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Factor IXa Inhibition Aptamer Technology Overview and First Results with RB006/RB007. Mauricio G. Cohen, MD Associate Professor of Medicine Director, Cardiac Cath Lab. Disclosure Statement of Financial Interest. - PowerPoint PPT Presentation
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Factor IXa InhibitionAptamer Technology Overview and
First Results with RB006/RB007Mauricio G. Cohen, MD
Associate Professor of MedicineDirector, Cardiac Cath Lab
Disclosure Statement of Financial InterestDisclosure Statement of Financial Interest
Within the past 12 months, I or my spouse/partner have had a Within the past 12 months, I or my spouse/partner have had a financial interest/arrangement or affiliation with the organization(s) financial interest/arrangement or affiliation with the organization(s) listed below.listed below.
Affiliation/Financial RelationshipAffiliation/Financial Relationship CompanyCompany
Grant/Research SupportGrant/Research Support REGADO BIOSCIENCESREGADO BIOSCIENCES
Search for the Ideal Anticoagulant
• Efficacy Ability to prevent thrombosis
• Safety Low risk of bleeding
• Titratability Ability to adjust the level of anticoagulation to individual clinical needs
• Reversibility Ability to safely, rapidly and predictably neutralize the anticoagulant effect when clinically indicated
• Convenience Daily single-bolus injections without need for continuous infusions or routine monitoring
MonoclonalAntibody
Aptamer
Aptamers: Nucleic Acids and Monoclonal Antibodies
Rusconi CP et al., Nature 2002;419:90-94
Aptamer ReversalAgent
Aptamers Encode Their Own Control Agents
Rusconi CP et al., Nature 2002;419:90-94
Aptamer
ReversalAgent
Aptamers Encode Their Own Control Agents
Rusconi CP et al., Nature 2002;419:90-94
REG1 Anticoagulant System
RB006 Anticoagulant aptamer
RB007Active control agent
• Synthetic single strand oligonucleotides
• Metabolized by nucleases in the blood with no ‘active’ metabolites
• No protein binding
• Specific affinityfor RB006
• Very short half life(<5min)
• 5 Kda (15 nucleotides)
7
• Specific affinityfor Factor IXa
• Long half life (>24hr)
• 50 Kda (31 nucleotides+ 40 kDa PEG)
Rationale for Targeting FIXa
TF-bearing cellTF-bearing cell
Activated plateletlatelet
PlateletPlatelet
VIIaVIIa
X
XaXa
VIIaVIIa
IXIX
IXaIXa
IXaIXa
XIaXIa
IXIX
II
X
IIaIIa
II
Propagation
Amplification
Initiation
XaXa IIaIIa
FIXa inhibitorFIXa inhibitor
TF Va
TF
VIIIaVa
Monroe DM. Arterioscler Thromb Vasc Biol 2002;22:1381-1389.
Rationale for Targeting Factor IXa
• FVIIIa/FIXa activation of FX is the rate limiting step in thrombin generation FIX knockout mice lack occlusive clot formation following vascular
injury due to insufficient generation of thrombin to form platelet aggregates.
