1. Efficacy and Safety of Vernakalant Hydrochloride Injection for the Treatment of Atrial Fibrillation After Valvular or Coronary Artery Bypass Surgery Peter Kowey, MD Lankenau Hospital, Wynnewood, Pennsylvania Denis Roy, MD University of Montréal, Montréal, Canada Craig Pratt, MD The Methodist DeBakey Heart Center, Houston, Texas Peter J. Schwartz, MD University of Pavia, Pavia, Italy Paul Dorian, MD University of Toronto, Toronto, Canada L. Brent Mitchell, MD University of Calgary, Calgary, Canada Egon Toft, MD Aalborg University, Aalborg, Denmark

2. Presenter Disclosure Information The following relationships exist related to this presentation: Vernakalant hydrochloride injection (RSD1235) is under investigation for the treatment of atrial fibrillation. Peter Kowey, MD Honoraria from and consultant, advisory board member, and speaker’s bureau member for Cardiome Pharma Corp. and Astellas Pharma US, Inc. Denis Roy, MD Honoraria from and consultant for Astellas Pharma US, Inc. Consultant and advisory board member for and ownership interest in Cardiome Pharma Corp. Craig Pratt, MD Consultant and advisory board member for Cardiome Pharma Corp. and Astellas Pharma US, Inc. Speaker’s bureau member for Cardiome Pharma Corp. Peter J. Schwartz, MD None Paul Dorian, MD Honoraria from Cardiome Pharma Corp. and Astellas Pharma US, Inc. Research grant received from and consultant and advisory board member for Cardiome Pharma Corp. L. Brent Mitchell, MD Honoraria and research grant received from, ownership interest in, and consultant, advisory board member, and speaker’s bureau member for Cardiome Pharma Corp. Egon Toft, MD None

3. Background Atrial fibrillation (AF) is the most common clinically significant arrhythmia, affecting an estimated 2.3 million US adults AF develops after cardiothoracic surgery in up to 40% of patients Antiarrhythmic drugs are used often in patients with recent-onset AF to restore sinus rhythm (SR) –Available agents are suboptimal due to effects on ventricular tissue; they prolong ventricular refractoriness or slow conduction velocity in ventricle Vernakalant (RSD1235) is a novel antiarrhythmic that blocks multiple ion channels, which preferentially prolongs atrial refractoriness and rapidly converts AF to SR –Blocks early-activating K + channels and frequency-dependent Na + channels Go AS, et al. JAMA. 2001;285:2370-2375; Allessie MA, et al. Circulation. 2001;103:769-777; Dorian P, et al. J Cardiovasc Pharmacol. 2007;50:35-40; Fedida D, et al. J Cardiovasc Eletrophysiol. 2005;16:1227-1238.

4. ACT II ( A trial arrhythmia C onversion T rial II ) Study Objectives Primary objective: To evaluate the efficacy of vernakalant, compared with placebo, in converting AF or atrial flutter (AFL) to SR after recent coronary artery bypass graft (CABG) or valvular surgery Secondary objective: To evaluate the safety of vernakalant in this patient population

5. ACT II Study Design Randomized, double-blind, placebo-controlled, parallel-group, multinational, multicenter study In-Hospital Observation 024 h10 25 90 min 1st Infusion: vernakalant (3 mg/kg) or placebo 2nd Infusion (if in AF/AFL): vernakalant (2 mg/kg) or placebo 35 Hour 24 Visit Efficacy Period Discharge (up to 14 d) Follow-up Visit Time2 h Continuous Holter Monitoring Randomization (2:1) Electrical cardioversion and other drugs permitted Pre- and Post- Surgery Screening Telephone Follow-up 30 d

6. ACT II Key Inclusion and Exclusion Criteria Inclusion criteria: Age  18 y CABG or valvular surgery within 7 days ECG showing normal SR prior to surgery ECG showing AF or AFL (3–72 h duration) with onset occurring within 24 hours to 7 days after surgery Exclusion criteria: Prolonged QT interval, long QT syndrome, previous torsade de pointes, Brugada syndrome Unstable New York Heart Association (NYHA) class IV heart failure Bradycardia or sick-sinus syndrome* ECG evidence of 2  /3  AV block* Intravenous class I or III antiarrhythmic drug given postsurgery Hemodynamically unstable *Unless controlled by pacemaker.

