메지온, Mezzion Pharma Submits Protocol for Confirmatory Pivotal Phase 3 Trial ("FUEL-2") in Fontan Subjects

 

번역

한국, 서울, 2023년 2월 21일 / PR Newswire/ -- 메지온파마 주식회사(메지온파마)는 확인의 중추적인 폰탄 피험자 3상 임상시험을 식품의약국(FDA)에 제출했다.

FDA와 메지온 간의 B형 회의에서, FDA는 메지온에게 우데나필을 사용한 폰탄 피험자의 치료에 대한 FDA 승인을 위한 명확한 경로를 제공했다. B형 회의에서 FDA와 3상 임상시험에 대한 요구사항에 대한 합의가 이루어졌다. 메지온은 B형 회의에서 FDA와 합의한 내용과 일치하는 FUEL-2 시험을 위한 새로운 프로토콜을 심장신장학부에 제출했다고 보고했다.

폰탄 피험자의 심혈관 효율은 청소년기를 거쳐 성인기까지 악화된다. 이러한 악화는 운동 능력의 감소와 심부전 증상, 입원 및 사망률의 증가와 관련이 있다. Mzzion은 FUEL-2 확인 실험이 만성 우데나필 치료가 그들의 운동 능력을 향상시켜 심각한 질병의 발병까지 잠재적으로 시간을 연장시킬 것이라고 믿는다.

FUEL-2 Trial 프로토콜은 원래의 3단계 FUEL Trial과 FDA와의 합의에서 배운 내용을 기반으로 합니다. 연구 인구는 기준 심폐 운동 테스트 성능을 기반으로 운동 능력을 향상시킬 가능성이 가장 높은 퐁탄 완화 및 퐁탄 생리학을 가진 단일 심실 심장 질환 피험자가 될 것이다. 개정된 포함/제외 기준에 따라 FUEL-2는 "슈퍼 폰탄"으로 정의된 대상 대상을 제외한다."

원래 FUEL 시험에서 슈퍼 폰탄을 제외한 약 300명의 피험자의 유사 모집단에 대한 애드혹 분석은 약 150명의 피험자의 우데나필 처리 그룹과 약 150명의 위약 그룹의 평균 피크 VO2를 비교하여 p-값 0.023에서 통계적으로 유의했다. 환기 혐기성 임계값("VAT"), 작업 속도, VAT에서의 산소 소비량 및 환기 효율성의 중요한 2차 엔드포인트도 평가된다. 이러한 2차 엔드포인트는 모두 FUEL Trial에서 약 200명의 피험자에 대해 통계적으로 유의했다.

FUEL-2는 약 400명의 피실험자의 표본 크기를 가진 이중 블라인드 위약 대조 시험으로 설계되었다. 일차 효능 끝점은 최대 심폐 운동 테스트에 의해 측정된 최대 산소 소비량(VO2 mL/kg/min)이 기준에서 26주로 변경되는 것이다. FDA와 합의한 바와 같이, 성공에 대한 통계적 기준은 10%의 유의성의 양면 수준(p<0.1)이 될 것이다. 중간 분석은 피험자의 약 50%가 90% 출력에서 0.1의 양면 알파의 통계적 기준을 충족하기 위해 필요한 최종 표본 크기를 결정하기 위해 시험을 완료할 때 수행된다. 

FUEL-2의 주요 목적은 일차 종점의 통계적 중요성을 얻는 것이기 때문에 FUEL-2는 FUEL 시험에 비해 절차가 적을 것이다. 따라서 메지온은 FUEL-2 프로토콜이 FUEL Trial 프로토콜보다 더 간단하고 간단하다고 믿는다. 메지온은 또한 FUEL-2 프로토콜이 피험자들에게 더 편리하고, 현장 수준에서 임상 운영을 용이하고 신속하게 할 것이며, 등록 및 모집 과정을 간소화할 것이라고 믿는다. 

전 세계적으로 약 30개의 사이트가 새로운 FUEL-2 확인 시험에 참여할 것이다. 스터디 등록은 앞으로 몇 주 안에 시작될 것으로 예상됩니다.

Fontan 절차 및 이후 기대 사항

폰탄 시술은 단 하나의 기능적 펌핑 챔버를 특징으로 하는 선천성 심장질환을 가지고 태어난 아이들의 생존을 가능하게 하는 수술적 중재이다. 이 절차는 단일 심실이 혈액을 폐로 가져오는 동맥에 직접 대정맥을 연결하면서 혈액을 몸으로 펌프질할 수 있도록 순환을 재구성하는 것으로 구성된다. 이 "폰탄 순환"에서 몸에서 돌아오는 혈액은 심장을 우회하여 전용 우심실 펌프실의 도움 없이 폐로 이동한다. Fontan 시술의 목표는 정맥혈을 폐로 직접 이동시킴으로써 전신 순환과 폐 순환을 분리하고 산소 수준을 향상시키는 것입니다.

Fontan 시술은 안정적인 순환을 만드는 반면, Fontan 시술 후 2~30년에는 입원 및 심장사의 위험이 크게 증가하며, 이는 운동능력 저하와 관련된 위험이다. 퐁탄 순환은 또한 단백질 손실 장염, 플라스틱 기관지염, 간부전과 같은 비심박 합병증과 관련이 있으며, 이 모든 것은 중앙 정맥압의 만성 상승과 만성적인 심박출량 감소에 기인할 수 있다.

 

원문

SEOUL, South Korea, Feb. 21, 2023 /PRNewswire/ -- 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.

Mezzion Pharma Co., Ltd.

Mezzion Pharma Co., Ltd. is headquartered in Korea. Mezzion 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 patients that have undergone the Fontan operation, 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, Deerfield, Illinois, USA, Tel: +1-847-2122679Email: james.yeager@mezzion.com

Mr. S.I. Noh, Seoul, Korea, Tel: +82 2 560 8000Email: 09428lgtokyo@mezzion.co.kr

SOURCE Mezzion Pharma Co. Ltd.