Presentation is loading. Please wait.

Presentation is loading. Please wait.

A Randomized, Partially-Blinded, Multi-Center, Active-Controlled, Dose-Ranging Study Assessing the Safety, Efficacy, and Pharmacodynamics of the REG1 Anticoagulation.

Similar presentations


Presentation on theme: "A Randomized, Partially-Blinded, Multi-Center, Active-Controlled, Dose-Ranging Study Assessing the Safety, Efficacy, and Pharmacodynamics of the REG1 Anticoagulation."— Presentation transcript:

1 A Randomized, Partially-Blinded, Multi-Center, Active-Controlled, Dose-Ranging Study Assessing the Safety, Efficacy, and Pharmacodynamics of the REG1 Anticoagulation System Compared to Unfractionated Heparin or Low Molecular Weight Heparin in Subjects with Acute Coronary Syndromes: Primary Results of the RADAR Randomized Clinical Trial Thomas J. Povsic, MD, PhD on behalf of the RADAR Investigators

2 All Rights Reserved, Duke Medicine 2007 Disclosures RADAR was funded by REGADO Biosciences Inc. Duke Clinical Research Institute receives research funding from REGADO Biosciences RADAR ACC11 LBCT: 2

3 All Rights Reserved, Duke Medicine 2007 REG1: Pegnivacogin + Anivamersen Regado Biosciences, Inc Novel Anticoagulation System –RNA aptamer –Factor IXa inhibitor –Controlling agent Active Specific Immediate Titratable Prior studies –Phase 1a, 1b, 1c (n = 174) –Phase 2a PCI (n = 26) Raises aPTT in relation to degree of FIX inhibition anivamersen (RB007) pegnivacogin (RB006) Factor IXa Rusconi CP et al., Nature 2002 Dyke C et al., Circulation 2006 Chan MY et al., J Thromb Haemost 2008 Cohen M et al., Circulation, 2010 RADAR ACC11 LBCT: 3

4 All Rights Reserved, Duke Medicine 2007 Objectives In patients with NSTE-ACS undergoing early cardiac catheterization to: 1.Verify that a 1 mg/kg dose of pegnivacogin results in near complete factor IX inhibition. 2.Determine the dose response of anivamersen mediated pegnivacogin reversal to allow prompt safe sheath removal post procedure. 3.Assess the efficacy of REG1 (based on ischemic event rates) as an anticoagulation system in an invasively managed population. RADAR ACC11 LBCT: 4

5 All Rights Reserved, Duke Medicine 2007 Objectives In patients with NSTE-ACS undergoing early cardiac catheterization to: 1.Verify that a 1 mg/kg dose of pegnivacogin results in near complete factor IX inhibition. Povsic et al., abstract presented at AHA, 2010 RADAR ACC11 LBCT: 5

6 All Rights Reserved, Duke Medicine 2007 Objectives In patients with NSTE-ACS undergoing early cardiac catheterization to: 1.Verify that a 1 mg/kg dose of pegnivacogin results in near complete factor IX inhibition. 2.Determine the dose response of anivamersen mediated pegnivacogin reversal to allow prompt safe sheath removal post procedure. 3.Assess the efficacy of REG1 (based on ischemic event rates) as an anticoagulation system in an invasively managed population. RADAR ACC11 LBCT: 6

7 All Rights Reserved, Duke Medicine 2007 Pegnivacogin 1mg/kg n = 600 Pegnivacogin 1mg/kg n = mg/kg Anivamersen (75%) n = mg/kg Anivamersen (75%) n = mg/kg Anivamersen (50%) n = mg/kg Anivamersen (50%) n = 100 Open Label Blinded Anivamersen Reversal Immediate Sheath Removal Randomize Femoral Access Cardiac Catheterization / PCI 1 mg/kg Anivamersen (100%) n = mg/kg Anivamersen (100%) n = 200 Standard care n = 200 Standard care n = 200 NSTE-ACS n=800 Planned catheterization < 24 h NSTE-ACS n=800 Planned catheterization < 24 h mg/kg Anivamersen (25%) n = mg/kg Anivamersen (25%) n = 200 Heparin n = 200 Heparin n = 200 Open Label 100% Reversal for Persistent Bleeding or CABG Planned DSMB assessments at 100, 200 and 400 patients to consider termination of a reversal arm based upon excess bleeding c/w heparin and historical rates Sheath Removal < 6 h Povsic, AHJ 161:261 (2011) Phase 2B RADAR Adaptive Design RADAR ACC11 LBCT: 7

