Cardiac Gene Therapy: What Else is Happening?

CardioGenesis Corporation Mark Hodge, General Manager, CardioGenesis Corporation, Foothill Ranch, California, with input from: Emerson Perin, MD, Texas Heart Institute, Houston, Texas, and Samuel DeMaio, MD, Austin Cardiovascular Associates, Austin, Texas CardioGenesis designs and distributes laser-based surgical products that promote cardiac angiogenesis currently via Transmyocardial Revascularization (TMR). TMR is a surgical procedure performed on the beating or arrested heart, in which a delivery system is used to focus laser energy on cardiac tissue. This laser energy is used to create pathways (transmural channels) through the myocardium. The purpose of these pathways is NOT to remain patent and carry blood to the myocardium, but rather to stimulate an angiogenic response within the myocardium so that new blood vessels may relieve the localized ischemia. TMR reduces angina symptoms in patients with refractory angina and is performed using several different surgical approaches, including open chest surgery and minimally invasive surgery through small openings in the chest. TMR offers end-stage cardiac patients who are not candidates for PTCA or CABG a means to alleviate their symptoms and improve their quality of life. It is performed both as a sole therapy and in conjunction with CABG. There is a catheter-based approach to TMR, called Percutaneous Myocardial Revascularization (PMR). PMR is currently available internationally and is being reviewed by the FDA for use in the United States. Clinical trials such as PACIFIC, BELIEF, and PMR10 have demonstrated significant clinical benefit (> 2 class angina improvement and exercise tolerance improvement) and it has been postulated and demonstrated that these benefits are resultant of an angiogenic response to cardiac tissue inflammation created by the PMR laser channels: 1. PMR, with the CardioGenesis Ho:YAG laser system, in a study by Wiemer (Heart Center North Rhine-Westphalia, Bad Oeynhausen, Germany “ Presented to AHA 2001, Anaheim, California, Pending Publication), et al, shows improved myocardial perfusion 6 months after PMR and this improvement was statistically significant and correlated to observed clinical improvement. 2. PMR, with the CardioGenesis Ho:YAG laser system, has been shown to increase amounts of neutrophils (both circulating and inside the treated myocardial areas) along with raising the levels of procalcitonin (Bortone, et al, Annals of Thoracic Surgery 2000; 70:1134-8). This systemic and intramyocardial inflammatory response is the likely underlying mechanism that gives rise to angiogenesis. The potential addition of the exciting new frontier of gene and cell therapies to this proven angiogenic device may provide new and significant synergistic solutions to the treatment of advanced coronary artery disease. Hughes, et al, (Cardiovascular Research 1999:44(1): 81-90) have demonstrated that laser revascularization + gene therapy is feasible. The momentum of clinical work with human gene and cell therapies is rapidly accelerating within the field of cardiovascular disease treatment. We are at the forefront of an exciting new path involving both device and genomic solutions in treating patients suffering from coronary artery disease. We look forward to supporting the important research which will ultimately determine the specific treatment algorithms, for the range of CAD indications, involving the combination of Holmium:YAG laser delivery and gene/cell therapy. GenVec, Inc. GenVec, Inc., a biopharmaceutical company developing gene-based medicines, has completed patient accrual in the Phase II clinical trial of its lead cardiovascular product candidate, BioBypass angiogen, in coronary artery disease. Injection of BioBypass delivers the Vascular Endothelial Growth Factor, or VEGF, gene directly to areas of the heart with poor blood flow. Based upon preclinical mechanism of action studies, the gene stimulates localized production of the VEGF protein to promote angiogenesis, or growth of new blood vessels, and to improve blood circulation. The study involved 20 clinical trial sites in North America and 71 people with severe coronary artery disease were enrolled. It is one of the largest randomized, controlled studies reported to date with intramyocardial injection of genes coding for angiogenic growth factor. In this Phase II clinical trial, GenVec tested BioBypass in patients with highly advanced coronary artery disease. These patients generally have severe chest pain despite maximal medical treatment and their medical condition prevents them from being candidates for standard revascularization procedures, such as angioplasty and coronary bypass grafts. The 71 patients enrolled in the study were randomized into two groups where 36 patients were assigned angiogenic gene transfer with BioBypass and 35 patients received best available medical treatment and served as a control group. The primary endpoint used to measure impact of the treatment will be changes in Exercise Treadmill Time (ETT). This is the standard test to measure clinical benefit in these patients and data will be collected at 3 and 6 months after treatment. GenVec plans to submit 3 and 6 month data from the Phase II clinical trial of BioBypass in coronary artery disease at an appropriate scientific meeting such as the upcoming Annual Meeting of the American Heart Association or the American College of Cardiology. The Phase II studies of BioBypass in coronary artery disease were conducted by Pfizer under a research and development agreement with GenVec for BioBypass. As previously announced, this agreement between Pfizer and GenVec is scheduled to end in July 2002.