A first-in-human exploratory clinical study of JV101 in patients with dilated cardiomyopathy caused heart failure

Introduction Dilated cardiomyopathy (DCM) is a non-ischemic cardiomyopathy with structural and functional abnormalities of the myocardium. The World Health Organization (WHO) defines DCM as a serious cardiac disease that can lead to substantial morbidity and mortality. Telomeres are cap-like structures of DNA repeat sequences located at the ends of chromosomes. Recent studies suggest that telomere length can influence cardiac function and plays an important role in telomere-related cardiomyopathies. JV101 is an AAV9-based gene therapy product that delivers a catalytically inactivated human telomerase reverse transcriptase (CI-TERT) gene into cardiomyocytes, thereby restoring the telomere deprotection status. Methods This study adopts an open-label, single-arm, single-center, dose-escalation design to explore the safety, pharmacokinetics, immunogenicity, and preliminary efficacy of a single intracoronary administration of JV101 Injection in patients with DCM-caused heart failure (HF). Two dose levels were evaluated: 2×1011 vg/kg and 6×1011 vg/kg. Each dose cohort enrolled 6 patients (NYHA class II-IV). After dosing, patients were observed for 28 days for dose-limiting toxicity (DLT) assessment. Clinical chemistry, echocardiography combined with LVO and CMR assessments were performed at designated time courses after dosing. Results No DLT was reported within 28 days in both low-dose group (2×1011 vg/kg) and high-dose group (6×1011 vg/kg), and the maximum-tolerated dose (MTD) was not reached. No serious adverse events (SAEs) related to JV101 were observed. No safety risks clearly attributed to immunogenicity were identified. The efficacy data demonstrated a sustained increasing trend in left ventricular ejection fraction (LVEF), accompanied by decreasing in left ventricular end-diastolic volume (LVEDV), indicating a reduction in left ventricular dilatation with structural remodeling and progressive improvement in left ventricular systolic function. In addition, the enhancement of right ventricular performance was observed. More than 50% of subjects demonstrated improvement in exercise capacity and approximately 50% subjects showed improvement in HF symptoms and quality of life, with overall downward trend of NT-proBNP levels. Conclusion A single intracoronary administration of JV101 at doses of 2×1011 vg/kg and 6×1011 vg/kg demonstrated a favorable safety profile, efficacy data showed that both dose groups promoted cardiac reverse remodeling and functional improvement, supporting further exploration of JV101 in larger scale clinical studies.