438
H. Jin
In 2008 [92], Nucleo incinitiated a phase I clinical trial in healthy volunteers to
determine NU172’s potential to achieve rapid onset and offset of anticoagulation.
NU172 showed a dose-dependent anticoagulating effect without adverse events.
In 2011, ARCA Biopharma, Inc [211] sponsored a phase II, multi-center, openlabel study of NU172 for anticoagulation in patients undergoing coronary artery
bypass graft surgery off-pump. Although the current status of the study is unknown,
NU172 is the only thrombin binding aptamer evaluated in Phase II clinical trials
(ClinicalTrials.gov identifier NCT00808964) for anticoagulation in heart disease
treatments.
REG1
The REG1 anticoagulation system is an aptamer-based direct inhibitor of factor
IXa and its active control agent being developed by Regado Biosciences, Inc. (NJ,
USA) for use in the setting of ACS, percutaneous coronary interventions (PCI) and
open-heart surgery. It consists of two components, the active aptamer drug known
as pegnivacogin, which is an RNA aptamer that acts as a direct factor IXa inhibitor,
and the active control agent known as anivamersen, which binds to and inactivates
pegnivacogin with rapid kinetic.
In 2005 [212], the first phase 1 study of REG1was carried on with 85 healthy
volunteer subjects enrolled, it represents a first-in-human trial of an RNA aptamer
and its complementary oligonucleotide antidote used as an anticoagulant system.
REG1 was overall well tolerated with similar adverse bleeding events to placebo.
In 2008–2010, the Phase II study was proceeded as the first clinical application of REG1 in patients undergoing percutaneous coronary intervention. This trial
demonstrated the feasibility of supporting percutaneous coronary intervention (PCI)
with the REG1 system [213]. Another phase II clinical trial named RADAR tested
different levels of reversal of pegnivacogin by anivamersen compared with heparin
in 640 patients with acute coronary syndrome undergoing cardiac catheterization.
RADAR confirmed that a dose of 1 mg/kg of pegnivacogin could effectively achieve
>99% inhibition of factor IXa [214]. It also demonstrated that at least 50% reversal
with anivamersen is required for safe femoral artery sheath removal and suggested
that with higher doses of reversal (75 or 100%), there may be less bleeding than
with UFH [215]. There was a trend of less frequent acute ischemic complications in
REG1 as compared to heparin anticoagulation [215].
Encouraged by the results of phase II studies, in 2013, a larger clinical phase III
trial commenced to evaluate the efficacy of REG1 versus bivalirudin for percutaneous
coronary intervention in more than 13,000 patients. This trial terminated in 2014
because of 10 severe allergic reactions to pegnivacogin (including one fatality) [216].
The following studies revealed that pre-existing higher level circulating anti-PEG
antibody has a strong correlation with the patient who has the most severe reaction,
which means that the fatal allergic reaction originated from PEG moiety instead of
the aptamer component of pegnivacogin [217, 218]. Although no further clinical trial
was carried on REG1, the aptamer-based inhibition of factor IXa is still a promising
strategy in the future development of anticoagulant treatment.
H. Jin
In 2008 [92], Nucleo incinitiated a phase I clinical trial in healthy volunteers to
determine NU172’s potential to achieve rapid onset and offset of anticoagulation.
NU172 showed a dose-dependent anticoagulating effect without adverse events.
In 2011, ARCA Biopharma, Inc [211] sponsored a phase II, multi-center, openlabel study of NU172 for anticoagulation in patients undergoing coronary artery
bypass graft surgery off-pump. Although the current status of the study is unknown,
NU172 is the only thrombin binding aptamer evaluated in Phase II clinical trials
(ClinicalTrials.gov identifier NCT00808964) for anticoagulation in heart disease
treatments.
REG1
The REG1 anticoagulation system is an aptamer-based direct inhibitor of factor
IXa and its active control agent being developed by Regado Biosciences, Inc. (NJ,
USA) for use in the setting of ACS, percutaneous coronary interventions (PCI) and
open-heart surgery. It consists of two components, the active aptamer drug known
as pegnivacogin, which is an RNA aptamer that acts as a direct factor IXa inhibitor,
and the active control agent known as anivamersen, which binds to and inactivates
pegnivacogin with rapid kinetic.
In 2005 [212], the first phase 1 study of REG1was carried on with 85 healthy
volunteer subjects enrolled, it represents a first-in-human trial of an RNA aptamer
and its complementary oligonucleotide antidote used as an anticoagulant system.
REG1 was overall well tolerated with similar adverse bleeding events to placebo.
In 2008–2010, the Phase II study was proceeded as the first clinical application of REG1 in patients undergoing percutaneous coronary intervention. This trial
demonstrated the feasibility of supporting percutaneous coronary intervention (PCI)
with the REG1 system [213]. Another phase II clinical trial named RADAR tested
different levels of reversal of pegnivacogin by anivamersen compared with heparin
in 640 patients with acute coronary syndrome undergoing cardiac catheterization.
RADAR confirmed that a dose of 1 mg/kg of pegnivacogin could effectively achieve
>99% inhibition of factor IXa [214]. It also demonstrated that at least 50% reversal
with anivamersen is required for safe femoral artery sheath removal and suggested
that with higher doses of reversal (75 or 100%), there may be less bleeding than
with UFH [215]. There was a trend of less frequent acute ischemic complications in
REG1 as compared to heparin anticoagulation [215].
Encouraged by the results of phase II studies, in 2013, a larger clinical phase III
trial commenced to evaluate the efficacy of REG1 versus bivalirudin for percutaneous
coronary intervention in more than 13,000 patients. This trial terminated in 2014
because of 10 severe allergic reactions to pegnivacogin (including one fatality) [216].
The following studies revealed that pre-existing higher level circulating anti-PEG
antibody has a strong correlation with the patient who has the most severe reaction,
which means that the fatal allergic reaction originated from PEG moiety instead of
the aptamer component of pegnivacogin [217, 218]. Although no further clinical trial
was carried on REG1, the aptamer-based inhibition of factor IXa is still a promising
strategy in the future development of anticoagulant treatment.