• FIXa concentration is lower than Xa and thrombin, making high levels of target inhibition more readily achievable
• High Factor IX levels are associated with increase in ACS and venous thromboembolism Transgenic mice overexpressing FIXa have a shorter lifespan and
develop arterial thrombosis and myocardial fibrosis with vascular distribution patterns similar to those of ischemic cardiomyopathy in humans
• Hemophilia B Carriers-Reduced CHD Mortality
• Foreign materials (eg. catheters and guidewires) lead directly to FIX activation
REG1 Phase 1 Studies- Overview
10
Study Design Treatment Groups nSingle dose, dose escalation in healthy volunteers
IV injection of RB006 (15, 30, 60, 90 mg) and RB007 (30, 60, 120, 180 mg) alone and in combination
84
Single dose, dose escalation in patients with stable coronary artery disease (CAD)
IV injection of RB006 (15, 30, 50, 75 mg) alone and in combination with RB007 (30, 60, 120, 150 mg)
49
Multiple dose in healthy volunteers
IV injection of RB006 (0.75 mg/kg) followed by RB007 (dose ranging from 0.094 to 2 mg/kg) every other day for 6 days
39
Dyke C, et al. Circulation 2006;114:2490-2497Chan MY, et al. Circulation 2008;117:2865-2874
Chan MY, et al. J Thromb Haemost 2008; 6:789–96
Total: 172 Total: 172
CLIN101 – Phase 1A Study
• Study Design 85 healthy volunteers Multi-center, randomized, subject blinded, placebo controlled Evaluate safety of dose escalation of REG1 system or components and
pharmacokinetic/pharmacodynamic relationships Single-dose, dose escalation through 4 dose levels RB006, RB007, and REG1 treatment arms at each dose level
• Results 1 SAE but no trend of safety signals RB006 produced dose dependent aPTT levels RB007 neutralized observed pharmacodynamic effects of RB006
CLIN101 – REG1 Activity in Healthy Volunteers
ULN
LLN
Inject RB007
Time Post RB006 Injection (hrs)
AP
TT (
secon
ds)
Placebo/Placebo
15 mg RB006/30 mg RB007
30 mg RB006/60 mg RB007
60 mg RB006/120 mg RB007
90 mg RB006/180 mg RB007
Time Post RB006 Injection (hrs)
AP
TT (
secon
ds)
Inject RB007
ULN
LLN
Placebo/Placebo
Dyke C, et al. Circulation 2006;114:2490-2497
Stable CAD – Phase 1B Study
Study Design 50 patients w/ stable CAD on aspirin/clopidogrel
• 56-68 years of age
Multi-center, randomized, double-blind, placebo-controlled Evaluate safety of dose escalation of the REG1 system and
pharmacokinetic/pharmacodynamic relationships Single-dose, dose escalation through 4 dose levels RB006 and REG1 treatment arms at each dose level
Results No SAE’s or safety signals RB006 produced dose-dependent aPTT levels RB007 neutralized observed pharmacodynamic effects of RB006
Stable CAD – Phase 1B StudyResults
Time Post RB006 Administration (hrs)
AP
TT (
secon
ds)
Placebo/Placebo
15 mg RB006/30 mg RB007
30 mg RB006/60 mg RB007
50 mg RB006/100 mg RB007
75 mg RB006/150 mg RB007
Inject RB007
ULN
LLN
Chan MY, et al. Circulation 2008;117:2865-2874
Repeat-dose – Phase IC Study
Study Design 38 healthy volunteers Single-center, randomized, double-blind, placebo controlled Primary endpoints:
• Evaluate safety and tolerability of repeated doses of REG1 system
• Determine the optimal dose ratio for RB007 and RB006
3 consecutive weight-adjusted, drug-antidote treatment cycles or double placebo
Fixed doses of RB006 followed by titrated dose of RB007 (2:1 – 0.125)
Results Achieved highly reproducible aPTT levels with repeat doses of RB006 Reversed aPTT levels with RB007 dose-dependently and reproducibly
