VEGF-165 Plasmid Gene Therapy in Patients with Refractory Angina Fails to Improve Outcomes in the Northern Trial

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C. Michael Gibson, M.S., M.D.

WASHINGTON D.C. Administration of VEGF-165 plasmid gene therapy in patients with refractory angina has failed to improve clinical outcomes in the Northern Trial.

There are currently few options for those patients who do not have coronary anatomy that is suitable for either PCI or CABG. For over a decade now there has been intense interest in therapies to grow new small caliber vessels to supply the myocardium in a process called "angiogenesis". Pre-clinical studies in animal models have demonstrated the potential benefit of vascular endothelial growth factors or VEGF. Despite these positive pre-clinical studies, there has been a slew of failed human clinical trials including the FIRST, VIVA, REVASC and AGENT trials. Researchers have been unsure of the proper route and dose of administration. A significant "training effect" where placebo patients improve in the absence of therapy has also dogged angiogenesis research. VEGF can be a vasodilator and result in hypotension and this has limited the dose that can be administered.

Instead of administering low dose angiogeneic agents via an intravenous or intracoronary route, the NORTHERN investigators evaluated the administration of higher doses via a direct percutaneous intramyocardial gene transfer of VEGF165 plasmid DNA using NOGA mapping. A total of 93 patients were randomized in a double blind fashion to receive either VEGF165 plasmid (n=48) or saline (n=45).

The primary endpoint was SPECT perfusion which did not differ between the two arms. Likewise, there was also no difference in symptom class or exercise tolerance at 3 or 6 months in the two arms.

It should be noted that as in prior studies, both active treatment and placebo patients both improved over baseline indicating that the placebo effect or spontaneous development of collaterals may play a poorly understood but important role in this population.