Dronedarone: Need to Perform a CV Outcome Safety Study

Dronedarone: Need to Perform a CV Outcome Safety Study Gerald V. Naccarelli M.D. Consultant: Glaxo-Smith-Kline, Pfizer, Sanofi, Boehringer-Ingelheim, Daiichi-Sankyo, Bristol Myers Squibb, Otsuka, Janssen

Clinical Profiles for Amiodarone and Dronedarone Amiodarone Dronedarone Iodine moiety Yes No T ½ 53 days 14-30 hours Blocks I Kr ; I Ks ; B 1 ; I Ca ; I to ; I Na Yes Yes Dosing Daily after loading bid with meals Food effect Yes Yes CYP4503A4 metabolism Yes Yes Inhibits tubular secretion of creatinine Yes Yes Increase QT but low TDP Yes Yes Efficacy in suppressing AF 65% 50% Efficacy in suppressing ventricular tachyarrhythmias Yes Not well studied Decreases CV hospitalization No Yes Warfarin interaction Yes No Pulmonary/thyroid toxicity Yes No Safety concerns in CHF SCD-HEFT NYHA III ANDROMEDA Wolbrette DL, et al. Vasc Health Risk Manag. 2010;(6):517-523.

Dronedarone: Clinical Trials DAFNE 1 EURIDIS/ ADONIS 2 ERATO 3 ATHENA 4 DIONYSOS 5 ANDROMEDA 6 Trial objective Dose finding study Effect of dronedarone on maintenance of sinus rhythm Effect of dronedarone in the control of mean 24-hour ventricular rate Evaluate the efficacy and safety of dronedarone in the prevention of CV hospitalization or all-cause death Investigate efficacy and safety of dronedarone versus amiodarone for the maintenance of sinus rhythm Evaluate the potential benefit of dronedarone on all cause death or hospitalization for worsening heart failure Patient population Patient status at baseline Number of patients Dronedarone Versus Primary endpoint Persistent AF In AF but eligible for AAD treatment and cardioversion Paroxysmal/ persistent AF In sinus rhythm Permanent AF In permanent AF Paroxysmal/ Persistent AF In sinus rhythm or AF but eligible for cardioversion Persistent AF In AF but eligible for AAD treatment and cardioversion Unstable recently decompensated CHF patients 102 1237 174 4628 504 627 Time to first AF recurrence Both arms received standard therapy* Time to first AF/AFL recurrence Both arms received standard therapy* Change in mean ventricular rate measured by 24- hour Holter on Day 14 compared to baseline Both arms received standard therapy* CV hospitalization or all-cause mortality Amiodarone Treatment failure defined as recurrence of AF OR premature study drug discontinuation for intolerance or lack of efficacy N/A Death from any cause or hospitalization for worsening heart failure 1. Touboul P, et al. Eur Heart J. 2003;24:1481-7. 2. Singh BN, et al. N Engl J Med. 2007;357:987-99. 3. Davy et al. Am Heart J. 2008;156:527.e1-527.e9. 4. Hohnloser SH, et al. N Engl J Med 2009;360:668-78. 5. Le Heuzey JY et al. J Cardiovasc Electrophysiol. 2010 Apr 6 Epub 6. Køber L, et al. N Engl J Med. 2008;358:2678-87. 2

DAFNE Dronedarone 400 mg bid increased median days in NSR from 5.3 days on placebo to 59.9 days with AF; RR=0.45 (0.28-0.72) *(P<.05) No benefit of higher doses with increased GI toxicity at 800 mg bid 400 bid 600 bid 800 bid N 48 54 54 43 Median days/nsr 5.3 59.9* 4.3 5.2 Time to AF recur (RR) 0.45 (0.28-.72) 0.95 (0.62-1.45) 0.68 (0.42-1.11) 22.6% discontinued drug due to GI adverse effects DAFNE = Dronedarone Atrial FibrillatioN study after Electrical Cardioversion Touboul et al. Eur Heart L 2003; 24:1481-1487

