Mezzion Pharma announces the presentation of the FUEL Trial data at the American Heart Association Meeting in Philadelphia

DEERFIELD, Ill., Nov. 17, 2019 /PRNewswire/ -- Mezzion Pharma Co. Ltd. (140410: KOSDAQ) today announces the presentation of data from its pivotal clinical trial for its new orphan drug for the treatment of adolescents with single ventricle heart disease.

Dr. David Goldberg, Pediatric Cardiologist, Children's Hospital of Philadelphia presented the top line results from the FUEL (Fontan Udenafil Exercise Longitudinal Trial) at the Annual Scientific Session of the American Heart Association (AHA) and in a Mezzion Sponsored scientific symposium titled "Fontan Physiology and Results of the FUEL Trial".  The primary aim of the FUEL trial was to improve the exercise capacity in adolescents with congenital single ventricle heart disease who have undergone a series of surgeries to palliate the effect of a missing ventricle in their heart.  The results of the 400 subject, double-blind, placebo-controlled study showed that the primary aim of improving exercise capacity in adolescents with congenital single ventricle heart disease (SVHD) was achieved. 

The top line data from the FUEL trial, which was designed to evaluate the safety and efficacy of udenafil for the treatment of SVHD adolescents,  showed that subjects taking udenafil over a 6-month period had a significant improvement in exercise capacity as measured by oxygen consumption at the ventilatory anerobic threshold (VO₂ at VAT).  Work rate at VAT and ventilatory equivalents of carbon dioxide at the VAT (VE/VCO₂) were likewise improved.  While peak VO₂ also improved, the data did not reach statistical significance. VO₂ at VAT measures the level of oxygen consumption at which one changes from aerobic to anaerobic activity, a clinically relevant level of exertion that is typical of what is encountered in routine exercise activity.  Work rate measures the power (watts) generated at the VAT while VE/VCO₂ is an index comparing the volume of CO₂ with the total respiratory volume. All of these measures demonstrated statistically significant improvement in the udenafil treated group compared to the placebo treated group, as described later in this Press Release.

The FUEL trial was conducted in partnership with the Pediatric Heart Network (PHN) at a total of 30 Pediatric Heart Network [http://www.pediatricheartnetwork.org] and auxiliary sites throughout the U.S., Canada, and Korea.  The PHN is funded by the National Heart, Lung, and Blood Institute, part of the National Institutes of Health. 

The Fontan Surgery

The Fontan operation is a palliative procedure for children born with functional single ventricle congenital heart disease.  Following the Fontan operation there is no ventricular pump to propel blood into the pulmonary arteries.  Instead the blood returns to the lungs via passive flow from the systemic veins.  This results in a circulation characterized by elevated central venous pressure and a chronically low cardiac output.  Over time, these inherent characteristics of Fontan physiology result in a predictable, persistent deterioration of cardiovascular efficiency, as marked by a progressive decline in exercise performance, a decline that accelerates after puberty.  This decline in cardiovascular efficiency is associated with the development of substantial morbidities and a significantly shortened life expectancy.

The Fontan Physiology and Exercise Capacity: VO₂ at VAT is the appropriate measure in Fontan subjects

Exercise capacity of study participants was measured in an exercise lab using a special stationary exercise bicycle that is programmed to increase resistance so that their maximum effort can be assessed.  The subject peddles the bicycle while wearing a special mask that allows for the measurement of oxygen consumption.  The bicycle automatically increases in resistance requiring the subjects to increase their effort and consume increasingly more oxygen up to their maximum effort.

In the symposium, Dr. Stephen Paridon, Pediatric Cardiologist and Exercise Physiologist, Children's Hospital of Philadelphia explained that exercise capacity can be measured by evaluating the maximal oxygen consumption at the subject's maximal effort (peak VO₂) or by measuring the oxygen consumption at the ventilatory anerobic threshold (VO₂ at VAT).  Peak VO₂ is the classical measurement of oxygen capacity in those with two functional ventricles, and therefore was used as the primary outcome measurement in the FUEL trial.  Dr. Paridon explained that the new finding from the FUEL trial and other relatively recent research suggest that peak VO₂ is not the most appropriate measurement to assess exercise capacity due the unique physiology resulting from the Fontan palliation.  Fontan subjects do not have a ventricle to pump the venous blood to the lung.  Blood flow to the lung depends solely on the central venous pressure in the body.  The central venous pressure in those who have undergone the Fontan operation is elevated at baseline, and typically rises 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.  While peak VO₂ demonstrated improvement of about 3.2% in the udenafil treated group vs 0% in the placebo group, statistical significance (p value=0.07) was not achieved.  

Dr. Paridon further explained that VO₂ at VAT, may be a more relevant measure of exercise capacity in the Fontan physiology because it occurs at a lower central venous pressure and appears to be less limited by this unique physiology.  VO₂ at VAT improved by 2.9% in the udenafil group versus a 1.0 % decline in the placebo group and was statistically significant (p value=0.009).  Significant improvement also was achieved in two other key parameters which independently demonstrate the Fontan subjects' improved exercise capacity at the ventilatory anerobic threshold: work rate at VAT and ventilatory efficiency (VE/VCO₂) at VAT.  Dr. Paridon explained that any improvement in VO₂ at VAT is clinically relevant to the SVHD patient population. 

Regulatory Status

A meeting with the Cardiovascular and Renal Division (DCaRP) of the US FDA was held on October, 8, 2019 for the purpose of presenting the topline data from the FUEL trial and to reach a concurrence with the FDA on the path forward toward submitting a new drug application (NDA) for the approval of udenafil for improving the exercise capacity in subjects with SVHD.

