Abstract Body (Do not enter title and authors here): Background: In hypertrophic cardiomyopathy (HCM), pathogenic and likely pathogenic mutations in the myosin-binding protein C (MYBPC3) gene lead to reduced levels of MyBP-C protein, resulting in progressive left ventricular (LV) hypertrophy, diastolic dysfunction, arrhythmias, and heart failure. TN-201 is a first-in-class adeno-associated virus 9 (AAV9) mediated MYBPC3 gene replacement therapy designed to increase MyBP-C protein levels, thereby potentially reversing disease progression and ameliorating symptoms of HCM. Initial clinical data on the first-in-human (FIH) trial of TN-201 has demonstrated early evidence of positive tolerability, increases in MyBP-C protein level, and reductions in hypertrophy. We will report new data on two dose levels of TN-201 in an FIH trial of TN-201 in MYBPC3+ HCM patients.
Methods: MyPEAK-1 (NCT05836259) is an open-label, dose escalation, FIH trial to evaluate the safety, tolerability, and efficacy of TN-201. We included MYBPC3+ HCM adult patients with LVEF ≥50%, New York Heart Association Class II/III, and N-terminal prohormone of brain natriuretic peptide (NT-proBNP) ≥300 pg/mL. The first 3 patients received a single TN-201 dose of 3x10¹³ vector genomes per kg (vg/kg), followed by another 3 patients who received a dose of 6x10¹³ vg/kg. Patients are monitored by an independent safety committee and take prophylactic immunosuppression before and after TN-201 infusion, using an individualized tapering regimen. Serial assessments, including endomyocardial biopsy (EMB) to measure molecular markers of TN-201’s effect, are performed, with follow-up through year 5.
Results: Six symptomatic MYBPC3+ HCM patients (5 females and 1 male, 48±13 years, all with nonobstructive HCM, all with ICDs, and 4 of 6 with history of septal myectomy) received a single intravenous infusion of TN-201. At baseline, mean LV ejection fraction and maximal LV wall thickness were 65±3.4% and 1.9±0.26 cm, respectively. Mean NT-proBNP was 827±593 pg/ml and mean peak oxygen consumption was 18±4.4 ml/kg/min. We will present data at both dose levels which indicate that TN-201 remains well-tolerated.
Conclusion: In symptomatic adult HCM patients with MYBPC3 mutations, we will share short- and long-term data from both 3E13 vg/kg and 6E13 vg/kg dose cohorts, respectively, on safety and tolerability, TN-201 effect on MyBP-C protein levels and other molecular markers from EMB, and efficacy from a Phase 1b/2a trial of TN-201 gene replacement therapy.