Post-Hoc FUEL Trial Analysis Shows Udenafil Significantly Improves Exercise Capacity in Fontan Patients with Reduced Baseline Function

SEOUL, South Korea, Aug. 12, 2025 /PRNewswire/ -- A newly published post-hoc analysis of the landmark FUEL (Fontan Udenafil Exercise Longitudinal) Trial demonstrates that udenafil, a PDE5 inhibitor, significantly improves peak oxygen consumption (peak VO₂) in adolescents with single ventricle congenital heart disease (SV-CHD) who have undergone the Fontan procedure and have reduced exercise capacity.

Published in the Journal of the American Heart Association: "Revisiting the Effect of Udenafil on Exercise Performance in Patients With Fontan Circulation: Results of a Post Hoc Analysis of the FUEL Trial"

The original multinational, randomized, placebo-controlled Phase 3 FUEL trial demonstrated statistically significant improvements in key secondary endpoints – such as VO₂ at ventilatory anaerobic threshold (VAT) and myocardial performance index (MPI) – but narrowly missed statistical significance for the primary endpoint of peak VO₂ in the overall population. Recognition of a high performing "Super Fontan" subgroup prompted further analysis stratifying participants by baseline peak VO₂ (<80% vs. ≥80% of predicted) to assess whether initial exercise capacity influenced treatment response.

Key findings from the post-hoc analysis:

• In the 302 patients with baseline peak VO₂ <80% predicted (80% of the evaluable cohort), udenafil significantly improved peak VO₂ compared to placebo (p=0.021).
• Significant improvements were also observed in VO₂ at VAT (p=0.023), work at VAT (p=0.032), and MPI (p=0.007).
• A significant interaction between baseline exercise capacity and treatment effect for peak VO₂ (p=0.036) suggests that including high-functioning patients, whose physiologic ceiling may limit measurable gains, could have masked the full treatment effect in the original trial.

"These results provide a possible physiologic explanation for the outcomes of the FUEL trial and support further investigation of udenafil in Fontan patients with reduced exercise capacity," said Dr. David Goldberg, lead author and pediatric cardiologist at Children's Hospital of Philadelphia. "This analysis highlights the need for a confirmatory clinical trial targeted to the large majority of Fontan patients who are most likely to demonstrate benefit using peak VO₂ as the primary endpoint."

"Importantly, the absence of a detectable change in peak VO₂ among higher-functioning Fontan patients may reflect– what may be termed a 'ceiling effect' – rather than a lack of therapeutic response," added Dr. Bryan H. Goldstein, senior author and Director of the Cardiac Catheterization Laboratory at UPMC Children's Hospital of Pittsburgh. "These patients still achieve meaningful improvements in submaximal exercise measures such as VO₂ at VAT and MPI. Moreover, as these younger, high-performing individuals age and are further exposed to ongoing Fontan circulatory stresses, their exercise capacity with decline and therefore, the need for targeted pharmacotherapy will likely increase."

The findings highlight the importance of selecting appropriate endpoints and stratifying populations in rare disease trials. Informed by FUEL, the ongoing confirmatory phase 3 FUEL-2 trial focuses on Fontan patients with reduced baseline exercise capacity – those in whom changes in peak VO₂ are most reliably measurable.

"This focused design increases the likelihood of demonstrating efficacy on the primary endpoint, while still capturing udenafil's broader therapeutic potential," said Dr. Rahul Rathod, Global Principal Investigator for FUEL-2 and Director of the Single Ventricle Program at Boston Children's Hospital. "Given the strong link between peak VO₂ and long-term outcomes in Fontan patients, a +1.13 mL/kg/min improvement over six months is clinically meaningful and may influence disease progression."

The FUEL trial was supported by the National Heart, Lung, and Blood Institute (NHLBI) and Mezzion Pharma Co., Ltd., the regulatory sponsor of udenafil development for Fontan patients.

About Mezzion

Mezzion Pharma Co., Ltd. is a biopharmaceutical company developing therapies for rare and orphan diseases. Udenafil is currently being evaluated in the Phase 3 FUEL-2 trial for improving exercise performance in adolescents and young adults with Fontan circulation.

For more information, please visit www.mezzion.com and www.FUEL2Study.com.

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SOURCE Mezzion Pharmaceuticals, Inc