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1
Mechanism of ActionMechanism of Action
Greg Beatch, Ph.D.Greg Beatch, Ph.D.Vice President, Scientific AffairsVice President, Scientific Affairs
Cardiome Pharma Corp.Cardiome Pharma Corp.
2
VernakalantVernakalantMechanism of ActionMechanism of Action
• Multiple ion channel blockerMultiple ion channel blocker– Targeted to AFTargeted to AF
• Relatively atrial selectiveRelatively atrial selective• Rapid conversion of atrial fibrillationRapid conversion of atrial fibrillation• Pharmacologic effects consistent with Pharmacologic effects consistent with
ion channel blocking profileion channel blocking profile
3
Vernakalant Blocks K+ Channels Vernakalant Blocks K+ Channels Important in Atrial RepolarizationImportant in Atrial Repolarization
Current IC50 (µM)
Ito 5-30
IKur 3-13
IKACh 10
IKr 7-21
IKs > 100
IK1 > 1000 100 200 300 400 ms
IKur
IKr
Ito
IKACh
0 mV
Fedida et al. J Cardiovasc Electrophysiol 2005Fedida et al. J Cardiovasc Electrophysiol 2005
4
Effects of Vernakalant on Effects of Vernakalant on Atrial Tissue from Humans with Atrial Tissue from Humans with
Atrial FibrillationAtrial FibrillationControl(n=7)
10 µM(n=7)
APD20 (ms) 25 ± 4 34 ± 6**
APD90 (ms) 229 ± 13 243 ± 16**
ERP (ms) 239 ± 11 259 ± 11**
Resting potential (mV) -76 ± 1 -74 ± 1
dV/dtmax (V/s) 244 ± 38 219 ± 32
Ravens et al. European Society of Cardiology 2007Ravens et al. European Society of Cardiology 2007Data collected at 60 bpm; ** P<0.01Data collected at 60 bpm; ** P<0.01
5
Vernakalant Prolongs Atrial Vernakalant Prolongs Atrial Refractory Period: Human EP StudyRefractory Period: Human EP Study
* P<0.05 vs. baseline* P<0.05 vs. baselineDorian et al. J Cardiovasc Pharmacol 2007Dorian et al. J Cardiovasc Pharmacol 2007
4 mg/kg4 mg/kg100 bpm pacing100 bpm pacing
**
0
10
20
30
40
AERP VERP
Cha
nge
from
Bas
elin
e (m
sec)
6
Data collected at 60 bpm; ** P<0.01Data collected at 60 bpm; ** P<0.01Ravens et al. European Society of Cardiology 2007Ravens et al. European Society of Cardiology 2007
Effects of Vernakalant on Effects of Vernakalant on Atrial Tissue from Humans with Atrial Tissue from Humans with
Atrial FibrillationAtrial FibrillationControl(n=7)
10 µM(n=7)
APD20 (ms) 25 ± 4 34 ± 6**
APD90 (ms) 229 ± 13 243 ± 16**
ERP (ms) 239 ± 11 259 ± 11**
Resting potential (mV) -76 ± 1 -74 ± 1
dV/dtmax (V/s) 244 ± 38 219 ± 32
7
Fedida et al. J Cardiovasc Electrophysiol 2005Fedida et al. J Cardiovasc Electrophysiol 2005Fedida. Curr Op Invest Drugs 2007Fedida. Curr Op Invest Drugs 2007
