Novel drug-antidote combination shown safe in humans

November 13, 2006

DURHAM, N.C. -- A new combination of a potent anticoagulant and an antidote that stops its action, has proved to be safe in its first clinical trial in humans, according to the team conducting the trial.

The effectiveness of the anticoagulant-antidote combination, developed at Duke University Medical Center, must yet be proven in additional trials, the team said.

If the treatment "system" works as hoped, physicians would have a powerful new tool for treating patients with heart disease, the researchers said. They added that the approach used to create the new chemical combination also could be used to devise other combination treatments in the areas of infectious diseases, cancer and rheumatologic disorders.

Physicians give anticoagulants to heart patients to prevent blood clots that block their coronary arteries and put them at risk of heart attack. Though current drugs are effective, they also can provoke excessive bleeding in treated patients, the researchers said.

In their "Phase 1" clinical trial of the new anticoagulant-antidote combination, the researchers found that the anticoagulant thinned the blood as expected and the antidote then reversed the anticoagulant's blood-thinning properties in less than five minutes. Phase 1 trials typically are small trials, conducted in healthy human volunteers, and are intended to detect any adverse effects of the agent before it is investigated in patients.

"This novel combination of anticoagulant and antidote represents an anticoagulation system with the potential to offer a rapid and effective 'on-off' switch," said cardiologist Christopher Dyke, M.D. He presented the findings Monday, Nov. 13, at the annual scientific sessions of the American Heart Association, in Chicago. Dyke was trained at the Duke Clinical Research Institute and served as the trial's principal investigator. The findings are also being published early online in the journal Circulation.

"In the 85 healthy volunteers enrolled in the trial, the antidote rapidly and fully reversed the anticoagulant effects and there were no major safety concerns with either the anticoagulant or its antidote," Dyke said. "This novel system holds promise for establishing a new paradigm for controlled anticoagulation."

The anticoagulant-antidote pair, called REG1, was developed by the pharmaceutical company Regado Biosciences Inc., based on technology that it licensed from Duke. Regado sponsored the clinical trial.

The new anticoagulant, which is a member of a class of therapeutic agents known as aptamers, is a short string of single-stranded nucleic acids --either DNA or RNA -- that bind to specific protein or small molecule targets. Aptamers are highly specific, produce little toxicity and are quickly cleared from the body, according to Richard C. Becker, M.D., director of Duke's Cardiovascular Thrombosis Center and senior member of the research team.

In the trial, the researchers used the aptamer-antidote pair to target a specific protein, called human coagulation factor IXa, that plays a pivotal role in the complex cascade of biochemical events that leads to a blood clot.

"When the aptamer binds to factor IXa, much like a lock and key, it blocks the series of reactions that lead to the formation of a blood clot," Becker said. "The antidote is designed as a mirror image to the aptamer. It binds to the aptamer and changes its shape so that it no longer can bind to factor IXa. The ability of the blood to clot then returns to normal."

With conventional anticoagulants, when a patient experiences an unwanted "bleeding event," physicians have little recourse except to wait for the drugs to be cleared from the body naturally, a potentially time-consuming process. Patients suspected of having a heart attack who are given conventional anticoagulants and who then must undergo emergency angioplasty or surgery also can face life-threatening delays, the researchers said.

Recognizing a need for better anticoagulants, two Duke basic scientists began working on the problem in 2001. Bruce Sullenger, Ph.D., and Chris Rusconi, Ph.D., set out to create from scratch the anticoagulant-antidote pair. The team published their initial observations in the journal Nature and Nature Biotechnology, and they are actively developing aptamers and their complementary antidotes to other coagulation proteins. Rusconi has since left Duke and now is vice president of discovery and development at Regado.

According to the researchers, the new anticoagulation system holds promise not only for providing physicians greater control over anticoagulation used in patients with cardiovascular diseases such as heart attacks, but could also be applied to surgery that requires use of a heart-lung machine.

