FUEL: Udenafil Improves Exercise Capacity After Fontan Surgery

Marlene Busko

November 26, 2019

PHILADELPHIA — In a phase 3 study, the phosphodiesterase-5 (PDE-5) inhibitor udenafil (Mezzion Pharma) did not improve the primary end point of oxygen consumption at peak exercise, but was associated with improved submaximal exercise in adolescents who were born with single ventricle heart disease and had palliative Fontan surgery.

David J. Goldberg

David J. Goldberg, MD, a pediatric cardiologist at the Children's Hospital of Philadelphia, presented these results from the Fontan Udenafil Exercise Longitudinal (FUEL) trial — a randomized multicenter study of 400 adolescents with single ventricle heart disease — here at the American Heart Association Scientific Sessions 2019.

A previous 5-day phase 1/2 trial in 36 adolescents who had undergone Fontan surgery established the dose of udenafil for this application, and also demonstrated short-term safety.

Now, the FUEL trial shows that compared with placebo, 6 months of oral udenafil therapy at a dose of 87.5 mg twice daily was not associated with a significant improvement in oxygen consumption at peak exercise (VO₂ max) — the classic measure of aerobic endurance or cardiovascular fitness — in adolescents with this congenital heart defect who had a Fontan procedure that creates a cardiopulmonary connection.

However, udenafil was associated with a significant improvement in oxygen capacity at the ventilatory anaerobic threshold (VO₂ at VAT).

"Oxygen consumption at the ventilatory anaerobic threshold is a measure of the efficiency of the cardiovascular system at moderate levels of exercise," Goldberg explained to theheart.org | Medscape Cardiology.

That is, treatment with udenafil allowed for better blood flow through the lungs and improved cardiac output and oxygen delivery during moderate exercise.

Craig A. Sable

"Although max VO₂ has been a generally accepted marker of hospitalization and death, it may not be an ideal efficacy measure in patients with a single ventricle," said Craig `A. Sable, MD, a pediatric cardiologist at Children's National Medical Center, Washington, DC, the assigned discussant for this study at the late-breaking trial session.

"VO₂ at VAT, which measures submaximal exercise, is more relevant for the Fontan circulation." he said.

According to Sable, "a medication that addresses the central deficiencies of Fontan physiology and results in improved exercise performance may allow for a longer period of symptom-free survival."

Goldberg told theheart.org | Medscape Cardiology that being born with one ventricle is rare, but patients with this genetic defect are now living longer— past their 30s and 40s — so cardiologists might be treating adults who have this heart defect and who have had this palliative surgery.

"It is our hope," he said, "that a chronic lowering of central venous pressure and a chronic improvement in cardiac output" with udenafil "will lead to better long-term outcomes, although this will have to be studied prospectively."

Cardiovascular Efficiency Slowly Deteriorates

Children who are born with a single functioning ventricle — such as tricuspid atresia or hypoplastic left heart syndrome — typically undergo two palliative surgeries as infants followed by the palliative Fontan procedure at the age of 2 or 3 years.

Fontan surgery allows blood from the lower part of the body to go directly to the lungs to pick up oxygen without having to pass through the heart. Instead of having a ventricular pump to propel blood into the pulmonary arteries, blood returns to the lungs via passive flow from the systemic veins.

The operation "confers a degree of chronic heart failure, characterized by diastolic dysfunction, and a circulation dependent on low pulmonary vascular resistance (PVR) in order to maintain an adequate cardiac output with a modestly elevated central venous pressure," Goldberg and colleagues write by way of background for the phase 1/2 trial.

With this type of circulation, patients have elevated central venous pressure and low cardiac output, he told the audience.

"While this circulation is typically stable through childhood," he added, "cardiovascular efficiency deteriorates over time, associated with a decline in exercise performance and the accrual of Fontan-associated morbidities."

The patients have an elevated central venous pressure that is limited in its ability to rise to the degree needed to meet metabolic demands at high levels of exertion, thereby creating a limit to the amount of exercise that can be achieved.

Patients with this physiology have a predictable, persistent deterioration of cardiovascular efficiency, characterized by a progressive decline in exercise performance, which accelerates after puberty and is associated with the development of substantial morbidities and a significantly shortened life expectancy.

Meanwhile, research has shown that PDE-5 inhibitors reduce PVR and improve ventricular performance in patients with pulmonary hypertension and myocardial dysfunction.

This "make this class of drug an appealing therapy to consider for patients with the Fontan circulation, in which the maintenance of low PVR and normal myocardial function are crucial determinants of long-term clinical outcomes," Goldberg and colleagues write in the phase 1/2 report.

The PDE-5 inhibitor udenafil is approved for the treatment of men with erectile dysfunction in Korea, Russia, and the Philippines, where it is marketed as Zydena, but udenafil had not been evaluated to see if it can be used to treat diminished exercise capacity in male and female adolescents with Fontan circulation.

FUELing Better Exercise Capacity?

From 2017 to 2019, researchers in the FUEL trial screened 1376 adolescents who were born with a single functional ventricle and had had Fontan surgery at 30 sites: two in Canada, two in South Korea, and 26 in the United States.

They enrolled and randomized 400 patients, aged 12 to 18 years. Half received 87.5 mg udenafil twice daily and half received placebo for 6 months.

The patients had a mean age of 15.5 years; about 40% were female and most were white (80%).

At 6 months, peak VO₂ increased by 44 mL/min in the udenafil group and decreased by 3.7 mL/min in the placebo group, which was not a significant difference (= .071).

However, the VO₂ at VAT increased by 33 mL/min in the udenafil group and decreased by 9.0 mL/min in the placebo group, which was a significant difference (P = .012).

And the work rate at VAT increased by 3.8 watts in the udenafil group and decreased by 0.34 watts in the placebo group, which was also a significant difference (P = .021).

Udenafil was well tolerated and safe, with no unexpected adverse events for this drug class.

The most common adverse events were headache/migraine — reported by more patients in the udenafil than placebo groups (35% vs 25%; P = .049) — and facial flushing (16% vs 6%; P = .002)

More males in the udenafil group than in the placebo group had increased erections (13 vs 2 patients; 12% vs 2%; = .002), and more patients in the udenafil group had epistaxis (6% vs 2% P = .053).

There were no significant differences in abdominal pain, dizziness, and nausea/vomiting, which were reported by no more than 8% of patients.

Upcoming NDA, Two Other Clinical Trials

Mezzion presented the topline results from FUEL to the US Food and Drug Administration (FDA) on October 8, and the FDA confirmed that the company can submit a New Drug Application (NDA) for udenafil for patients with single ventricle heart disease who have undergone palliative Fontan surgery.

In partnership with the Pediatric Heart Network, Mezzion is conducting two related studies:

  • FUELExten, a 12-month, open-label safety extension study of udenafil in adolescents

  • the Evaluation of Fontan-Associated Liver Disease (FALD) trial of liver disease in patients with Fontan circulation, who almost always develop liver fibrosis at an early age

FUEL was funded by Mezzion. Goldberg discloses grants from Mezzion and the National Heart, Lung, and Blood Institute. Sable has no relevant financial disclosures.  

American Heart Association (AHA) Scientific Sessions 2019: Abstract LBS 20942. Presented November 17, 2019.

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