Chicago, IL - A novel anticoagulant using RNA aptamer technology in early development is hoped to overcome many of the limitations of current agents in that it is selective, has a rapid onset of action, can be easily titrated, and is fully reversible with the use of an antidote [1].

The first tests in humans with the compound, which inhibits factor IXa, were described by Dr Christopher Dyke (Alaska Heart Institute, Anchorage) in a presentation at the recent American Heart Association 2005 Scientific Sessions and published online November 13, 2006 in Circulation.

Technology could target any small molecule

In an interview with heartwire, senior author Dr Richard Becker (Duke University, Durham, NC) explained that this technology is applicable not only to anticoagulation but to many different disease states. "With this technology, we can target just about any small molecule or protein, so the principle of making nucleic-acid therapeutics and specific antidotes could be used in many different disease areas, including cancer, infectious diseases, and rheumatology. In this instance we chose to target factor IX, but we could also make RNA aptamer inhibitors targeting cancer cells or microbes or many other pathogens. The implications are quite astounding," he said.

Becker explained that the beauty of the technology is that complementary oligonucleotides can also be rationally designed that inactivate the first compound, thus neutralizing its activity. The factor IX inhibitor (RB006), and its antidote (RB007)—the first drug-antidote pair derived from this technology to be tested in humans—are together known as the REG1 anticoagulant system.

Bleeding: An unacceptable trade-off of current drugs

In the Circulation paper, Dyke et al point out that bleeding is a common side effect of current anticoagulants, but they maintain that the acceptance of bleeding as a "trade-off" for effective anticoagulation should not be endorsed in contemporary practice, given its profound impact on patient outcomes. Accordingly, there is a substantial clinical need to develop anticoagulants with more favorable safety profiles. They note that an optimal parenteral anticoagulant should have a rapid onset of action and predictable dose-related pharmacodynamic effects, so that routine monitoring is not required; it should also be biologically selective and actively reversible.

The researchers note that RB006 is a direct factor IXa inhibitor that binds coagulation factor IXa with high affinity and specificity. RB006 is an RNA-based aptamer formulated to have a prolonged duration of effect. They explain that RB006 elicits an anticoagulant effect by selectively blocking the factor VIIIa/IXa-catalyzed conversion of factor X to factor Xa, a pivotal step in thrombin generation. Preclinical studies have demonstrated that RB006 can provide durable systemic anticoagulation and antithrombotic activity after intravenous bolus administration and that RB007 can rapidly and durably neutralize the anticoagulant activity of RB006 after intravenous bolus administration.

In the current dose-escalation clinical study, 85 healthy volunteers were randomized to a bolus of drug or placebo followed three hours later by a bolus of antidote or placebo. Results showed no significant differences in median hemoglobin, platelet, creatinine, or liver-function studies. There were no significant bleeding signals associated with RB006, and overall, both drug and antidote were well tolerated. One serious adverse event, an episode of transient encephalopathy, occurred in a subject receiving the low intermediate dose of RB006, but symptoms resolved rapidly, and no further sequelae occurred. Neurological examination and brain computed tomography failed to reveal any abnormalities or cause for the event and specifically excluded intracranial bleeding. A predictable dose pharmacodynamic response, reflected in activated partial thromboplastin time (APTT) measurements, was seen after administration of the bolus of the drug. In subjects treated with the drug, antidote administration reversed the pharmacological activity of the drug, with a rapid (one to five minutes) and sustained return of APTT to within the normal range.

A new era?

Dyke et al say that: "REG-1 heralds a new era in direct, selective, and actively reversible anticoagulants using target-specific oligonucleotide aptamers with their complementary antidotes. This novel construct represents, in essence, an anticoagulation system that provides a rapid and effective means to either attenuate or fully inhibit specific coagulation proteases while maintaining hemostatic control through tailored administration of an inherently safe neutralizing-specific antidote. In effect, this anticoagulation system offers a molecular 'on-off' switch to pharmacological anticoagulation."

They add that the current demonstration of a close correlation among aptamer dose, factor IX activity, and APTT prolongation, as well as the safety and durable effectiveness of antidote administration, provided the requisite understanding to begin a phase 1b study in patients with stable atherothrombotic coronary artery disease. "Planned phase 2 trials will further define optimal dosing strategies, improve our understanding of safety, and provide initial assessments of efficacy for the REG1 anticoagulant system," they conclude.

The science behind this technology was the idea of Duke scientists—Dyke was formerly at Duke. The factor IXa inhibitor and its antidote are now being developed by Regado Biosciences, a spin-off of the Duke department of surgery, and Duke University has an ownership interest in the company.