Pegnivacogin (RB006), a Direct Pegnivacogin (RB006), a Direct Factor IXa Inhibitor, Results in Factor IXa Inhibitor, Results in Consistent and Near Complete Consistent and Near Complete Inhibition of Factor IX Activity in Inhibition of Factor IX Activity in Patients with Acute Coronary Patients with Acute Coronary Syndromes: Syndromes: A Prospective RADAR Pharmacokinetic A Prospective RADAR Pharmacokinetic and Pharmacodynamic Substudy and Pharmacodynamic Substudy Thomas J. Povsic MD, PhD; William A. Wargin PhD; Thomas J. Povsic MD, PhD; William A. Wargin PhD; Mauricio G. Mauricio G. Cohen MD; Cohen MD; Roxana Mehran, MD; Roxana Mehran, MD; Christoph Bode MD; Christoph Bode MD; Joshua Krasnow Joshua Krasnow MD; MD; Merill Krolick DO; Merill Krolick DO; Christopher P. Rusconi PhD; Christopher P. Rusconi PhD; Steven L. Steven L. Zelenkofske DO; Zelenkofske DO; Richard A. Becker MD; Richard A. Becker MD; John H. Alexander MD, John H. Alexander MD, MHS MHS
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Pegnivacogin (RB006), a Direct Factor IXa Inhibitor, Results in Consistent and Near Complete Inhibition of Factor IX Activity in Patients with Acute Coronary.
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Pegnivacogin (RB006), a Direct Factor IXa Pegnivacogin (RB006), a Direct Factor IXa Inhibitor, Results in Consistent and Near Inhibitor, Results in Consistent and Near Complete Inhibition of Factor IX Activity in Complete Inhibition of Factor IX Activity in Patients with Acute Coronary Syndromes: Patients with Acute Coronary Syndromes: A Prospective RADAR Pharmacokinetic and A Prospective RADAR Pharmacokinetic and Pharmacodynamic SubstudyPharmacodynamic Substudy
Thomas J. Povsic MD, PhD; William A. Wargin PhD;Thomas J. Povsic MD, PhD; William A. Wargin PhD; Mauricio G. Cohen MD;Mauricio G. Cohen MD; Roxana Mehran, MD;Roxana Mehran, MD; Christoph Bode MD;Christoph Bode MD; Joshua Krasnow MD;Joshua Krasnow MD; Merill Krolick Merill Krolick DO; DO; Christopher P. Rusconi PhD;Christopher P. Rusconi PhD; Steven L. Zelenkofske DO;Steven L. Zelenkofske DO; Richard A. Richard A. Becker MD;Becker MD; John H. Alexander MD, MHSJohn H. Alexander MD, MHS
Disclosure Statement of Financial InterestDisclosure Statement of Financial Interest
Within the past 12 months, I or my spouse/partner have had a financial Within the past 12 months, I or my spouse/partner have had a financial interest/arrangement or affiliation with the organization(s) listed below. In interest/arrangement or affiliation with the organization(s) listed below. In addition, DCRI receives research funding from Regado Biosciences. addition, DCRI receives research funding from Regado Biosciences.
