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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