1. 1 Mechanism of Action Greg Beatch, Ph.D. Vice President, Scientific Affairs Cardiome Pharma Corp.

2. 2 Vernakalant Mechanism of Action Multiple ion channel blockerMultiple ion channel blocker –Targeted to AF Relatively atrial selectiveRelatively atrial selective Rapid conversion of atrial fibrillationRapid conversion of atrial fibrillation Pharmacologic effects consistent with ion channel blocking profilePharmacologic effects consistent with ion channel blocking profile

3. 3 Vernakalant Blocks K+ Channels Important in Atrial Repolarization CurrentIC 50 (µM) I to 5-30 I Kur 3-13 I KACh 10 I Kr 7-21 I Ks > 100 I K1 > 100 0100200300400 ms I Kur I Kr I to I KACh 0 mV Fedida et al. J Cardiovasc Electrophysiol 2005

4. 4 Effects of Vernakalant on Atrial Tissue from Humans with Atrial Fibrillation Control (n=7) 10 µM (n=7) APD 20 (ms)25 ± 434 ± 6** APD 90 (ms)229 ± 13243 ± 16** ERP (ms)239 ± 11259 ± 11** Resting potential (mV)-76 ± 1-74 ± 1 dV/dt max (V/s)244 ± 38219 ± 32 Ravens et al. European Society of Cardiology 2007 Data collected at 60 bpm; ** P<0.01

5. 5 Vernakalant Prolongs Atrial Refractory Period: Human EP Study * P<0.05 vs. baseline Dorian et al. J Cardiovasc Pharmacol 2007 4 mg/kg 100 bpm pacing * 0 10 20 30 40 AERPVERP Change from Baseline (msec)

6. 6 Data collected at 60 bpm; ** P<0.01 Ravens et al. European Society of Cardiology 2007 Effects of Vernakalant on Atrial Tissue from Humans with Atrial Fibrillation Control (n=7) 10 µM (n=7) APD 20 (ms)25 ± 434 ± 6** APD 90 (ms)229 ± 13243 ± 16** ERP (ms)239 ± 11259 ± 11** Resting potential (mV)-76 ± 1-74 ± 1 dV/dt max (V/s)244 ± 38219 ± 32

7. 7 Fedida et al. J Cardiovasc Electrophysiol 2005 Fedida. Curr Op Invest Drugs 2007 I Na IC 50 = 43 µM at -80 mV, 1 Hz I Na IC 50 = 9 µM at -80 mV, 20 Hz Vernakalant concentration (µM) Fractional current 1101001000 0.0 0.2 0.4 0.6 0.8 1.0 Plasma Levels in Patients 1 Hz 20 Hz Vernakalant’s Frequency-Dependent Block of Na Currents Targets AF

8. 8 Vernakalant Slows Atrial Conduction at Fibrillatory Heart Rates in Dogs 4 mg/kg ** * 0 20 40 60 80 100 200240300400 Pacing rates (beats/min) % Change in Conduction Time Nattel et al. European Society of Cardiology 2001

9. 9 Vernakalant Rapidly Converts Atrial Fibrillation in Dog Models Frequency of Conversion Time to Conversion (min) 1 mg/kg55%10.0 ± 4.1 2 mg/kg88%6.9 ± 2.5 4 mg/kg100%5.1 ± 3.4 8 mg/kg100%2.8 ± 2.5 Vernakalant dose dependently decreased time to conversion Nattel et al. European Society of Cardiology 2001

10. 10 Reduced Pro-arrhythmia in the Pig Acute MI Model Treatment Ischemia VT/VF Reperfusion VT/VF Total Mortality Saline4/72/36/7 Flecainide9/9– Vernakalant2/80/62/8* * P<0.05 Fishers Exact Test, compared to saline and compared to flecainide

11. 11 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] At Therapeutic Concentrations, Vernakalant has Little Effect on Blood Pressure in the Anesthetized Dog

12. 12 Mechanism of Action Greg Beatch, Ph.D. Vice President, Scientific Affairs Cardiome Pharma Corp.

