department of Surgery, Oncology and Gastroenterology, University of Padova, Gastroenterology Unit, University Hospital of Padova, RARE-LIVER ERN, Padova, Italy.
⁸ Department of Medicine, William Osler Health System, Brampton, Ontario, Canada.
⁹ Department of Hepatology, Frimley Health NHS Foundation Trust, Surrey, UK.
¹⁰ Clínica Universitária de Gastrenterologia, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.
¹¹ Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Berlin, Germany.
¹² Department of Gastroenterology, Hepatology, Infectious Diseases & Intoxications, Heidelberg University Hospital, Heidelberg, Germany.
¹³ Aspen Woods Clinic, Calgary, Alberta, Canada.
¹⁴ Division of Gastroenterology & Hepatology, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania, USA.
¹⁵ Division Hepatology and Abdominal Transplantation, Intermountain Health, Murray, Utah, USA.
¹⁶ Division of Gastroenterology and Hepatology, University of British Columbia, Vancouver, British Columbia, Canada.
¹⁷ Division of Gastroenterology and Hepatology, NYU Langone Health, New York City, New York, USA.
¹⁸ Barts Liver Centre, Blizard Institute, Queen Mary University of London, UK.
¹⁹ South Denver Gastroenterology, Englewood, Colorado, USA.
²⁰ VCU School of Medicine, Stravitz-Sanyal Institute for Liver Disease and Metabolic Health, Richmond, Virginia, USA.
²¹ Department of Medical Sciences, IRCCS Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.
²² Division of Gastroenterology and Liver Unit, University of Alberta, Edmonton, Alberta, Canada.
²³ Digestive Disorders Department, Aberdeen Royal Infirmary, Aberdeen, UK.
²⁴ Department of Gastroenterology, Hospital Universitario La Paz, Madrid, Spain.
²⁵ Department of Gastroenterology, UCHealth, Colorado Springs, Colorado, USA.
²⁶ Department of Internal Medicine, University Hospital of Modena, Modena, Italy.
²⁷ Division of Gastroenterology and Hepatology, University of Nebraska Medical Center, Omaha, Nebraska, USA.
²⁸ Liver Unit, Gastroenterology and Hepatology Department, CIBER-Ehd. Hospital General Universitario Gregorio Marañón, Universidad Complutense, Madrid, Spain.
²⁹ Liver Institute of Virginia, Bon Secours Mercy Health, Richmond, Virginia, USA.
³⁰ Goethe University Frankfurt, University Hospital, Department of Gastroenterology & Hepatology, Frankfurt/Main, Germany.
³¹ Queen Elizabeth University Hospital, Glasgow, UK.
³² Sheila Sherlock Liver Centre & UCL Institute for Liver & Digestive Health, Royal Free Hospital, London, UK.
³³ Clinical Professor of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA.
³⁴ National Institute of Health and Social Care Research Birmingham Biomedical Research Centre, Centre for Liver and Gastrointestinal Research, University of Birmingham, Birmingham, UK; Liver Unit, University Hospitals Birmingham, Birmingham, UK.
³⁵ Department of Gastroenterology and Hepatology, Pontevedra University Hospital Complex & Galicia Sur Health Research Institute, Pontevedra, Spain.
³⁶ Ipsen, Cambridge, Massachusetts, USA.
³⁷ Ipsen, Boulogne-Billancourt, France.
³⁸ Ipsen, London, UK.
³⁹ Ipsen, Les Ulis, France.
⁴⁰ Liver Institute Northwest, Seattle, Washington, USA.

PMID: 40350321
DOI: 10.1016/j.jhep.2025.04.025

Safety and efficacy of elafibranor in primary sclerosing cholangitis: The ELMWOOD phase II randomized-controlled trial

Cynthia Levy et al. J Hepatol. 2025.

. 2025 May 8:S0168-8278(25)00252-1.

doi: 10.1016/j.jhep.2025.04.025. Online ahead of print.

