Key Takeaways:
- TN-201, a first-in-class gene therapy, was well tolerated and showed stable cardiac gene expression, improved biomarkers, and symptom relief in patients with severe MYBPC3-associated hypertrophic cardiomyopathy.
- All treated patients improved from symptomatic NYHA class II/III at baseline to asymptomatic class I after TN-201 therapy, highlighting the potential clinical impact of gene replacement strategies in this challenging condition.
A novel gene therapy, TN-201, has demonstrated promising initial safety, tolerability, and early efficacy in patients with MYBPC3-associated hypertrophic cardiomyopathy (HCM), according to interim results from the MyPEAK-1 trial presented at the American College of Cardiology’s Annual Scientific Session (ACC.25).
The MyPEAK-1 study (NCT05836259) is an open-label, dose-escalation Phase 1b/2a trial assessing TN-201, an adeno-associated virus serotype 9 (AAV9)-based therapy designed to deliver a functional MYBPC3 gene directly to heart cells. MYBPC3 mutations are a major cause of HCM, leading to reduced levels of the essential protein Myosin-Binding Protein C (MyBP-C), cardiac dysfunction, and heart failure.
Three patients (mean age 39±10 years; two females, one male) received a single intravenous infusion of TN-201 at a dose of 3×10¹³ vector genomes/kg. These patients exhibited severe disease, including significant cardiac hypertrophy, prior myectomy surgeries, implanted defibrillators, and elevated cardiac biomarkers.
Results showed that TN-201 successfully reached cardiac tissue, demonstrating stable and increasing gene expression within cardiomyocytes. Cardiac biopsies confirmed the presence and stable persistence of TN-201 DNA and RNA, along with modest increases in MyBP-C protein levels. Cardiac biomarkers such as cardiac troponin I improved significantly, normalizing or nearing normal levels in two of the three patients by week 52. Cardiac structure and function were found to have improved or maintained stability as measured by left ventricular (LV) mass index, interventricular septum thickness, and LV posterior wall thickness. Heart failure symptoms also improved, with all patients progressing from NYHA class II or III at baseline to NYHA class I by week 26.
Safety evaluations indicated that TN-201 was generally well-tolerated. All three patients experienced transient, reversible elevations in liver enzymes managed successfully with prophylactic immunosuppression (prednisone and sirolimus). No significant cardiotoxicity or related serious adverse events occurred, and hematologic parameters remained stable throughout the follow-up.
These promising preliminary findings support ongoing enrollment and dose escalation to a higher dose of 6×10¹³ vg/kg in the next patient cohort.