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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.

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Factor ixa inhibition aptamer technology overview and first results with rb006 rb007

Factor IXa InhibitionAptamer 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

Disclosure Statement of Financial Interest

Within the past 12 months, I or my spouse/partner have had a financial interest/arrangement or affiliation with the organization(s) listed below.

Affiliation/Financial RelationshipCompany

Grant/Research Support REGADO BIOSCIENCES



Aptamers nucleic acids and monoclonal antibodies
Aptamers: Nucleic Acids and Monoclonal Antibodies

Monoclonal

Antibody

Aptamer

Rusconi CP et al., Nature 2002;419:90-94


Aptamers encode their own control agents
Aptamers Encode Their Own Control Agents

Aptamer

Reversal

Agent

Rusconi CP et al., Nature 2002;419:90-94


Aptamers encode their own control agents1
Aptamers Encode Their Own Control Agents

Aptamer

Reversal

Agent

Rusconi CP et al., Nature 2002;419:90-94


Reg1 anticoagulant system
REG1 Anticoagulant System

  • Synthetic single strand oligonucleotides

  • Metabolized by nucleases in the blood with no ‘active’ metabolites

  • No protein binding

RB006

Anticoagulant aptamer

RB007

Active control agent

  • Specific affinityfor Factor IXa

  • Long half life (>24hr)

  • 50 Kda (31 nucleotides+ 40 kDa PEG)

  • Specific affinityfor RB006

  • Very short half life(<5min)

  • 5 Kda (15 nucleotides)

6


Rationale for targeting fixa
Rationale for Targeting FIXa

X

Initiation

II

IIa

Va

TF

VIIa

Xa

TF-bearing cell

VIIa

TF

Platelet

IX

Amplification

IXa

FIXa inhibitor

X

II

VIIIa

IXa

Xa

IIa

Va

XIa

Activated platelet

IX

Propagation

Monroe DM. Arterioscler Thromb Vasc Biol 2002;22:1381-1389.


Rationale for targeting factor ixa
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
REG1 Phase 1 Studies- Overview

Total: 172

Dyke C, et al. Circulation 2006;114:2490-2497

Chan MY, et al. Circulation 2008;117:2865-2874

Chan MY, et al. J Thromb Haemost 2008; 6:789–96

9


Clin101 phase 1a study
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
CLIN101 – REG1 Activity in Healthy Volunteers

Inject RB007

Inject RB007

APTT (seconds)

Placebo/Placebo

Placebo/Placebo

15 mg RB006/30 mg RB007

30 mg RB006/60 mg RB007

ULN

60 mg RB006/120 mg RB007

LLN

90 mg RB006/180 mg RB007

APTT (seconds)

Time Post RB006 Injection (hrs)

ULN

LLN

Time Post RB006 Injection (hrs)

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 Study


Stable cad phase 1b study results
Stable CAD – Phase 1B StudyResults

Inject RB007

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

APTT (seconds)

ULN

LLN

Time Post RB006 Administration (hrs)

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 Study


Repeat dose phase ic study antidote dose response
Repeat-dose – Phase IC StudyAntidote Dose Response

Inject RB007

Placebo

2:1 AD:DR

1:1 AD:DR

0.5:1 AD:DR

0.3:1 AD:DR

0.2:1 AD:DR

0.125:1 AD:DR

APTT (seconds)

ULN

LLN

Time Post RB006 Administration (hrs)

Chan MY, et al. J Thromb Haemost 2008; 6:789–96


Repeat dose phase ic study activity in healthy volunteers
Repeat-dose – Phase IC StudyActivity In Healthy Volunteers

Low inter/intra-subject variability

100

n=38 (healthy volunteers)

Placebo

Group 1

80

Group 2

Group 3

60

APTT (sec)

40

20

0

Day 1

Day 3

Day 5

Chan MY, et al. J Thromb Haemost 2008; 6:789–96


Phase 1 program summary
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

Dyke C, et al. Circulation 2006;114:2490-2497

Chan MY, et al. Circulation 2008;117:2865-2874

Chan MY, et al. J Thromb Haemost 2008; 6:789–96

17


Pci pilot reversal pci
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 pci1
    PCI Pilot – Reversal PCI

    Stable CAD pts undergoing PCIAll on ASA and Clopidogrel preload (>6hs)

    Stable CAD pts undergoing PCIAll on ASA and Clopidogrel preload (>6hs)

    RB006 dose:1mg/kg in all subjects

    Roll-in Phase: 2 patientsReg 1 system + EptifibatideRB007:RB006 (0.2:1)

    Complete Reversal @ 4 hs

    Sheath Pull

    RB007:RB006 (1.8:1)

    Arm 1: 12 patients5:1 randomizationHeparin vs. Reg1 w/partial reversalRB007:RB006 (0.2:1)

    Complete Reversal @ 4 hs

    Sheath Pull

    RB007:RB006 (1.8:1)

    Safety Committee Review

    Arm 1: 12 patients5:1 randomization

    Heparin vs. Reg1 w/complete reversal

    Immediate Complete Reversal  Sheath Pull

    RB007:RB006 (2.0:1)


    Timeline of procedures
    Timeline of Procedures

    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

    Baseline Data

    14 daysEnd of Follow-up

    ACTPTT (lab)Whole Blood PTT (POC)

    PCI

    TnT, CKMB, CK q8h x 3

    End

    Immediately Post PCIRoll-In andGroup I:Partial Reversalor Group II:Complete Reversal andSheath Pull

    StudyDrug

    5 min

    15 min

    4 hoursRoll-In andGroup IComplete Reversal and Sheath PullorHeparinSheath Pull

    IndefiniteASA

    Clopidogrel recommend12 months




    Primary outcomes measures
    Primary Outcomes Measures

    * Through Hospital Discharge or 48 hrs, whichever occurs first

    ** Urgent TVR on D6, Index lesion/stent patent, not related to REG1


    Pharmacodynamics wb ptt poc
    Pharmacodynamics – WB PTT POC

    Stable and Predictable Anticoagulation

    200

    PartialReversal

    Median

    160

    151

    Interquartile range of max RB006 effect

    147

    145.5

    146.5

    145

    139

    Total Reversal

    Median

    120

    Whole blood PTT (seconds)

    Mean

    83

    82

    80

    40

    Baseline

    5 min Post

    Study Drug

    15 min Post

    Study Drug

    End of PCI


    Pharmacodynamics act
    Pharmacodynamics – ACT

    Stable and Predictable Anticoagulation

    350

    Arm 1:PartialReversal

    300

    250

    Arm 2: Total Reversal

    Activated Clotting Time (seconds)

    200

    Control: UFH

    150

    15 min post

    1st RB007 Dose

    15 min post

    2nd RB007 Dose

    Baseline

    5 min Post

    Study Drug

    15 min Post

    Study Drug

    End of PCI


    Conclusions reversal pci
    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
    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.


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