Authors

Affiliations

¹ Schiff Center for Liver Diseases, University of Miami, Miami, Florida, USA; Division of Digestive Health and Liver Diseases, University of Miami School of Medicine, Miami, Florida, USA. Electronic address: clevy@med.miami.edu.
² NHS Humber Health Partnership, Hull University Teaching Hospitals NHS Trust, Hull, UK.
³ Advent Health Transplant Institute, Denver, Colorado, USA; Rocky Mountain Gastroenterology, Denver, Colorado, USA.
⁴ Liver Center, Department of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
⁵ Division of Gastroenterology and Hepatology, UC Davis School of Medicine, Sacramento, California, USA.
⁶ Liver Unit, Hospital University Vall d'Hebron, Barcelona, Spain.
⁷ Department of Surgery, Oncology and Gastroenterology, University of Padova, Gastroenterology Unit, University Hospital of Padova, RARE-LIVER ERN, Padova, Italy.
⁸ Department of Medicine, William Osler Health System, Brampton, Ontario, Canada.
⁹ Department of Hepatology, Frimley Health NHS Foundation Trust, Surrey, UK.
¹⁰ Clínica Universitária de Gastrenterologia, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.
¹¹ Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Berlin, Germany.
¹² Department of Gastroenterology, Hepatology, Infectious Diseases & Intoxications, Heidelberg University Hospital, Heidelberg, Germany.
¹³ Aspen Woods Clinic, Calgary, Alberta, Canada.
¹⁴ Division of Gastroenterology & Hepatology, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania, USA.
¹⁵ Division Hepatology and Abdominal Transplantation, Intermountain Health, Murray, Utah, USA.
¹⁶ Division of Gastroenterology and Hepatology, University of British Columbia, Vancouver, British Columbia, Canada.
¹⁷ Division of Gastroenterology and Hepatology, NYU Langone Health, New York City, New York, USA.
¹⁸ Barts Liver Centre, Blizard Institute, Queen Mary University of London, UK.
¹⁹ South Denver Gastroenterology, Englewood, Colorado, USA.
²⁰ VCU School of Medicine, Stravitz-Sanyal Institute for Liver Disease and Metabolic Health, Richmond, Virginia, USA.
²¹ Department of Medical Sciences, IRCCS Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.
²² Division of Gastroenterology and Liver Unit, University of Alberta, Edmonton, Alberta, Canada.
²³ Digestive Disorders Department, Aberdeen Royal Infirmary, Aberdeen, UK.
²⁴ Department of Gastroenterology, Hospital Universitario La Paz, Madrid, Spain.
²⁵ Department of Gastroenterology, UCHealth, Colorado Springs, Colorado, USA.
²⁶ Department of Internal Medicine, University Hospital of Modena, Modena, Italy.
²⁷ Division of Gastroenterology and Hepatology, University of Nebraska Medical Center, Omaha, Nebraska, USA.
²⁸ Liver Unit, Gastroenterology and Hepatology Department, CIBER-Ehd. Hospital General Universitario Gregorio Marañón, Universidad Complutense, Madrid, Spain.
²⁹ Liver Institute of Virginia, Bon Secours Mercy Health, Richmond, Virginia, USA.
³⁰ Goethe University Frankfurt, University Hospital, Department of Gastroenterology & Hepatology, Frankfurt/Main, Germany.
³¹ Queen Elizabeth University Hospital, Glasgow, UK.
³² Sheila Sherlock Liver Centre & UCL Institute for Liver & Digestive Health, Royal Free Hospital, London, UK.
³³ Clinical Professor of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA.
³⁴ National Institute of Health and Social Care Research Birmingham Biomedical Research Centre, Centre for Liver and Gastrointestinal Research, University of Birmingham, Birmingham, UK; Liver Unit, University Hospitals Birmingham, Birmingham, UK.
³⁵ Department of Gastroenterology and Hepatology, Pontevedra University Hospital Complex & Galicia Sur Health Research Institute, Pontevedra, Spain.
³⁶ Ipsen, Cambridge, Massachusetts, USA.
³⁷ Ipsen, Boulogne-Billancourt, France.
³⁸ Ipsen, London, UK.
³⁹ Ipsen, Les Ulis, France.
⁴⁰ Liver Institute Northwest, Seattle, Washington, USA.