Repeat-dose – Phase IC StudyAntidote Dose Response
0.2:1 AD:DR
1:1 AD:DR
0.3:1 AD:DR
2:1 AD:DR
Placebo
0.125:1 AD:DR
Time Post RB006 Administration (hrs)
AP
TT (
secon
ds)
Inject RB007
ULN
LLN
A:D Ratio 0.5:1 0.3:1 0.2:1 0.125:1
% Reversal 84±2.7% 74±5.9% 51±6.4% 41±8.0%
Chan MY, et al. J Thromb Haemost 2008; 6:789–96
0.5:1 AD:DR
Repeat-dose – Phase IC StudyActivity In Healthy Volunteers
Low inter/intra-subject variability
Day 1 Day 3 Day 50
20
40
60
80
100 Placebo
Group 1
Group 2
Group 3
AP
TT (
sec)
n=38 (healthy volunteers)n=38 (healthy volunteers)
Chan MY, et al. J Thromb Haemost 2008; 6:789–96
Phase 1 Program Summary
Phase 1 Program Highlights:• Demonstrated safety of RB006, controlling agent (RB007)
and the overall REG1 system • Demonstrated controlling agent efficacy• No known drug interactions with common anti-platelet
therapy• Demonstrated RB006 and RB007 PK and elimination• Understanding of relationship between RB006 PK and PD• Identified optimal dose of RB006 for maximal FIXa inhibition• Demonstrated ability to titrate the controlling agent • Ability to proceed to Phase II development of REG1 in PCI
and ACS
18
Dyke C, et al. Circulation 2006;114:2490-2497Chan MY, et al. Circulation 2008;117:2865-2874
Chan MY, et al. J Thromb Haemost 2008; 6:789–96
PCI Pilot – Reversal PCI
• Feasibility study comparing the REG1 system with UFH in stable CAD patients undergoing elective PCI
• Multi-center, open-label, randomized (10/07–10/08) Black Hills Cardiology (Rapid City, SD)
Henry Ford Hospital (Detroit, MI)
University of North Carolina at Chapel Hill (NC)
The Care Group (Indianapolis, IN)
Hospital Italiano (Buenos Aires, Argentina)
• Central Coordination: Duke Clinical Research Institute
• Primary Endpoint Major Bleeding using the ACUITY bleeding criteria until hospital
discharge or 48 hours whichever occurs first. Composite of death, nonfatal myocardial infarct (MI), and urgent
target vessel revascularization (TVR) through Day 14
PCI Pilot – Reversal PCIStable CAD pts undergoing PCI
All on ASA and Clopidogrel preload (>6hs)Stable CAD pts undergoing PCI
All on ASA and Clopidogrel preload (>6hs)
Roll-in Phase: 2 patientsReg 1 system + Eptifibatide
RB007:RB006 (0.2:1)
Roll-in Phase: 2 patientsReg 1 system + Eptifibatide
RB007:RB006 (0.2:1)
Arm 1: 12 patients5:1 randomization
Heparin vs. Reg1 w/partial reversalRB007:RB006 (0.2:1)
Arm 1: 12 patients5:1 randomization
Heparin vs. Reg1 w/complete reversal
Complete Reversal @ 4 hsSheath Pull
Immediate Complete Reversal Sheath Pull
Complete Reversal @ 4 hsSheath Pull
Safety Committee Review
RB006 dose:1mg/kg in all subjects
RB007:RB006 (1.8:1)RB007:RB006 (1.8:1)
RB007:RB006 (1.8:1)RB007:RB006 (1.8:1)
RB007:RB006 (2.0:1)RB007:RB006 (2.0:1)
Timeline of Procedures
Baseline DataBaseline Data
StudyDrug
StudyDrug
5 min5 min 15 min15 min
ACTPTT (lab)
Whole Blood PTT (POC)
ACTPTT (lab)
Whole Blood PTT (POC)
EndEnd
PCIPCI
Informed consent will be executed prior to administration of any sedativesClopidogrel 600 mg loading dose and ASA 250-500 mg at least 4 hours prior to PCIPatients who receive heparin during diagnostic cath will wait at least 4 hours for the PCI procedure
Informed consent will be executed prior to administration of any sedativesClopidogrel 600 mg loading dose and ASA 250-500 mg at least 4 hours prior to PCIPatients who receive heparin during diagnostic cath will wait at least 4 hours for the PCI procedure
