ECG Studies Assessing Alfuzosin HCl Cardiac Repolarization Potential

1. ECG Studies Assessing Alfuzosin HCl Cardiac Repolarization Potential Alfuzosin: alpha-1 blocker for benign prostatic hyperplasia developed by Sanofi-Synthelabo Research

2. Focus • Studies employing a sensitive assay were adequate to assess a cardiac repolarization effect. • They detected a small alfuzosin QT increase of 2-3 msec at 4 times therapeutic dose. • This small increase is not clinically significant as confirmed by substantial clinical experience.

3. Alfuzosin QT Increase is Not Clinically Significant • This increase is the maximum likely to be produced. • It is well below increase of an approved control known to produce a modest increase. • Known problem drugs produce much higher increases. • Surveillance of extensive market use produced no risk signal.

4. Alfuzosin Presentation • Background: Jon Villaume, PhD, Sanofi-Synthelabo • Pharmacokinetics: Jim Oppermann, PhD, Sanofi-Synthelabo • ECG studies: Wocjiech Zareba, MD, PhD, University of Rochester • Conclusions: Jeremy Ruskin, MD, Massachusetts General Hospital

5. External Consultants • Pierre Maison-Blanche, MD, Hôpital Lariboisiere, Paris • Craig Pratt, MD, Methodist Hospital • Claus Roehrborn, MD, University of Texas • Joel Verter, PhD, Statistics Collaborative

6. Alfuzosin Marketing History • First approved in 1987 for benign prostatic hyperplasia (BPH) • Currently approved in all of Europe, Canada and Australia

7. Clinical Study Results in NDA • Improvement in BPH symptoms and urinary flow rate • Therapeutic dose: 10 mg once daily without titration • Well tolerated with favorable safety profile

8. Comparison of Inhibition of HERG Potassium Currents by Various Drugs Drug

9. NDA Cardiac Repolarization Assessment • No clinically significant QT effect using Holter Bin Method in Study 4532 • No ventricular arrhythmia signal and no report of torsades de pointe • From clinical studies or surveillance of 3.7 million patient years of marketed use

10. NDA Approvable Letter Issues • “The QTc interval must be measured using an FDA agreed upon validated methodology.” • Study assessing interaction with maximum ketoconazole dose lacking

11. Response to Approvable Letter Issues • Plan • Study 5105: Compare single doses of 10 and 40 mg alfuzosin and moxifloxacin to placebo • Study 5056 : Assess interaction with maximum dose of ketoconazole (400 mg) • FDA agreement with plan obtained

12. Alfuzosin Pharmacokinetic Profile Jim Oppermann, PhDSenior Vice President Drug Safety EvaluationSanofi-Synthelabo Research

13. Outline • QT interval evaluation after single dose is appropriate • The 40 mg dose in the QT interval studies provided exposure exceeding that achieved in the clinical situation

14. Factors Impacting Single Dose vs. Multiple Dose ECG Designs • Time to reach steady state for alfuzosin • Exposure after single administration vs. exposures after repeated administration • Accumulation of metabolites after repeated administration

15. Time to Reach Steady State - Alfuzosin Individual and mean (SD) trough levels observed over 5 days of repeated administration (10 mg OD) Steady state is reached after a single dose

16. Factors Impacting Single Dose vs. Multiple Dose ECG Designs • Time to reach steady state for Alfuzosin • Exposure after single administration vs. exposures after repeated administration • Accumulation of metabolites after repeated administration

17. Comparison of Exposure After Single and Multiple Administration Mean ± SD

18. Comparison of Exposure after Single and Multiple Administration Mean ±SD

19. Comparison of Exposure After Single and Multiple Administration • Exposure after repeated administration is similar to single dose

20. Factors Impacting Single Dose vs. Multiple Dose ECG Designs • Time to reach steady state for Alfuzosin • Exposure after single administration vs. exposures after repeated administration • Accumulation of metabolites after repeated administration

21. Accumulation of Metabolites Profile of plasma 14C 1 hour after oral administration of 14C-alfuzosin in man Alfuzosin Glucuronides of Alfuzosin & O-Desmethyl Alfuzosin 0.0 min 50.0 min • Alfuzosin is the major circulating compound. • Major metabolites are glucuronide conjugates.

22. Accumulation of Metabolites 14C and alfuzosin plasma concentrations after administration of 14C-alfuzosin (10 mg) to three human subjects Mean ± SD • Metabolites rapidly formed and eliminated with similar half-life as alfuzosin • No accumulation of metabolites expected

23. Single Dose Design for Alfuzosin QT Evaluation is Appropriate

24. The 40 mg Dose in the QT Interval Studies Provides Exposure Exceeding That Achieved in the Clinical Situation

25. Factors that Increase Exposure to Alfuzosin • Alfuzosin elimination primarily by metabolism through CYP3A4 • Interaction with ketoconazole Study 5056 • 12 healthy male volunteers • Alfuzosin 10 mg single alone or plus ketoconazole (at Day 7 of the keto treatment period) • Ketoconazole 400 mg for 8 days

26. Alfuzosin Interaction with Ketoconazole Study 5056 With ketoconazole 400 mg •  Cmax x 2.3 :  AUC X 3 35 Alfuzosin alone 30 Alfuzosin + ketoconazole Mean ± SD 25 20 Alfuzosin concentration (ng/mL) 15 10 5 LOQ 0 0 1 2 4 6 8 10 14 24 48 Time (hours)

