Safety and efficacy of elafibranor in primary sclerosing cholangitis: The ELMWOOD phase II randomized-controlled trial
Levy, Cynthia Abouda, George F Bilir, Bahri M Bonder, Alan Bowlus, Christopher L Campos-Varela, Isabel Cazzagon, Nora Chandok, Natasha Cheent, Kuldeep Cortez-Pinto, Helena
Levy, Cynthia
Abouda, George F
Bilir, Bahri M
Bonder, Alan
Bowlus, Christopher L
Campos-Varela, Isabel
Cazzagon, Nora
Chandok, Natasha
Cheent, Kuldeep
Cortez-Pinto, Helena
Affiliation
University of Miami; Hull University Teaching Hospitals NHS Trust; Advent Health Transplant Institute; Rocky Mountain Gastroenterology; Beth Israel Deaconess Medical Center; Harvard Medical School; UC Davis School of Medicine; Hospital University Vall d'Hebron; University of Padova; University Hospital of Padova; William Osler Health System; Frimley Health NHS Foundation Trust; Universidade de Lisboa; Charité Universitätsmedizin Berlin; Heidelberg University Hospital; Aspen Woods Clinic; Thomas Jefferson University Hospital; Intermountain Health; University of British Columbia; NYU Langone Health; Queen Mary University of London; South Denver Gastroenterology; Virginia Commonwealth University; IRCCS Ospedale Casa Sollievo della Sofferenza; University of Alberta; NHS Grampian; Hospital Universitario La Paz; University of Colorado Health; University Hospital of Modena; University of Nebraska Medical Center; Hospital General Universitario Gregorio Marañón; Bon Secours Mercy Health; Goethe University Frankfurt; NHS Greater Glasgow and Clyde; Royal Free London NHS Foundation Trust; University of Maryland; University of Birmingham; University Hospitals Birmingham NHS Foundation Trust; Pontevedra University Hospital; Ipsen; Liver Institute Northwest
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Publication date
2025-05-08
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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.
Citation
Levy C, Abouda GF, Bilir BM, Bonder A, Bowlus CL, Campos-Varela I, Cazzagon N, Chandok N, Cheent K, Cortez-Pinto H, Demir M, Dill MT, Eksteen B, Fenkel JM, Gilroy R, Ko HH, Jacobson IM, Kallis Y, Kugelmas M, Luketic V, Mangia A, Montano-Loza AJ, Mukhopadhya A, Olveira A, Patel BC, Pietrangelo A, Pradhan F, Salcedo M, Shiffman ML, Sprinzl K, Swann R, Thorburn D, Thuluvath PJ, Trivedi PJ, Turnes J, Zein CO, Gomes da Silva H, Jaitly S, Miller B, Milligan C, Tavenard A, Kowdley KV. Safety and efficacy of elafibranor in primary sclerosing cholangitis: The ELMWOOD phase II randomized-controlled trial. J Hepatol. 2025 May 8:S0168-8278(25)00252-1. doi: 10.1016/j.jhep.2025.04.025. Epub ahead of print.
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Article