Immediately Post PCI
Roll-In andGroup I:
Partial Reversalor
Group II:Complete Reversal
andSheath Pull
Immediately Post PCI
Roll-In andGroup I:
Partial Reversalor
Group II:Complete Reversal
andSheath Pull
4 hoursRoll-In and
Group IComplete Reversal
and Sheath Pullor
HeparinSheath Pull
4 hoursRoll-In and
Group IComplete Reversal
and Sheath Pullor
HeparinSheath Pull
TnT, CKMB, CK q8h x 3TnT, CKMB, CK q8h x 3
IndefiniteASA
Clopidogrel recommend12 months
IndefiniteASA
Clopidogrel recommend12 months
14 daysEnd of Follow-up
14 daysEnd of Follow-up
Baseline Characteristics
REG 1 System Control
Partial Reversal
N = 10
CompleteReversal
N = 10
UFHN = 4
Age 63 (58, 68) 64 (55, 65) 64 (61, 71)
Male gender 7 (70%) 8 (80%) 1 (25%)
Weight (kg) 86 (80, 89) 101 (93, 115) 96 (90, 101)
Diabetes 2 (20%) 4 (40%) 1 (25%)
Serum Cr (mg/dL) 1.0 (0.9, 1.2) 1.0 (0.9, 1.1) 0.9 (0.9, 1.0)
Current smoker 1 (10%) 2 (20%) 1 (25%)
Prior MI 3 (30%) 3 (30%) 0
Prior PCI 5 (50%) 5 (50%) 1 (25%)
Procedural CharacteristicsREG 1 System Control
Part ReversalN = 10
Comp ReversalN = 10
UFHN = 4
Lesions treated 14 9* 5
Two-vessel PCI 4 (40%) 1 (10%) 1 (25%)
Procedure duration (min) 20 (13,37) 16 (11,30) 39 (33,41)
Diameter Stenosis (%) 90 (70, 90) 90 (80, 90) 90 (80, 90)
Stent use per patient DES (% of stents) Stent diameter (mm) Stent length (mm)
10 (100%)4 (40%)
3.0 (3.0, 3.5)17 (12, 24)
9 (90%)5 (55%)
2.9 (2.5, 3.0)14 (12, 28)
4 (100%)3 (75%)
2.9 (2.8, 3.3)16 (14, 20)
Post-proc TIMI 3 flow 14 (100%) 10 (100%) 5 (100%)
Time RB006 to RB007 Partial reversal (min) Complete reversal (min)
62 (36, 89)278 (272, 284)
…54 (49, 58)
……
Time to sheath pull (min) 282 (266,308) 46 (42,52) 217 (130,300)
Primary Outcomes Measures
REG1 System Control
Partial Reversal
N = 10
TotalReversal
N = 10
UFHN = 4
Modified Acuity Bleeding Events*
0/10 0/10 1/4
Death, MI or Urgent TVR through 14 days
1/10 1/10** 1/4
* Through Hospital Discharge or 48 hrs, whichever occurs first** Urgent TVR on D6, Index lesion/stent patent, not related to REG1
PartialReversalMedian
Pharmacodynamics – WB PTT POC
Total ReversalMedian
Baseline 5 min PostStudy Drug
15 min PostStudy Drug
End of PCI
Wh
ole
blo
od
PTT (
secon
ds)
40
120
80
160
200
82 83
151 147 145.5 146.5 145 139
Mean
Stable and Predictable Anticoagulation
Interquartile range of max RB006 effect
Arm 1:Partial
Reversal
Arm 2: Total
Reversal
Acti
vate
d C
lott
ing
Tim
e (
secon
ds)
150
250
200
300
350
Control: UFH
Baseline 5 min PostStudy Drug
15 min PostStudy Drug
End of PCI 15 min post 1st RB007
Dose
15 min post2nd RB007 Dose
Pharmacodynamics – ACTStable and Predictable Anticoagulation
Conclusions: Reversal PCI
• All procedures were successfully completed.
• No signs of catheter or guidewire thrombosis.
• Monitoring by ACT, POC aPTT and plasma aPTT demonstrated measurable differences in both partial and total RB007 reversal doses.
• The REG1 System was well tolerated.
• RB007 facilitated early sheath removal.
• RB006 (1mg/kg) demonstrated rapid onset with consistent coagulation measures during PCI.
In Summary…
• The REG 1 System offers the possibility of balancing the bleeding-ischemia risk in PCI patients
• This concept can be expanded to other clinical scenarios in which anticoagulation can be tailored to individual patient needs
• The Phase 2b RADAR trial will evaluate the safety and efficacy of the REG1 System in 800 acute coronary syndrome patients undergoing cardiac catheterization.