Udenafil study shows lower ELF scores in Fontan-associated liver disease

A newly published exploratory substudy of the FUEL Open Label Extension (OLE) adds biomarker data on Fontan-associated liver disease (FALD) in adolescents and young adults treated with udenafil for 12 months, according to Mezzion Pharmaceuticals.¹ The report, published in Pediatric Cardiology, evaluated liver fibrosis biomarkers and liver stiffness measures in patients with Fontan circulation, a population at risk for progressive hepatic injury over time.²

“As patients with Fontan circulation continue to live longer, understanding and addressing the long-term complications of Fontan physiology has become increasingly important,” Kurt Schumacher, MD, chief of pediatric cardiology at University of Michigan Health C.S. Mott Children’s Hospital and lead author of the publication, said in the company announcement.¹

The FUEL FALD analysis was an exploratory substudy of the FUEL OLE, not a registrational trial. Investigators assessed participants who received 12 months of udenafil, a phosphodiesterase type 5 (PDE5) inhibitor being studied for patients with Fontan circulation. The substudy focused on noninvasive markers of liver fibrosis and stiffness, including Enhanced Liver Fibrosis (ELF) score, ultrasound shear wave elastography (SWE), and magnetic resonance elastography (MRE).¹,²

At study entry, 95% of participants had elevated ELF scores, which the authors described as consistent with at least moderate fibrosis based on thresholds used in other liver diseases. After 12 months of udenafil treatment, the investigators reported a statistically significant decrease in ELF score, with 84% of participants showing a reduction over the study period. Liver stiffness measurements by SWE and MRE did not significantly change.¹,²

The findings suggest a possible effect of udenafil on circulating or tissue-associated fibrosis biology in Fontan physiology, but the discordance between ELF score improvement and unchanged stiffness measures underscores the need for cautious interpretation. ELF is a noninvasive biomarker associated with fibrotic remodeling; however, FALD is complex, and liver stiffness in Fontan patients may reflect congestion, fibrosis, hemodynamics, and technical measurement factors rather than fibrosis alone.²,⁴

FALD has become a major long-term issue as survival after Fontan palliation has improved. The Fontan operation, used for selected patients with single-ventricle congenital heart disease, directs systemic venous return to the pulmonary arteries without a subpulmonary ventricle. This circulation is associated with chronically elevated central venous pressure and reduced preload, contributing to hepatic congestion, fibrosis, portal hypertension, and, in some patients, cirrhosis or hepatocellular carcinoma risk.⁴

Current management is largely surveillance-based and supportive, including attention to Fontan hemodynamics, assessment for portal hypertension or advanced liver disease, and multidisciplinary evaluation when heart or combined heart-liver transplantation is being considered. No therapy is approved specifically for FALD.⁴

Udenafil targets the nitric oxide–cyclic guanosine monophosphate pathway through PDE5 inhibition. The rationale in Fontan circulation is that pulmonary vascular resistance and endothelial function may influence exercise performance and Fontan efficiency. In the randomized FUEL trial, udenafil did not significantly improve the primary end point of peak oxygen consumption, but investigators reported improvements in some secondary measures of exercise performance, including ventilatory anaerobic threshold and work rate.³

Mezzion stated that the broader FUEL program has evaluated udenafil across exercise capacity, ventricular performance, cardiovascular safety, nitric oxide pathway biology, patient-reported experience, and liver fibrosis biomarkers.¹ The company is also conducting FUEL-2, described as a global confirmatory phase 3 trial evaluating exercise capacity in adolescents and young adults with Fontan circulation.¹

References

1. Mezzion Pharmaceuticals Inc. FUEL FALD Study Published in Pediatric Cardiology. PR Newswire. Published July 16, 2026. Accessed July 16, 2026. https://www.prnewswire.com/news-releases/fuel-fald-study-published-in-pediatric-cardiology-302827612.html

2. Schumacher KR, et al. The FUEL FALD Study: Effects of Udenafil on Liver Stiffness and Fibrosis after Fontan. Pediatr Cardiol. Published online 2026. doi:10.1007/s00246-026-04334-9

3. Goldberg DJ, Zak V, Goldstein BH, et al. Results of the Fontan Udenafil Exercise Longitudinal (FUEL) Trial. Circulation. 2020;141(8):641-651. doi:10.1161/CIRCULATIONAHA.119.044352

4. Rychik J, Atz AM, Celermajer DS, et al. Evaluation and management of the child and adult with Fontan circulation: a scientific statement from the American Heart Association. Circulation. 2019;140(6):e234-e284. doi:10.1161/CIR.0000000000000696