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(Circulation. 2006;114:2490-2497.)
© 2006 American Heart Association, Inc.

Vascular Medicine

First-in-Human Experience of an Antidote-Controlled Anticoagulant Using RNA Aptamer Technology

A Phase 1a Pharmacodynamic Evaluation of a Drug-Antidote Pair for the Controlled Regulation of Factor IXa Activity

Christopher K. Dyke, MD; Steven R. Steinhubl, MD; Neal S. Kleiman, MD; Richard O. Cannon, MD; Laura G. Aberle, MS; Min Lin, PhD; Shelley K. Myles, BS, RN; Chiara Melloni, MD; Robert A. Harrington, MD; John H. Alexander, MD; Richard C. Becker, MD; Christopher P. Rusconi, PhD

From the Duke Clinical Research Institute, Durham, NC (C.K.D., L.G.A., A.L., S.K.M., C.M., R.A.H., J.H.A., R.C.B.); University of Kentucky, Lexington (S.R.S.); Methodist DeBakey Heart Center, Houston, Tex (N.S.K.); National Heart, Lung, and Blood Institute, Bethesda, Md (R.O.C.); and Regado Biosciences, Inc, Durham, NC (C.P.R). Dr Dyke is now affiliated with the Alaska Heart Institute, Anchorage, Alaska.

Reprint requests to Christopher K. Dyke, MD, or Richard C. Becker, MD, Duke University School of Medicine, Duke Clinical Research Institute, 2400 Pratt St, Durham, NC 27715. E-mail cdyke{at}alaskaheart.com or becke021@mc.duke.edu

Received October 5, 2006; revision received October 24, 2006; accepted October 27, 2006.

Background— Selectivity, titratability, rapidity of onset, and active reversibility are desirable pharmacological properties of anticoagulant therapy administered for acute indications and collectively represent an attractive platform to maximize patient safety. A novel anticoagulation system (REG1, Regado Biosciences), developed using a protein-binding oligonucleotide to factor IXa (drug, RB006) and its complementary oligonucleotide antidote (RB007), was evaluated in healthy volunteers. The primary objective was to determine the safety profile and to characterize the pharmacodynamic responses in this first-in-human study.

Methods and Results— Regado 1a was a subject-blinded, dose-escalation, placebo-controlled study that randomized 85 healthy volunteers to receive a bolus of drug or placebo followed 3 hours later by a bolus of antidote or placebo. Pharmacodynamic samples were collected serially. Subject characteristics were the following: median age, 32 years (interquartile range, 23 to 39 years); female gender, 35%; and median weight, 79 kg (interquartile range, 70 to 87 kg). No significant differences were found 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. The subject’s symptoms resolved rapidly, and no further sequelae occurred. A predictable dose-pharmacodynamic response, reflected in activated partial thromboplastin time measurements, was seen after administration of the bolus of drug, with a clear correlation between the peak posttreatment activated partial thromboplastin time and post hoc weight-adjusted dose of drug (correlation coefficient, 0.725; P<0.001). In subjects treated with drug, antidote administration reversed the pharmacological activity of the drug, with a rapid (mean time, 1 to 5 minutes across all dose levels) and sustained return of activated partial thromboplastin time to within the normal range. The activated clotting time followed a similar anticoagulant response and reversal pattern. As anticipated, prothrombin time remained unchanged compared with baseline.

Conclusions— These observations represent a first-in-human experience of an RNA aptamer and its complementary oligonucleotide antidote used as an anticoagulant system. The findings contribute to an emerging platform of selective, actively reversible anticoagulant drugs for use among patients with thrombotic disorders of the venous and arterial circulations.

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