By Rex Graham
While tiny startups making smartphone apps can turn hot ideas into sizzling million-dollar success stories overnight, Cardium Therapeutics (NYSE MKT: CXM) has been patiently moving forward with a promising gene therapy for more than a decade. The San Diego biotech company is developing Generx, a gene therapy treatment to boost the growth of blood vessels in the hearts of patients suffering from coronary artery disease. Cardium advanced Generx with the start of an international Phase 3 registration study based on new important research findings.
Federal approval of any new drug can take decades of scientific and clinical research and more than $1 billion to develop. Even then, there is no sure thing: only one in 10 drug candidates makes it to market. However, Cardium researchers are convinced that a decade of fine-tuning Generx, which is designed to stimulate the heart’s natural healing process, will successfully induce the growth of small blood vessels in the heart, thereby avoiding the need for surgery to improve cardiac blood flow.
The human heart, when injured, has the ability to grow small blood vessels, commonly referred to as “collateral circulation.” Generx is designed to boost that collateral circulation with a replication-deficient adenovirus vector type 5 that carries a gene for human fibroblast growth factor 4 (Ad5FGF-4). It is delivered inexpensively to the heart with a standard catheter to leverage a process called “angiogenesis,” the natural growth of small blood vessels.
Angiogenesis can occur in many situations, including a response to exercise. Collateral blood vessels also grow naturally over many years in response to worsening coronary artery disease. Angina, or chest pain due to lack of blood flow, is the body’s way of saying artery-narrowing plaque buildup has outpaced natural angiogenesis.
In attempts to relieve angina and prevent heart attacks, cardiologists rely on anti-angina medications, angioplasty with stenting, or coronary artery bypass surgery. Each of the three increasingly vigorous approaches is intended to improve blood flow in the heart.
The development of new drugs and therapies has waned as many biotech companies that once focused on heart disease have switched to developing drugs to treat cancer or for orphan medical indications, which sometimes carry astonishingly high reimbursement coverage. With the product pipelines of big pharmaceutical companies running low, biotech companies like Cardium are increasingly seen as vital potential sources of the scientific creativity needed to generate new therapies.
The initial scientific discoveries responsible for Cardium’s subsequent gene therapy came from the University of California, San Diego. Researchers there found that a growth factor gene carried by an adenovector can trigger a stunning revascularization of a heart with coronary artery blockages.
The delivery of the human fibroblast growth factor 4 (FGF-4) gene to the heart is accomplished by a simple, nonsurgical catheter procedure, similar to a routine angiogram diagnostic procedure performed by cardiologists. In experiments involving pigs, a preclinical animal model that mimicked coronary artery disease in humans, UCSD researchers documented a remarkable angiogenic response. They used a sophisticated imaging technique to document that a Generx-like gene therapy was nearly as effective as bypass surgery in re-establishing blood flow to heart muscle. The results were reported in 1996 in Nature Medicine.
In 1996, Chris Reinhard, currently chairman and CEO of Cardium Therapeutics, co-founded Collateral Therapeutics to advance the UCSD technology to clinical trials and commercialization. Shortly thereafter, Schering AG, a large German-based pharmaceutical company (now part of Bayer Healthcare) entered into a strategic partnership with Collateral.
Following the successful completion of the AGENT 2 mechanism-of-action study reported in 2003 in the Journal of the American College of Cardiology, Schering acquired Collateral in a stock-for-stock transaction valued at $160 million. Schering formed a division with its Collateral portfolio and Reinhard and Gabor M. Rubanyi, MD, PhD (Cardium’s current Chief Scientific Officer) advanced the Generx clinical development program.
The Generx AGENT 3 and AGENT 4 studies enrolled more than 500 patients at medical centers in the U.S., Europe and other international locations. The studies concluded in January 2004, when a planned interim analysis of AGENT-3 initially yielded unexpectedly disappointing results: the treatment was viewed by reviewers as unlikely to yield a statistically significant improvement (over baseline) in an exercise treadmill assessment at the 12-week primary endpoint. But that wasn’t the end of the story for Generx.
Looking further, Cardium researchers found new hope in the findings of a pre-specified meta-analysis of the data from these trials. The results were published in 2007 in the Journal of the American College of Cardiology. Usually, ischemia, a restriction in blood supply to cardiac muscle, would be regarded as an unwanted condition. However, Cardium researchers discovered that ischemia plays an important and necessary role in efficient “gene transfection,” or delivery of the FGF-4 gene by the adenovector. The data revealed why many of the patients in the study didn’t respond to the treatment: they didn’t have a significant level of ischemia. On the other hand, patients with higher levels of ischemia showed significant improvements when treated with Generx.
