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G. Yang and Y. Huang
In succession, aptamers for vascular endothelial growth factor (VEGF), TFPI, activated protein C (APC), von Willebrand disease factor (vWF), and other coagulation
factors were screened (Table 6.2). At present, four coagulation-related therapeutic
aptamers have undergone clinical trials.
6.3.1 REG1 Targeting Coagulation Factor IXa
Coagulation factor IXa is a proximal driving factor of thrombosis, and the blocking
of FIXa activating factor X is one of the main strategies for antithrombotic therapy.
REG1 (Regato Biosciences) is an aptamer-based anticoagulation system with FIXa
activity regulation as the functional mechanism, consisting of two RNA sequences,
RB006 and RB007. Among them, RB006 is a 37 nt-modified RNA aptamer [40],
which is tightly bound to the catalytic domain of FIXa and completely blocks its activation function [41], thus prolonging the coagulation time [42]. In preclinical studies,
RB006 was more therapeutic than heparin in preventing the bleeding caused by arterial thrombosis. During the treatment of patients with acute coronary syndrome,
intravenous injection of RB006 at a weight adjusted dose of 1 mg/kg achieved a high
level of FIXa activity inhibition, which resulted in a three-fold increase in activated
partial thromboplastin time (APTT) [43]. FIXa activity was inhibited by RB006 in a
dose-dependent manner in phase 1 clinical trials. FIXa of all volunteers was almost
completely inhibited at the highest dose, and no safety issues were observed [44].
REG1 has exhibited good patient tolerance in phase 1 and phase 2 clinical trials [45–
48]; meanwhile, REG1 is feasible and controllable for anticoagulation and reversal
for curing coronary heart disease or acute coronary syndrome patients performed by
percutaneous coronary intervention (PCI) and cardiac catheterization [49–51].
In 2014, Regado conducted a large-scale phase 3 clinical trials on 13,000 patients
undergoing percutaneous coronary intervention [52], comparing the efficacy of
REG1 with that of bivarudin, a specific reversible direct thrombin inhibitor (DTI)
[53]. However, the trial was aborted early after patients developed severe allergic
reactions to the REG1 formula. Therefore, no experimental results have proved that
REG1 is superior to bivarudin in the treatment of ischemic or bleeding complications.
In 2016, Ganson et al. [54] and Povsic et al. [48] conducted RADAR and regularPCI, and the results showed that the anaphylactic reaction caused by REG1 formula
was related to the preexisting PEG antibody in patients, indicating that the PEG
modification of RB006 was the main cause of the adverse reaction. This significant
finding indicates that in the similar clinical application of aptamers, it is necessary to
screen the individual with PEG antibody and exclude them from kindred therapies,
or to introduce PEG substitutes. In view of this, researchers combined the aptamers
with albumin and designed self-assembly micelle-type amphiphilic molecules for
therapeutic agents development [55–57].
G. Yang and Y. Huang
In succession, aptamers for vascular endothelial growth factor (VEGF), TFPI, activated protein C (APC), von Willebrand disease factor (vWF), and other coagulation
factors were screened (Table 6.2). At present, four coagulation-related therapeutic
aptamers have undergone clinical trials.
6.3.1 REG1 Targeting Coagulation Factor IXa
Coagulation factor IXa is a proximal driving factor of thrombosis, and the blocking
of FIXa activating factor X is one of the main strategies for antithrombotic therapy.
REG1 (Regato Biosciences) is an aptamer-based anticoagulation system with FIXa
activity regulation as the functional mechanism, consisting of two RNA sequences,
RB006 and RB007. Among them, RB006 is a 37 nt-modified RNA aptamer [40],
which is tightly bound to the catalytic domain of FIXa and completely blocks its activation function [41], thus prolonging the coagulation time [42]. In preclinical studies,
RB006 was more therapeutic than heparin in preventing the bleeding caused by arterial thrombosis. During the treatment of patients with acute coronary syndrome,
intravenous injection of RB006 at a weight adjusted dose of 1 mg/kg achieved a high
level of FIXa activity inhibition, which resulted in a three-fold increase in activated
partial thromboplastin time (APTT) [43]. FIXa activity was inhibited by RB006 in a
dose-dependent manner in phase 1 clinical trials. FIXa of all volunteers was almost
completely inhibited at the highest dose, and no safety issues were observed [44].
REG1 has exhibited good patient tolerance in phase 1 and phase 2 clinical trials [45–
48]; meanwhile, REG1 is feasible and controllable for anticoagulation and reversal
for curing coronary heart disease or acute coronary syndrome patients performed by
percutaneous coronary intervention (PCI) and cardiac catheterization [49–51].
In 2014, Regado conducted a large-scale phase 3 clinical trials on 13,000 patients
undergoing percutaneous coronary intervention [52], comparing the efficacy of
REG1 with that of bivarudin, a specific reversible direct thrombin inhibitor (DTI)
[53]. However, the trial was aborted early after patients developed severe allergic
reactions to the REG1 formula. Therefore, no experimental results have proved that
REG1 is superior to bivarudin in the treatment of ischemic or bleeding complications.
In 2016, Ganson et al. [54] and Povsic et al. [48] conducted RADAR and regularPCI, and the results showed that the anaphylactic reaction caused by REG1 formula
was related to the preexisting PEG antibody in patients, indicating that the PEG
modification of RB006 was the main cause of the adverse reaction. This significant
finding indicates that in the similar clinical application of aptamers, it is necessary to
screen the individual with PEG antibody and exclude them from kindred therapies,
or to introduce PEG substitutes. In view of this, researchers combined the aptamers
with albumin and designed self-assembly micelle-type amphiphilic molecules for
therapeutic agents development [55–57].