8 All Rights Reserved, Duke Medicine 2007 Endpoints Primary: 30-d ACUITY bleeding –Major: intracranial, intraocular, retroperitoneal, access site requiring intervention, 5 cm hematoma at puncture site, re-operation for bleeding, transfusion, hemarthrosis, clinically overt bleeding with drop in Hgb > 3 g/dL, any drop in Hgb > 4 g/dL –Minor: all clinically overt non-major bleeding –Excluded events after CABG surgery Secondary: 30-d composite of death, MI, urgent TVR, recurrent ischemia –Excluded events after CABG surgery RADAR ACC11 LBCT: 8

9 All Rights Reserved, Duke Medicine 2007 Steering Committee John Alexander (Chair) Richard Becker Christoph Bode Christopher Buller Mauricio Cohen Jan Cornel Jaroslaw Kasprzak Roxana Mehran Gilles Montalescot Thomas Povsic Steven Zelenkofske DSMB Ronald Waksman, Chair Jack Ansell Stephan James Victor Hasselblad Enrolling Sites Poland (240 patients at 22 sites) University Clinical Center, Dr. Rynkiewicz (87) SP Hospital Klodzko, Dr. Berkowski (36) Clinical Hospital Katowice, Dr. Trusz-Gluza (25) United States (198 patients at 40 sites) Heart Center Research LLC, Dr. Krasnow (21) Heart Clinics Northwest, Dr. Ring (18) Temple University, Dr. Brown (16) Germany (167 patients at 22 sites) Hospital of Ludwigshafen, Dr. Zeymer (32) University of Freiberg, Dr. Ahrens (23) Quedlinburg Hospital, Dr. Fischer (22) Canada (21 patients at 6 sites) Hamilton Health Sciences, Dr. Natarajan (10) France (12 patients at 6 sites) Hospital Francois Mitterrand, Dr. Delarche (9) Netherlands (2 patients at 1 site) Medical Center Alkmaar, Dr. Cornel (2) RADAR ACC11 LBCT: 9

10 All Rights Reserved, Duke Medicine 2007 Heparin n = 161 Heparin n = 161 Open Label Randomize Femoral Access Cardiac Catheterization / PCI NSTE-ACS N = 640 Planned catheterization < 24 h NSTE-ACS N = 640 Planned catheterization < 24 h RADAR Final Enrollment Blinded Anivamersen Reversal Immediate Sheath Removal Sheath Removal < 6 h 75% Reversal n = % Reversal n = % Reversal n = % Reversal n = % Reversal n = 41 25% Reversal n = % Reversal n = % Reversal n = 201 Standard care n = 161 Standard care n = 161 Pegnivacogin 1 mg/kg n = 479 Pegnivacogin 1 mg/kg n = 479 RADAR ACC11 LBCT: 10

11 All Rights Reserved, Duke Medicine 2007 Demographics REG1 n = 479 Heparin n = 161 Median age, yrs Male, % DM, % Tobacco, % Prior MI, % Prior PCI, % Prior CABG, % Enrollment Criteria Elevated biomarkers, % ST changes, % History of CAD, % RADAR ACC11 LBCT: 11