The FDA provided very helpful and constructive guidance.  Based on its initial review of the top line data from the FUEL trial, the FDA confirmed that Mezzion can proceed with the submission of the NDA for udenafil for improving the exercise capacity of SVHD subjects and that the submission would be "fileable" provided that the submission contained all of the required information.

Accordingly, in view of the positive results from the FUEL Trial and the safety data collected about udenafil, and in view of the constructive guidance by the FDA, Mezzion intends to expeditiously submit a New Drug Application to the FDA to seek approval for the use of udenafil to treat patients with SVHD who have undergone Fontan palliation.

Mezzion's Clinical Program

In addition to the pivotal FUEL trial, Mezzion continues forward in its clinical program in partnership with the PHN with a long-term study to evaluate the safety of udenafil (FUEL-OLE Study) ClinicalTrials.gov Identifier: NCT03013751) and a study to evaluate the effect of treatment on Fontan-associated Liver Disease (FALD study).  Because of the elevated central venous pressure, liver fibrosis, which can lead to liver cirrhosis, is prevalent in almost all Fontan subjects starting at a very early age.  (ClinicalTrials.gov Identifier: NCT03430583).   

Orphan Drug and Rare Pediatric Disease Status

On 31 August 2015, The Office of Orphan Products Development (OOPD) granted orphan drug status for udenafil in the treatment of single ventricle congenital heart disease with Fontan physiology [FDA Letter, OOPD, Designation Request #14-4497].  On 20 April 2017, OOPD designated udenafil for treatment of single ventricle congenital heart disease as a drug for "rare pediatric disease".

New Patents

Mezzion has submitted patent filings based on the new findings from the FUEL trial.  The new patents, if the claims are allowed, should further strengthen the patent position for Mezzion in the United States and elsewhere.  Mezzion is not only protected by different patent families, but its exclusivity is further enhanced by other forms of protection such as regulatory and proprietary know-how.  We believe that this matrix of intellectual property provides Mezzion with a unique position to provide a much-needed new pharmacotherapy to Fontan patients.

Udenafil

Udenafil is a unique phosphodiesterase (PDE)-5 inhibitor being developed in the United States (US) to improve and maintain exercise capacity in adolescents with Fontan physiology.  PDE5 inhibitors are a class of medications that have demonstrated utility in reducing pulmonary vascular resistance and improving ventricular performance in patients with pulmonary hypertension (Galie et al 2005; Humpl et al 2005; Behling et al 2008; Nagayama et al 2009; Guazzi et al 2011).  Udenafil is a unique PDE5 inhibitor that that has undergone Phase III testing in adolescents with Fontan physiology and has demonstrated excellent safety and tolerability in this population, in which cardiac output and exercise are limited by the absence of a sub-pulmonary ventricle.

Mezzion Pharma Co. Ltd.

Mezzion Pharma is headquartered in South Korea.  Mezzion Pharma and its wholly owned subsidiary, Mezzion Pharmaceuticals, Inc., have administrative offices in Deerfield, Illinois and Boca Raton, Florida.  Mezzion Pharma is an innovation-driven pharmaceutical company that is focused on discovering, developing, and commercializing novel therapeutics in the field of rare pediatric diseases.  Mezzion Pharma is a publicly-listed pharmaceutical company in Korea on the Korean stock exchange under (140410:KOSDAQ).

Forward-Looking Statements

Statements contained in this press release regarding matters that are not historical facts are "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995. Because such statements are subject to risks and uncertainties, actual results may differ materially from those expressed or implied by such forward-looking statements. Such statements include, but are not limited to, statements regarding: Mezzion Pharma's expectations regarding the potential benefits of udenafil; Mezzion Pharma's expectations regarding the anticipated timing of any future clinical trials; Mezzion Pharma's expectations on regulatory submissions for marketing approval of udenafil for the treatment of Fontan patients to improve exercise capacity in the United States, including the timing of these submissions; and Mezzion Pharma's expectations regarding the potential commercial launch of udenafil, including the timing of a potential approval of udenafil. Risks and uncertainties that contribute to the uncertain nature of the forward-looking statements include: the expectation that Mezzion Pharma will need additional funds to finance its operations; Mezzion Pharma's or any of its collaborative partners' ability to initiate and/or complete clinical trials; the unpredictability of the regulatory process; the possibility that Mezzion Pharma's or any of its clinical trials will not be successful; Mezzion Pharma's dependence on the success of udenafil; Mezzion Pharma's reliance on third parties for the manufacture of Mezzion Pharma's udenafil and udenafil tablets; possible regulatory developments in the United States and foreign countries; and Mezzion Pharma's ability to attract and retain senior management personnel.

These and other risks and uncertainties are described more fully in Mezzion Pharma's most recent filings with the Statements under the Private Securities Litigation Reform Act: with the exception of the historical information contained in this release, the matters described herein contain forward-looking statements that involve risk and uncertainties that may individually or mutually impact the matters herein described, including but not limited to FDA review and approval, product development and acceptance, manufacturing, competition, and/or other factors, which are outside the control of Mezzion Pharma. All forward-looking statements contained in this press release speak only as of the date on which they were made. Mezzion undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made.

Contact:

Dr. James Yeager
Tel: +1-847-2122679
Email: james.yeager@mezzion.com 
Deerfield, Illinois, USA

Mr. YT Song
Tel: +82 2 560 8011
Email: ytsong@mezzion.co.kr 
Seoul, Korea

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