A long-term study published in 2007 in Circulation provided key evidence indicating that men and women with coronary artery disease with more “recruitable” collateral circulation have a better chance of surviving a heart attack than patients who have less ability to do so. Rather than focus solely on subjective descriptions of angina pain, this study quantitatively evaluated cardiac blood flow in 845 patients with coronary artery disease. During a 10-year follow-up period, long-term cardiac mortality was approximately 66 percent lower in patients with a highly developed collateral vessel blood supply.
Cardium researchers were both excited and relieved that for the first time, a large independent study documented the importance of collateral circulation. Indeed, the study indicated the potential for long-term benefits from Generx therapy that could go well beyond the capacity to simply relieve angina.
With the pending merger of Schering AG and Bayer, Reinhard engaged Schering in discussions to re-acquire the Generx product opportunity. He formed Cardium Therapeutics as the financing vehicle to drive the transaction.
Cardium paid $5.0 million and a patent-based royalty payment based on commercial success. It was a bargain: more than $200 million had been invested by Schering and Collateral to commercially advance Generx and Schering had earlier paid $160 million to acquire Collateral.
In March 2012, Cardium initiated a 100-patient Phase 3 registration clinical trial (ASPIRE study) in the Russian Federation. Russia’s cardiovascular death rate is four times that of the United States, which represents a significant market opportunity that Cardium is aggressively pursuing.
Reinhard believes the market for Generx is actually larger outside of the U.S.; however, Cardium plans to return to the U.S. following successful registration of Generx in Russia and other international markets. Cardium has a Phase 3 study approved in the U.S., which the company inactivated as the current U.S. registration pathway is for refractory or end-stage patients, making recruitment from a smaller pool of patients difficult.
In the Russian ASPIRE study, Reinhard and his team have incorporated new adenovector delivery techniques discovered in pre-clinical research performed at Emory University for Cardium. The researchers demonstrated that cardiac ischemia, while an indicator of serious illness, also is an important facilitator for efficient transfection of the adenovector-carried gene used in the Generx formulation.
The Emory researchers found that brief transient ischemia appears to alter the permeability barrier of the vascular endothelium in the heart and may expose the coxsackie-adenovirus receptor (CAR), which mediates uptake of the adenovector from the blood. There is greater than a 100-fold increase in adenovector-based gene transfection with transient-ischemia induction.
The Emory University findings were presented in May at the American Society of Gene & Cell Therapy annual meeting. Based on the new findings, investigators in the ASPIRE study use a standard balloon angioplasty catheter to induce transient ischemia, as well as to infuse the vasodilator nitroglycerin into the heart to enhance vascular endothelium permeability and expose CAR receptors prior to the administration of Generx.
The ASPIRE trial quantifies revascularization with SPECT (single photon emission computed tomography) imaging to measure efficacy for patients with myocardial ischemia due to coronary artery disease. This quantitative, objective method was used in the successful Generx AGENT 2 study instead of the more subjective measurement of time spent on an exercise treadmill required to experience angina. (The U.S. Food and Drug Administration requires the exercise treadmill test for all angina studies.) The Cedars-Sinai Medical Center Nuclear Cardiology Core Laboratory in Los Angeles, Calif., will analyze the imaging data received electronically from the Russian medical centers participating in the study.
When the ASPIRE study is completed, Cardium’s Generx clinical development program will have enrolled more than 750 patients at over 100 medical centers throughout the U.S., Canada, South America, Western Europe and Russia.
“With positive safety and efficacy data from this single registration study, a Generx clinical dossier would become eligible for submission for marketing and sales in the Russian Federation and countries of the Commonwealth of Independent States, comprising former republics under the Soviet Union,” Reinhard said in a recent news release. “The ASPIRE study is also specifically designed to 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 such as Brazil, India, Europe and the United States.”
Can Cardium compete with pharmaceutical Goliaths to develop a blockbuster treatment for heart disease?
“Our decade-long journey is shared with a small team of passionate people who have a great deal of persistence and expertise and who all share in the same common goal of developing a novel therapeutic that could change the quality of lives of millions. We continue to marvel at the beauty of biology and the human body’s powerful healing process,” Reinhard said. After all the research and clinical development, Cardium is now quietly leading what Reinhard calls “the evolution of a revolution” as it focuses on new regenerative biological tools for physicians and their patients.
Financial support was provided by Cardium Therapeutics in connection with the production of this story. High standards of objectivity, fairness and accuracy to the greatest degree possible are used in the production of this and every story published on this website.