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.
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

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