Unmet Need in Primary Sclerosing Cholangitis
PRIMARY sclerosing cholangitis (PSC) is a rare, progressive cholestatic liver disease characterised by inflammation and fibrosis of the bile ducts, frequently leading to cirrhosis, liver failure, and the need for transplantation. Despite its significant morbidity, there remains no approved disease-modifying therapy, and current management options are limited. This unmet clinical need has driven interest in therapies targeting metabolic and inflammatory pathways implicated in PSC pathogenesis.
ELMWOOD Trial Evaluates Elafibranor
Elafibranor, a dual peroxisome proliferator-activated receptor (PPAR)-α/δ agonist, was evaluated in the phase II ELMWOOD trial, a 12-week, randomized, double-blind, placebo-controlled study. The trial enrolled 68 adults with PSC and elevated alkaline phosphatase (ALP) levels of at least 1.5 times the upper limit of normal. Participants were randomized to receive elafibranor 80 mg, elafibranor 120 mg, or placebo. At baseline, over half of participants had inflammatory bowel disease, nearly half had elevated enhanced liver fibrosis (ELF) scores, and the majority were receiving ursodeoxycholic acid.
Biochemical Improvements and Safety Profile
Elafibranor was well tolerated across both dose groups, with treatment-emergent adverse event rates comparable to placebo and no serious adverse events reported in elafibranor-treated participants. Notably, significant reductions in ALP were observed with both elafibranor doses compared with placebo, with the greatest effect seen in the 120 mg group. ALP normalization occurred exclusively in participants receiving elafibranor. Improvements in ELF scores suggested stabilization of fibrosis-related markers, while patients receiving elafibranor 120 mg also appeared to experience greater improvements in pruritus, a symptom that substantially impacts quality of life in PSC.
Clinical Implications and Next Steps
These findings demonstrate that elafibranor provides clinically meaningful biochemical improvements over a short treatment period, with a favorable safety profile. The dose-dependent response observed supports further investigation of elafibranor as a potential therapeutic option for PSC. Larger and longer-term studies will be essential to determine whether these early improvements translate into reduced disease progression, improved survival, and better patient-reported outcomes.
Reference
Levy C et al. Safety and efficacy of elafibranor in primary sclerosing cholangitis: The ELMWOOD phase II randomized-controlled trial. J Hepatol. 2025; DOI:10.1016/j.jhep.2025.04.025.
