Cardiovascular Biologics: Generx

About Generx

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 (perfusion) in patients who have insufficient blood flow due to atherosclerotic plaque build up in the coronary arteries. 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 (e.g. 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 by SPECT imaging (single photon emission computed tomography stress test) or another advanced imaging technique, showing improvements in the underlying physiologic condition, i.e. insufficient blood flow under stress.

Generx as “Front-Line Care” in Developing Countries

View Cardium Biologics Gene Therapy Presentation

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 many newly-industrializing 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 in many of these countries are unable to provide wide access to relatively expensive procedures such as coronary angioplasty and stenting, or cardiac bypass surgery (which in the U.S. can cost $50,000 to $100,000 over a five-year period following initial treatment).

The FDA has cleared Generx for a Phase 3 clinical study in the U.S. for women with late stage coronary artery disease who are unresponsive to traditional drug therapy and are not appropriate candidates for mechanical revascularization (angioplasty/stents or by-pass surgery), in connection with which Cardium previously announced plans to introduce an improved formulation of Generx that would not require storage at -70 degrees C. In view of published results from an independent 10-year study among men and women with chronic coronary heart disease showing that improved collateral circulation was associated with approximately 66% lower cardiac mortality, and prior studies showing that a one-time infusion of Generx has the potential to achieve improved coronary collateral circulation in both men and women at levels approximately equivalent to bypass surgery as measured by SPECT imaging, the Company believes that Generx could potentially be developed as a cost effective front-line therapy for patients with coronary artery disease in the large markets of newly-industrializing countries who often do not have access to costly procedures such as bypass surgery. Having such additional clinical evidence confirming the safety and effectiveness of Generx for improving coronary collateral circulation in men and women with severe coronary artery disease could also potentially be used to optimize and broaden commercial development pathways in the U.S. and other major markets such as Europe.

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 Clinical Development Chronology

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