Coronary artery disease is the leading cause of death worldwide, accounting for approximately 7.3 million deaths annually.[i] In the U.S. there are approximately 15.4 million patients with coronary artery disease, of which 7.8 million have been diagnosed with angina pectoris. An independent long-term prospective study found that men and women with more recruitable collateral circulation have a better chance of surviving a heart attack than patients who have less developed collateral circulation.[ii] For the first time, this study showed the importance of collateral circulation beyond simply the relief of angina and provided further support of the potential for long term benefits from angiogenic therapy, the primary premise behind Generx’s therapeutic potential. Generx is being developed by Taxus Cardium as a pioneering gene therapy for Cardiac Microvascular Insufficiency (“CMI”) in patients with myocardial ischemia and symptomatic chronic stable angina pectoris due to advanced coronary artery disease. CMI is a principal cause of Coronary Microvascular Dysfunction (CMD), a well-recognized clinical condition characterized by functional and structural abnormalities of the microvasculature (smaller blood vessels of the heart), which leads to myocardial ischemia and angina pectoris in the absence of large artery/obstructive disease.[iii][iv] CMD, which is also sometimes referred to as “microvascular angina”, frequently cannot be addressed using traditional surgical approaches such as coronary artery bypass graft (CABG) or percutaneous coronary intervention (PCI, i.e. angioplasty and stents). In particular, many patients (1) have coronary artery disease that is not limited or localized to large vessels, (2) continue to experience angina after CABG or PCI, and/or (3) are not suitable candidates for surgical interventions. It is estimated that 12% of patients with obstructive coronary artery disease continue to experience angina because their underlying medical condition is not fully addressed or cannot be resolved by chronic drugs or surgical/mechanical interventions.[v] In addition, a recent meta-analysis reported that approximately 20% of patients who have a coronary angiography due to ongoing angina do not have obvious large vessel disease, a condition generally referred to as Cardiac Syndrome X, many of whom are presumed to have coronary disease that is diffuse and/or affects smaller vessels within the heart that are not reachable through surgical intervention.[vi] Generx is designed to be a one-time non-surgical treatment that may help many of such patients by directly addressing their underlying microvascular angina, as well as providing a non-surgical option for patients in whom coronary intervention is either contraindicated or not desirable. Four clinical classes of CMD have been identified.
Generx is being developed by Taxus Cardium for two of these types (1 and 3) and for no-option patients. Type 1 is microvascular angina with normal coronary arteries (including Syndrome X patients). Type 3 is obstructive coronary artery disease with microvascular dysfunction as a component. Generx could also be after PCI or bypass surgery in the significant fraction of patients who still experience angina or other dysfunction even after surgical interventions – many of whom would be expected to have CMD that cannot be effectively addressed only by treating the large stenoses reachable through surgery.
The company’s extensive preclinical and clinical experience with Generx has enabled the establishment of measurable parameters for the identification of patients with CMI and who may therefore benefit from Generx therapy, which is designed to biologically enhance cardiac perfusion by the promotion of collateral vessel formation and myocardial perfusion. For example, adenosine single-photon emission computed tomography (SPECT) perfusion imaging has been implemented as a quantitative diagnostic and efficacy endpoint tool in the ASPIRE international trial. Myocardial ischemia, including that associated with CMI, can be effectively diagnosed and its potential treatment quantified using SPECT imaging. SPECT has both diagnostic and prognostic value in the management of patients with coronary artery disease because it identifies and quantitatively measures regions of the heart muscle that are at greatest risk during periods of ischemia, such as that brought on during exertion. Some of the main criteria for selecting patients with high probability of responsiveness to Generx treatment include, i) Either no-option large coronary artery disease, or “microvascular angina”, and ii) Develop reversible ischemia under stress with viable myocardium (measured as ≥ 9 % RPDS on SPECT imaging). These criteria indicate not only high medical need, but also the presence of CMI.
[i] WHO Cardiovascular Diseases Fact Sheet No. 317 (March 2013). [ii] Meier et al., Circulation. 2007;116(9):975-83. [iii] Crea et al., Eur Heart J., 2013; doi:10.1093/eurheartj/eht513 [iv] Hermann et al., Eur Heart J., 2012; 33:2271-2781 [v] Mukherjee et al., Am J Cardiol. 1999; 84(5):598-600. [vi] Vermeltfoort et al., Clin Res Cardiol. 2010; 99:475-481