Children’s Hospital of Philadelphia (CHOP) served as lead clinical investigative site for the largest-ever clinical trial of a medication for pediatric cardiology patients who found that an oral drug significantly improved exercise capacity in adolescent patients with severe, congenital single ventricle heart defects. The physiologic benefits represent a milestone in the care of those who have undergone the Fontan procedure, a palliative operation for single-ventricle disease. The study was conducted by investigators in the Pediatric Heart Network. CHOP and South Korean biotech own the underlying patent so there are significant commercial tries underlying this trial.

Single-Ventricle Disease

Patients born with single-ventricle heart defects have a severely underdeveloped pumping chamber in their hearts. A series of complex surgeries culminating in the Fontan procedure has greatly improved survival of patients with single-ventricle disease. However, surgical corrections do not offer normal blood circulation, and survivors have low cardiac output and long-term complications. Among those complications is exercise intolerance, associated with increased morbidity and mortality.

Fontan Udenafil Exercise Longitudinal Assessment Trial (FUEL)

The FUEL trial was a randomized, double-blinded, efficacy trial of the effects of udenafil versus a placebo on the background of standard therapy on maximal VO2 (ml/kg/min) from baseline to six months in adolescent survivors on the Fontan procedure. The target sample size was 400 participants (200 per group) and the trial ran from 2016 to 2019.

The Phase III trial was sponsored by biopharmaceutical company Mezzion Pharma Co., Ltd. and occurred in 30 clinical investigational sites in the United States, Canada, and South Korea within the Pediatric Heart Network. One of the co-investigators, David J. Goldberg reported, “This study of udenafil provides the first evidence of clinical benefit for a medication in this unique population of children with single-ventricle heart disease.” 

Interestingly another study, the FUEL Open-Label Extension (FUEL OLE) Trial is presently proceeding, with the goal of measuring treatment tolerability and safety over a long period for this patient population.

Results

Dr. Goldberg reported on the FUEL Trial recently at the 2019 Scientific Sessions of the American Heart Association in Philadelphia and was the lead author of an article published concurrently in the Journal Circulation.

The research team noted that FUEL trial participants evidenced statistically significant improvements in oxygen consumption and other measures of exercise capacity during moderate levels of activity. There was also a numeric improvement in oxygen consumption at peak exercise, although this did not achieve statistical significance. Goldberg reported that the results from the FUEL Trial results in “better circulatory function and should correlate with better long-term circulatory health for patients who have undergone the Fontan procedure.”

Side Effects

Generally the treatment was well tolerated. Side effects were limited to those previously known from phosphodiesterase type 5 inhibitors, more commonly including headache, facial flushing, abdominal pain, nosebleed and erection (among males).

What is the Fontan Procedure?

The Fontan Procedure is a palliative surgical procedure used in children with univentricular hearts. It involves diverting the venous blood from the inferior vena cava (IVC) and superior vena cava (SVC) to the pulmonary arteries without passing through the morphologic right ventricle: i.e. the systemic and pulmonary circulations are placed in series with the functional single ventricle. The procedure was initially performed in 1968 by Francis Fontan and Eugene Baudet and additionally described in 1973 by Guillermo Kreutzer.

Who Funded this Study & Financial Interests

The study was funded by biotech company Mezzion Pharma Co., Ltd. and the National Heart, Lung and Blood Institute of the National Institutes of Health.

Interestingly, the patent underlying the treatment is owned by both investigators, Dr. Goldberg and Dr. Paridon, along with Mezzion. The patent is for the use of Udenafil in Fontan physiology. CHOP holds the patent rights (as Goldberg and Paridon work for them) along with Mezzion.

Who is Mezzion Pharma Co., Ltd.?

Mezzion Pharma is a South Korean-based emerging biotech company. They have a wholly owned subsidiary, Mezzion Pharmaceuticals, Inc., in America with administrative offices in Deerfield, IL, and Boca Rotan, FL. They focus on pediatric disease. Mezzion is publicly traded on the Korean Stock Exchange under the symbol KOSDAQ.

They have a handful of different assets in clinical trials. They are the developer of the drug in this study, Udenafil, a unique PDE5i drug that was used to treat single ventricle congenital heart disease (SVHD) patients with Fontan physiology. 

Lead Research/Investigator

David J. Goldberg, MD Pediatric Cardiologist, CHOP

Steve Paridon

Call to Action: If you or a loved one have someone in the family that has severe, congenital single ventricle defect and may have Fontan physiology, then this study should be of interest. The underlying patented treatment will be submitted to the FDA as part of a new drug application (NDA). TrialSite News will monitor the FULE OLE study as well.

Source: EurekAlert!

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