INa IC50 = 43 µM at -80 mV, 1 HzINa IC50 = 9 µM at -80 mV, 20 Hz
Vernakalant concentration (µM)
Frac
tiona
l cur
rent
1 10 100 10000.0
0.2
0.4
0.6
0.8
1.0
Plasma Levels in Patients
1 Hz
20 Hz
Vernakalant’s Frequency-Dependent Vernakalant’s Frequency-Dependent Block of Na Currents Targets AFBlock of Na Currents Targets AF
8
Vernakalant Slows Atrial Conduction Vernakalant Slows Atrial Conduction
at Fibrillatory Heart Rates in Dogsat Fibrillatory Heart Rates in Dogs
4 mg/kg4 mg/kg
****
**
0
20
40
60
80
100
200 240 300 400Pacing rates (beats/min)
% C
hang
e in
Con
duct
ion
Tim
e
Nattel et al. European Society of Cardiology 2001Nattel et al. European Society of Cardiology 2001
9
Vernakalant Rapidly Converts Vernakalant Rapidly Converts Atrial Fibrillation in Dog ModelsAtrial Fibrillation in Dog Models
Frequency ofConversion
Time toConversion (min)
1 mg/kg 55% 10.0 ± 4.1
2 mg/kg 88% 6.9 ± 2.5
4 mg/kg 100% 5.1 ± 3.4
8 mg/kg 100% 2.8 ± 2.5
Vernakalant dose dependently decreased time to conversionVernakalant dose dependently decreased time to conversion
Nattel et al. European Society of Cardiology 2001Nattel et al. European Society of Cardiology 2001
10
Reduced Pro-arrhythmia in theReduced Pro-arrhythmia in thePig Acute MI ModelPig Acute MI Model
TreatmentIschemia
VT/VFReperfusion
VT/VFTotal
Mortality
Saline 4/7 2/3 6/7
Flecainide 9/9 – 9/9
Vernakalant 2/8 0/6 2/8*
* P<0.05 Fishers Exact Test, compared to saline and compared to flecainide* P<0.05 Fishers Exact Test, compared to saline and compared to flecainide
11
10 min IV infusion (0, 2, 8, 16 mg/kg), 30 min dose increment; Results - mean ± sem (n = 6);10 min IV infusion (0, 2, 8, 16 mg/kg), 30 min dose increment; Results - mean ± sem (n = 6);*Denotes statistical significance compared to vehicle control (P<0.05); [Qtest Study SPD06-004]*Denotes statistical significance compared to vehicle control (P<0.05); [Qtest Study SPD06-004]
0 5000 10000 15000 20000 250000
20
40
60
80
100
120
Cmax in patients
SystolicDiastolic
*
Cplasma (ng/mL)
Blo
od P
ress
ure
(mm
Hg)
At Therapeutic Concentrations, At Therapeutic Concentrations, Vernakalant has Little Effect on Blood Vernakalant has Little Effect on Blood
Pressure in the Anesthetized DogPressure in the Anesthetized Dog
12
Mechanism of ActionMechanism of Action
Greg Beatch, Ph.D.Greg Beatch, Ph.D.Vice President, Scientific AffairsVice President, Scientific Affairs
Cardiome Pharma Corp.Cardiome Pharma Corp.
