By Scott Dance, The Baltimore Sun
3:10 PM EDT, April 26, 2013
A Sinai Hospital cardiologist is launching a clinical trial of a type of coronary artery disease drug not yet tested in humans, building on a history at the Baltimore hospital of research to develop more effective treatments to prevent blood clotting.
Dr. Paul Gurbel is studying an intravenous drug for patients undergoing cardiac stenting, when mesh tubes are implanted to widen blocked arteries. The drug, known for now as PZ-128, would be given to patients after stent implantation to prevent platelets from sticking together around the device, potentially leading to heart attack.
The study follows past research by Gurbel addressing gaps in drug treatment for coronary artery disease. One Sinai study found that Plavix, which has long dominated the market, is not effective in some groups, while another led to U.S. Food and Drug Administration approval of Brilinta, a key alternative to Plavix.
Gurbel has grander plans to further explore why, genetically, some people don't respond to certain drugs, but difficulty in retaining National Institutes of Health funding has delayed that project. In the meantime, the new drug being studied could further improve treatment of coronary artery disease by limiting bleeding risks and revealing new ways to target disease on a molecular level.
"This type of strategy has never been investigated in an intravenous type of therapy," Gurbel said. "It's a totally new class of drugs. ... It's very exciting for us to be looking at this."
Gurbel is working with researchers at Tufts Medical Center in Boston who developed the drug and are leading exploration of it. Athan Kuliopulos, a Tufts medical professor who earned his medical degree and a doctorate in biochemistry at the Johns Hopkins University, has been working with Gurbel in the area known as anti-platelet therapy for the past several years.
They plan to recruit nearly three dozen volunteers at Sinai who have at least two coronary artery disease risk factors, which can include obesity, high blood pressure, high cholesterol, a history of smoking or diabetes. In the initial phase of clinical trials, researchers will look for evidence the drug is safe and shows signs of effectiveness.
Given that the drug is administered directly into the bloodstream and can act immediately, any such signs should be clear, Kuliopulos said. Existing drugs like Plavix and Brilinta, both tested at Sinai, are given orally and remain in the body for days, posing a bleeding risk.
On a microscopic level, the drug is blocking a receptor by passing through blood cell walls, something no competing drugs on the market currently do, Kuliopulos said. The other drugs attempt to block receptors from the outside of blood cells.
While it's not clear whether that will mean more effective treatment, it does explore a drug delivery method that is new to coronary artery disease therapy.
"Half of the receptor has never been targeted before. It's on the other side of the barrier, so to speak," Kuliopulos said. "You have an opportunity to look for drugs on a part that's never been looked at before."
The researchers planned to start recruiting candidates this month, aiming to gather enough by October and complete the trial by the end of the year. If they prove safety and efficacy, the research would move on to a second phase of clinical trials, involving 600 to 800 patients from at least three different hospitals who are undergoing angioplasty, when narrowed arteries are widened in surgery. The second phase could take about three years.
The NIH has committed to funding the research to that point, assuming that the first phase of trials is successful. Beyond that, a large partner like a pharmaceutical company would be needed to fund a third stage of trials to prove that any benefits in treatment from the drug are statistically significant.
Meanwhile, Gurbel is pursuing a related study that could further explain why drugs like Plavix don't work the same in all patients. Gurbel and Dr. Alan Shuldiner, a professor at the University of Maryland School of Medicine, wrote research published in the Journal of the American Medical Association in 2009 that revealed the treatment gap.
They are planning a follow-up study that would show that using alternatives in patients who don't respond to Plavix improves health outcomes. But that effort was stalled last year when it became clear that more subjects would be needed than could be afforded under an NIH grant.
Gurbel said he isn't deterred from delving into the science further.
"Just like we do with deciding certain cancer drugs, where there are certain genotypes that predict a response to certain chemotherapy strategies, we're trying to do a similar type of thing for people with coronary artery disease who undergo stenting," Gurbel said. "We're trying to personalize therapy to optimize outcomes."
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