1. 1 Tedisamil for Conversion of Atrial Fibrillation Thomas A. Marciniak, M.D. Division of Cardiovascular and Renal Products U.S. Food & Drug Administration

2. 2 Fundamental question: Not whether tedisamil works, BUT Is the benefit/risk tradeoff favorable enough to justify approval?

3. 3 Fundamental benefit question: What is the NET benefit? Issue: Most recent onset afib converts spontaneously (although not in the first 1-2 hours.)

4. 4 Spontaneous conversion rates in the medical literature Annals Int Med ‘03:0-76% The Lancet ‘06:20% @ 3h (onset < 48h)60% @ 24h 80% @ 48h JACC ’03:35-64% @ 24h (onset <48h-7d – meta-analysis of amiodarone studies)

5. 5 Success rates @24h for onset ≤ 48h studynplacebo dose 0.160.240.320.480.64 10714028%17% 11210934%21%32%25% 1148455%1%20%5% 11610242%11%3% 1175526%34% 1183639%11%

6. 6 Success rates @24h for onset > 48h studynplacebo dose 0.160.240.320.480.64 10720% 112954%6%26%43% 1141150%4%15%16% 1162171%4%13% 117410%4% 1181000%6%

7. 7 Success rates @24h by gender studysexplacebo dose 0.320.480.64 107F25%7%10% M31%19%21% 112F13%8%-1%16% M23%8%28%36%

8. 8 Success rates @24h for flutter studyplacebo dose 0.160.240.320.480.64 %p%p%p%p%p 1070%9%0.37%0.3 11222%-11%0.53%0.928%0.3 11417%8%0.717%0.5-4%0.8 11623%10%0.68%0.7 11725%- 25% 0.08 11838%- 38% 0.04 *

9. 9 What is the NET benefit? For atrial fibrillation: –In men, 20-30% with onset ≤ 48h –10-20% with onset > 48h –Less in women For atrial flutter –No clear evidence of benefit

10. 10 Fundamental safety questions: What is the impact of the pro- arrhythmic effects? Are there any other safety concerns?

11. 11 One death temporally associated with tedisamil: … an Asian female, aged 80, with AFib… died of an AE of AFib, cardiac arrest, electromechanical dissociation and hypotension NOS. According to the investigator’s judgment the events were found to be unrelated to the drug treatment. The subject had a history of coronary artery disease NOS and age indeterminate myocardial infarction and essential hypertension. Ten minutes after the initiation of infusion, the subject experienced bradycardia, asystole and low blood pressure and the infusion was stopped. During the infusion a wide QRS complex occurred. The subject underwent cardiopulmonary resuscitation and was intubated… [and never recovered.]

12. 12 Ventricular tachycardia, fibrillation, or arrest on day 1 dose FM subjects% % placebo2392.9%2315.6% 0.1610.0%660.0% 0.241223.3%60.0% 0.322253.1%1727.6% 0.32-0.48728.6%1010.0% 0.48348.8%20711.1% 0.48-0.7240.0%1520.0% 0.641020.0%5223.1%

13. 13 Bradycardia and hypotension on day 1 dose FMBoth No BBBBNo BBBBNo BBBB 00% 0.160% 0.240% 0.320%1%0% 0.32-0.480%20%0% 8% 0.480% 1%0%1%0% 0.48-0.720%33%0%11%0%17% 0.640% 5%0%5%

14. 14 Thromboembolic events within 2 weeks doseFMBoth 00.8%0.4%0.6% 0.160.0%1.5% 0.241.6%0.0%1.6% 0.323.6%1.2%2.5% 0.32-0.480.0% 0.480.0%1.0%0.8% 0.48-0.720.0% 0.6410.0%5.8%6.5%

15. 15 There could be mechanisms for delayed thromboembolism: Antonelli et al., Am J Card ’99: We studied left atrial function in 55 patients undergoing electrical (n = 23) or chemical (intravenous administration of propafenone, n = 32) attempts at cardioversion from atrial fibrillation. Chemical attempts at cardioversion revealed a significant increase in spontaneous echo contrast and a significant decrease in left atrial appendage Doppler flow, even in patients who did not have successful conversion to sinus rhythm.

16. 16 Dosing

17. 17 Safety concerns With widespread use if approved: There will be deaths from ventricular arrhythmias. There will be deaths from bradycardia and hypotension. Is there an increased thromboembolic risk? What will happen to safety in real world use, particularly considering the complex dosing?

18. 18 Benefit/Risk?