Udenafil Shows Promising Results in Improving Exercise Capacity in Fontan Patients with Reduced Baseline Function

Recent post-hoc analysis of the landmark FUEL (Fontan Udenafil Exercise Longitudinal) Trial has revealed that udenafil, a phosphodiesterase type 5 (PDE5) inhibitor, significantly enhances exercise capacity in adolescents with single-ventricle congenital heart disease (SV-CHD) who have undergone the Fontan procedure. Specifically, the study focused on patients with diminished baseline exercise performance, demonstrating that udenafil can lead to noteworthy improvements in peak oxygen consumption (peak VO₂), a key indicator of cardiovascular fitness.

The original Phase 3 FUEL trial was multinational, randomized, and placebo-controlled. It showed statistically significant improvements in secondary endpoints such as VO₂ at ventilatory anaerobic threshold (VAT) and myocardial performance index (MPI), although it narrowly missed achieving statistical significance for the primary endpoint of peak VO₂ in the overall population. Recognizing a subgroup of high-performing "Super Fontan" patients who had baseline peak VO₂ ≥80%, further analysis was conducted to explore whether initial exercise capacity influenced treatment response.

Results from this post-hoc investigation indicated that among 302 patients with baseline peak VO₂ less than 80% predicted, udenafil significantly increased peak VO₂ compared to placebo (p=0.021). Additional benefits were observed in VO₂ at VAT (p=0.023), work at VAT (p=0.032), and MPI (p=0.007). Furthermore, a significant interaction between baseline exercise capacity and treatment effect suggests that including high-functioning patients may have masked potential benefits in the original trial, due to a 'ceiling effect'.

According to Dr. David Goldberg, lead author and pediatric cardiologist, these findings offer a physiologic explanation for the trial's outcomes and support further research into udenafil's role in treating Fontan patients with reduced exercise capacity. Dr. Goldberg emphasizes that a dedicated clinical trial targeting this subgroup could provide clearer insights. Dr. Bryan H. Goldstein notes that despite the absence of peak VO₂ improvements in higher-functioning patients, meaningful gains in submaximal exercise measures like VAT and MPI were achieved, which remain clinically relevant. As affected individuals age, ongoing circulatory stresses may further decline exercise capacity, underscoring the potential need for pharmacological intervention.

Building on these insights, the ongoing Phase 3 FUEL-2 trial specifically focuses on Fontan patients with limited baseline exercise capacity. This targeted approach increases the likelihood of demonstrating udenafil's efficacy through changes in peak VO₂ and might lead to broader application in this patient population. The trial aims to determine whether udenafil can produce a meaningful long-term impact on disease progression, with researchers indicating that a modest 1.13 mL/kg/min increase in peak VO₂ over six months could significantly influence future patient outcomes.

Overall, these findings highlight the importance of appropriately selecting endpoints and patient populations in rare disease research, paving the way for more precise therapies that address specific impairments in Fontan circulation.