The debate continues. Is the path to cardiovascular health paved by drugs, by devices, or some combination thereof?
On Wednesday, a panel of drug manufacturers at the Biotechnology Industry Organization’s CEO & Investor Conference in New York argued that too many therapies in this sector simply treat symptoms, but that pharmaceuticals may offer the road to true cures. That view was tempered, however, by a balancing counterpoint that the real key in this sector may be new drug delivery systems and sophisticated drug/device combinations.
The panel discussion at the venerable Waldorf-Astoria Hotel was sponsored by the investment banking firm of Adams, Harkness & Hill with Carol Werther, a company managing director and biotech analyst, laying out the discussion’s main themes.
Commercialized pharmacology has made good strides, but still tends to offer only palliations of heart disease symptoms. This leaves a true cure for cardiovascular disease a large unmet need, she said. On the device side, she highlighted the current broad use of stents, but noted that this approach “won’t solve the entire problem; not every artery can be stented.” And she pointed to what every stent manufacturer would be quick to acknowledge that in-stent restenosis remains a large problem yet to be solved with a proven, and commercialized, drug-coated stent product.
New possibilities for delivering heparin, a drug already considered important in this sector, were outlined by Michael Goldberg, chairman and chief executive officer of Emisphere Technologies Inc., of Tarrytown, N.Y.
Currently, heparin generally is administered via injection to reduce blood clotting following surgery and other invasive procedures, but Emisphere is pursuing its oral administration for several indications, including specific cardiovascular applications such as prevention of deep vein thrombosis.
Oral heparin “is not just an anti-thrombotic, it’s a lot more,” Goldberg said. As an oral medication, “What we’re delivering is the full heparin molecule,” he said. “There are a lot of properties in heparin now being discovered and being used but not yet well understood. We’re delivering the entire range of heparin molecular weight for all activities we’re looking at.”
The company’s primary target, he said, is treatment of arterial inflammation, with the oral form of heparin both able to dissolve clots and showing the potential for reducing restenosis after stent placement.
Besides promoting the potential uses of the company’s oral heparin product, Goldberg outlined Emisphere’s strategy for examining what he called “arterial injury” via analysis of “gene arrays” and the way arterial inflammation can be turned on or off. Heparin, he said, “can down-regulate, cool down the inflammatory condition, and anti-inflammatory cytokines can be up-regulated.” The company’s current studies are in the process of addressing these approaches, with dosing amounts being a key control factor, he said.
“There are large under-served markets for an agent like heparin. It can have a very, very important role now that it is orally available,” Goldberg said.
Like Emisphere, Myogen Inc., of Denver, is interested in the root causes of cardiovascular disease and its potential genetic risk factors, according to Bill Freytag, president and CEO of the company, with specific focus on congestive heart failure.
“We’re making a primary effort to understand heart failure at the molecular level,” Freytag said, and attempting to develop “therapeutics that are truly disease modifying,” rather than simply addressing symptoms.
The company’s precise target is congestive heart failure, in which the heart gradually loses pumping ability, tends to expand in a remodeling process and then becomes flacid. This cascade of events, Freytag said, follows some “insult to the heart, a stress on the heart and the heart goes into overdrive.”
Myogen’s search has resulted in “three important discoveries to develop therapeutics,” he said. It had found that congestive heart failure could originate as early as birth, with certain genes turned off and later turned on, resulting in interference with the heart’s function. It had also found pathways for intervening in this switching on/off process and finally had “targeted the ability to move in and develop drugs that can reverse this fetal gene expression program.”
The company’s primary cardiovascular treatment is enoximone, an oral formulation delivered intravenously and working at the “neuro-hormonal” level, Freytag said, to break the cycle of pumping failure and reduce patient hospitalizations and mortality.
The company’s studies are demonstrating three primary applications: besides the treatment of advanced heart failure, the treatment of kidney failure and pulmonary hypertension.
Efforts in developing another therapeutic compound, AGI 1067, were described by Russell Medford, president and CEO of AtheroGenics Inc., of Atlanta, with the company’s name suggesting its primary disease target: atherosclerosis.
Medford described atherosclerosis as a chronic inflammatory disease whose progress could be blocked by AGI 1067, which he described as a small-molecule therapeutic addressing the fundamental process of intracellular signaling within the vasculature.
While angioplasty treats only specific areas of concern in an artery, AtheroGenics’ approach provides a systemic approach to what Metzger termed “a very diffuse disease.”
Bringing the discussion full circle to drug-coated stents was Martin Leon, clinical professor of medicine at Georgetown University Medical Center in Washington and director and CEO of the Cardiovascular Research Foundation.
After reviewing several current trials in this area and providing what has become the standard warning against expecting too much, too soon from this technology, Leon described what he considered to be key endpoints for potential commercialization of these products.
The rate of restenosis has to be reduced from double digits to single digits, and those treatments are likely to be accomplished only by “a very aggressive site-specific therapy, not a systemic approach,” Leon said.
Besides requiring a good stent and a strongly therapeutic drug, the critical factor will be their combined ability to achieve very specific drug delivery. “The dynamics of delivering a drug at a certain concentration over a specific time period is fundamental to this process,” he said, adding that this requires “the proper integration of device and drug.”
Adding a “note of caution” concerning the difficulty of achieving this, Leon said that, based on proof of concept studies, this drug/device combination “could really work it has the potential.”