Patients on heart-lung machines must be given a blood-thinner in order to prevent their blood from clotting as it passes through the machine's tubing during surgery, the researchers said. The same is true for patients undergoing kidney dialysis. The most commonly used anticoagulant is heparin. But the "reversal" drug used to counteract heparin's anticoagulant effects, called protamine, has a variety of unwanted side effects, the researchers said.

REG1 potentially may give surgeons much more control over the intensity of anticoagulation, they said.

"The new anticoagulant-antidote pair represents an important platform for maximizing patient safety," Becker said. "The anticoagulant is highly specific to factor IXa, it is effective, it is fast-acting and it is quickly reversible. The recent clinical trial that demonstrated these highly favorable properties gives us the requisite and scientifically founded confidence to proceed with the next level of testing."

Duke cardiologists, in collaboration with seven academic centers in the United States, are conducting the next Phase 1clinical trial of REG1, in which they are testing the agent's safety in patients with stable heart disease who are already taking aspirin and/or clopidogrel, two commonly used medications designed to prevent blood clots. The trial, which is expected to enroll 50 patients, is already underway, the researchers said.
-end-
Other members of the study team were Steven Steinhubl, Neal Kleiman, Richard Cannon, Laura Aberle, Min Lin, Shelley Myles, Chiara Melloni, Robert Harrington and John Alexander.

Duke University Medical Center

Related Heart Disease Articles from Brightsurf:

Cellular pathway of genetic heart disease similar to neurodegenerative disease
Research on a genetic heart disease has uncovered a new and unexpected mechanism for heart failure.

Mechanism linking gum disease to heart disease, other inflammatory conditions discovered
The link between periodontal (gum) disease and other inflammatory conditions such as heart disease and diabetes has long been established, but the mechanism behind that association has, until now, remained a mystery.

New 'atlas' of human heart cells first step toward precision treatments for heart disease
Scientists have for the first time documented all of the different cell types and genes expressed in the healthy human heart, in research published in the journal Nature.

With a heavy heart: How men and women develop heart disease differently
A new study by researchers from McGill University has uncovered that minerals causing aortic heart valve blockage in men and women are different, a discovery that could change how heart disease is diagnosed and treated.

Heart-healthy diets are naturally low in dietary cholesterol and can help to reduce the risk of heart disease and stroke
Eating a heart-healthy dietary pattern rich in vegetables, fruits, whole grains, low-fat dairy products, poultry, fish, legumes, vegetable oils and nuts, which is also limits salt, red and processed meats, refined-carbohydrates and added sugars, is relatively low in dietary cholesterol and supports healthy levels of artery-clogging LDL cholesterol.

Pacemakers can improve heart function in patients with chemotherapy-induced heart disease
Research has shown that treating chemotherapy-induced cardiomyopathy with commercially available cardiac resynchronization therapy (CRT) delivered through a surgically implanted defibrillator or pacemaker can significantly improve patient outcomes.

Arsenic in drinking water may change heart structure raising risk of heart disease
Drinking water that is contaminated with arsenic may lead to thickening of the heart's main pumping chamber in young adults, according to a new study by researchers at Columbia University Mailman School of Public Health.

New health calculator can help predict heart disease risk, estimate heart age
A new online health calculator can help people determine their risk of heart disease, as well as their heart age, accounting for sociodemographic factors such as ethnicity, sense of belonging and education, as well as health status and lifestyle behaviors.

Wide variation in rate of death between VA hospitals for patients with heart disease, heart failure
Death rates for veterans with ischemic heart disease and chronic heart failure varied widely across the Veterans Affairs (VA) health care system from 2010 to 2014, which could suggest differences in the quality of cardiovascular health care provided by VA medical centers.

Heart failure: The Alzheimer's disease of the heart?
Similar to how protein clumps build up in the brain in people with some neurodegenerative diseases such as Alzheimer's and Parkinson's diseases, protein clumps appear to accumulate in the diseased hearts of mice and people with heart failure, according to a team led by Johns Hopkins University researchers.

Read More: Heart Disease News and Heart Disease Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.