rb-006 and Acute-Coronary-Syndrome

Antithrombotic agents including anticoagulants and antiplatelets are the cornerstone of treatment of acute coronary syndromes. Currently available anticoagulants have several important limitations including unpredictable pharmacodynamics, immunogenicity, and difficulty in reversibility. A potent anticoagulant that has predictable efficacy, is easily reversible should the clinical need arise, and reduces ischemic events without an increase in bleeding risk would overcome many of the current limitations. Inhibition of factor IX in the coagulation cascade has shown promise as a target for development of a novel anticoagulant with a favorable bleeding risk. Aptamers are small oligonucleotides that can be developed to inhibit specific protein targets with high affinity and used as active drugs. Because aptamers are made of oligonucleotide sequences, they provide the code for their own complement (reversal agent) that can be developed and used to inhibit their function. The REG1 anticoagulation system is a novel, aptamer-based, factor IXa inhibitor that is being developed for use in patients undergoing percutaneous coronary intervention and the treatment of acute coronary syndrome.

Topics: Acute Coronary Syndrome; Anticoagulants; Aptamers, Nucleotide; Blood Coagulation; Factor IXa; Fibrinolytic Agents; Humans; RNA

We sought to determine the feasibility of conducting percutaneous coronary intervention (PCI) in high-risk acute coronary syndrome (ACS) patients utilising the REG1 system consisting of pegnivacogin, an aptameric factor IXa inhibitor, and its controlling agent anivamersen.. In RADAR, ACS patients were randomised to pegnivacogin 1 mg/kg with 25%, 50%, 75%, or 100% anivamersen reversal or unfractionated heparin. Of the 640 patients randomised, 388 (61%) underwent PCI. Major modified ACUITY 30-day bleeding rates were 18% (25% reversal), 12% (50% reversal), 9% (75% reversal), and 7% (100% reversal), compared with 11% with heparin. The corresponding total bleeding rates were 68%, 39%, 35%, 34%, and 38% (heparin). Ischaemic events were less frequent in those receiving pegnivacogin versus heparin (4.4% vs. 7.3%, p=0.3). Thirty-day urgent TVR (1.1% vs. 0.9%, p=1.0), myocardial infarction (4.0% vs. 6.4%, p=0.3), and angiographic complication (11.2% and 10.8%, p=0.9) rates were similar with pegnivacogin and heparin. There were no incidences of clot formation on guidewires or catheters.. High-level factor IXa inhibition in ACS patients undergoing PCI, with at least 50% reversal, has a favourable bleeding profile and appears effective at suppressing ischaemic events and thrombotic complications. Larger phase trials in PCI are warranted.. ClinicalTrials.gov NCT00932100.

Topics: Acute Coronary Syndrome; Aged; Anticoagulants; Aptamers, Nucleotide; Female; Hemorrhage; Heparin; Humans; Male; Middle Aged; Myocardial Infarction; Percutaneous Coronary Intervention; Treatment Outcome

We sought to determine the degree of anticoagulation reversal required to mitigate bleeding, and assess the feasibility of using pegnivacogin to prevent ischaemic events in acute coronary syndrome (ACS) patients managed with an early invasive approach. REG1 consists of pegnivacogin, an RNA aptamer selective factor IXa inhibitor, and its complementary controlling agent, anivamersen. REG1 has not been studied in invasively managed patients with ACS nor has an optimal level of reversal allowing safe sheath removal been defined.. Non-ST-elevation ACS patients (n = 640) with planned early cardiac catheterization via femoral access were randomized 2:1:1:2:2 to pegnivacogin with 25, 50, 75, or 100% anivamersen reversal or heparin. The primary endpoint was total ACUITY bleeding through 30 days. Secondary endpoints included major bleeding and the composite of death, myocardial infarction, urgent target vessel revascularization, or recurrent ischaemia. Enrolment in the 25% reversal arm was suspended after 41 patients. Enrolment was stopped after three patients experienced allergic-like reactions. Bleeding occurred in 65, 34, 35, 30, and 31% of REG1 patients with 25, 50, 75, and 100% reversal and heparin. Major bleeding occurred in 20, 11, 8, 7, and 10% of patients. Ischaemic events occurred in 3.0 and 5.7% of REG1 and heparin patients, respectively.. At least 50% reversal is required to allow safe sheath removal after cardiac catheterization. REG1 appears a safe strategy to anticoagulate ACS patients managed invasively and warrants further investigation in adequately powered clinical trials of patients who require short-term high-intensity anticoagulation.

