First-in-class gene therapy for HCM

A potential first-in-class gene therapy for patients with MYBPC3-associated hypertrophic cardiomyopathy (HCM) delivered promising results in a first analysis from the phase 1b/2a MyPEAK-1 trial.

The investigational gene therapy TN-201 was designed to deliver a full-length functional copy of the MYBPC3 gene to cardiomyocytes, targeting the cause of MYBPC3-associated HCM. “It is expected that expression of the MYBPC3 gene increases myosin-binding protein C (MyBP-C) protein levels and restores sarcomeric function,” explained Dr Milind Desai (Cleveland Clinic, OH, USA) [1]. The MyPEAK-1 trial (NCT05836259) evaluated 2 dose levels across 2 cohorts, with 3 participants enrolled per cohort. “The included participants had New York Heart Association (NYHA) class II or III,” added Dr Desai.

Two treatment-related adverse events (AEs) were reported: a case of moderate transaminase elevation, treated with intravenous steroids in the hospital, and a case of mild complement elevation, monitored in the hospital. In addition, 4 participants experienced reversible elevations in liver enzymes. “All 6 participants have tapered off prophylactic immunosuppression with prednisone and sirolimus,” noted Dr Desai. “Another positive element was that we did not see signs of cardiotoxicity.”

The research team observed relative increases in MyBP-C protein levels of 5%, 2%, 5%, and 14% in participants 1, 2, 3, and 6, respectively. “The first patient from cohort 2, the higher dose cohort, demonstrated a dramatic increase in MyBP-C protein after only 12 weeks of therapy,” Dr Desai commented regarding participant 6. Furthermore, all 3 participants from cohort 1 with at least 26 weeks of follow-up improved to New York Heart Association (NYHA) class 1. Lastly, reductions in left ventricular posterior wall thickness suggested favourable cardiac remodelling.

The investigational first-in-class gene therapy for HCM was generally well tolerated, demonstrated a functional mechanism, and was associated with cardiac remodelling. “I’m excited to see more data from this study and its expansion study in the near future,” Dr Desai concluded.

1. Desai M, et al. Interim data from MYPEAK-1, a phase 1b/2a study of TN-201 gene therapy for MYBPC3-associated HCM. AHA scientific sessions 2025, 7-10 November, New Orleans, LA, USA.

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Posted on 5 December 202515 December 2025