HMN 2025: How Analysis shows udenafil significantly improves exercise capacity in Fontan patients with reduced baseline function

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 VO?) in adolescents with single-ventricle congenital heart disease (SV-CHD) who have undergone the Fontan procedure and have reduced exercise capacity.

The original multinational, randomized, placebo-controlled Phase 3 FUEL trial demonstrated statistically significant improvements in key secondary endpoints—such as VO? at ventilatory anaerobic threshold (VAT) and myocardial performance index (MPI)—but narrowly missed statistical significance for the primary endpoint of peak VO? in the overall population.

Recognition of a high performing “Super Fontan” subgroup prompted further analysis stratifying participants by baseline peak VO? (published in the Journal of the American Heart Association.

Key findings from the post-hoc analysis

• In the 302 patients with baseline peak VO? p=0.021).
• Significant improvements were also observed in VO? 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 VO? (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 VO? 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 VO? 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 VO? 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 VO? 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.”

Provided by
Mezzion Pharmaceuticals, Inc