13. 13 Vernakalant Mechanism of Action Multiple ion channel blockerMultiple ion channel blocker –Targeted to AF Relatively atrial selectiveRelatively atrial selective Rapid conversion of atrial fibrillationRapid conversion of atrial fibrillation Pharmacologic effects consistent with ion channel blocking profilePharmacologic effects consistent with ion channel blocking profile

14. 14 Vernakalant Blocks K+ Channels Important in Atrial Repolarization CurrentIC 50 (µM) I to 5-30 I Kur 3-13 I KACh 10 I Kr 7-21 I Ks > 100 I K1 > 100 0100200300400 ms I Kur I Kr I to I KACh 0 mV Fedida et al. J Cardiovasc Electrophysiol 2005

15. 15 Effects of Vernakalant on Atrial Tissue from Humans with Atrial Fibrillation Control (n=7) 10 µM (n=7) APD 20 (ms)25 ± 434 ± 6** APD 90 (ms)229 ± 13243 ± 16** ERP (ms)239 ± 11259 ± 11** Resting potential (mV)-76 ± 1-74 ± 1 dV/dt max (V/s)244 ± 38219 ± 32 Ravens et al. European Society of Cardiology 2007 Data collected at 60 bpm; ** P<0.01

16. 16 Vernakalant Prolongs Atrial Refractory Period: Human EP Study * P<0.05 vs. baseline Dorian et al. J Cardiovasc Pharmacol 2007 4 mg/kg 100 bpm pacing * 0 10 20 30 40 AERPVERP Change from Baseline (msec)

17. 17 Data collected at 60 bpm; ** P<0.01 Ravens et al. European Society of Cardiology 2007 Effects of Vernakalant on Atrial Tissue from Humans with Atrial Fibrillation Control (n=7) 10 µM (n=7) APD 20 (ms)25 ± 434 ± 6** APD 90 (ms)229 ± 13243 ± 16** ERP (ms)239 ± 11259 ± 11** Resting potential (mV)-76 ± 1-74 ± 1 dV/dt max (V/s)244 ± 38219 ± 32

18. 18 Fedida et al. J Cardiovasc Electrophysiol 2005 Fedida. Curr Op Invest Drugs 2007 I Na IC 50 = 43 µM at -80 mV, 1 Hz I Na IC 50 = 9 µM at -80 mV, 20 Hz Vernakalant concentration (µM) Fractional current 1101001000 0.0 0.2 0.4 0.6 0.8 1.0 Plasma Levels in Patients 1 Hz 20 Hz Vernakalant’s Frequency-Dependent Block of Na Currents Targets AF

19. 19 Vernakalant Slows Atrial Conduction at Fibrillatory Heart Rates in Dogs 4 mg/kg ** * 0 20 40 60 80 100 200240300400 Pacing rates (beats/min) % Change in Conduction Time Nattel et al. European Society of Cardiology 2001

20. 20 Vernakalant Rapidly Converts Atrial Fibrillation in Dog Models Frequency of Conversion Time to Conversion (min) 1 mg/kg55%10.0 ± 4.1 2 mg/kg88%6.9 ± 2.5 4 mg/kg100%5.1 ± 3.4 8 mg/kg100%2.8 ± 2.5 Vernakalant dose dependently decreased time to conversion Nattel et al. European Society of Cardiology 2001

21. 21 Reduced Pro-arrhythmia in the Pig Acute MI Model Treatment Ischemia VT/VF Reperfusion VT/VF Total Mortality Saline4/72/36/7 Flecainide9/9– Vernakalant2/80/62/8* * P<0.05 Fishers Exact Test, compared to saline and compared to flecainide

22. 22 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] At Therapeutic Concentrations, Vernakalant has Little Effect on Blood Pressure in the Anesthetized Dog

23. 23 8/7/2015 5:07 PM Vernakalant Effects on Purkinje Fiber Action Potential Duration * P<0.05, ** P<0.01, ‡ P<0.005 vs. predrug Orth et al. Cardiovasc Res 2006

24. 24 Vernakalant Abolishes EADs in Rabbit Purkinje Fibers Orth et al. Cardiovasc Res 2006 3 s 300nMdofetilide, 3 min EAD EADs 300nMdofetilide 15 min 0 mV -80 mV 3 s Stimartifact -

25. 25 8/7/2015 5:07 PM Vernakalant Suppresses Torsade de Pointes in vivo * P<0.05 Fishers Exact Test Orth et al. Cardiovasc Res 2006 Clofilium-induced torsade de pointes was suppressed by vernakalant in a rabbit model Incidence of TdP 0.0 0.2 0.4 0.6 0.8 7/9 7/9 6/9 1/9 * Control0.10.31 Dose of vernakalant (µmol/kg/min) * Duration of TdP (s) 0.10.31 Dose of vernakalant (µmol/kg/min) Control 150 1.0

26. 26 8/7/2015 5:07 PM Mechanism of Action Summary Multiple ion channel blockerMultiple ion channel blocker Activity potentiated in atria during AFActivity potentiated in atria during AF Converts AF rapidly and suppresses torsade de pointes in animal modelsConverts AF rapidly and suppresses torsade de pointes in animal models Pharmacologic effects consistent with ion channel blocking profilePharmacologic effects consistent with ion channel blocking profile