This clinical trial investigates the safety and preliminary effectiveness of YAP101, a gene therapy designed to improve heart function in adults with ischemic heart failure and reduced ejection fraction (HFrEF). Ischemic heart failure, often resulting from a prior heart attack, leads to poor heart function and quality of life. Current treatments are limited, and there is an urgent need for new therapies. YAP101 works by delivering a gene therapy using a specialized vector to heart cells, targeting a pathway involved in heart repair. By temporarily activating heart muscle regeneration, YAP101 aims to restore damaged tissue, reduce scarring, and improve the heart's pumping ability. The study will enroll participants who will receive a one-time dose of YAP101 via a minimally invasive cardiac injection. Researchers will monitor participants over 12 months to assess safety and changes in heart function, exercise tolerance, and quality of life.
This Phase I, single-center, open-label, dose-escalation trial evaluates the safety, tolerability, and preliminary efficacy of YAP101 in adults with ischemic heart failure and reduced ejection fraction (HFrEF). YAP101, a novel gene therapy, delivers adeno-associated virus with a cardiomyocyte-specific promoter to express short hairpin RNAs (shRNAs) targeting Salvador 1 (SAV1), a key regulator of the Hippo signaling pathway. By transiently suppressing this pathway, YAP101 aims to induce cardiomyocyte regeneration, reduce fibrosis, and improve myocardial function. Eligible subjects will undergo a one-time transendocardial injection of YAP101 at one of three dose levels (5.0e12, 1.0e13, or 5.0e13 viral genomes/subject) using an investigational cardiac injection catheter. Following administration, subjects will be monitored for safety and functional outcomes through a series of outpatient visits over 12 months. Primary endpoints include the incidence of dose-limiting toxicities, adverse events, and the determination of the maximum tolerated dose (MTD). Secondary endpoints include changes in cardiac function assessed via MRI, biomarkers, exercise tolerance, and quality of life metrics. Safety will be overseen by an independent Safety Review Team (SRT), which will assess data before dose escalation. The study employs a 3+3 dose-escalation design to identify the MTD while minimizing risks. Subjects who complete the study will have the option to enroll in a long-term follow-up study for up to 5 years. The trial addresses the significant unmet need for regenerative therapies in heart failure, leveraging preclinical evidence of efficacy and safety. YAP101 has shown promising results in animal models, improving cardiac function, reducing fibrosis, and enhancing myocardial repair without significant adverse effects.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
24
YAP101 delivered using YAPCATH-101
Texas Heart Institute
Houston, Texas, United States
RECRUITINGIncidence of the following: DLTs and AEs
Incidence of dose limiting toxicities and adverse events
Time frame: 12 months
Maximum tolerated dose
Maximum tolerated dose
Time frame: 12 months
Exercise tolerance by six minute walk test (6MWT)
6MWT distance change from baseline in meters
Time frame: 12 months
New York Heart Association (NYHA) Classification
NYHA Classification change from baseline (lower values indicate less severe disease, scale from class I to class IV)
Time frame: 12 months
Major Adverse Cardiac Events (MACE), including death, MI, revascularization with or without stroke, MACCE
Incidence
Time frame: 12 months
Hospitalization for HF and/ or other exacerbation of HF (non-hospitalization)
Incidence
Time frame: 12 months
Cumulative days alive and out of the hospital
Days and total days out-of-hospital as a % of total days alive post study intervention
Time frame: 12 months
LVEF by cardiac MRI
Change from baseline, %
Time frame: 12 months
LVEFI by cardiac MRI
Change from baseline, % per kg
Time frame: 12 months
LVEDV by cardiac MRI
Change from baseline, mL
Time frame: 12 months
LVEDVI by cardiac MRI
Change from baseline, mL per kg
Time frame: 12 months
LVESV by cardiac MRI
Change from baseline, mL
Time frame: 12 months
LVESVI by cardiac MRI
Change from baseline, mL per kg
Time frame: 12 months
Premature ventricular contraction (PVC) burden
Change from baseline, %
Time frame: 12 months
Atrial fibrillation (AFib) burden
Change from baseline, %
Time frame: 12 months
BNP (cardiac biomarker)
Change from baseline, %
Time frame: 12 months
NT-proBNP (cardiac biomarker)
Change from baseline, %
Time frame: 12 months
Health related quality of life as assessed by Minnesota Living with Heart Failure Questionnaire (MLHF)
Change in Score from baseline (lower values indicate higher quality of life, scale from 0-105)
Time frame: 12 months
Survival
Days
Time frame: 12 months
Cardiac transplant
Incidence
Time frame: 12 months
Left ventricular assist device (LVAD) implantation
Incidence
Time frame: 12 months
Anti-AAV9 capsid antibodies
Change in titer from baseline
Time frame: 12 months
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