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


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.
Chan
Mark Y
MY
Duke Clinical Research Institute, 2400 Pratt St, Terrace Level Room 0311, Durham, NC 27705, USA.
Cohen
Mauricio G
MG
Dyke
Christopher K
CK
Myles
Shelley K
SK
Aberle
Laura G
LG
Lin
Min
M
Walder
James
J
Steinhubl
Steven R
SR
Gilchrist
Ian C
IC
Kleiman
Neal S
NS
Vorchheimer
David A
DA
Chronos
Nicholas
N
Melloni
Chiara
C
Alexander
John H
JH
Harrington
Robert A
RA
Tonkens
Ross M
RM
Becker
Richard C
RC
Rusconi
Christopher P
CP
D000368:Aged; D000931:Antidotes; D052157:Aptamers, Nucleotide / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D001241:Aspirin / Q000627:therapeutic use; D000077144:Clopidogrel; D003324:Coronary Artery Disease; D004311:Double-Blind Method; D004338:Drug Combinations; D015949:Factor IXa / Q000037:antagonists & inhibitors*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009841:Oligonucleotides / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D013988:Ticlopidine / Q000031:analogs & derivatives / Q000627:therapeutic use; D016896:Treatment Outcome
D000931:Antidotes; D052157:Aptamers, Nucleotide; D004338:Drug Combinations; D009841:Oligonucleotides; C515724:RB 006; C515725:RB 007; D000077144:Clopidogrel; D015949:Factor IXa; D013988:Ticlopidine; D001241:Aspirin