A phase 1 ascending dose study of a subcutaneously administered factor IXa inhibitor and its active control agent.
Journal Article
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.Full Text
Duke Authors
Cited Authors
- Vavalle, JP; Rusconi, CP; Zelenkofske, S; Wargin, WA; Alexander, JH; Becker, RC
Published Date
- July 2012
Published In
Volume / Issue
- 10 / 7
Start / End Page
- 1303 - 1311
PubMed ID
- 22500821
Pubmed Central ID
- 22500821
Electronic International Standard Serial Number (EISSN)
- 1538-7836
International Standard Serial Number (ISSN)
- 1538-7933
Digital Object Identifier (DOI)
- 10.1111/j.1538-7836.2012.04742.x
Language
- eng