PMID: 40350321
DOI: 10.1016/j.jhep.2025.04.025

Abstract

Background & aims: Primary sclerosing cholangitis (PSC) is a rare, chronic liver disease. Elafibranor, a dual peroxisome proliferator-activated receptor-α/δ agonist, was investigated in the phase II ELMWOOD trial (NCT05627362).

Methods: This 12-week, double-blind trial enrolled adults with PSC and alkaline phosphatase (ALP) ≥1.5× the upper limit of normal. The primary endpoint was elafibranor safety vs. placebo. Additional endpoints included relative mean change from baseline in ALP and enhanced liver fibrosis (ELF) score.

Results: A total of 68 participants (male: 54.4%; mean age: 46.3 years; inflammatory bowel disease: 55.9%) were randomized to elafibranor 80 mg (n = 22), elafibranor 120 mg (n = 23), or placebo (n = 23). At baseline, 70.6% were on ursodeoxycholic acid, 48.5% had ELF scores >9.8, and the mean ALP level was 369.5 U/L. At Week 12, rates of treatment-emergent adverse events (TEAEs) and TEAEs leading to discontinuation in participants on elafibranor 80 mg, 120 mg, and placebo were 68.2%, 78.3%, and 69.6%, and 4.5%, 4.3%, and 8.7%, respectively. Serious TEAEs occurred only in participants on placebo (4.3%). Participants on elafibranor 80 mg and 120 mg had reductions in ALP vs. placebo (least squares mean treatment difference [95% CI]: -35.3% [-49.2, -21.4] and -54.7% [-68.3, -41.0], respectively). ALP normalization occurred only in participants on elafibranor 80 mg (9.1%) and 120 mg (17.4%). The LS mean treatment differences (95% CI) in change from baseline in ELF scores in participants on elafibranor 80 mg and 120 mg vs. placebo were -0.19 (-0.52, +0.15) and -0.28 (-0.62, +0.06), respectively.

Conclusions: Elafibranor was well tolerated in people with PSC and associated with greater biochemical improvements over 12 weeks compared with placebo. A greater magnitude of response was observed with elafibranor 120 mg compared with 80 mg.

Impact and implications: For people with primary sclerosing cholangitis (PSC), there is a need for a well-tolerated and effective treatment that will enhance quality of life, prevent disease progression, and improve long-term outcomes. Here, we present results from the double-blind period of the phase II ELMWOOD trial in PSC, wherein elafibranor, a peroxisome proliferator-activated receptor-α/δ agonist, demonstrated a favorable safety profile, provided greater biochemical improvements over 12 weeks compared with placebo, and appeared to stabilize markers of fibrosis and improve pruritus. These findings support larger and longer term investigations of elafibranor to explore its therapeutic potential as a treatment for people with PSC.

Keywords: cholestatic diseases; clinical trial; elafibranor; liver disease; primary sclerosing cholangitis.

