About Generx
Generx (Ad5FGF-4)
Cardium Therapeutics' Generx® product candidate (alferminogene tadenovec, Ad5FGF-4) is a DNA-based angiogenic growth factor therapeutic being developed for the potential treatment of patients with advanced coronary artery disease. Generx is designed to stimulate the growth of supplemental collateral blood vessels in the heart in order to enhance myocardial blood flow in patients who have insufficient blood flow due to atherosclerotic plaque restricting flow in the coronary arteries that supply the heart. Generx has progressed through four randomized, placebo-controlled clinical studies at over 100 medical centers in the United States and Western Europe that have enrolled over 650 patients.
Generx is designed as a disease-modifying regenerative medicine therapeutic that can elicit structural and physiologic changes in the heart (the growth of new collateral blood vessels) following a one-time intracoronary administration from a standard cardiac infusion catheter. In contrast, traditional drug therapies such as nitrates and beta blockers provide transient symptomatic relief of anginal chest pain without changing the underlying disease. In the United States, anti-anginal drugs have traditionally been registered by the FDA based on improvements in exercise treadmill tolerance testing (ETT), which can confirm short-term symptomatic relief of angina. Based on the disease-modifying nature of Generx, Cardium believes that a more objective and appropriate measure to assess the effectiveness of angiogenic therapy is cardiac perfusion, the actual blood flow in the heart under stress using SPECT imaging (single photon emission computed tomography) or another advanced imaging technique. Cardiac perfusion directly shows and quantifies improvements in the underlying physiologic condition, i.e. insufficient blood flow under stress. Generx is currently being developed for international markets outside United States as a treatment alternative for patients who may not have access to or may not be candidates for costly and invasive surgical revascularization procedures, such as coronary artery bypass surgery and angioplasty/stents.
Generx as POTENTIAL “Front-Line Care”
While there has been progress in the care and treatment of patients with cardiovascular disease in the industrialized world, heart disease remains a very serious problem in the U.S. and Europe, and advanced surgical procedures have been associated with considerable and increasing expense within already-burdened healthcare systems. The situation is even worse in other parts of the world. In more recently industrialized countries such as China, India and Russia, as well as in Latin America and the Middle East, the incidence of heart disease is rapidly increasing, and healthcare systems are unable to provide wide access to relatively expensive and invasive surgical procedures such as coronary angioplasty and stenting (PCI), or cardiac bypass surgery (CABG), which in the U.S. can cost $50,000 to $100,000 over a five-year period following initial treatment.
Traditional interventional cardiology approaches such as PCI and CABG are not only more invasive and costly, they can only directly address larger vessels that are susceptible to treatment and accessible through mechanical intervention. In contrast, Generx can be administered non-surgically, using a standard cardiac infusion catheter as is used for diagnosis, and it can stimulate the natural process of blood vessel growth in the heart's microcirculation that is not reachable by surgical intervention.
ASPIRE PHASE 3 REGISTRATION STUDY
The ASPIRE clinical study is a randomized, controlled, parallel group, multi-center study designed to evaluate the safety and efficacy of Cardium's Generx product candidate using SPECT imaging to measure improvements in microvascular cardiac perfusion following a one-time, non-surgical administration of Generx through a standard cardiac infusion catheter. As designed, the ASPIRE clinical study is expected to enroll approximately 100 men and women with myocardial ischemia due to coronary artery disease at several leading medical institutions in Moscow, which has a large number of patients with cardiovascular disease and well-established treatment centers. The study's primary efficacy endpoint will be the improvement in reversible perfusion defect size as measured by SPECT myocardial perfusion imaging. SPECT can be used to quantitatively confirm the effectiveness of Generx by measuring improved myocardial blood flow under stress, a key prognostic indicator that is associated with the regenerative process of new collateral vessel formation within and around regions of ischemia. While walking time during exercise tolerance testing (ETT) has been a traditional efficacy measure of anti-anginal drugs, ETT is based on a subjective assessment of chest pain (angina pectoris), does not directly measure improvements in cardiac blood flow, and can be affected by other variables such as heart rate, blood pressure and other medications.