PEG-conjugated aptamers PEG-conjugated aptamers cleared by nucleolytic breakdown cleared by nucleolytic breakdown in the bloodin the blood
Manufactured by a solid phase Manufactured by a solid phase chemical processchemical process 44
SELEXSELEXTMTM
Pegnivacogin (RB006): Pegnivacogin (RB006): An anticoagulant aptamerAn anticoagulant aptamer
Targets factor IXTargets factor IX
Long half lifeLong half life
Metabolized by Metabolized by nucleases in the bloodnucleases in the blood
Titratable as part of Titratable as part of REG1 systemREG1 system
AptamerAptamer ControllingControlling
AgentAgent
REG1: An aptameric system REG1: An aptameric system
Rusconi CP et al., Rusconi CP et al., Nature 2002;419:90-94Nature 2002;419:90-94
PegnivacoginPegnivacogin AnivamersenAnivamersen
AptamerAptamer
ControllingControlling
AgentAgent
Aptamers Encode Their Own Aptamers Encode Their Own Controlling AgentsControlling Agents
Rusconi CP et al., Rusconi CP et al., Nature 2002;419:90-94Nature 2002;419:90-94
Rationale for Targeting Factor IXaRationale for Targeting Factor IXa
Factor IXa is the proximal driver of clot propagationFactor IXa is the proximal driver of clot propagation
Factor IXa is ~7 fold more thrombogenic then factor Xa and ~60 fold Factor IXa is ~7 fold more thrombogenic then factor Xa and ~60 fold more thrombogenic than thrombin on a molar basismore thrombogenic than thrombin on a molar basis
FVIIIa/FIXa activation of FX is the rate limiting step in thrombin FVIIIa/FIXa activation of FX is the rate limiting step in thrombin generationgeneration
FIXa concentration is lower than Xa and thrombin, making high levels FIXa concentration is lower than Xa and thrombin, making high levels of target inhibition more readily achievableof target inhibition more readily achievable
High Factor IX levels are associated with increase in ACS and venous High Factor IX levels are associated with increase in ACS and venous thromboembolismthromboembolism
Factor IX depletion (Hemophilia B) characterized by aPTT Factor IX depletion (Hemophilia B) characterized by aPTT prolongation proportional to degree of diseaseprolongation proportional to degree of disease
8888
CLIN101: Pegnivacogin Provides CLIN101: Pegnivacogin Provides Predictable and Durable AnticoagulationPredictable and Durable Anticoagulation
Time (hrs)Time (hrs)
Ac
tiv
ate
d P
art
ial
Th
rom
bo
pla
sti
n T
ime
(s
ec
on
ds
)A
cti
va
ted
Pa
rtia
l T
hro
mb
op
las
tin
Tim
e (
se
co
nd
s)
Dyke, C et al, Dyke, C et al, CirculationCirculation 2006 2006
90 mg pegnivacogin90 mg pegnivacogin
60 mg pegnivacogin60 mg pegnivacogin
30 mg pegnivacogin30 mg pegnivacogin
15 mg pegnivacogin15 mg pegnivacogin
PlaceboPlacebo
120120
100100
9090
8080
7070
6060
5050
4040
3030
2020
00 11 22 33
1010
aPTT is Reflective of FIX DepletionaPTT is Reflective of FIX Depletion
CLIN101 and 102:CLIN101 and 102:Combined Dosing AnalysisCombined Dosing Analysis
Verify adequacy of a 1 mg/kg pegnivacogin dose Verify adequacy of a 1 mg/kg pegnivacogin dose to achieve:to achieve:
• Target plasma concentrations of 18-30 Target plasma concentrations of 18-30 g/mlg/ml• Near complete factor IX inhibition in an ACS cohortNear complete factor IX inhibition in an ACS cohort
Assess stability of anticoagulation during the Assess stability of anticoagulation during the treatment periodtreatment period
szelenkofske
we targeted 18-30 ug/ml
szelenkofske
is this target levels or reproducibility of pk/pd in this population
John H. Alexander
Are we really able to evaluate #3. I might just stick to 1 and 2.
• Therapeutic plasma concentrationsTherapeutic plasma concentrations• Near complete inhibition of factor IXNear complete inhibition of factor IX• Stable levels of anticoagulation throughout Stable levels of anticoagulation throughout
period of catheterization/PCI period of catheterization/PCI
• Findings consistent with early phase resultsFindings consistent with early phase results
• Higher doses unlikely to be beneficialHigher doses unlikely to be beneficial
• Clinical utility of REG1 awaits RADAR and future Clinical utility of REG1 awaits RADAR and future larger studieslarger studies• Sets the foundation for interpretation of Sets the foundation for interpretation of
RADAR and future clinical trialsRADAR and future clinical trials
szelenkofske
see prior comment
szelenkofske
is this approx 2.5?
Standard CurveStandard Curve
Rationale for Targeting FIXaRationale for Targeting FIXa
TF-bearing cellTF-bearing cell
Activated plateletActivated platelet
PlateletPlatelet
VIIaVIIa
XX
XaXa
VIIaVIIa
IXIX
IXaIXa
IXaIXa
XIaXIa
IXIX
IIII
XX
IIaIIa
IIII
PropagationPropagation
AmplificationAmplification
InitiationInitiation
XaXa IIaIIa
FIXa inhibitorFIXa inhibitor
TFTF VaVa
TFTF
VIIIaVIIIaVaVa
Monroe DM. Arterioscler Thromb Vasc Biol 2002;22:1381-1389. Monroe DM. Arterioscler Thromb Vasc Biol 2002;22:1381-1389.