PubMed Disclaimer

Conflict of interest statement

Conflicts of interest CLe: Received grants from Calliditas, CymaBay, Escient, Gilead, GlaxoSmithKline, Intercept, Ipsen, Kowa, Mirum, Target RWE and Zydus. GFA: Nothing to disclose. BMB: Nothing to disclose. ABo: Received consulting fees from Alnylam, Chemobab, Cymabay, Ipsen, Intercept and GSK; Received PI grants from Chemobab, Cymabay, Gilead, Ipsen and Mirium; Medical monitor for Pfizer. CLB: Received grants from Calliditas, Chemomab, COUR, CymaBay, Gilead, GlaxoSmithKline, Hanmi, Intercept, Ipsen, Mirum, Novartis, Novo Nordisk, Pliant Therapeutics, Viking and Zydus; Received consulting fees from Chemomab, CymaBay, GlaxoSmithKline, Ipsen, Mirum, NGM Bio and Pliant Therapeutics. IC-V: Received travel grant from Chiesi; Received lecture fees from Astellas and Chiesi. NCa: Received grants or contracts from Orphalan; Received consulting fees from Albireo by Ipsen, Gilead, GlaxoSmithKline, Ipsen and Orphalan; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Advanz, Albireo by Ipsen, Gilead, Ipsen and Orphalan; Received support for attending meeting and/or travel from Albireo, Ipsen and Orphalan. NCh: Nothing to disclose. KCh: Received consulting fees from Dr Falk Pharma and Ipsen. HC-P: Received lectures and advisory board fees from Advanz, Boehringer Ingelheim, Novo Nordisk and Orphalan. MDe: Received grants from Echosens, Intercept and Merz; Received consulting fees from Boehringer Ingelheim, Gilead, GlaxoSmithKline and Ipsen; Received speaker fees from AbbVie, Advanz, AstraZeneca, Boehringer Ingelheim, Falk, Gilead, Ipsen, Merz and Sanofi; Received support for attending meetings and/or travel from AbbVie, Gilead and Ipsen. MTD: Received grants from AstraZeneca, Dr Falk Pharma, Gilead, Ipsen and Pliant Therapeutics; Received consulting fees from AstraZeneca and Eisai; Received speaker fees from AstraZeneca and Roche. BEk: Nothing to disclose. JMF: Received research support to institution from Alexion, Gilead and Ipsen; Received consulting fees from Bristol Myers Squib, Gilead and Madrigal. RGi: Nothing to disclose. HHK: Received consulting fees and honoraria from Advanz, Gilead, GlaxoSmithKline, Ipsen and Sanofi. IMJ: Received grants from AstraZeneca, AusperBio, CymaBay, Eli Lilly, Gilead, GlaxoSmithKline, Inventiva, Intercept, Ipsen, Madrigal, Merck, Mirum and Novo Nordisk; Received consulting fees from Arbutus, CymaBay, Gilead, GlaxoSmithKline, Intercept, Madrigal, Merck, Moderna and Precision Biosciences; Participated in a Data Monitoring Committee for Aligos, Altimmune, GlaxoSmithKline and Takeda. YKa: Received consulting fees from Dr Falk Pharma and Ipsen; Received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Advanz, Dr Falk Pharma and Ipsen; Received support for attending meetings and/or travel from Advanz, Dr Falk Pharma and Ipsen. MKu: Received grants from, Akero, Altimmune, AstraZeneca, Bausch, Boehringer Ingelheim, Celgene, CymaBay, GENFIT, Genentech, Gilead, Intercept, Ionis, Inventiva, Ipsen, Madrigal, Northsea, Viking and 89bio; Received consulting fees from AbbVie, CymaBay, Gilead, Intercept, Ipsen, Madrigal, Mallinkrodt, Novo-Nordisk and Salix; Received speaker fees from Madrigal, Novo-Nordisk, Ipsen, CymaBay, Intercept, Gilead, AbbVie and Mallinkrodt. VLu: Received grants from Akero, AstraZeneca, Bristol Myers Squib, Chemomab, CymaBay, Elobix, GENFIT, Gilead, GlaxoSmithKline, Hanmi, Intercept, Inventiva, Ipsen, Madrigal, Mirum, Novo Nordisk, Pfizer, Pliant Therapeutics, Takeda, Target RWE, Zydus and 89bio. AMa: Received consulting fees from Akero, Angelini Pharma, Gilead and Madrigal; Received research support from AstraZeneca, Gilead, Madrigal and Roche. AJM-L: Participated on advisory boards for Intercept. AMu: Received grants or contracts from Ipsen; Received support for attending meetings and/or travel from Ipsen. AOl: Received consulting fees from Advanz, Gilead, GlaxoSmithKline and Ipsen; Received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Advanz, Gilead and Ipsen. BCP: Nothing to disclose. APi: Nothing to disclose. FPr: Participated on an Advisory Board for