Mezzion Pharma Receives Clear FDA Path Forward for the Approval of Udenafil for Single Ventricle Heart Disease
Mezzion Pharma Co., Ltd. (Mezzion Pharma) met with the FDA Division of Cardiology and Nephrology (DCN) on Friday, May 27th to discuss with the FDA the path forward for the regulatory approval of udenafil for the treatment of single ventricle heart disease (SVHD) in children with Fontan physiology. More specifically, Mezzion sought clarity on the critical elements of an additional clinical trial that may be needed to complete the NDA submission.
The FDA responded to the Meeting Background Package that was submitted by Mezzion to DCN with detailed advice and direction for the path forward for an FDA approval. Specifically, only one new clinical trial, FUEL-2, will be needed. FUEL-2 will be similar to the previously completed FUEL-1 trial (Double-Blind, Placebo Controlled Safety and Efficacy Trial) in the adolescent and young adult population. The primary difference in FUEL-2 will be the exclusion of 'Super Fontan' patients with peak VO₂ ≥ 80% of predicted to avoid de-enriching the FUEL-2 study population. We learned from FUEL-1 that 'Super Fontan" patients are at near-maximum physiologic value and, thus, their peak VO2 cannot be meaningfully further improved. We therefore learned from FUEL-1 that, when the 'Super Fontan' patients were excluded (n=300) from the FUEL-1 study population, the subgroup met both the primary (p-value=0.023) and secondary endpoints. We are therefore confident that we will achieve similar statistical significance for the primary and secondary endpoints in FUEL-2 with an enriched target population.
If the additional new trial meets statistical significance on the primary endpoint, then FDA agreed that it will be considered a positive trial and sufficient for approval. The FDA also advised that meeting statistical significance on the secondary endpoints, while enhancing the potential labeling for the product, would not be a prerequisite for approval. Mezzion anticipates enrolling the first patient within the next few months.
The FDA agreed with Mezzion regarding the specific primary and secondary endpoints to use for the measurement of function capacity in trial subjects in the new trial, FUEL-2, and further agreed that the protocol for this new trial would be reviewed by DCN under a Special Protocol Assessment.
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.