7. ACT II Concomitant Therapy Rate-control drugs, including  -blockers, calcium channel antagonists, or digoxin were allowed, providing –Heart rate >50 bpm –Loading dose or bolus of these drugs was given at least 2 hours before study treatment Electrical cardioversion or additional antiarrhythmic medication was withheld until ≥2 hours after study drug administration, unless deemed medically necessary Alcohol, caffeine, smoking, and over-the-counter medications not allowed from postsurgery screening until 24 hours after dosing

8. ACT II Endpoints Primary efficacy endpoint: Percentage of patients with treatment-induced conversion of AF/AFL to SR occurring within 90 min of first exposure to study medication and lasting for a minimum duration of 1 min –“Responders” Secondary endpoints: Time to conversion of all responders Percentage of treatment-induced conversion of AF to SR within 90 min for  1 min Time to conversion of AF to SR

9. ACT II Patient Disposition Randomized (N=190) Placebo (n=63) Vernakalant (n=127) Treated (n=54; 86%) Vernakalant (n=107; 84%) Completed Study (n=54) Completed Study (n=106) Not Treated (n=9) Spontaneous conversion to SR (n=7) Investigator decision (n=1) Erroneously entered (n=1) Not Treated (n=20) Spontaneous conversion to SR (n=17) Withdrew consent (n=2) Prohibited concomitant medication (n=1) Discontinued (n=1) Withdrew consent (n=1)

10. ACT II Demographics and Baseline Characteristics Placebo (n=54) Vernakalant (n=107) Male40 (74%)81 (76%) Caucasian50 (93%)101 (94%) Age, y: mean (SD) ≥65 y ≥75 y 68 (6.4) 40 (74%) 7 (13%) 68 (7.7) 79 (74%) 25 (23%) CABG Valvular surgery Both 37 (69%) 10 (18%) 7 (13%) 71 (66%) 28 (26%) 8 (8%) AF AFL 50 (93%) 4 (7%) 100 (93%)* 6 (6%)* *One patient in the vernakalant group was judged by the Clinical Events Committee (CEC) to be in SR on all baseline and postbaseline ECGs.

11. ACT II Percentage Demonstrating Conversion of AF/AFL to SR Within 90 Min AF/AFL Responders, % P=.0002 (n=107) 45% 0 10 20 30 40 50 Vernakalant 48/107 15% (n=54) Placebo 8/54

12. ACT II Median Time to Conversion of AF/AFL to SR Time to Conversion, min Percentage 020406080100 0 20 40 60 Placebo 45% responders P=.0002 Median time to conversion among responders=12 min Vernakalant 1030507090 50 30 10

13. ACT II Percentage Demonstrating Conversion of AF to SR Within 90 Min AF Responders, % P=.0001 47% 14% 0 10 20 30 40 50 (n=50)(n=100) 7/5047/100 PlaceboVernakalant

14. ACT II Median Time to Conversion of AF to SR Time to Conversion, min Percentage 020406080100 0 20 40 60 P=.0001 Placebo 47% responders Vernakalant Median time to conversion among responders=12 min 1030507090 50 30 10

15. ACT II Conversion to SR After 1 Dose of Vernakalant 75% of responders given vernakalant demonstrated conversion after the first dose Responders Demonstrating Conversion to SR After 1 Dose, % (n=48)(n=47) 75% 74% 0 20 40 60 80 36/4835/47 AF/AFLAF

16. ACT II Maintenance of SR Among Responders* Patients in SR, % AF/AFL (n=48) *Based on life table estimates. 60% 57% 0 20 40 60 80 24 Hours7 Days

17. ACT II Summary of Deaths, Discontinuations, and AEs Entire Study First 24 Hours Event, no. (%) Placebo (n=54) Vernakalant (n=107) Placebo (n=54) Vernakalant (n=107) Death0000 Discontinuation due to AEs 03 (3)0 Serious AEs6 (11)10 (9)02 (2) Any AEs24 (44)61 (57)17 (32)41 (38) AE=adverse event.