The ASPIRE study will represent the fifth clinical study under Generx's clinical development program that when completed will have enrolled more than 750 patients at over 100 medical centers throughout the U.S., Canada, South America, Western Europe and Russia. Based on the specified clearance for the Russian Health Authority, with positive safety and efficacy data from this single registration study, Cardium's Russian sponsor and development partner, Advanced Biosciences Research, an affiliate of the contract research organization bioRASI, would be in a position to consider the submission of an application for marketing and sales of Generx in the Russian Federation, and to advance forward with applications and submissions seeking approval for marketing and sales of Generx in certain other countries of the Commonwealth of Independent States, comprising former republics under the Soviet Union. The ASPIRE study could also provide additional clinical evidence regarding the safety and effectiveness of Generx that would be useful for optimizing and broadening commercial development pathways in other industrialized countries.
Clinical Research
Positive results from the Phase 2a mechanism of action clinical study (Grines et al., J Am Coll Cardiol 2003; 42:1339-47) showed that Generx improved myocardial blood flow in the ischemic region of the hearts of men and women following a single intracoronary infusion as measured by the objective efficacy endpoint of SPECT imaging. As noted in the publication, the mean change observed in Generx-treated patients was a 4.2% absolute reduction (which represents a 20% relative reduction) in the reversible perfusion defect size from baseline at eight weeks (p<0.001), while the placebo group showed only a 1.6% absolute reduction from baseline (not significant) at eight weeks following treatment. The observed treatment effect for patients receiving Generx was similar in magnitude to that reported in the literature for patients undergoing angioplasty/stent or revascularization procedures with reversible perfusion defects of comparable size at one year following these procedures.
The Generx Phase 2b U.S. and Western European clinical studies evaluated the angiogenic effects of Generx using traditional ETT as the primary efficacy endpoint. These studies demonstrated that Generx was safe and well tolerated by patients and a subgroup analysis undertaken by investigators (Henry TD, et al. J Am Coll Cardiol 2007; 50(11):1028-1046) concluded that older patients and patients with more advanced coronary artery disease (consisting largely of women) showed a dose-dependent and statistically significant response in a number of primary and secondary efficacy measures (at three and six months) that included improvement in exercise duration, time to onset of angina, as well as time to 1mm ST segment depression.
An independent long-term study published in Circulation (Meier et al, Circ. 2007; 116:975-983) provided key evidence indicating 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. This important study quantitatively evaluated coronary collateral blood flow in 845 patients with coronary artery disease during a 10-year follow-up period and showed that long-term cardiac mortality was approximately 66% lower in patients with a highly developed collateral vessel blood supply (p=0.019). 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.
![Generx [Ad5-FGF4] Clinical Study Summary](images/GenerxchartLG.gif)
RECENT RESEARCH FINDINGS
Recent pre-clinical research findings published in Human Gene Therapy Methods (Weiwei S., Rubanyi, G., et al. Human Gene Therapy Methods. doi:10.1089/hgtb.2012.048) demonstrate that cardiac ischemia plays an important role in adenovector gene transfection (delivery) in mammalian hearts. Based on this understanding, using a standard balloon angioplasty catheter, researchers have developed and tested a new method to induce transient ischemia during a non-surgical interventional cardiac procedure, which when coupled with the infusion of nitroglycerin, boosts the delivery (cell transfection) of an adenovector gene construct into heart cells. The increase in adenovector-based gene transfection with the new technique is over two orders of magnitude (>100 fold).
This new method of adenovector delivery takes advantage of the findings that transient ischemia appears to alter the permeability barrier of the vascular endothelium and may expose the blood to the coxsackie-adenovirus receptor mediating adenovector uptake by the heart. Balloon angioplasty catheters have been used for many years to dilate blocked coronary arteries, sometimes with use of a stent, and these catheters have also been used safely by cardiologists in patients with coronary artery disease to study the effects of brief ischemia. Cardium's recently initiated Russian-based ASPIRE Phase 3 / registration clinical study uses transient ischemia techniques during non-surgical percutaneous catheterization with a standard angioplasty catheter together with the intracoronary infusion of nitroglycerin with the Generx product candidate for the treatment of patients with myocardial ischemia and stable angina pectoris.