A phase 1 ascending dose study of a subcutaneously administered factor IXa inhibitor and its active control agent.
Publication/Presentation Date
7-1-2012
Abstract
BACKGROUND: The REG2 anticoagulation system consists of pegnivacogin, a subcutaneously administered aptamer factor IXa inhibitor, and its intravenous control agent, anivamersen.
OBJECTIVES: To assess the safety, tolerability and pharmacokinetic and pharmacodynamic responses of REG2.
PATIENTS/METHODS: In this phase 1a study, 36 healthy volunteers were enrolled into five cohorts and given one dose of pegnivacogin. Cohorts 1 (n = 6) and 1A (n = 4) received 0.5 mg kg(-1); cohort 2 (n = 6) received 1.0 mg kg(-1); cohort 3 (n = 6) received 3.0 mg kg(-1); and cohort 4 (n = 8) received 2.0 mg kg(-1) . In cohorts 1-3, two subjects were randomized to placebo. Cohort 4 subjects were subsequently randomized to single-dose (n = 4) or multidose (n = 4) anivamersen.
RESULTS: The mean maximum observed concentrations of pegnivacogin in cohorts 1, 1A, 2 and 3 at median time were 5.16 μg mL(-1) at 84 h, 5.19 μg mL(-1) at 72 h, 9.32 μg mL(-1) at 90 h, and 32.5 μg mL(-1) at 84 h, respectively. The maximum relative activated partial thromboplastin time and time needed to achieve this were 1.18 at 2 days, 1.16 at 2 days, 1.27 at 3 days, and 1.85 at 2 days, respectively. The calculated mean half-life and mean residence times of pegnivacogin were 6.12 days and 9.6 days, respectively. There was rapid reversal with intravenous anivamersen, although subsequent reaccumulation of pegnivacogin was observed.
CONCLUSIONS: In our first-in-human study, REG2 was well tolerated and provided dose-proportional anticoagulation for several days after a single subcutaneous dose, with complete, although transient, reversal by its control agent. This study demonstrates the first application of a subcutaneously administered aptamer, and represents a potential advance in aptamer therapeutics.
Volume
10
Issue
7
First Page
1303
Last Page
1311
ISSN
1538-7836
Published In/Presented At
Vavalle, J. P., Rusconi, C. P., Zelenkofske, S., Wargin, W. A., Alexander, J. H., & Becker, R. C. (2012). A phase 1 ascending dose study of a subcutaneously administered factor IXa inhibitor and its active control agent. Journal of thrombosis and haemostasis : JTH, 10(7), 1303–1311. https://doi.org/10.1111/j.1538-7836.2012.04742.x
Disciplines
Medicine and Health Sciences
PubMedID
22500821
Department(s)
Cardiology Division
Document Type
Article