Medical & Scientific Literature

Generx [Ad5FGF-4]

Intracoronary gene transfer of fibroblast growth factor-5 increases blood flow and contractile function in an ischemic region of the heart. Giordano et al., Nature Medicine. 1996; 2(5):534-9.

This preclinical work demonstrated for first time that intracoronary FGF gene transfer induces angiogenesis and increased blood flow and function in ischemic regions of the pig heart, and is the foundation for the Ad5FGF-4 (Generx) clinical development program.

Increased regional function and perfusion after intracoronary delivery of adenovirus encoding fibroblast growth factor 4: report of preclinical data. Gao et al., Hum Gene Ther. 2004;15(6):574-87.
http://online.liebertpub.com/doi/pdf/10.1089/104303404323142024

This manuscript reports on the preclinical biodistribution and toxicology studies performed in support of Generx clinical studies. Using the pig model of stress-induced myocardial ischemia, two weeks after intracoronary injection of Ad5FGF-4, transgene protein (human FGF-4) was detected in hearts, but not in any extracardiac site, including plasma. By the highly sensitive method of PCR, Ad5FGF-4 DNA was detected in extracardiac tissues, primarily in animals treated at the highest dose, but no mRNA was detected in any tissue positive for DNA. Histological evaluations identified no evidence of toxicity in any organ examined. This work supports the safety of intracoronary delivery of Generx.

Angiogenic Gene Therapy (AGENT) trial in patients with stable angina pectoris. Grines et al., Circulation, 2002; 105(11):1291-7.
http://circ.ahajournals.org/content/105/11/1291.full.pdf

This manuscript reports on findings from AGENT-1, the first ever clinical study of intracoronary Ad5FGF-4 gene delivery in patients with stable exertional angina. Single intracoronary delivery was found to be safe, and showed a trend toward improvement in exercise treadmill time (ETT) following administration of Ad5FGF-4 (pooled active groups) compared to placebo.

A randomized, double-blind, placebo-controlled trial of Ad5FGF-4 gene therapy and its effect on myocardial perfusion in patients with stable angina. Grines et al., J Am Coll Cardiol. 2003; 42(8):1339-47.
http://content.onlinejacc.org/article.aspx?articleid=1132725

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.

Effects of Ad5FGF-4 in patients with angina: an analysis of pooled data from the AGENT-3 and AGENT-4 trials. Henry et al., J Am Coll Cardiol. 2007 Sep 11;50(11):1038-46
http://www.sciencedirect.com/science/article/pii/S0735109707019997

A by-patient analysis of the pooled data from two large, multi-center, international studies using ETT as the clinical endpoint (AGENT-3 and AGENT-4) revealed a substantial placebo response in males but not in females. Analysis of the AGENT-3 data identified a significant reduction in angina class in the Ad5FGF-4 treated patients at both 6 and 12 months and a statistically significant increase in ETT duration at 12 weeks in females. This report supports use of quantitative SPECT imaging as the clinical endpoint in order to avoid placebo effects.

Ischemia-reperfusion increases transfection efficiency of intracoronary adenovirus type 5 in pig heart in situ. Shi et al., Hum Gene Ther Methods. 2012; 23(3):204-12.
http://online.liebertpub.com/doi/pdf/10.1089/hgtb.2012.048

This preclinical study provides evidence that ischemia/reperfusion increases DNA uptake following intracoronary delivery of adenovirus and is the basis for the Company’s proprietary method of enhanced cardiovascular gene delivery that utilizes an intracoronary angioplasty balloon catheter to produce transient myocardial ischemia during intracoronary Generx administration.

Mechanistic, technical, and clinical perspectives in therapeutic stimulation of coronary collateral development by angiogenic growth factors. Rubanyi GM. Mol Ther. 2013 Apr;21(4):725-38

Dr. Gabor Rubanyi, the Company’s Chief Scientific Officer, authored this comprehensive review on angiogenic growth factor therapy, highlighting the mechanistic, technical and clinical insights that have contributed to and been exploited by Taxus Cardium in the clinical development of Generx.

Cardiac Microvascular Insufficiency

Coronary microvascular dysfunction in the clinical setting: from mystery to reality. Herrmann et al., Eur Heart J. 2012; 33:2771-2781.
http://eurheartj.oxfordjournals.org/content/33/22/2771.full.pdf

This review describes the functional and structural abnormalities of the coronary microvasculature that can lead to myocardial ischemia despite normal coronary angiograms (“microvascular angina”). It reports that, “~50% of patients undergoing angiography with signs and/or symptoms of myocardial ischemia are found to have normal, or ‘near normal (non-obstructed)’ coronary arteries”. This establishes a scientific basis for and a substantial target patient population for Generx gene therapy.

Coronary microvascular dysfunction: an update. Crea et al., Eur Heart J. 2013; 33:2771-2781.

This review identifies coronary microvascular dysfunction (CMD) as a third potential mechanism of myocardial ischemia (along with atherosclerotic and vasoplastic diseases), and with a patient population of 3-4 million in the U.S. alone. The four classes of CMD are described (Type 1: in the absence of myocardial diseases and obstructive CAD; Type 2: in the presence of myocardial diseases; Type 3: in obstructive CAD; Type 4: iatrogenic).

Direct myocardial revascularization and angiogenesis–how many patients might be eligible? Mukherjee et al., Am J Cardiol. 1999;84(5):598-600.

The need for non-traditional, non-surgical methods of myocardial angiogenesis such as that provided by Generx gene therapy is demonstrated by this assessment of patients with known or suspected coronary artery disease, in which a large percentage were found to have diffuse coronary disease involving multiple large and smaller coronary arteries, small distal vessels or other co-morbidities that make them ineligible or poor candidates for traditional methods of treatment. These “poor or no-option” patients represent approximately 12 % (over 1.0 million) of all patients with symptomatic CAD in the United States alone.

Beneficial effect of recruitable collaterals: a 10-year follow-up study in patients with stable coronary artery disease undergoing quantitative collateral measurements. Meier et al., Circulation. 2007;116(9):975-83.
http://circ.ahajournals.org/content/116/9/975.full.pdf+html

This independent long-term prospective study 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, the primary premise behind Generx’s therapeutic potential.

Assessment and impact of the human coronary collateral circulation on myocardial ischemia and outcome. Seiler C. Circ Cardiovasc Interv. 2013; 6(6):719-28.

This recent article reviews the history of and current methods for assessing collateral function and impact on myocardial ischemia. Included is a review of qualitative, semi-quantitative, and quantitative methodology, as well as a review of the literature pertaining to the favorable impact of coronary collateral development on outcomes.