Novel drug-antidote strategy provides greater control of drug action

10/13/04

DURHAM, N.C. – In a discovery that could give physicians more control over the actions of medications, researchers at Duke University Medical Center have developed a novel drug pair – a potent anti-coagulant with a matched "antidote."

Using this combination pharmaceutical on-off switch, whose unique properties were demonstrated in animal models, researchers could quickly and effectively neutralize the effects of the drug. The finding could open up a new approach to the development of medications. Instead of developing agents to treat the side effects of existing drugs, researchers could develop matched drug-antidote pairs at the beginning of the drug development process to enable the control of drug activity in patients.

The results of the Duke experiments were published Oct. 17, 2004, as an Advance Online Publication of the journal Nature Biotechnology. The study was supported by the National Institutes of Health (NIH), the American Heart Association, and Duke's Department of Surgery.

"These findings have the possibility to significantly change how we care for heart patients," said Bruce Sullenger, Ph.D., vice chairman of research for Duke's surgery department and senior member of the research team.

Sullenger, and his colleague Chris Rusconi, Ph.D., were inspired by Duke cardiologists who said they needed a reliable blood-thinning agent that they could give to patients without the accompanying risks of bleeding. When bleeding events occur, cardiologists have little recourse except to wait for the drug to be cleared from the body naturally, a potentially time-consuming process. Patients who have received anticoagulants and who then must undergo emergency surgery can also face life-threatening delays, said Sullenger.

"One of the biggest problems we face as cardiologists is that one of the major side effects of drugs we use to 'thin the blood' is bleeding," said cardiologist Robert Califf, M.D., director of the Duke Clinical Research Institute. "We can't easily stop or reverse the action of these drugs quickly. If this new approach works out, it should give us much greater control in so many situations where a drug is long-lasting but has potential side effects."

The researchers took the challenge, and decided to create a drug-antidote pair from scratch. Their target was human coagulation factor IXa, a pivotal clotting factor in the complex cascade of biochemical events that ultimately leads to the formation of a blood clot. Past studies have shown an association between elevated levels of factor IXa and the onset of acute coronary syndrome.

The researchers discovered anticoagulant aptamers that target factor IXa. Aptamers are single-stranded nucleic acids (RNA or DNA) that bind to specific protein targets with high affinity and specificity. The first drug from this new class of therapeutics, Eyetech's Macugen, recently demonstrated high efficacy for the treatment of age-related macular degeneration in Phase III clinical trials.

"As soon as the drug is developed, the antidote comes relatively easily," Sullenger said. "Once we determined the identity of our drug, we were able to design an antidote that would bind to the drug at a specific site, causing a conformational change, which rapidly and durably neutralizes the activity of the drug."

The Duke researchers previously described the discovery and design of this anti-factor IXa aptamer-antidote pair and demonstrated the blood-thinning activity of the drug and the neutralization activity of the antidote in the test tube in a paper published in Nature (Sept. 5, 2002).

In their current experiments, the researchers first demonstrated that the factor IXa inhibitor was an effective anticoagulant in pigs. Then, once the blood was anticoagulated, they injected the antidote into the treated pigs.

"The antidote neutralized more than 95 percent of the anticoagulant effects of the drug within 10 minutes, and continued to neutralize the anticoagulant activity more than an hour later," Sullenger said.

In studies conducted by colleagues from the University of Michigan, the aptamer drug-antidote pair was successful in mouse models. The drug effectively prevented arterial thrombosis in murine thrombosis models, and the additional safety of the drug conferred by the antidote was demonstrated in murine surgical challenge models. Mice were treated with high doses of the anticoagulant and the ends of their tails were clipped off. Mice who were not given the antidote experienced significant bleeding in response to this surgical challenge, whereas mice given the antidote after the tail clipping experienced no increased blood loss.

"Our studies demonstrate that the aptamer anticoagulant is effective in clinically predictive animal models of cardiovascular disease and that its antidote prevents the potential side effects of this new drug," Sullenger said.

The researchers said that while there will be many potential uses of this new approach to drug development, the first clinical application will likely be in the area of open heart surgery. In order to place a heart on the heart-lung machine, the blood must be thinned to prevent clotting in the machine's tubing during surgery. However, once the surgery is complete, the blood must be returned to its proper state.

"For decades, surgeons have used heparin to thin the blood of these patients, and the only agent available to block the effect of heparin is protamine," Rusconi said. "However, heparin and protamine are imperfect drugs, with many unwanted side effects. This new aptamer-based drug and its antidote have the potential to give surgeons much more control over anti-coagulation."

Cardiologists routinely use blood-thinning or anti-coagulant agents as an urgent treatment for a suspected heart attack and during angioplasty procedures. However, since bleeding is a major concern of such anticoagulation, physicians must constantly monitor blood levels to ensure that the drug remains within therapeutic ranges.

"With this new drug-antidote pair, physicians will have a more predictably reversible anticoagulant that is easier to use and will require significantly less monitoring," Rusconi continued.

Rusconi recently left Duke to co-found Regado Biosciences, Inc. with Sullenger. Regado is based in Research Triangle Park, N.C. and has venture backing from the Durham-based Aurora funds. The company has licensed the antidote technology as well as the factor IXa aptamer-antidote pair, known as REG1, from Duke, and plans to initiate clinical testing of REG1 early next year.

"An advance such as this is a perfect example of translational medicine, where clinicians work with basic scientists to solve the problems facing physicians," said Sullenger, who is director of Duke's Center for Translational Research. "Clinicians typically are not as well versed in molecular biology as we are, and we may not have conceived of this approach had we not spent time talking to clinicians about their needs."

Other Duke members of the research team were George Pitoc, Shahid Nimjee, Rebekah White, M.D., George Quick, and Elizabeth Scardino. Joseph Roberts and William Fay from the University of Michigan were also part of the team.

Source: Eurekalert & others

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