The novel anticoagulant REG1 and its antidote have been found to be safe in their first human trial, according to a presentation at a Special Clinical Trials session at the American Heart Association meeting.

“There were no major safety concerns attributed to the drug, the antidote or their combination,” said co-author Richard C. Becker, MD, professor of medicine and director of the Cardiovascular Thrombosis Center at Duke University Medical Center in Durham, N.C. “Drug-antidote systems also could be used across a broad spectrum of diseases, including infectious diseases, rheumatologic disorders and cancer treatment.”

The drug-antidote approach was studied in 85 healthy people (average age 32 years, 34 percent women). The successful results have already led to a new trial in patients with stable coronary heart disease.

“With many existing limitations of traditional anticoagulants, we recognized an opportunity to develop a new system - a new paradigm for safe, patient-specific and potentially disease-specific care. We believe that is what we’ve done,” Becker said.

The development of REG1 is a product of molecular research aimed at creating drugs that work only on one specific molecule. The anticoagulant, a protein-binding, single-stranded nucleic acid called an aptamer, targets activated factor IXa, one of several key molecules involved in the regulation of blood clotting.

“The word aptamer is derived from Latin and means ‘to fit,’” Becker said.

The REG1 aptamer folds into a three-dimensional shape, fitting precisely into one target - factor IXa. When it locks into that molecule, the drug blocks biologic activity and participation in the coagulation cascade. The drug’s antidote is a complementary nucleic acid, which binds rapidly and actively to the aptamer, changing shape so it can no longer inhibit factor IXa activity. The ability to reverse the clotting is another novel function of the drug-antidote system.

The REG1 technology was developed at Duke University, where researchers have also developed aptamers targeted to clotting factors VIIa and Xa, and a variety of functionally important proteins on platelets - small circulating blood cells that contribute to clotting and inflammation.

The trial was coordinated by Duke scientists and conducted at four other medical centers. Researchers recruited and carefully screened the healthy volunteers who entered the multiphase, randomized study.

Participants were first assigned to receive a single injection of the antidote or a placebo. Then they were randomized to receive 15, 30, 60 or 90 milligrams of the drug, followed three hours later by the antidote. In the final phase of the study, they were given the drug or placebo.

This series of experiments enabled the researchers to assess not only the safety of the drug and antidote, but their affects in the body, as well. For instance, they found there was no difference in bleeding between people who received anticoagulant, antidote, combination, or placebo. No participant had a side effect association with activation of the complement system, and no antibodies to the nucleic acids involved in the REG1 system were identified.

The anticoagulant showed a definite dose-dependent response. At three dose levels (30, 60 and 90 milligrams), it produced a measurable anticoagulant effect and effect rose with dose. The antidote worked as designed. Researchers found a prompt and durable reversal of the anti-clotting effect induced by the drug within one to five minutes after injection.

From the new REG1 trial now enrolling patients at five US academic institutions, researchers hope to gain greater insight into the system’s safety for patients with coronary artery disease. The study will examine the drug-antidote combination in 50 patients with stable heart disease who are age 55 years or older and who are taking aspirin and/or clopidogrel for anticoagulation.