Mezzion's udenafil cuts liver fibrosis marker in Fontan patients, not liver stiffness
A published substudy of the FUEL extension trial found a biomarker drop in 84% of Fontan patients on udenafil, but liver stiffness scans showed no change after 12 months.
Executive Summary
- A published substudy of Mezzion's Phase 3 udenafil extension trial found a fibrosis biomarker improved in most treated patients after a year of treatment, but a direct imaging measure of liver stiffness in the same patients did not change.
- The analysis addresses Fontan-associated liver disease, a progressive complication of Fontan circulation with no approved treatment, using a biomarker meant to serve as a proxy for fibrosis rather than a direct measure of it.
- The sponsor's release emphasizes the biomarker improvement while acknowledging the physical stiffness measurements were unchanged, a split result that a company statement frames as supportive but that the study's own authors describe only as suggestive and warranting further study.
- The company is completing enrollment in a separate, confirmatory Phase 3 trial that will be the basis for any regulatory submission, and that trial, not this substudy, will carry the weight of any future approval decision.
The publication
Mezzion Pharmaceuticals said the journal Pediatric Cardiology published "The FUEL FALD Study: Effects of Udenafil on Liver Stiffness and Fibrosis after Fontan," reporting an exploratory substudy of the FUEL Open Label Extension trial (NCT03013751). The substudy evaluated Fontan-associated liver disease (FALD), a progressive liver injury and fibrosis complication in patients living with Fontan circulation, a condition for which the company said no therapy is specifically indicated. At study entry, 95% of the 301 enrolled participants had elevated Enhanced Liver Fibrosis (ELF) scores, consistent with at least moderate fibrosis by thresholds used in other liver diseases. NCT03013751+1A Extension Study of Udenafil in AdolescentsNCT03013751FUEL FALD Study Published in Pediatric CardiologyJul 16, 2026
How it was assessed
The substudy tracked ELF score, a blood-based composite biomarker associated with fibrotic remodeling, alongside two imaging measures of liver stiffness: ultrasound shear wave elastography (SWE) and magnetic resonance elastography (MRE). Participants had received udenafil for 12 months as part of the open-label extension, which enrolled 301 patients across the United States, South Korea and Canada and completed as an interventional, single-arm, open-label study without a placebo comparator for this analysis. The trial's primary registered outcome measure was treatment-emergent adverse events, not a liver-specific endpoint. FUEL+1FUEL FALD Study Published in Pediatric CardiologyJul 16, 2026A Extension Study of Udenafil in AdolescentsNCT03013751
The result
After 12 months of treatment, 84% of participants showed a reduction in ELF score, a decrease the publication's investigators reported as statistically significant (p<0.05). Liver stiffness on SWE and MRE did not change significantly over the same period. Kurt Schumacher, chief of pediatric cardiology at University of Michigan Health C.S. Mott Children's Hospital and the publication's lead author, said the findings "contribute to our growing understanding of Fontan-associated liver disease and reinforce the importance of continuing to investigate therapies that may address this serious long-term complication". The authors themselves framed the result as suggesting udenafil "may alter the overall Fontan fibrotic milieu" and as warranting further study, stopping short of describing it as an established treatment effect. FUELFUEL FALD Study Published in Pediatric CardiologyJul 16, 2026
Safety and design caveats
The substudy did not report a distinct safety profile for the liver analysis, and the underlying trial's separately posted results describe adverse events across the full 301-patient population, including 54 participants with a serious adverse event over 52 weeks, most commonly cardiac and gastrointestinal in nature. The design is a limiting factor for interpreting the biomarker result: an open-label extension with no placebo arm for this substudy, an exploratory rather than prespecified primary analysis, and a biomarker endpoint that diverged from a direct anatomic measure of the same disease process. NCT03013751A Extension Study of Udenafil in AdolescentsNCT03013751
Competitive and regulatory context
No other industry trial is testing a PDE5A inhibitor in single ventricle congenital heart disease, and udenafil's own competitive set in this indication consists of trials in a different Fontan-related population rather than a head-to-head comparator. Mezzion said it is completing enrollment in FUEL-2, its confirmatory Phase 3 trial, and that the study is designed to evaluate exercise capacity and support a potential regulatory submission for udenafil in Fontan circulation. That confirmatory trial, not the FALD substudy, is the one the company has tied to a regulatory filing. FUELFUEL FALD Study Published in Pediatric CardiologyJul 16, 2026
This analysis was produced using AI-assisted reporting systems, AppliedXL data, and official public records. These systems undergo editorial review, quality checks, and regular audits by human experts. Errors may still occur, as with any automated system. Always consult the linked primary sources. Read our AI Editorial Policy.