a randomized, partially-blinded, multi-center, active-controlled, dose-ranging study assessing the...
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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, PhDon behalf of the RADAR Investigators
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
All Rights Reserved, Duke Medicine 2007
REG1: Pegnivacogin + AnivamersenRegado 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 2002Dyke C et al., Circulation 2006
Chan MY et al., J Thromb Haemost 2008Cohen M et al., Circulation, 2010
RADAR ACC11 LBCT: 3
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
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, 2010RADAR ACC11 LBCT: 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.
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
All Rights Reserved, Duke Medicine 2007
Pegnivacogin 1mg/kg n = 600
0.4 mg/kg Anivamersen
(75%)n = 100
0.2 mg/kg Anivamersen
(50%)n = 100
Open Label
Blinded Anivamersen ReversalImmediate Sheath Removal
RandomizeFemoral Access
Cardiac Catheterization / PCI
1 mg/kg Anivamersen
(100%)n = 200
Standard care
n = 200
NSTE-ACSn=800
Planned catheterization < 24 h
0.075 mg/kg Anivamersen
(25%)n = 200
Heparin n = 200
Open Label 100% Reversal for Persistent Bleeding or CABGPlanned 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 RADARAdaptive Design
RADAR ACC11 LBCT: 7
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
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
All Rights Reserved, Duke Medicine 2007
Heparinn = 161
Open Label
RandomizeFemoral Access
Cardiac Catheterization / PCI
NSTE-ACSN = 640
Planned catheterization < 24 h
RADAR FinalEnrollment
Blinded Anivamersen ReversalImmediate Sheath Removal
Sheath Removal < 6 h
75% Reversaln = 120
50% Reversaln = 117
25% Reversal
n = 41
100% Reversaln = 210
Standard care
n = 161
Pegnivacogin1 mg/kgn = 479
RADAR ACC11 LBCT: 10
All Rights Reserved, Duke Medicine 2007
DemographicsREG1
n = 479Heparinn = 161
Median age, yrs 64.9 62.5
Male, % 67.4 70.8
DM, % 32.8 26.1
Tobacco, % 56.8 59.6
Prior MI, % 48.4 46.6
Prior PCI, % 43.4 42.9
Prior CABG, % 14.4 14.3
Enrollment Criteria
Elevated biomarkers, % 52.6 54.7
ST changes, % 24.6 28.6
History of CAD, % 50.9 48.4
RADAR ACC11 LBCT: 11
All Rights Reserved, Duke Medicine 2007
Treatment REG1n = 473
Heparinn = 161
Study Drug, % 98.3 95.0
Anivamersen (of Pts Txt w/REG1, %) 99.4 -
Aspirin, % 99.6 95.7
Thienopyridine, % 79.9 82.6
Glycoprotein 2b/3a Inhibitor, % 9.7 16.6
Vascular Closure Device, % 12.9 16.8
Median Time to Sheath Removal (min) 24 (17,42) 180 (10, 315)
Management Strategy
Catheterization, % 99.4 99.4
Medical Therapy, % 30.9 25.5
PCI, % 58.4 68.9
CABG, % 9.1 6.2
RADAR ACC11 LBCT: 12
All Rights Reserved, Duke Medicine 2007
N 40 113 119 194 160
Events 26 38 41 59 50
ACUITY Bleeding
Ble
edin
g ,%
*REG1-25% v. REG1-100% OR 0.2, 95% CI 0.1-0.5p< 0.0001
**REG1-100% vs. Heparin OR 1.0, 95% CI 0.6-1.6
p = 0.9
RADAR ACC11 LBCT: 13
All Rights Reserved, Duke Medicine 2007
N 40 113 119 194 160
Events 26 38 41 59 50
Open Reversal 12 (30.8%) 6 (5.3%) 6 (5.1%) 9 (4.6%) NA
ACUITY Bleeding
Ble
edin
g ,%
*REG1-25% v. REG1-100% OR 0.2, 95% CI 0.1-0.5p< 0.0001
**REG1-100% vs. Heparin OR 1.0, 95% CI 0.6-1.6
p = 0.9
RADAR ACC11 LBCT: 14
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N 40 113 119 194 160
Events 26 / 8 38 / 12 41 / 10 59 / 14 50 / 16
Open Reversal
12 (30.8%) 6 (5.3%) 6 (5.1%) 9 (4.6%) NA
ACUITY Bleeding
Ble
edin
g ,%
RADAR ACC11 LBCT: 15
All Rights Reserved, Duke Medicine 2007
REG125%
n = 40
REG150%
n = 113
REG175%
n = 120
REG1100%
n = 193
REG1Overalln = 466
Heparin
n = 158
n (%) n (%) n (%) n (%) n (%) n (%)
Composite 3 (7.5) 1 (0.9) 5 (4.2) 5 (2.6) 14 (3.0) 9 (5.7)
Death 0 - 0 - 1 (0.8) 0 - 1 (0.2) 1 (0.6)
MI 3 (7.5) 1 (0.9) 4 (3.4) 4 (2.1) 12 (2.6) 7 (4.5)
Urg TVR 1 (2.5) 0 - 1 (0.8) 1 (0.5) 3 (0.6) 1 (0.6)
Ischemic Events
RADAR ACC11 LBCT: 16
All Rights Reserved, Duke Medicine 2007
N 466 158
Events 14 9
Ischemic Events
De
ath
, MI,
Re
curr
en
t Is
ch
em
ia, U
rge
nt
TV
R,%
RADAR ACC11 LBCT: 17
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 hrsREG1
n = 465Heparinn = 163
Hives, % 0.2 –
Hypotension, % 2.4 1.9
Rash, % – 0.7
Dyspnea, % 0.9 –
RADAR ACC11 LBCT: 18
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
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
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