13
VernakalantVernakalantMechanism of ActionMechanism of Action
• Multiple ion channel blockerMultiple ion channel blocker– Targeted to AFTargeted to AF
• Relatively atrial selectiveRelatively atrial selective• Rapid conversion of atrial fibrillationRapid conversion of atrial fibrillation• Pharmacologic effects consistent with Pharmacologic effects consistent with
ion channel blocking profileion channel blocking profile
14
Vernakalant Blocks K+ Channels Vernakalant Blocks K+ Channels Important in Atrial RepolarizationImportant in Atrial Repolarization
Current IC50 (µM)
Ito 5-30
IKur 3-13
IKACh 10
IKr 7-21
IKs > 100
IK1 > 1000 100 200 300 400 ms
IKur
IKr
Ito
IKACh
0 mV
Fedida et al. J Cardiovasc Electrophysiol 2005Fedida et al. J Cardiovasc Electrophysiol 2005
15
Effects of Vernakalant on Effects of Vernakalant on Atrial Tissue from Humans with Atrial Tissue from Humans with
Atrial FibrillationAtrial FibrillationControl(n=7)
10 µM(n=7)
APD20 (ms) 25 ± 4 34 ± 6**
APD90 (ms) 229 ± 13 243 ± 16**
ERP (ms) 239 ± 11 259 ± 11**
Resting potential (mV) -76 ± 1 -74 ± 1
dV/dtmax (V/s) 244 ± 38 219 ± 32
Ravens et al. European Society of Cardiology 2007Ravens et al. European Society of Cardiology 2007Data collected at 60 bpm; ** P<0.01Data collected at 60 bpm; ** P<0.01
16
Vernakalant Prolongs Atrial Vernakalant Prolongs Atrial Refractory Period: Human EP StudyRefractory Period: Human EP Study
* P<0.05 vs. baseline* P<0.05 vs. baselineDorian et al. J Cardiovasc Pharmacol 2007Dorian et al. J Cardiovasc Pharmacol 2007
4 mg/kg4 mg/kg100 bpm pacing100 bpm pacing
**
0
10
20
30
40
AERP VERP
Cha
nge
from
Bas
elin
e (m
sec)
17
Data collected at 60 bpm; ** P<0.01Data collected at 60 bpm; ** P<0.01Ravens et al. European Society of Cardiology 2007Ravens et al. European Society of Cardiology 2007
Effects of Vernakalant on Effects of Vernakalant on Atrial Tissue from Humans with Atrial Tissue from Humans with
Atrial FibrillationAtrial FibrillationControl(n=7)
10 µM(n=7)
APD20 (ms) 25 ± 4 34 ± 6**
APD90 (ms) 229 ± 13 243 ± 16**
ERP (ms) 239 ± 11 259 ± 11**
Resting potential (mV) -76 ± 1 -74 ± 1
dV/dtmax (V/s) 244 ± 38 219 ± 32
18
Fedida et al. J Cardiovasc Electrophysiol 2005Fedida et al. J Cardiovasc Electrophysiol 2005Fedida. Curr Op Invest Drugs 2007Fedida. Curr Op Invest Drugs 2007
INa IC50 = 43 µM at -80 mV, 1 HzINa IC50 = 9 µM at -80 mV, 20 Hz
Vernakalant concentration (µM)
Frac
tiona
l cur
rent
1 10 100 10000.0
0.2
0.4
0.6
0.8
1.0
Plasma Levels in Patients
1 Hz
20 Hz
Vernakalant’s Frequency-Dependent Vernakalant’s Frequency-Dependent Block of Na Currents Targets AFBlock of Na Currents Targets AF
19
Vernakalant Slows Atrial Conduction Vernakalant Slows Atrial Conduction
at Fibrillatory Heart Rates in Dogsat Fibrillatory Heart Rates in Dogs
4 mg/kg4 mg/kg
****
**
0
20
40
60
80
100
200 240 300 400Pacing rates (beats/min)
% C
hang
e in
Con
duct
ion
Tim
e
Nattel et al. European Society of Cardiology 2001Nattel et al. European Society of Cardiology 2001
20
Vernakalant Rapidly Converts Vernakalant Rapidly Converts Atrial Fibrillation in Dog ModelsAtrial Fibrillation in Dog Models
Frequency ofConversion
Time toConversion (min)
1 mg/kg 55% 10.0 ± 4.1
2 mg/kg 88% 6.9 ± 2.5
4 mg/kg 100% 5.1 ± 3.4
8 mg/kg 100% 2.8 ± 2.5