Dronedarone: AF Trials ADONIS (American-Australian-African trial on DronedarONe In atrial fibrillation or flutter patients for the maintenance of Sinus rhythm) Dronedarone 400 mg BID vs. placebo Primary Endpoint: First AF/AFl recurrence (Dronedarone reduced AF; p=.0017) Prolonged time to first AF/AFL symptomatic recurrence (p=0.021) Median time to first AF 59 days for placebo vs. 158 days for dronedarone (RR=.725; CI = 0.59-0.89)(p=.0017) Rate during recurrence, 12 bpm slower (116.6 to 104.6 bpm) on dronedarone (p<.001) EURIDIS (EURopean trial In atrial fibrillation or flutter patients receiving Dronedarone for the maintenance of Sinus rhythm) Dronedarone 400 mg BID vs. placebo Primary Endpoint: First AF/AFl recurrence (Dronedarone reduced AF by 22%; p=.0017) Prolonged time to first AF/AFL symptomatic recurrence (p=0.0055) Median time to first AF 41 days for placebo vs. 96 days for dronedarone (RR=.784; CI = 0.64-.095) (p=0.0138) Rate during recurrence, 15 bpm slower (117.5 to 102.3 bpm) on dronedarone (p<.0001) Singh BN et al. NEJM 2007;357:987-999

Cumulative Incidence Singh BN, et al. N Engl J Med 2008;358:2678-2687 EURIDIS / ADONIS: Effect on Death or CV Hospitalization (Post-Hoc Analysis) 0.5 0.4 0.3 0.2 Trial Dronedarone Relative risk (95% CI) EURIDIS 35 / 201 54 / 411 0.73 (0.48-1.12) ADONIS 29 / 208 57 / 417 0.89 (0.56-1.39) Pooled 64 / 409 111 / 828 0.80 (0.59-1.09) HR= 0.80 (0.59 1.09) 400 mg BID 0.1 Number at risk: 400 mg BID 0.0 0 60 120 180 270 360 Days 409 328 285 58 224 828 687 619 83 522 200 470

ANDROMEDA: Inclusion Criteria Recently hospitalized patients Having symptomatic heart failure (current NYHA class II-IV) with the following: At least 1 episode of decompensation corresponding to NYHA class III-IV within the last month WMI 1.2 (~LVEF 35%) These patients may have been clinically improved at the time of enrollment, and it is the history of decompensation that characterized them Patients were to be enrolled whether or not they had a history of atrial fibrillation or flutter; AF (if present) may have been long-standing or recent onset. WMI = wall motion index. MULTAQ [package insert], sanofi-aventis US LLC: 2009. Køber L et al. N Engl J Med. 2008;358:2678-2687. Kober L, et al. N Engl J Med 2008:358;2678-2687

ANDROMEDA: Primary End Point Time to death or hospitalization for worsening HF (n=317) Dronedarone 400 mg BID (n=310) Patients reaching end point (n) 40 53 RR 1.38 95% CI 0.918 2.088 Log-rank s test result (p value) 0.118. Kober L, et al. N Engl J Med 2008:358;2678-2687

Cumulative Incidence ANDROMEDA: Mortality Results at Time of DSMB Recommendation 0.3 Drug # Events / # at Risk Relative Risk (95% CI) 12 / 317 Dronedarone 25 / 310 2.13 (1.07-4.25) 0.2 Mean duration of follow-up = 2 months 0.1 Dronedarone 0.0 At risk 0 30 60 90 120 150 180 210 240 Days Following Randomization PBO 317 256 181 103 50 18 6 1 DRO 310 257 174 104 59 22 5 1 Kober L, et al. N Engl J Med 2008:358;2678-2687

