Mezzion Pharma Submits Protocol for Confirmatory Pivotal Phase 3 Trial ("FUEL-2") in Fontan Subjects
Mezzion Pharma Co., Ltd. (Mezzion Pharma) has submitted a confirmatory pivotal Phase 3 Clinical Trial in Fontan subjects to the Food and Drug Administration (FDA).
In the Type B meeting between the FDA and Mezzion, the FDA provided Mezzion with a clear path forward to FDA approval for the treatment of Fontan subjects with udenafil. In the Type B meeting, an agreement was reached with the FDA regarding its requirement for a confirmatory Phase 3 clinical trial. Mezzion reports that it has submitted a new protocol for the FUEL-2 Trial to the Division of Cardiology and Nephrology consistent with the agreement reached with the FDA in Type B meeting.
The cardiovascular efficiency of the Fontan subjects deteriorates through adolescence and into adulthood. This deterioration correlates with a decline in exercise capacity and an increase in the prevalence of heart failure symptoms, hospitalization and mortality. Mezzion believes that the FUEL-2 confirmatory trial in Fontan subjects will show that chronic udenafil therapy will improve their exercise capacity and thus potentially prolong the time to the onset of serious morbidity.
The protocol for the FUEL-2 Trial is based on what was learned from the original Phase 3 trial FUEL Trial and the agreement reached with the FDA. The study population will be single ventricle heart disease subjects with Fontan palliation and Fontan physiology who will most likely improve their exercise capacity based on their baseline cardiopulmonary exercise testing performance. Under the revised inclusion/exclusion criteria, FUEL-2 will exclude those target subjects who are defined as "Super Fontans."
The Ad Hoc analysis of a similar population of about 300 subjects excluding the Super Fontans in the original FUEL trial, comparing the mean peak VO2 of the udenafil treated group of about 150 subjects versus the placebo group of also about 150 subjects was statistically significant at a p-value of 0.023. The important secondary endpoints of exercise capacity at the Ventilatory Anaerobic Threshold ("VAT"), Work Rate, Oxygen Consumption at VAT and Ventilatory Efficiency will also be evaluated. These secondary endpoints were all statistically significant for the entire treatment arm, about 200 subjects, in the FUEL Trial.
FUEL-2 is designed as a double-blind, placebo-controlled trial with a sample size of approximately 400 subjects. The primary efficacy endpoint is the change in peak oxygen consumption (VO2 mL/kg/min) from Baseline to Week 26, as measured by maximal cardiopulmonary exercise testing. As agreed with the FDA, the statistical criteria for success will be at a 2-sided level of significance of 10% (p<0.1). An interim analysis will be conducted when approximately 50% of the subjects complete the trial to determine what final sample size is needed to meet the statistical criteria of a 2-sided alpha of 0.1 at 90% power.
Because the principal objective of FUEL-2 is to obtain statistical significance of the primary end point, FUEL-2 will have fewer procedures compared to the FUEL Trial. Mezzion therefore believes that the FUEL-2 protocol is simpler and more straightforward than the FUEL Trial protocol. Mezzion also believes that the FUEL-2 protocol will be more convenient for the subjects, it will facilitate and expedite the clinical operation at the site level, and it will streamline the enrollment and recruitment process.
Approximately 30 sites throughout the world will participate in the new FUEL-2 confirmatory trial. Study enrollment is expected to be initiated within the next few weeks.
About the Fontan Procedure and Subsequent Expectations
The Fontan procedure is a surgical intervention that allows for the survival of children born with congenital heart disease characterized by only a single functional pumping chamber. This procedure consists of re-configuring the circulation to allow the single ventricle to pump blood to the body while connecting the great veins directly to the arteries that bring blood to the lungs. In this "Fontan circulation" the blood returning from the body bypasses the heart and travels to the lungs without the assistance of a dedicated right ventricle pumping chamber. The goal of the Fontan procedure is to separate the systemic and pulmonary circulations and to improve oxygen levels by redirecting venous blood directly to the lungs.
While the Fontan procedure creates a stable circulation, the risk of hospitalization and cardiac death rises significantly in the second and third decades after Fontan completion, a risk that is associated with a decline in exercise capacity. The Fontan circulation is also associated with non-cardiac complications such as protein-losing enteropathy, plastic bronchitis, and liver failure, all of which can be attributed to a chronic elevation in central venous pressure and a chronically reduced cardiac output. For all of these reasons, a 35-year-old patient who has gone through Fontan palliation has the approximate life expectancy of a 75-year-old with normal, but serious age-advanced, cardiac physiology.
