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(Circulation. 2008;117:2865-2874.)
© 2008 American Heart Association, Inc.

Coronary Heart Disease

Phase 1b Randomized Study of Antidote-Controlled Modulation of Factor IXa Activity in Patients With Stable Coronary Artery Disease

Mark Y. Chan, MD, MHS; Mauricio G. Cohen, MD; Christopher K. Dyke, MD; Shelley K. Myles, BSPH, RN; Laura G. Aberle, MS; Min Lin, PhD; James Walder, MD; Steven R. Steinhubl, MD; Ian C. Gilchrist, MD; Neal S. Kleiman, MD; David A. Vorchheimer, MD; Nicholas Chronos, MD; Chiara Melloni, MD, MHS; John H. Alexander, MD, MHS; Robert A. Harrington, MD; Ross M. Tonkens, MD; Richard C. Becker, MD; Christopher P. Rusconi, PhD

From the Duke Clinical Research Institute (M.Y.C., S.K.M., L.G.A., M.L., C.M., J.H.A., R.A.H., R.C.B.), Durham, NC; Division of Cardiology (M.G.C.), University of North Carolina, Chapel Hill; Alaska Heart Institute (C.K.D.), Anchorage; Black Hills Cardiology (J.W.), Rapid City, SD; Cardiovascular Research Center (S.R.S.), University of Kentucky, Lexington; Hershey Medical Center (I.C.G.), Pennsylvania State University, Hershey; Methodist DeBakey Heart Center (N.S.K.), Baylor College of Medicine, Houston, Tex; Mount Sinai Medical Center (D.A.V.), New York University Hospital, New York; Saint Joseph’s Translational Research Institute (N.C.), Atlanta, Ga; and Regado Biosciences (R.M.T., C.P.R.), Durham, NC.

Correspondence to Richard C. Becker, MD, Professor of Medicine, Duke University School of Medicine, Director, Cardiovascular Thrombosis Center, Duke Clinical Research Institute, 2400 Pratt St, Terrace Level Room 0311, Durham, NC 27705. E-mail richard.becker{at}duke.edu

Received October 23, 2007; accepted March 21, 2008.

Background— Whether selective factor IXa inhibition produces an appropriate anticoagulant effect when combined with platelet-directed therapy in patients with stable coronary artery disease is unknown. REG1 consists of RB006 (drug), an injectable RNA aptamer that specifically binds and inhibits factor IXa, and RB007 (antidote), the complementary oligonucleotide that neutralizes its anti-IXa activity.

Methods and Results— We evaluated the safety, tolerability, and pharmacodynamic profile of REG1 in a randomized, double-blind, placebo-controlled study, assigning 50 subjects with coronary artery disease taking aspirin and/or clopidogrel to 4 dose levels of RB006 (15, 30, 50, and 75 mg) and RB007 (30, 60, 100, and 150 mg). The median age was 61 years (25th and 75th percentiles, 56 and 68 years), and 80% of patients were male. RB006 increased the activated partial thromboplastin time dose dependently; the median activated partial thromboplastin time at 10 minutes after a single intravenous bolus of 15, 30, 50, and 75 mg RB006 was 29.2 seconds (25th and 75th percentiles, 28.1 and 29.8 seconds), 34.6 seconds (25th and 75th percentiles, 30.9 and 40.0 seconds), 46.9 seconds (25th and 75th percentiles, 40.3 and 51.1 seconds), and 52.2 seconds (25th and 75th percentiles, 46.3 and 58.6) (P<0.0001; normal 25th and 75th percentiles, 27 and 40 seconds). RB007 reversed the activated partial thromboplastin time to baseline levels within a median of 1 minute (25th and 75th percentiles, 1 and 2 minutes) with no rebound increase through 7 days. No major bleeding or other serious adverse events occurred.

Conclusions— This is the first experience of an RNA aptamer drug-antidote pair achieving inhibition and active restoration of factor IXa activity in combination with platelet-directed therapy in stable coronary artery disease. The preliminary clinical safety and predictable pharmacodynamic effects form the basis for ongoing studies in patients undergoing elective revascularization procedures.

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CLINICAL PERSPECTIVE

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