PURPOSE: The REG2 system, consisting of the subcutaneous (SC) aptamer RB006, a direct FIXa inhibitor, and active control agent, IV RB007 has been previously shown to provide stable, prolonged anticoagulation. This was the first human experience with a SC aptamer. Elevated levels of Factor IX (FIX) have been shown to be associated with the development of venous thromboembolism (VTE). We evaluated the inhibition of FIXa after a single SC injection of RB006 and the reversal effect of IV RB007.
METHODS: This Phase Ia partially blinded, 5 arm, single ascending dose study was conducted in 36 healthy volunteers. SC RB006 was administered subcutaneously as a one-time injection. Each dose was escalated after safety evaluation (Groups 1, 1a: 0.5mg/kg; Group 2: 1mg/kg; Group 3: 3 mg/kg). A fifth cohort received planned reversal with RB007 (Group 4a: RB006 2mg/kg+ RB007 1mg/kg at 72 hrs; Group 4b: RB006 2mg/kg + RB007 1mg/kg at 24, 72, 120 hrs). Groups 1, 2 and 3 were blinded. Levels of FIXa inhibition were determined at each dose.
RESULTS: A total of 36 subjects were treated (30 RB006, 6 placebo), mean age 29.7 yrs, mean weight 76.4 kg, 21 male (58%). RB006 demonstrated dose- dependant inhibition of FIXa. Onset of FIXa inhibition was demonstrated at 12 hours (24.1, 13.1, 58.5, 89.7% FIXa inhibition, respectively), high levels of inhibition were achieved by 24 hours (47.5, 66.2, 88.5, 97.8% FIXa inhibition, respectively), peak effect was at 72 hours (62.1, 76.8, 86.8, 98.7% FIXa inhibition, respectively) and inhibition was sustained beyond 7 days. RB007 reversed the level of FIXa inhibition towards baseline. Injections were well tolerated with no significant adverse events and no dose- related adverse effects.
CONCLUSION: RB006 demonstrated sustained, stable FIXa inhibition after a single subcutaneous injection with successful reversal by IV RB007.
CLINICAL IMPLICATIONS: The REG2 system provides a potentially new approach to the management of patients at risk for and those with VTE. Further studies are needed to test its clinical application.
DISCLOSURE: Steven Zelenkofske, Employee Steven Zelenkofske, Chris Rusconi and Carolyn Darmiento are employees of Regado Biosciences.; Consultant fee, speaker bureau, advisory committee, etc. William Wargin is a consultant to Regado Biosciences and received fees.Richard Becker is a consultant to Regado Biosciences and received fees.; Product/procedure/technique that is considered research and is NOT yet approved for any purpose. The REG2 system (components RB006 and RB007) is an investigational agent(s)and has not been approved for use. This is Phase 1a research for the REG2 system.