In interim data from the MyPEAK-1 Phase 1b/2a study of TN-201 in MYBPC3-associated hypertrophic cardiomyopathy, three patients treated at 3E13 vg/kg showed sustained biomarker and structural improvements through 52–78 weeks: cardiac troponin I declined 48%–74% to normal or near-normal, left ventricular posterior wall thickness fell 21%–39%, and two of three reduced left ventricular mass index by 12%–22%. All improved at least one NYHA class by Week 26 and are now Class I. Early readouts at 6E13 vg/kg indicate dose-responsive pharmacology: the first evaluable patient showed a 14% increase in MyBP-C protein at Week 12 and transduction and mRNA expression that were more than double the Cohort 1 averages. Safety across both cohorts (n=6) showed no dose-limiting toxicities, no declines in LVEF, and no clinical myocarditis or ventricular arrhythmias; reversible Grade 1–3 transaminase elevations were the most common adverse events. Two treatment-related events were classified as serious for monitoring or inpatient management: Grade 2 transaminase elevation that responded to steroids and a transient Grade 1 complement factor rise that resolved without intervention.
The core development is Tenaya’s presentation of these AHA late-breaking data, including longer-term follow-up for Cohort 1 and initial Cohort 2 pharmacodynamics, alongside simultaneous journal publication. The study enrolled severely affected, nonobstructive HCM patients with high baseline risk, reflected by universal ICD use and prior myectomy in four of six. An FDA clinical hold complicates the program’s trajectory, announced the day before the presentation, following a DSMB decision in July that supported expansion at either dose level.
Strategically, the dataset offers the type of disease-modifying signal gene therapy proponents have sought in cardiomyopathies: directionally consistent normalization across biomarkers, hypertrophy metrics, and symptoms after a single dose, with emerging dose response on transduction and protein restoration. Just as necessary operationally, Cohort 2 incorporated protocol refinements that yielded faster immunosuppression tapers and lower cumulative steroid exposure despite the higher vector dose. This execution detail matters for scalability and site burden. The hold now becomes the central gating factor. Without further information on its basis, the most plausible pressure points are those that typically trigger review in AAV9 programs—precisely the levers Tenaya has been tuning—such as hepatic enzyme dynamics, complement activation, and immunosuppression management.
For sites, the pause stalls momentum just as workflows for IV AAV administration, biopsy-based pharmacodynamics, hepatic and complement monitoring, and individualized immunosuppression are being operationalized. Expansion-cohort activation, pharmacy preparation, vector storage, and steroid taper protocols will remain idle pending protocol amendments, with implications for staffing and budgeting. For sponsors and CROs, the signal supports a path to dose selection and late-stage planning, but the hold raises timelines, manufacturing lot planning, and regulatory engagement risk. Regulators are likely to scrutinize durability beyond 12 months, the relationship between protein restoration and clinically meaningful outcomes, and the feasibility of broader deployment given the need for high-touch monitoring.
Next steps hinge on how quickly Tenaya resolves the hold and what changes are required—additional safety monitoring, adjusted taper schedules, biopsy timing, or exclusion criteria. Near-term readouts to watch include maturing Cohort 2 pharmacodynamics at 26 and 52 weeks, 24-month durability in Cohort 1, and consistency of structural regression across patients. Dose selection will signal whether the program prioritizes maximal transduction or operational margin in terms of safety and immunosuppression. Long-run risks include immunogenicity that precludes re-dosing, manufacturing scale at 6E13 vg/kg, and endpoint strategy for registration in a genetically defined HCM subset. If the hold is resolved with manageable protocol updates and the dose-response persists with sustained clinical benefit, TN-201 could become a leading test case for cardiac gene replacement, moving into late-stage development.
Jon Napitupulu is Director of Media Relations at The Clinical Trial Vanguard. Jon, a computer data scientist, focuses on the latest clinical trial industry news and trends.