Topics: Acute Coronary Syndrome; Anticoagulants; Aptamers, Nucleotide; Cardiac Catheterization; Coagulants; Factor IXa; Feasibility Studies; Female; Hemorrhage; Heparin; Humans; Male; Middle Aged; Myocardial Infarction; Myocardial Revascularization; Oligonucleotides; Secondary Prevention; Treatment Outcome

Anticoagulants are the cornerstone of current acute coronary syndrome (ACS) therapy; however, anticoagulation regimens that aggressively reduce ischemic events are almost uniformly associated with more bleeding. REG1, an anticoagulation system, consists of RB006 (pegnivacogin), an RNA oligonucleotide factor IXa inhibitor, and RB007 (anivamersen), its complementary controlling agent. Phase I and IIa studies defined predictable relationships between doses of RB006, RB007, and degree of antifactor IX activity. The efficacy and safety of REG1 for the treatment of patients with ACS managed invasively and the safety of reversing RB006 with RB007 after cardiac catheterization are unknown. Randomized, partially-blinded, multicenter, active-controlled, dose-ranging study assessing the safety, efficacy, and pharmacodynamics of the REG1 anticoagulation system compared to unfractionated heparin or low molecular heparin in subjects with acute coronary syndrome (RADAR) is designed to assess both the efficacy of the anticoagulant RB006 and the safety of a range of levels of RB006 reversal with RB007. The objectives of RADAR are (1) to determine the safety of a range of levels of RB006 reversal with RB007 after catheterization, (2) to confirm whether a dose of 1 mg/kg RB006 results in near-complete inhibition of factor IXa in patients with ACS, and (3) to assess the efficacy of RB006 as an anticoagulant in patients with ACS undergoing percutaneous coronary intervention.

Topics: Acute Coronary Syndrome; Aptamers, Nucleotide; Clinical Trials, Phase II as Topic; Humans; Multicenter Studies as Topic; Oligonucleotides; Randomized Controlled Trials as Topic

Establishing factor IX inhibition in patients with acute coronary syndrome/non-ST-elevation myocardial infarction (ACS/NSTEMI), a setting characterized by increased factor IX activity, is critical to investigate the REG1 system in this target population. The REG1 system (Regado Biosciences, Basking Ridge, NJ) consists of pegnivacogin (RB006), an RNA aptamer that directly inhibits factor IXa, and anivamersen (RB007), its complementary control agent.. RADAR is a Phase 2b study investigating the use of pegnivacogin in patients (n = 800) with ACS undergoing planned early cardiac catheterization. To validate dose selection and stability of anticoagulation throughout the time of cardiac catheterization at an early stage of the clinical trial, 33 patients, 22 of whom had not received recent prior heparin, underwent thorough pharmacokinetic and pharmacodynamic assessment. Fold prolongation of activated partial thromboplastin time (aPTT) was used to impute factor IX inhibition. Pegnivacogin 1 mg/kg rapidly achieved a high pegnivacogin plasma concentration (26.1 ± 4.6 µg/mL), prolonged the aPTT (mean aPTT 93.0 ± 9.5 s), and approached near complete factor IX inhibition (mean fold increase from baseline 2.9 ± 0.3). These levels remained stable from the time of drug administration through completion of the catheterization.. Pegnivacogin administered at a weight-adjusted dose of 1 mg/kg consistently achieves a high level of factor IX activity inhibition among patients with ACS and provides stable anticoagulation during cardiac catheterization. These findings support the dose of pegnivacogin selected for the RADAR study.

Topics: Acute Coronary Syndrome; Aged; Anticoagulants; Aptamers, Nucleotide; Factor IXa; Female; Humans; Infusions, Intravenous; Male; Middle Aged; Myocardial Infarction; Partial Thromboplastin Time; Treatment Outcome

Topics: Acute Coronary Syndrome; Anticoagulants; Aptamers, Nucleotide; Female; Hemorrhage; Humans; Male; Myocardial Infarction; Percutaneous Coronary Intervention