ANDROMEDA: Adjudicated Mode of Cardiovascular Death Dronedarone Cardiovascular death 9 24 Sudden death 6 10 Nonsudden death 3 14 Myocardial infarction 2 0 Worsening heart failure 2 10 Documented arrhythmia 2 6 Procedure related 0 1 Other cardiovascular 0 2 Presumed cardiovascular 3 5 No arrhythmia or sudden death was related to torsade de pointes

ANDROMEDA: Possible Explanations A chance finding related to the uncertainty associated with the frequent interim monitoring of small numbers of events in a trial that was terminated early. A true finding related to differences in the use of certain background medications following randomization. A true finding that can be explained by a deleterious effect of dronedarone in recently unstable patients who were hospitalized for decompensated heart failure and who did not have nonpermanent atrial fibrillation.

Cumulative Incidence (%) 50 40 30 20 10 0 ATHENA: Primary Endpoint (CV Hospitalization or Death) 4628 patients with paroxysmal or persistent AF were randomized if they met the following: 75 years of age with or without additional risk factors or 70 years of age and 1 risk factor (HTN, diabetes, prior stroke/tia, LA diameter 50 mm, LVEF 0.40) 0 Dronedarone 6 12 18 24 30 24% reduction in relative risk Exclusion Criteria Permanent AF Unstable hemodynamic condition (ie, decompensated heart failure within HR previous = 0.76 4 wk) NYHA class IV CHF P<.001 Bradycardia <50 bpm PR interval >280 msec Months ATHENA = A Trial With Dronedarone to Prevent Hospitalization or Death in Patients With Atrial Fibrillation. Hohnloser SH, et al. N Engl J Med. 2009;360(7):668-678.

ATHENA Fatal Outcomes Outcome (n=2327) Dronedarone (n=2301) Hazard Ratio 95% CI P Value All deaths 139 116 0.84 0.66-1.08.18 Non-CV deaths 49 53 1.10 0.74-1.62.65 CV deaths 90 63 0.71 0.51-0.98.03 Cardiac nonarrhythmic deaths Cardiac arrhythmic deaths 18 17 0.95 0.49-1.85.89 48 26 0.55 0.34-0.88.01 Vascular noncardiac 24 20 0.84 0.47-1.52.57.Hohnloser et al. N Engl J Med. 2009;360:668-678 (A).

Treatment Emergent Adverse Events in Randomized and Treated Patients 20 (N=2313) Dronedarone (N=2291) Patients with any TEAE 1603 (69%) 1649 (72%) Gastro-intestinal 508 (22%) 600 (26%) Respiratory 337 (15%) 332 (15%) Skin 176 (8%) 237 (10%) Creatinine increase 31 (1%) 108 (4.7%) Patients with any serious TEAE 489 (21%) 456 (20%) Gastro-intestinal 68 (3%) 81 (4%) Respiratory 45 (2%) 41 (2%) Skin 6 (0.3%) 7 (0.3%) Creatinine increase 1 (<0.1%) 5 (0.2%) Patients permanently discontinued study drug for any TEAE 187 (8%) 290 (13%)

Mortality Results of ATHENA Are Discordant With Those of ANDROMEDA ANDROMEDA Drug # Events / # at Risk Relative Risk (95% CI) 12 / 317 2.13 Dronedarone 25 / 310 (1.07-4.25) Drug ATHENA # Events / # at Risk Relative Risk (95% CI) 139 / 2327 0.84 Dronedarone 116 / 2301 (0.66-1.08)

Assessment of Risk: Subgroup Analysis of All-Cause Mortality in ATHENA LV ejection fraction NYHA Class Diuretics Betablockers ACE inhibitors Subgroup # Patients Relative risk (95% CI) Dronedarone: placebo < 0.35 179 0.55 (0.25-1.21) 0.35 4365 0.89 (0.69-1.15) III 200 0.66 (0.32-1.34) I-II 1165 0.93 (0.59-1.47) Yes 2492 0.58 (0.41-0.81) No 2136 1.36 (0.93-1.98) Yes 3269 0.74 (0.55-1.01) No 1359 1.08 (0.71-1.64) Yes 3216 0.80 (0.59-1.08) No 1412 0.95 (0.62-1.45)