Vernakalant dose dependently decreased time to conversionVernakalant dose dependently decreased time to conversion
Nattel et al. European Society of Cardiology 2001Nattel et al. European Society of Cardiology 2001
21
Reduced Pro-arrhythmia in theReduced Pro-arrhythmia in thePig Acute MI ModelPig Acute MI Model
TreatmentIschemia
VT/VFReperfusion
VT/VFTotal
Mortality
Saline 4/7 2/3 6/7
Flecainide 9/9 – 9/9
Vernakalant 2/8 0/6 2/8*
* P<0.05 Fishers Exact Test, compared to saline and compared to flecainide* P<0.05 Fishers Exact Test, compared to saline and compared to flecainide
22
10 min IV infusion (0, 2, 8, 16 mg/kg), 30 min dose increment; Results - mean ± sem (n = 6);10 min IV infusion (0, 2, 8, 16 mg/kg), 30 min dose increment; Results - mean ± sem (n = 6);*Denotes statistical significance compared to vehicle control (P<0.05); [Qtest Study SPD06-004]*Denotes statistical significance compared to vehicle control (P<0.05); [Qtest Study SPD06-004]
0 5000 10000 15000 20000 250000
20
40
60
80
100
120
Cmax in patients
SystolicDiastolic
*
Cplasma (ng/mL)
Blo
od P
ress
ure
(mm
Hg)
At Therapeutic Concentrations, At Therapeutic Concentrations, Vernakalant has Little Effect on Blood Vernakalant has Little Effect on Blood
Pressure in the Anesthetized DogPressure in the Anesthetized Dog
23 05/03/23 21:39
Vernakalant Effects on Purkinje Vernakalant Effects on Purkinje Fiber Action Potential DurationFiber Action Potential Duration
* P<0.05, ** P<0.01, ‡ P<0.005 vs. predrug* P<0.05, ** P<0.01, ‡ P<0.005 vs. predrugOrth et al. Cardiovasc Res 2006Orth et al. Cardiovasc Res 2006
Drug Concentration (µM)0.001 0.01 0.1 1 10 100
% C
hang
e in
act
ion
pote
ntia
l d
urat
ion
(APD
)
0
20
40
60
80
100
120
* **
****
***
vernakalant
dofetilide
▲ APD50
APD90
‡
**
**
‡
24
Vernakalant Abolishes EADs in Vernakalant Abolishes EADs in Rabbit Purkinje FibersRabbit Purkinje Fibers
Orth et al. Cardiovasc Res 2006Orth et al. Cardiovasc Res 2006
3 s
300 nMdofetilide, 3 minEAD
Control: 60 beats/min
500 ms
0 mV
-80 mV-
3 s
300 nMdofetilide+ 30 µM vernakalant
0 mV
-80 mV-
EADs
300 nMdofetilide15 min
0 mV
-80 mV 3 s Stimartifact
-
25 05/03/23 21:39
Vernakalant Suppresses Vernakalant Suppresses Torsade de Pointes in vivoTorsade de Pointes in vivo
* P<0.05 Fishers Exact Test* P<0.05 Fishers Exact TestOrth et al. Cardiovasc Res 2006Orth et al. Cardiovasc Res 2006
Clofilium-induced torsade de pointes was suppressed by Clofilium-induced torsade de pointes was suppressed by vernakalant in a rabbit modelvernakalant in a rabbit model
Inci
denc
e of
TdP
0.0
0.2
0.4
0.6
0.8 7/97/9 7/97/96/96/9
1/91/9*
ControlControl 0.10.1 0.30.3 11Dose of vernakalantDose of vernakalant
(µmol/kg/min)(µmol/kg/min)
*
Dur
atio
n of
TdP
(s)
0.10.1 0.30.3 11Dose of vernakalantDose of vernakalant
(µmol/kg/min)(µmol/kg/min)
ControlControl
1501.0
26 05/03/23 21:39
Mechanism of ActionMechanism of ActionSummarySummary
• Multiple ion channel blockerMultiple ion channel blocker
• Activity potentiated in atria during AFActivity potentiated in atria during AF
• Converts AF rapidly and suppresses Converts AF rapidly and suppresses torsade de pointes in animal modelstorsade de pointes in animal models
• Pharmacologic effects consistent with ion Pharmacologic effects consistent with ion channel blocking profilechannel blocking profile