18. ACT II Most Common AEs Entire StudyFirst 24 Hours Event, no. (%) Placebo (n=54) Vernakalant (n=107) Placebo (n=54) Vernakalant (n=107) Most common AEs* Atrial fibrillation Nausea Constipation Weight increase Dyspnea 8 (15) 3 (6) 1 (2) 2 (4) 0 22 (20) 6 (6) 5 (5) 5 (9) 2 (4) 1 (2) 2 (4) 0 9 (8) 6 (6) 0 2 (2) Most common drug-related AEs † Atrial fibrillation 1st-degree atrioventricular block Nausea 000000 3 (3) 000000 1 (1) 3 (3) *Occurring in  5% of patients given vernakalant and at a higher rate than with placebo. † Occurring in  3% of patients given vernakalant and at a higher rate than with placebo.

19. ACT II Summary of Key Safety Events Entire StudyFirst 24 Hours Event, no. (%) Placebo (n=54) Vernakalant (n=107) Placebo (n=54) Vernakalant (n=107) Any ventricular arrhythmia event* Ventricular tachycardia Ventricular fibrillation Torsade de pointes 9 (17%) 7 (13%) 0 19 (18%) 18 (17%) 0 9 (17%) 7 (13%) 0 19 (18%) 18 (17%) 0 Any bradycardia event † 8 (15%)20 (19%)2 (4%)15 (14%) Any hypotension event ‡ 15 (28%)27 (25%) 13 (24%) 23 (22%) *Derived from AE reports, 12-lead-ECG, and Holter monitoring (ventricular tachycardia defined as wide complex events  3 beats with heart rate  100 bpm). † Derived from AE reports, 12-lead-ECG, and Holter monitoring (bradycardia defined as heart rate <40 bpm [<60 bpm for sinus bradycardia]). ‡ Derived from AE reports and vital signs (hypotension defined as a decrease from baseline in systolic pressure  30 mm Hg, decrease in diastolic pressure  15 mm Hg, or systolic pressure <90 mm Hg).

20. ACT II Conclusions Vernakalant was significantly more effective than placebo in converting AF to SR after CABG, valvular surgery, or both –Conversion rate: 47% vs 14%, P=.0001 Seventy-five percent of patients who responded did so after the first vernakalant infusion –Median time to conversion: 12 min Vernakalant was well tolerated in this patient population –2 serious AEs in 1st 24 hours –3% discontinued treatment due to AEs –No deaths or cases of torsade de pointes –Overall incidences of ventricular arrhythmia, bradycardia, and hypotension events similar to those with placebo Vernakalant is a new option for converting AF/AFL to SR after CABG or valvular surgery

21. Backup Slides

22. ACT II Percentage of Responders by Surgery Type AF/AFL Responders, % (n=10) (n=71)(n=37) P=.002 P=.562 CABG SurgeryValvular Surgery 20% 36% 0 10 20 30 40 50 60 PlaceboVernakalant (n=28) 10/282/1034/715/37 14% 48% 0 10 20 30 40 50 60 PlaceboVernakalant

23. ACT II Maintenance of SR Among Responders* Patients, % AF/AFL (n=48) *Based on a review of 12-lead ECG data by the CEC. 34/48 71% 0 10 20 30 40 50 60 70 80 24 Hours7 Days

24. ACT II QRS Duration Over Time (all patients, excluding those with pacemakers) MinutesHours Time QRS Duration, ms Infusion #1 Infusion #2 130 120 110 100 90 80 70 Baseline102535501.524624Follow-up Placebo Vernakalant *P<.05 vs placebo. * * * * * * * *

25. ACT II QTcF Interval Over Time (all patients, excluding those with pacemakers) MinutesHours Time QT Fridericia Correction, ms Infusion #1 Infusion #2 Baseline102535501.524624Follow-up *P<.05 vs placebo. 500 450 400 350 300 Placebo Vernakalant * * * * * * * *

26. ACT II QTcB Interval Over Time (all patients, excluding those with pacemakers) MinutesHours Time QT Bazett Correction, ms Infusion #1 Infusion #2 Baseline102535501.524624Follow-up *P<.05 vs placebo. 550 500 450 400 350 300 Placebo Vernakalant * *