Was ATHENA a CV Outcome Study That Helped the Selection of Appropriate Patient for Dronedarone? Appropriate Patient Patients with paroxysmal or persistent atrial fibrillation (AF) or atrial flutter (AFL), with a recent episode of AF/AFL and associated cardiovascular risk factors (ie, age >70, hypertension, diabetes, prior cerebrovascular accident, left atrial diameter 50 mm or left ventricular ejection fraction [LVEF] <40%), who are in sinus rhythm or who will be cardioverted Dronedarone is an antiarrhythmic drug indicated to reduce the risk of cardiovascular hospitalization If heart failure develops or worsens, consider the suspension or discontinuation of Dronedarone Advise patients to consult a physician if they develop signs and symptoms of heart failure, such as weight gain, dependent edema, or increasing shortness of breath Inappropriate Patient Patients with NYHA class IV heart failure NYHA class II III heart failure with recent decompensation requiring hospitalization or referral to a specialized heart failure clinic This unstable population above corresponds to the population of the ANDROMEDA trial, in which patients receiving Dronedarone had a greater than 2-fold increase in mortality compared to placebo NYHA = New York Heart Association. MULTAQ [package insert], sanofi-aventis US LLC: 2009.

Post-Hoc ATHENA: Cardiovascular Hospitalization or Death in Permanent AF HR=0.67 p=0.069 On Treatment 17

PALLAS Permanent Atrial fibrillation outcome Study DRONEDARONE Screen Permanent AF 6m + CV risk No NYHA unstable III or IV NYHA CHF R 2 years, recruitment; 12 m min FU common end-date 10,800 patients; 844 events 90% power for 20% RRR and 2 sided alpha of 5% PLACEBO 1 0 Outcomes 1 st Co-primary (Stroke/MI/SEE/CV Death) 2 nd Co-primary (All Death/Unplanned CV Hospitalization) Dronedarone (n = 1619) (n = 1617) Dronedarone vs Events %/yr Events %/yr HR 95% CI P value 43 8.2 19 3.6 2.29 127 25.3 67 12.9 1.95 1.34-3.94 1.45-2.62 0.002 <0.001 Connolly S. et al. N Engl J Med. 2011 Nov 14. [Epub ahead of print]

PALLAS Trial: Baseline Demographics Patients with paroxysmal or persistent AF excluded Characteristic Dronedarone (N=1619) (N=1617) CAD 40.8% 41.2% Symptomatic HF 14.4% 14.8% LVEF 40% 21.3% 20.7% Previous Stroke or TIA 26.9% 28.3% PAD 11.6% 13.2% Age 75 + HTN and DM 18.2% 17.1% Permanent AF >2 years 69.1% 69.5% HF 68.4% 66.9% Class I 14.5% 12.9% Class II 45.2% 46.3% Class III 8.7% 7.7% Connolly, SJ et al. Dronedarone in high-risk permanent atrial fibrillation. N Engl J Med. 2011; DOI: 10.1056/NEJMoa1109867. Published Nov 14, 2011. Accessed Nov 15, 2011.

