Generx: Science & Technology
Overview | Myocardial Revascularization| Cardium’s Approach
Illustration by Bryan Christie
OVERVIEW
Generx® is being developed for the potential treatment of myocardial ischemia (insufficient blood flow within the heart muscle) that gives rise to angina symptoms associated with coronary heart disease. Generx represents a new therapeutic class of cardiovascular biologics designed to leverage the body’s natural healing processes in response to repeated ischemic stress associated with severe coronary heart disease. The natural biologic response to repeated myocardial ischemia (insufficient oxygen levels in heart muscle) is angiogenesis, the growth of new collateral blood vessels. Newly formed vessels can effectively augment blood flow and oxygen delivery to the patient’s heart downstream from a partial or complete blockage in a coronary artery. In many patients however, including those with recurrent angina, collateral coronary vessel formation remains insufficient to meet the heart’s needs during exercise or stress. Currently available anti-anginal drugs, which may provide temporary symptomatic relief, are generally designed to alter the oxygen demand of the heart muscle or dilate vessels to relieve angina without changing the underlying medical condition. Generx is being developed as a one-time intracoronary administration to facilitate collateral blood vessel growth which will lead to long-term relief of stress-inducted myocardial ischemia.
MYOCARDIAL REVASCULARIZATION
There is currently no approved therapy designed to increase blood flow and oxygen supply by increasing the growth of recruitable collateral vessels in the heart. Revascularization procedures like angioplasty and stenting as well as coronary artery bypass graft (CABG) surgery can be effective treatments for the repair of large conduit vessels of the heart when they become narrowed with plaque or blocked by thrombus. While these procedures can be performed to mechanically open or surgically bypass blockages of the large epicardial blood vessels that surround the myocardium, neither of these approaches are believed to be capable of also addressing blockages affecting the mid-size to smaller blood vessels which are located deeper within the heart muscle. These deeper and smaller vessels deliver oxygenated blood to the adjacent heart tissue so that oxygen transfer can take place. Many patients who undergo revascularization interventions on accessible portions of the large upstream blood vessels to relieve their angina continue to experience myocardial ischemia and the associated angina symptoms or a return of angina. In addition, many patients are not candidates for revascularization due to the extent of disease, co-morbidities, anatomically unfavorable coronary disease, or the high risks associated with repeated CABG surgery.
CARDIUM’S APPROACH
Illustration by Bryan Christie
Cardium’s therapeutic approach uses a standard diagnostic cardiac catheter, familiar to the interventional cardiologist, for non-surgical intracoronary delivery of cardiovascular-directed angiogenic growth factor therapy during cardiac catheterization. Angiogenic growth factors are normally secreted locally in response to ischemia or stress and are effective only in the local micro-environment, a fraction of a millimeter from where they are secreted. Intracoronary infusion of Generx, consisting of an adenovector construct carrying the angiogenic gene FGF-4, results in the myocardial production of FGF-4 protein, a naturally occurring biologic growth factor. The locally produced and secreted FGF-4 protein is believed to stimulate the production of other (downstream) angiogenic growth factors that in the setting of ischemia can stimulate the growth and maturation of new collateral blood vessels in regions of the heart that are deprived of oxygenated blood.
There are several unique features of Cardium’s technology for activating the angiogenic response to myocardial ischemia. The Company’s technique of intracoronary infusion of the adenovector encoding the angiogenic FGF-4 gene results in direct delivery into the heart’s extensive coronary microcirculation. This targeted delivery method takes advantage of the unique anatomy of the coronary circulation designed by nature for highly efficient oxygen and nutrient extraction.
Compared with other methods for DNA transfer, the adenovector encoding FGF-4 is taken up with high efficiency by cells in the heart especially under ischemic/hypoxic conditions. The transfected heart cells then transcribe the FGF-4 gene into messenger RNA, and translate that RNA into FGF-4 protein, with a signal sequence to cause its secretion. FGF-4 protein secretion continues for a period of several weeks. This limited production is beneficial for therapeutic angiogenesis since the newly formed blood vessels remain in areas of need such as ischemic areas of the heart muscle. Neither the adenovector nor the FGF-4 gene is incorporated into the transfected cell’s chromosomes and therefore they do not integrate or cause any disruption within the cell’s own genome. Generx, in combination with ischemic stress, is therefore designed to promote collateral vessel growth precisely when and where it is needed.
Cardium’s therapeutic approach has been the focus of the most widely-conducted clinical studies for Angiogenic Gene Therapy (AGENT-1 through AGENT-4), which to date have involved 663 patients, including 450 who received Generx. Cardium believes that the Company’s angiogenic therapeutic approach differs markedly from other potential angiogenic therapies currently at various stages of development, and that Cardium’s approach offers several advantages over competitors. Cardium’s intracoronary delivery technique using a standard diagnostic catheter offers the potential for a broader distribution of therapeutic material throughout the heart than by direct needle injections into portions of the heart muscle.