12 All Rights Reserved, Duke Medicine 2007 Treatment REG1 n = 473 Heparin n = 161 Study Drug, % Anivamersen (of Pts Txt w/REG1, %)99.4- Aspirin, % Thienopyridine, % Glycoprotein 2b/3a Inhibitor, % Vascular Closure Device, % Median Time to Sheath Removal (min)24 (17,42)180 (10, 315) Management Strategy Catheterization, %99.4 Medical Therapy, % PCI, % CABG, % RADAR ACC11 LBCT: 12

13 All Rights Reserved, Duke Medicine 2007 N Events ACUITY Bleeding Bleeding,% *REG1-25% v. REG1-100% OR 0.2, 95% CI p < **REG1-100% vs. Heparin OR 1.0, 95% CI p = 0.9 RADAR ACC11 LBCT: 13

14 All Rights Reserved, Duke Medicine 2007 N Events Open Reversal 12 (30.8%)6 (5.3%)6 (5.1%)9 (4.6%)NA ACUITY Bleeding Bleeding,% *REG1-25% v. REG1-100% OR 0.2, 95% CI p < **REG1-100% vs. Heparin OR 1.0, 95% CI p = 0.9 RADAR ACC11 LBCT: 14

15 All Rights Reserved, Duke Medicine 2007 N Events26 / 838 / 1241 / 1059 / 1450 / 16 Open Reversal 12 (30.8%)6 (5.3%)6 (5.1%)9 (4.6%)NA ACUITY Bleeding Bleeding,% RADAR ACC11 LBCT: 15

16 All Rights Reserved, Duke Medicine 2007 REG1 25% n = 40 REG1 50% n = 113 REG1 75% n = 120 REG1 100% n = 193 REG1 Overall n = 466 Heparin n = 158 n(%)n n n n n Composite3(7.5)1(0.9)5(4.2)5(2.6)14(3.0)9(5.7) Death0-0-1(0.8)0-1(0.2)1(0.6) MI3(7.5)1(0.9)4(3.4)4(2.1)12(2.6)7(4.5) Urg TVR1(2.5)0-1(0.8)1(0.5)3(0.6)1 Ischemic Events RADAR ACC11 LBCT: 16

17 All Rights Reserved, Duke Medicine 2007 N Events149 Ischemic Events Death, MI, Recurrent Ischemia, Urgent TVR,% RADAR ACC11 LBCT: 17

18 All Rights Reserved, Duke Medicine 2007 Adverse Events AEs and SAEs other than bleeding and ischemic events were rare and evenly distributed among arms. 3 patients had allergic-like SAEs shortly after receiving pegnivacogin clustered late in the trial and in Europe. Investigation into the etiology of these allergic-like reactions is proceeding. AE < 24 hrs REG1 n = 465 Heparin n = 163 Hives, %0.2– Hypotension, % Rash, %–0.7 Dyspnea, %0.9– RADAR ACC11 LBCT: 18

19 All Rights Reserved, Duke Medicine 2007 Conclusions RADAR is the first significant clinical use of REG1 –1st use of REG1 in pts with ACS (>99% FIX inhibition) –Novel target (FIX) –Aptameric antithrombotic therapy –Specific, immediate, and titratable active reversal RADAR defined the anivamersen dosing necessary for early sheath removal –At least 50% reversal is required for hemostasis –75% and 100% reversal may result in less bleeding c/w heparin RADAR ACC11 LBCT: 19

20 All Rights Reserved, Duke Medicine 2007 Conclusions Pegnivacogin (1 mg/kg) with partial or complete reversal resulted in numerically fewer ischemic events than heparin. High intensity FIX inhibition with active control may represent an attractive strategy to favorably impact both ischemic and bleeding endpoints. These data support the further development of REG1 in adequately powered clinical trials to assess the safety and efficacy of controllable anticoagulation in populations of patients who require short-term high intensity anticoagulation. RADAR ACC11 LBCT: 20


Download ppt "A Randomized, Partially-Blinded, Multi-Center, Active-Controlled, Dose-Ranging Study Assessing the Safety, Efficacy, and Pharmacodynamics of the REG1 Anticoagulation."

Similar presentations


Ads by Google