Rate per 100 Patient-Years PALLAS Trial: Dronedarone in Permanent AF PALLAS enrolled 3236 patients 65 years with >6 month history of permanent AF and risk factors for major vascular events. The study was stopped for safety reasons. 30 P<.001 Dronedarone P<.001 25 25.3 23.2 20 15 P =.002 12.9 P =.02 10 8.2 P =.049 P =.02 8.3 10.7 5 0 3.6 Stroke, MI, Systemic Embolism, or CVD Death or Unplanned CV Hospitalization 4.7 4.4 2.4 1.9 4.6 Death Stroke Hospitalization for HF Connolly, SJ et al.. N Engl J Med. 2011 HF Episode or Hospitalization

ATHENA (Overall) vs PALLAS Risk Factors PALLAS Risk Factors ATHENA (Overall) Dronedarone n = 2301 % n = 2327 % Dronedarone (n = 1619) % PALLAS (n = 1617) % CAD 28.7 31.3 40.9 41.2 Prior Stroke/TIA 7.3 7.1 26.9 28.3 Symptomatic HF - - 14.4 14.8 LVEF < 40% 4.2 4.7 21.3 20.7 Peripheral Arterial Disease Age > 75 with HTN & Diabetes - - 11.6 13.2 2.1 2.7 18.2 17.1 Hohnloser SH, et al. N Engl J Med. 2009;360:668-78 Connolly S. et al. N Engl J Med 2011 Dec 15;365(24):2268-76

Baseline characteristics Events Patient Populations and Outcomes in ATHENA, ANDROMEDA and PALLAS ATHENA PALLAS ANDROMEDA Type of AF Non-Permanent AF (75% in sinus rhythm at baseline) Permanent AF Not an AF Study (patients hospitalized for moderate to severe CHF) CHF Status (dronedarone arm) No CHF = 70.8% CHF I II = 25.2% CHF III = 4.3% No CHF = 30.9% CHF I II = 60.9% CHF III = 8.2% No CHF = 0% CHF I II = 42.3% CHF III IV =57.7% All deaths (D vs P) Stroke Outcome (D vs P) CHF Hospitalizations (D vs P) 5% vs 6% 1% vs 0.44% 8.1% vs 3.8% 1.2% vs.1.8% 1.1% vs 0.44% 1.3% v. 0.9%* 4.9% vs 5.7% 7.3% vs. 3.2% 9.8% v. 12.6% * 4 in D group vs 3 in P group

Reporting rate ( Nb of cases per 1000 patient-years**) Dronedarone Post-marketing Safety: What is Role of Post-Marketing Data? 20 15 CCSI v3: liver failure added CCSI v5: ILD added PALLAS prematurate termination CCSI v6 10 5 0 1 July 2009 / 31 Jan. 2010 1 Feb. 2010 / 31 July 2010 PSUR=Periodic Safety Update Report (Number of patients exposure per PSUR period) 1 Aug. 2010 / 31 Jan. 2011 1 Feb. 2011 / 31 July 2011 1 Aug. 2011 / 31 Jan. 2012 CCSI=Company Core Safety Information ILD=Interstitial Lung Disease 1 Feb. 2012 / 31 July 2012 * SOC: System Organ Class **Exposure: patient- years calculation = (Nb tablets sold/ daily dose (2 tablets) / 365 days a year ***CSI: Company Safety Information HCP=Healthcare professional

Dronedarone AF Development Program: Lessons Learned Better dose ranging needed Patient selection important: SHD, CHF, Permanent AF Readjust further trials based on issues from early trials after discussion with FDA Clinical endpoints more important than surrogate endpoints Studies can be designed to assess CV safety as part of PI indication Some long-term safety can be assessed by keeping patients on study drug after trial is complete and there is a role for post-marketing studies

Summary Slide: Dronedarone What Was The CV Safety Issue Leading to Outcome Study Requirement Weight of Evidence Increased mortality in patients with NYHA class II III heart failure with recent decompensation Doubling of mortality in this population Presence of a Likely MOA for Risk Benefit:Risk Relationship for Drug? Is perceived risk: Generalizable to Other Drugs in Class or with Same Efficacy MOA? Lesions Learned Negative inotropy? No evidence of worsened mortality in ATHENA when above patients excluded from study Possible similar explanation to worsened mortality with amiodarone in SCD-HeFT in NYHA class III With antiarrhythmic drugs, patients populations matter for CV drug safety