Transcript 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.

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
Disclosures
• RADAR was funded by REGADO Biosciences Inc.
• Duke Clinical Research Institute receives research
funding from REGADO Biosciences
RADAR ACC11 LBCT: 2
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REG1: Pegnivacogin + Anivamersen
Regado Biosciences, Inc
Factor IXa
• Novel Anticoagulation System
– RNA aptamer
– Factor IXa inhibitor
– Controlling agent
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•
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
RADAR ACC11 LBCT: 3
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pegnivacogin
(RB006)
anivamersen
(RB007)
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
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
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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
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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
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Phase 2B RADAR
Adaptive Design
Povsic,
AHJ 161:261
(2011)
NSTE-ACS
n=800
Planned
catheterization < 24 h
Open Label
Pegnivacogin
1mg/kg
n = 600
Randomize
Femoral Access
Cardiac Catheterization / PCI
Blinded Anivamersen Reversal
Immediate Sheath Removal
0.075 mg/kg
Anivamersen
(25%)
n = 200
0.2 mg/kg
Anivamersen
(50%)
n = 100
0.4 mg/kg
Anivamersen
(75%)
n = 100
Heparin
n = 200
Sheath
Removal < 6 h
1 mg/kg
Anivamersen
(100%)
n = 200
Standard
care
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
RADAR ACC11 LBCT: 7
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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
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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
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Steering Committee
•
•
•
•
•
•
•
•
•
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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
RADAR
Final
Enrollment
NSTE-ACS
N = 640
Planned catheterization < 24 h
Open Label
Pegnivacogin
1 mg/kg
n = 479
Randomize
Femoral Access
Cardiac Catheterization / PCI
Blinded Anivamersen Reversal
Immediate Sheath Removal
25%
Reversal
n = 41
RADAR ACC11 LBCT: 10
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50%
Reversal
n = 117
75%
Reversal
n = 120
Heparin
n = 161
Sheath
Removal < 6 h
100%
Reversal
n = 210
Standard
care
n = 161
Demographics
REG1
n = 479
Heparin
n = 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
Elevated biomarkers, %
52.6
54.7
ST changes, %
24.6
28.6
History of CAD, %
50.9
48.4
Enrollment Criteria
RADAR ACC11 LBCT: 11
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Treatment
REG1
n = 473
Heparin
n = 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
24 (17,42)
180 (10, 315)
99.4
99.4
Medical Therapy, %
30.9
25.5
PCI, %
58.4
68.9
CABG, %
9.1
6.2
Median Time to Sheath Removal (min)
Management Strategy
Catheterization, %
RADAR ACC11 LBCT: 12
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ACUITY Bleeding
Bleeding ,%
*REG1-25% v. REG1-100%
OR 0.2, 95% CI 0.1-0.5
p< 0.0001
**REG1-100% vs. Heparin
OR 1.0, 95% CI 0.6-1.6
p = 0.9
N
40
113
119
194
160
Events
26
38
41
59
50
RADAR ACC11 LBCT: 13
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ACUITY Bleeding
Bleeding ,%
*REG1-25% v. REG1-100%
OR 0.2, 95% CI 0.1-0.5
p< 0.0001
**REG1-100% vs. Heparin
OR 1.0, 95% CI 0.6-1.6
p = 0.9
N
40
113
119
194
160
Events
26
38
41
59
50
12 (30.8%)
6 (5.3%)
6 (5.1%)
9 (4.6%)
NA
Open
Reversal
RADAR ACC11 LBCT: 14
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Bleeding ,%
ACUITY Bleeding
N
Events
Open
Reversal
RADAR ACC11 LBCT: 15
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40
113
119
194
160
26 / 8
38 / 12
41 / 10
59 / 14
50 / 16
12 (30.8%)
6 (5.3%)
6 (5.1%)
9 (4.6%)
NA
Ischemic Events
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
(%)
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)
RADAR ACC11 LBCT: 16
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Death, MI, Recurrent
Ischemia, Urgent TVR,%
Ischemic Events
N
466
158
Events
14
9
RADAR ACC11 LBCT: 17
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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.
REG1
n = 465
Heparin
n = 163
Hives, %
0.2
–
Hypotension, %
2.4
1.9
–
0.7
0.9
–
AE < 24 hrs
Rash, %
Dyspnea, %
• Investigation into the etiology of these allergic-like
reactions is proceeding.
RADAR ACC11 LBCT: 18
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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
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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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