United Therapeutics Receives FDA Clearance for First Human Trial of Genetically Modified Pig Heart Transplant
核心洞察
United Therapeutics Corporation received FDA clearance to begin the EXPRESS clinical trial, marking the first human study of a xenoheart intended for potential regulatory approval through a Biologics License Application.
The UHeart (搜索) is derived from pigs with 10 gene modifications, including six added human genes for immunological compatibility and four knocked-out porcine genes to reduce rejection risk.
The phase 1/2/3 trial will initially enroll up to two participants with end-stage heart failure, with potential expansion based on safety and efficacy data from the first transplants.
United Therapeutics Corporation announced that the U.S. Food and Drug Administration has granted clearance under the company's Investigational New Drug application to proceed with a clinical study of its investigational UHeart (搜索) derived from a pig with 10 gene edits. The study, known as EXPRESS, represents the first-ever human clinical trial of a xenoheart intended to support potential registration through the submission of a Biologics License Application to the FDA.
The trial will enroll an initial cohort of up to two participants, with United Therapeutics providing the FDA with safety and efficacy data from the first UHeart (搜索) xenotransplant recipient before enrolling a second participant. Following FDA review of available safety and efficacy data from the initial two transplants, the study may be further expanded to support a Biologics License Application.
Revolutionary Xenotransplantation Platform
"Moving a porcine-derived heart into human clinical trials represents another defining advancement for the field of xenotransplantation," said Kristina DeSmet, Ph.D., DABT, Senior Director, Product Development at United Therapeutics. "The heart is one of the most complex solid organs to transplant, and proceeding into the clinic reflects years of coordinated scientific progress."
This milestone represents United Therapeutics' third clinical trial in xenotransplantation and underscores the breadth of the company's platform, spanning end-stage renal disease and now life-threatening heart disease. The development reinforces the company's commitment to expanding transplant options for patients who currently have no other alternatives.
EXPRESS Trial Design and Endpoints
The study is designed as a phase 1/2/3 trial, sometimes referred to as a "phaseless" study, to evaluate safety and efficacy of the UHeart (搜索) seamlessly without moving through separate phase 1, phase 2, and phase 3 studies typically associated with conventional drug approvals. The trial will start at a single center, with potential expansion to additional centers if initial data are supportive.
Participants will receive a UHeart (搜索) transplant followed by a 24-week post-transplant follow-up period, including evaluation of all study endpoints and safety assessments. After the 24-week period, participants will continue to be followed for the rest of their lives, including for survival, UHeart survival, and screening for zoonotic infections.
Safety and efficacy data will be reviewed frequently by an independent Data Monitoring Committee. After at least 12 weeks post-transplant of the first participant, United Therapeutics will provide data to FDA prior to initiating a second transplant.
Primary Efficacy Measures
Efficacy endpoints include participant survival rate, UHeart (搜索) survival rate, UHeart function, change in quality of life in participants at 24 weeks post-transplant, and participant exercise capacity. Overall survival time of participants receiving a UHeart and overall survival time of the UHearts themselves are also efficacy endpoints.
Safety Monitoring
Safety endpoints include the incidence of adverse events and serious adverse events, all-cause mortality, and the incidence of arrhythmias, thromboembolic and ischemic strokes, zoonotic infections, and opportunistic infections.
Patient Population and Eligibility
Key participation criteria include patients 50 years of age or older, diagnosed with end-stage or advanced heart failure classified as American College of Cardiology/American Heart Association stage D and New York Heart Association Class IV, with no remaining therapeutic options. Participants will be screened using a crossmatch assay to assess expected immunological compatibility with the UHeart (搜索).
Exclusion criteria include patients needing multiple organ transplants, those with prior solid organ transplants, patients requiring venoarterial ECMO support, and those with severe medical co-morbidities including chronic liver disease, severe central vascular disease, severe neurologic diseases, and uncontrolled diabetes.
Addressing Critical Medical Need
According to the Journal of Cardiac Failure, nearly 6.7 million adults 20 years of age or older have heart failure in the United States, and in 2023, heart failure was responsible for 14.6% of all causes of death according to a CDC report. In 2023, only a fraction of Americans with heart failure were considered candidates and waitlisted for a human heart transplant (0.12% or 8,000 Americans), and only approximately 4,000 heart transplants were performed.
"Patients with end stage heart disease continue to face profound limitations in available treatment options," said Noah Byrd, Ph.D., RAC, Vice President, Global Regulatory Affairs at United Therapeutics. "This FDA clearance to proceed with our EXPRESS clinical trial will allow us to begin evaluating an innovative therapeutic option designed to address this unmet need."
UHeart Technology
United Therapeutics' xenoheart, known by the proposed trade name UHeart (搜索), is an investigational xenoheart from a pig with 10 gene edits. Six human genes are added to the pig genome to facilitate immunological acceptance and compatibility of the organ in the human recipient. Four porcine genes are inactivated or "knocked out" to reduce the risk of organ rejection and to moderate growth.
The development represents a significant advancement in xenotransplantation technology, potentially offering a solution to the critical shortage of donor hearts available for transplantation.