Skip to main content

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

Publication ,  Journal Article
Chan, MY; Cohen, MG; Dyke, CK; Myles, SK; Aberle, LG; Lin, M; Walder, J; Steinhubl, SR; Gilchrist, IC; Kleiman, NS; Vorchheimer, DA ...
Published in: Circulation
June 3, 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.

Duke Scholars

Altmetric Attention Stats
Dimensions Citation Stats

Published In

Circulation

DOI

EISSN

1524-4539

Publication Date

June 3, 2008

Volume

117

Issue

22

Start / End Page

2865 / 2874

Location

United States

Related Subject Headings

  • Treatment Outcome
  • Ticlopidine
  • Oligonucleotides
  • Middle Aged
  • Male
  • Humans
  • Female
  • Factor IXa
  • Drug Combinations
  • Double-Blind Method
 

Citation

APA
Chicago
ICMJE
MLA
NLM
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., Mauricio G. Cohen, Christopher K. Dyke, Shelley K. Myles, Laura G. Aberle, Min Lin, James Walder, et al. “Phase 1b randomized study of antidote-controlled modulation of factor IXa activity in patients with stable coronary artery disease.Circulation 117, no. 22 (June 3, 2008): 2865–74. https://doi.org/10.1161/CIRCULATIONAHA.107.745687.
Chan MY, Cohen MG, Dyke CK, Myles SK, Aberle LG, Lin M, et al. Phase 1b randomized study of antidote-controlled modulation of factor IXa activity in patients with stable coronary artery disease. Circulation. 2008 Jun 3;117(22):2865–74.
Chan, Mark Y., et al. “Phase 1b randomized study of antidote-controlled modulation of factor IXa activity in patients with stable coronary artery disease.Circulation, vol. 117, no. 22, June 2008, pp. 2865–74. Pubmed, doi:10.1161/CIRCULATIONAHA.107.745687.
Chan MY, Cohen MG, Dyke CK, Myles SK, Aberle LG, Lin M, Walder J, Steinhubl SR, Gilchrist IC, Kleiman NS, Vorchheimer DA, Chronos N, Melloni C, Alexander JH, Harrington RA, Tonkens RM, Becker RC, Rusconi CP. Phase 1b randomized study of antidote-controlled modulation of factor IXa activity in patients with stable coronary artery disease. Circulation. 2008 Jun 3;117(22):2865–2874.

Published In

Circulation

DOI

EISSN

1524-4539

Publication Date

June 3, 2008

Volume

117

Issue

22

Start / End Page

2865 / 2874

Location

United States

Related Subject Headings

  • Treatment Outcome
  • Ticlopidine
  • Oligonucleotides
  • Middle Aged
  • Male
  • Humans
  • Female
  • Factor IXa
  • Drug Combinations
  • Double-Blind Method