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Efficacy and Safety of Vernakalant Hydrochloride Injection for the Treatment of Atrial Fibrillation After Valvular or

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

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Efficacy and Safety of Vernakalant Hydrochloride Injection for the Treatment of Atrial Fibrillation After Valvular or

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  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. 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. Presenter Disclosure Information The following relationships exist related to this presentation: 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 Vernakalant hydrochloride injection (RSD1235) is under investigation for the treatment of atrial fibrillation.

  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 (Atrial arrhythmia Conversion Trial 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. Randomized, double-blind, placebo-controlled, parallel-group, multinational, multicenter study ACT IIStudy Design Randomization (2:1) TelephoneFollow-up In-Hospital Observation Pre- and Post- Surgery Screening Follow-upVisit Efficacy Period Hour 24 Visit Discharge(up to 14 d) Time 0 10 35 90 min 2 h 24 h 30 d 25 1st Infusion: vernakalant (3 mg/kg) or placebo 2nd Infusion (if in AF/AFL): vernakalant (2 mg/kg) or placebo Electrical cardioversion and other drugs permitted Continuous Holter Monitoring

  6. 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 ACT IIKey Inclusion and Exclusion Criteria *Unless controlled by pacemaker.

  7. ACT IIConcomitant 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 IIEndpoints 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 IIPatient Disposition Randomized (N=190) Placebo (n=63) Vernakalant (n=127) • 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 concomitantmedication (n=1) Treated (n=54; 86%) Vernakalant (n=107; 84%) • Discontinued (n=1) • Withdrew consent (n=1) Completed Study (n=54) Completed Study (n=106)

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

  12. ACT IIMedian Time to Conversion of AF/AFL to SR 60 45%responders 50 Vernakalant 40 P=.0002 Percentage 30 Median time to conversion among responders=12 min 20 Placebo 10 0 0 10 20 30 40 50 60 70 80 90 100 Time to Conversion, min

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

  14. ACT IIMedian Time to Conversion of AF to SR 60 47% responders 50 Vernakalant 40 P=.0001 Percentage 30 Median time to conversion among responders=12 min 20 Placebo 10 0 0 20 40 60 80 100 10 30 50 70 90 Time to Conversion, min

  15. ACT IIConversion to SR After 1 Dose of Vernakalant 80 75% 74% 60 Responders Demonstrating Conversion to SR After 1 Dose, % 40 20 36/48 35/47 0 AF/AFL AF (n=48) (n=47) • 75% of responders given vernakalant demonstrated conversion after the first dose

  16. ACT IIMaintenance of SR Among Responders* 80 60% 57% 60 Patients in SR, % 40 20 0 24 Hours 7 Days AF/AFL (n=48) *Based on life table estimates.

  17. ACT IISummary of Deaths, Discontinuations, and AEs AE=adverse event.

  18. ACT IIMost Common AEs *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 IISummary of Key Safety Events *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 IIConclusions • 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 IIPercentage of Responders by Surgery Type P=.562 P=.002 60 60 48% 50 50 40 40 36% AF/AFL Responders, % AF/AFL Responders, % 30 30 20% 20 20 14% 10 10 5/37 34/71 2/10 10/28 0 0 Placebo Vernakalant Placebo Vernakalant (n=37) (n=71) (n=10) (n=28) CABG Surgery Valvular Surgery

  23. ACT IIMaintenance of SR Among Responders* 80 71% 71% 70 60 50 Patients, % 40 30 20 10 34/48 34/48 0 24 Hours 7 Days AF/AFL (n=48) *Based on a review of 12-lead ECG data by the CEC.

  24. ACT IIQRS Duration Over Time(all patients, excluding those with pacemakers) 130 120 110 100 90 80 70 Placebo Vernakalant * * * * * * * * QRS Duration, ms Infusion #1 Infusion #2 Baseline 10 25 35 50 1.5 2 4 6 24 Follow-up Minutes Hours Time *P<.05 vs placebo.

  25. ACT IIQTcF Interval Over Time (all patients, excluding those with pacemakers) 500 450 400 350 300 Placebo Vernakalant * * * * * * * * QT Fridericia Correction, ms Infusion #1 Infusion #2 Baseline 10 25 35 50 1.5 2 4 6 24 Follow-up Minutes Hours Time *P<.05 vs placebo.

  26. ACT IIQTcB Interval Over Time (all patients, excluding those with pacemakers) 550 500 450 400 350 300 Placebo Vernakalant * * QT Bazett Correction, ms Infusion #1 Infusion #2 Baseline 10 25 35 50 1.5 2 4 6 24 Follow-up Minutes Hours Time *P<.05 vs placebo.

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