Tenaya Therapeutics announced encouraging early data from the Phase 1b MyPEAK-1 clinical trial of TN-201, a gene therapy being developed for MYBPC3-associated hypertrophic cardiomyopathy (HCM). The initial results, presented in December 2024, offer a cautiously optimistic outlook on the potential of TN-201 to address the underlying genetic cause of this heart condition. The study is designed to assess the safety, tolerability, and clinical efficacy of a one-time intravenous infusion of TN-201 gene replacement therapy.
The MyPEAK-1 trial is enrolling symptomatic adults (New York Heart Association Class II or III) diagnosed with MYBPC3-associated HCM. The trial is testing doses of 3E13 vg/kg and 6E13 vg/kg in two cohorts of three patients each and may enroll up to 24 MYBPC3-associated HCM adults with either nonobstructive or obstructive forms of HCM in planned dose expansion cohorts.
Initial Findings from MyPEAK-1
Preliminary data from the first cohort of three patients, who received a 3E13 vg/kg dose of TN-201, indicated that the gene therapy was generally well-tolerated. The most notable adverse event was isolated elevations in liver enzymes, which were managed with corticosteroids and not associated with other signs of liver damage. No cardiac toxicities, complement activation-associated adverse effects, or thrombotic microangiopathy (TMA)-related events were observed.
According to Tenaya, vector DNA was readily detectable in the heart tissue of the treated patients, with evidence of transgene RNA expression. Serial biopsies showed increasing TN-201 mRNA and MyBP-C protein levels over time. Circulating biomarkers of cardiac muscle strain and injury remained largely stable, and certain clinical markers of disease showed stability or directional improvement in the first two individuals dosed.
Key Observations
- Safety and Tolerability: TN-201 demonstrated a manageable safety profile at the initial dose level.
- Cardiac Transduction: The AAV9 capsid facilitated robust delivery of the TN-201 transgene to heart muscle cells.
- Protein Expression: Increasing RNA expression and an increase in MyBP-C protein levels were observed at one year in one patient.
- Clinical Measures: Circulating biomarkers and other clinical measures mostly remained stable or improved from baseline.
Milind Desai, an investigator for the MyPeak-1 Phase 1b/2 clinical trial, noted, "The goal of gene therapy is to halt or even reverse the steady decline in MYBPC3-associated HCM by addressing the underlying genetic cause of disease. Initial data from this first-in-human clinical trial of TN-201 demonstrate tolerability and early evidence of protein expression support additional investigation to build on these findings."
Next Steps for TN-201
Tenaya Therapeutics has initiated dosing in Cohort 2 of the MyPEAK-1 trial, which will evaluate a higher dose of TN-201. The company anticipates reporting additional data from Cohort 1 in the first half of 2025, including 52-week biopsy data for Patient 2 and baseline and post-dose biopsy data for Patient 3. Initial data from Cohort 2 are expected in the second half of 2025.
About MYBPC3-Associated Hypertrophic Cardiomyopathy
MYBPC3-associated HCM is a genetic heart condition caused by mutations in the MYBPC3 gene, leading to insufficient levels of MyBP-C protein. This deficiency results in hypercontractility and thickening of the left ventricle, causing symptoms such as chest pain, shortness of breath, and palpitations. Approximately 20% of HCM cases are attributed to MYBPC3 mutations, affecting an estimated 120,000 individuals in the United States alone.
TN-401 for ARVC
Tenaya is also advancing TN-401, a gene therapy for PKP2-associated arrhythmogenic right ventricular cardiomyopathy (ARVC). Initial data from the RIDGE-1 Phase 1b clinical trial of TN-401 are expected in the second half of 2025. TN-401 is designed to deliver a functional PKP2 gene to heart muscle cells, addressing the underlying cause of ARVC.
Strategic Priorities for 2025
Tenaya Therapeutics is focused on driving the advancement of TN-201 and TN-401 gene therapies for cardiomyopathies. The company plans to present data from its pediatric non-interventional natural history study, MyClimb, in the second half of 2025, and data from the non-interventional natural history and seroprevalence study (RIDGE) in the first half of 2025.