Madrigal. MSa: Received grants from Astellas and Chiesi; Received consulting from Intercept; Speaker for Chiesi and Mirum. MLS: Received grants from CymaBay, GENFIT, Intercept, Mirum and Zydus; Received consulting fees from CymaBay, Intercept and Ipsen; Received payment or honoraria from CymaBay, Intercept and Mirum; Received support for attending meetings and/or travel from CymaBay and Intercept; Speaker for Ipsen. KSp: Received consulting fees from Gilead, Ipsen and Janssen; Received lecture fees from AbbVie, Bristol Myers Squibb, Chemomab and Gilead; Received grant support from Gilead. RSw: Nothing to disclose. DTh: Received consulting fees from Chemomab, Mirum and Pliant Therapeutics; Received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Chemomab, Mirum and Pliant Therapeutics; Received support for attending meetings and/or travel from Ipsen; Participated on a Data Safety Monitoring Board or Advisory Board for GlaxoSmithKline, Mirum and Pliant Therapeutics. PJTh: Received honoraria from AbbVie, Akero, Alnylam, AstraZeneca, Gilead, Mallinckrodt and UpToDate; Received grants from Abbvie, Bayer, BioVie, Bristol Myers Squibb, Cirius Therapeutics, Corrona, CymaBay, Exact Sciences, Gilead, Hanmi, HighTide Biopharma, Intercept, Inventiva, Ipsen, Madrigal, NGM Bio, Novo Nordisk, Roche, Salix, Synthis Bio, Target, Viking and 89bio. PJTr: Receives institutional salary support from the NIHR Birmingham BRC. This paper presents independent research supported by the Birmingham NIHR BRC based at the University Hospitals Birmingham National Health Service Foundation Trust and the University of Birmingham, UK. The views expressed are those of the author(s) and not necessarily those of the National Health Service, the NIHR, or the Department of Health. PJTr has received consulting fees from Advanz/Intercept, Albireo/Ipsen, Chemomab, CymaBay/Gilead, Dr Falk Pharma, GlaxoSmithKline, Kowa, Mirium and Pliant Therapeutics; Received lecture fees from Advanz/Intercept, Albireo/Ipsen, Dr Falk Pharma, Perspectum Ltd and Zambon; Received grants from Bristol Myers Squibb, Core (Guts UK), EASL, Gilead, GlaxoSmithKline, Intercept, Ipsen, LifeArc, Medical Research Foundation UK, Mirium, NIHR, PSC Support, Regeneron and The Wellcome Trust. JTu: Received research grants AbbVie, AstraZeneca, Gilead and Novo Nordisk; Received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AbbVie, AstraZeneca, EISAI, Gilead, Ipsen, MSD and Roche; Participated on advisory boards for AbbVie, AstraZeneca, Gilead, Ipsen, Novo Nordisk and Roche. COZ: Former employee of Ipsen. HGdS, SJa, BMi, CMi, ATa: Employees and shareholders of Ipsen. KVK: Received grants from Boston Scientific, Corcept, CymaBay, GENFIT, Gilead, GlaxoSmithKline, Hanmi, Intercept, Ipsen, Janssen, Madrigal, Mirum, Novo Nordisk, NGM Bio, Pfizer, Pliant Therapeutics, Terns, Viking, Zydus and 89bio; Received royalties or licenses from UpToDate; Received consulting fees from CymaBay, Enanta, GENFIT, Gilead, HighTide, Inipharm, Intercept, Ipsen, Madrigal, Mirum, NGM Bio, Pliant Therapeutics, Pfizer, Protagonist, Zydus and 89bio; Received payment or honoraria from AbbVie, Gilead and Intercept; Received payment for expert testimony from the US Department of Justice; Participant on a Data Safety Monitoring Board or Advisory Board for CTI, Medpace, Labcorp and Worldwide Clinical Trials; Stockholder in Inipharm; Receipt of equipment, materials, drugs, medical writing, gifts or other services from Velacur. Please refer to the accompanying ICMJE disclosure forms for further details.

Associated data

Actions
- Search in PubMed
- Search in ClinicalTrials.gov

LinkOut - more resources

Full Text Sources
- ClinicalKey

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Safety and efficacy of elafibranor in primary sclerosing cholangitis: The ELMWOOD phase II randomized-controlled trial

Affiliations

Safety and efficacy of elafibranor in primary sclerosing cholangitis: The ELMWOOD phase II randomized-controlled trial

Authors

Affiliations

Abstract

Conflict of interest statement

Associated data

LinkOut - more resources

Full Text Sources