Long-term safety and efficacy of intramyocardial adenovirus-mediated VEGF-DΔNΔC gene therapy eight-year follow-up of phase I KAT301 study

Abstract

In phase I KAT301 trial, intramyocardial adenovirus-mediated vascular endothelial growth factor -D^ΔNΔC (AdVEGF-D) gene therapy (GT) resulted in a significant improvement in myocardial perfusion reserve and relieved symptoms in refractory angina patients at 1-year follow-up without major safety concerns. We investigated the long-term safety and efficacy of AdVEGF-D GT. 30 patients (24 in VEGF-D group and 6 blinded, randomized controls) were followed for 8.2 years (range 6.3-10.4 years). Patients were interviewed for the current severity of symptoms (Canadian Cardiovascular Society class, CCS) and perceived benefit from GT. Medical records were reviewed to assess the incidence of major cardiovascular adverse event (MACE) and other predefined safety endpoints. MACE occurred in 15 patients in VEGF-D group and in five patients in control group (21.5 vs. 24.9 per 100 patient-years; hazard ratio 0.97; 95% confidence interval 0.36-2.63; P = 0.95). Mortality and new-onset comorbidity were similar between the groups. Angina symptoms (CCS) were less severe compared to baseline in VEGF-D group (1.9 vs. 2.9; P = 0.006) but not in control group (2.2 vs. 2.6; P = 0.414). Our study indicates that intramyocardial AdVEGF-D GT is safe in the long-term. In addition, the relief of symptoms remained significant during the follow-up.

Fig. 1. Incidence of major adverse cardiovascular event (MACE).

A The solid line represents the cumulative incidence of MACE in the VEGF-D group and the dashed line represents the incidence in the control group. B The bars show the proportion of patients with MACE or its individual component during the follow-up. ACS acute coronary syndrome, CABG coronary artery bypass grafting, CV cardiovascular, GT gene therapy, MACE major adverse cardiovascular event, PCI percutaneous coronary intervention, VEGF-D vascular endothelial growth factor D.

Fig. 2. Canadian Cardiovascular Society (CCS) score at baseline and after the follow-up.

The bars represent mean with 95% confidence interval. CCS Canadian Cardiovascular Society, VEGF-D vascular endothelial growth factor D.