A phase 1 ascending dose study of a subcutaneously administered factor IXa inhibitor and its active control agent

. 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 13, 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 mu g mL-1 at 84 h, 5.19 mu g mL-1 at 72 h, 9.32 mu g mL-1 at 90 h, and 32.5 mu g 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.