A Randomized, Partially-Blinded, Multi-Center, Active-Controlled, Dose-Ranging Study Assessing the...

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


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


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


Objectives



Povsic et al., abstract presented at AHA, 2010RADAR ACC11 LBCT: 5


Objectives



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


Pegnivacogin 1mg/kg n = 600

0.4 mg/kg Anivamersen

(75%)n = 100


(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


(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


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


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


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


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



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



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



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



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 ,%



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



N 466 158

Events 14 9

Ischemic Events

De

ath

, MI,

Re

curr

en

t Is

ch

em

ia, U

rge

nt

TV

R,%



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 –



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



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.


A Randomized, Partially-Blinded, Multi-Center, Active-Controlled, Dose-Ranging Study Assessing the...

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