Tenaya Therapeutics Reveals Critical Risk Factors in Largest Pediatric MYBPC3-Associated HCM Study
核心洞察
Tenaya Therapeutics presented interim data from MyClimb, the largest natural history study of pediatric MYBPC3-associated hypertrophic cardiomyopathy (搜索) with 213 participants under 18 years old.
The study revealed that 93% of participants had nonobstructive HCM with no approved treatments, and genetic inheritance patterns significantly predict disease severity and outcomes.
Left Ventricular Mass Index emerged as a significant predictor of risk, with every 10-unit increase associated with 10% higher hazard of serious events.
Tenaya Therapeutics has unveiled critical findings from the largest natural history study of pediatric MYBPC3-associated hypertrophic cardiomyopathy (搜索) (HCM), revealing distinct genetic risk profiles that could transform how clinicians approach treatment decisions for children with this rare heart condition. The interim data from the MyClimb study, presented at the European Society of Cardiology Congress, analyzed 213 patients diagnosed before age 18 and identified key predictors of disease severity and progression.
Genetic Inheritance Patterns Drive Disease Severity
The study stratified participants into three genetic inheritance groups, each showing dramatically different clinical outcomes. Homozygous patients, born with two pathogenic truncating variants in MYBPC3 (搜索), experienced the most severe disease course with nearly all requiring heart transplant or dying before age one. Compound heterozygous participants, carrying one truncating variant and one missense variant, had a median diagnosis age of 2.9 years and faced severe cardiomyopathy with 63% requiring heart failure (搜索)-related hospitalization and 27% experiencing transplant or death.
Heterozygous children, with one pathogenic variant, showed a later median diagnosis age of 6.5 years, though 27% still experienced heart failure (搜索)-related hospitalizations and 13% developed arrhythmia-related symptoms.
"The interim data from MyClimb presented at ESC highlight the distinct risks of complications, heightened severity and rapid rate of disease progression experienced by pediatric patients with MYBPC3 (搜索)-associated HCM," said Georgia Brugada, M.D., Pediatric Cardiologist at SJD Barcelona Children's Hospital (搜索) and MyClimb study investigator.
Left Ventricular Mass Index Emerges as Key Prognostic Marker
Initial modeling identified Left Ventricular Mass Index (LVMI) as a significant predictor of risk in compound heterozygous and heterozygous groups. Every 10-unit (g/m²) increase in LVMI was associated with a 10% higher hazard of serious events, suggesting LVMI could serve as a surrogate marker for evaluating early effectiveness of gene therapy in future pivotal studies.
"Data obtained from MyClimb offer actionable information for predicting those severe MYBPC3 (搜索)-associated HCM pediatric patients who may be at higher risk of death or severe complications, such as life-threatening ventricular arrhythmias (搜索), cardiovascular-related hospitalizations, heart failure (搜索), sudden cardiac arrest (搜索), and/or heart transplant," said Whit Tingley, M.D., Ph.D., Tenaya's Chief Medical Officer.
Massive Unmet Medical Need Highlighted
The study revealed that 93% of participants had the nonobstructive HCM phenotype, for which no approved treatment options currently exist. This finding underscores the significant therapeutic gap in pediatric HCM management, where current interventions like implantable cardioverter defibrillators and heart transplant are highly invasive and don't address the underlying genetic cause.
Study Design and Population
MyClimb enrolled participants from 27 centers across the U.S., Canada, Spain, and the UK, with retrospective data available for 173 participants and prospective data for 42. The study, initiated in 2021, represents the largest investigation of pediatric MYBPC3 (搜索)-associated HCM ever conducted.
MYBPC3 (搜索)-associated pediatric-onset HCM comprises approximately 17% of all MYBPC3-driven HCM cases, with 2% presenting in infancy. In the U.S. alone, an estimated 3,000 children currently have the condition, with 13,000 individuals diagnosed before age 18 who are now adults.
Implications for Gene Therapy Development
The findings provide crucial insights for advancing TN-201, Tenaya's AAV9-based gene therapy designed to deliver a functional MYBPC3 (搜索) gene to heart muscle cells. The therapy aims to increase MyBP-C protein (搜索) levels and address the underlying cause of MYBPC3-associated HCM through a single intravenous infusion.
TN-201 has received Fast Track, Orphan Drug, and Rare Pediatric Drug Designations from the FDA, along with orphan medicinal product designation from the European Commission. Tenaya plans to report longer-term follow-up data from its first cohort and initial data from a second cohort in the fourth quarter of 2025.
The MyClimb data will inform clinical trial design by helping establish endpoints and eligibility criteria for pediatric gene therapy studies, potentially accelerating development of disease-modifying treatments for this vulnerable population with high unmet medical need.