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

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

Research output: Contribution to journalArticle

109 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)2865-2874
Number of pages10
JournalCirculation
Volume117
Issue number22
DOIs
StatePublished - Jun 1 2008

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Factor IXa
Antidotes
Partial Thromboplastin Time
Nucleotide Aptamers
Coronary Artery Disease
clopidogrel
Blood Platelets
Safety
Oligonucleotides
Pharmaceutical Preparations
Anticoagulants
Aspirin
Placebos
Hemorrhage
Injections
Therapeutics

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Chan, M. Y., Cohen, M. G., Dyke, C. K., Myles, S. K., Aberle, L. G., Lin, M., ... Rusconi, C. P. (2008). Phase 1b randomized study of antidote-controlled modulation of factor IXa activity in patients with stable coronary artery disease. Circulation, 117(22), 2865-2874. https://doi.org/10.1161/CIRCULATIONAHA.107.745687
Chan, Mark Y. ; Cohen, Mauricio G. ; Dyke, Christopher K. ; Myles, Shelley K. ; Aberle, Laura G. ; Lin, Min ; Walder, James ; Steinhubl, Steven R. ; Gilchrist, Ian ; Kleiman, Neal S. ; Vorchheimer, David A. ; Chronos, Nicholas ; Melloni, Chiara ; Alexander, John H. ; Harrington, Robert A. ; Tonkens, Ross M. ; Becker, Richard C. ; Rusconi, Christopher P. / Phase 1b randomized study of antidote-controlled modulation of factor IXa activity in patients with stable coronary artery disease. In: Circulation. 2008 ; Vol. 117, No. 22. pp. 2865-2874.
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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 Min Lin and James Walder and Steinhubl, {Steven R.} and Ian Gilchrist and Kleiman, {Neal S.} and Vorchheimer, {David A.} and Nicholas Chronos and Chiara Melloni and Alexander, {John H.} and Harrington, {Robert A.} and Tonkens, {Ross M.} and Becker, {Richard C.} and Rusconi, {Christopher P.}",
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Chan, MY, Cohen, MG, Dyke, CK, Myles, SK, Aberle, LG, Lin, M, Walder, J, Steinhubl, SR, Gilchrist, I, Kleiman, NS, Vorchheimer, DA, Chronos, N, Melloni, C, Alexander, JH, Harrington, RA, Tonkens, RM, Becker, RC & Rusconi, CP 2008, 'Phase 1b randomized study of antidote-controlled modulation of factor IXa activity in patients with stable coronary artery disease', Circulation, vol. 117, no. 22, pp. 2865-2874. https://doi.org/10.1161/CIRCULATIONAHA.107.745687

Phase 1b randomized study of antidote-controlled modulation of factor IXa activity in patients with stable coronary artery disease. / Chan, Mark Y.; Cohen, Mauricio G.; Dyke, Christopher K.; Myles, Shelley K.; Aberle, Laura G.; Lin, Min; Walder, James; Steinhubl, Steven R.; Gilchrist, Ian; Kleiman, Neal S.; Vorchheimer, David A.; Chronos, Nicholas; Melloni, Chiara; Alexander, John H.; Harrington, Robert A.; Tonkens, Ross M.; Becker, Richard C.; Rusconi, Christopher P.

In: Circulation, Vol. 117, No. 22, 01.06.2008, p. 2865-2874.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Phase 1b randomized study of antidote-controlled modulation of factor IXa activity in patients with stable coronary artery disease

AU - Chan, Mark Y.

AU - Cohen, Mauricio G.

AU - Dyke, Christopher K.

AU - Myles, Shelley K.

AU - Aberle, Laura G.

AU - Lin, Min

AU - Walder, James

AU - Steinhubl, Steven R.

AU - Gilchrist, Ian

AU - Kleiman, Neal S.

AU - Vorchheimer, David A.

AU - Chronos, Nicholas

AU - Melloni, Chiara

AU - Alexander, John H.

AU - Harrington, Robert A.

AU - Tonkens, Ross M.

AU - Becker, Richard C.

AU - Rusconi, Christopher P.

PY - 2008/6/1

Y1 - 2008/6/1

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.

AB - 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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