Phase 1b randomized study of antidote-controlled modulation of factor IXa activity in patients with stable coronary artery disease. Export

@article{citeulike:5376170, abstract = {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.}, author = {Chan, Mark Y. and Cohen, Mauricio G. and Dyke, Christopher K. and Myles, Shelley K. and Aberle, Laura G. and Lin, Min and Walder, James and Steinhubl, Steven R. and Gilchrist, Ian C. and Kleiman, Neal S. and Vorchheimer, David A. and Chronos, Nicholas and Melloni, Chiara and Alexander, John H. and Harrington, Robert A. and Tonkens, Ross M. and Becker, Richard C. and Rusconi, Christopher P.}, citeulike-article-id = {5376170}, citeulike-linkout-0 = {http://dx.doi.org/10.1161/CIRCULATIONAHA.107.745687}, citeulike-linkout-1 = {http://view.ncbi.nlm.nih.gov/pubmed/18506005}, citeulike-linkout-2 = {http://www.hubmed.org/display.cgi?uids=18506005}, day = {3}, doi = {10.1161/CIRCULATIONAHA.107.745687}, issn = {1524-4539}, journal = {Circulation}, keywords = {aptamer}, month = {June}, number = {22}, pages = {2865--2874}, posted-at = {2009-08-06 03:16:08}, priority = {2}, title = {Phase 1b randomized study of antidote-controlled modulation of factor IXa activity in patients with stable coronary artery disease.}, url = {http://dx.doi.org/10.1161/CIRCULATIONAHA.107.745687}, volume = {117}, year = {2008} }

TY - JOUR ID - citeulike:5376170 L3 - citeulike-article-id:5376170 N2 - 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. IS - 22 JF - Circulation SN - 1524-4539 EP - 2874 TI - Phase 1b randomized study of antidote-controlled modulation of factor IXa activity in patients with stable coronary artery disease. VL - 117 SP - 2865 KW - aptamer AU - Chan, Mark AU - Cohen, Mauricio AU - Dyke, Christopher AU - Myles, Shelley AU - Aberle, Laura AU - Lin, Min AU - Walder, James AU - Steinhubl, Steven AU - Gilchrist, Ian AU - Kleiman, Neal AU - Vorchheimer, David AU - Chronos, Nicholas AU - Melloni, Chiara AU - Alexander, John AU - Harrington, Robert AU - Tonkens, Ross AU - Becker, Richard AU - Rusconi, Christopher PY - 2008/06/03/ UR - http://dx.doi.org/10.1161/CIRCULATIONAHA.107.745687 ER -