27. Factors that Increase Exposure to Alfuzosin Alfuzosin: Special Populations/Interaction 5 C Dose 40 mg AUC max 4 Hepatic impairment With Ketoconazole 400 mg 3 Fold-increase Repeateddosevs.singledose Renal impairment With Diltiazem Age > 75yrs 2 Moderate Severe 1 0

28. Comparison of Exposure at 40 mg Single Dose and Peak (10-14 hours) Plasma Concentration in Patients 40 mg Alfuzosin Mean ±SD 10 mg Alfuzosin N=72 N=83 N=56 Day 28 Day 56 Day 84 Study 5105 Cmax achieved after 40 mg single dose exceeds peak levels in Phase III studies

29. Predicted Cmax and AUC at Steady State in Various Populations Co-treated with Ketoconazole vs. 40 mg Single Dose

30. Conclusion • QT interval evaluation after single dose is appropriate: • Steady state is reached on Day 1 • Exposure after repeated administration is similar to single dose • Metabolites are formed rapidly and have a similar half-life as alfuzosin (formation rate limited) • The 40 mg dose in the QT interval studies provides exposure exceeding that achieved in the clinical situation

31. Alfuzosin ECG TrialsMethods and Results Wojciech Zareba, MD, PhDAssociate Professor of CardiologyUniversity of Rochester,Rochester, NY

32. Alfuzosin ECG TrialsOverview • Heart rate increase and impact on QT interval assessment • Holter Bin Method • Study designs • Results

33. Heart Rate Changes with Alfuzosin *HR differences vs. placebo – Study 5105

34. Methods for QT Interval Correction Traditional QT correction formulae Bazett QTcB (QTcB = QT/RR1/2) Fridericia QTcF (QTcF = QT/RR1/3) Study-population based QTcN: regression modeling (QTcN = QT/RRB) Individual subject-specific QTcNi:regression modeling (QTcNi = QT/RRBi)

35. QT Correction for Changing Heart Rate Typical subject in study 5105 (QTcNi=QT/RR0.24 ) 24 ms over-correction

36. Alfuzosin ECG Trials • Heart Rate increase and impact on QT interval assessment • Holter Bin Method • Study designs • Results

37. 1. RR interval measurement 995 msec 1000 msec 1005 msec 995 msec 1007 msec 1005 msec 1006 msec 2. Classification of ECG complexes into 10 ms groups « Bins » 1000 msec RR Bin 1010 msec RR Bin 3. Averaging of complexesand measurementof QT intervals QT1000 QT1010

38. Holter Bin Method • Controls rather than corrects for heart rate • Wide range of RR interval explored for each subject allowing: • Direct comparison of absolute QT at the same HR between placebo and drug (non parametric) • Development of QT / RR regression model

39. Drug QT800 QT1200 QT1000 Holter Bin MethodIndividual QT/RR Relationship QT = Ai*RRBi 460 Placebo 440 420 400 QT (msec) 380 360 340 320 700 800 900 1000 1100 1200 1300 RR (msec)

40. Alfuzosin ECG Trials • Heart Rate increase and impact on QT interval assessment • Holter Bin Method • Study designs • Results

41. Alfuzosin ECG Trials • Study 4532: included in original NDA • Study 5105: comparison of single doses of 10 and 40 mg alfuzosin and 400 mg moxifloxacin to placebo

42. Study 4532 • Single-center, randomized, double-blind, 4-way crossover study • 24 healthy male volunteers • Alfuzosin 10, 20, and 40 mg and placebo • The study included Holter recordings at: • Screening • 4 periods of single-dose administration

43. Study 4532 – ResultsHolter Bin Method

44. Study 5105: Objectives • To validate the Holter Bin Method by using both a positive control and QT corrections from 12-lead ECG recordings • To re-assess the effect of alfuzosin on QT interval using the Holter Bin Method

45. Design of Study 5105 • Single-center, randomized, double-dummy, 4-way crossover study • 45 subjects • Alfuzosin 10 and 40 mg, placebo, and moxifloxacin 400 mg (positive control) • Each period consisted of: • A run-in placebo • Followed by a single-dose administration • Washout of 5 to 9 days between successive periods 

46. Study Endpoints Primary (Holter Bin Method): • Change in QT1000 • Change in QT at RR bin with the largestnumber of complexes • Change in QT averaged over all RR bins Secondary (Standard 12-lead ECGs) • Individual based correction QTcNi • Population based correction QTcN • Traditional formulae QTcF, QTcB Exploratory (Holter Bin Method) • QT at any fixed RR bin (QT800, …, QT1200)

47. Holter Bin Method Time Window Holter Period Alfuzosin 10 mg Alfuzosin 40 mg 50 3500 Moxifloxacin 400 mg 45 3000 40 2500 35 30 2000 Alfuzosin concentration (ng/mL) Moxifloxacin concentration (ng/mL) 25 1500 20 15 1000 10 500 5 0 0 0 2 4 5 6 7 8 9 10 11 12 16 20 24 Time (hours)

48. Power Considerations • More than 80% power to detect a moxifloxacin DQTcB as small as 5 msec (to confirm assay sensitivity) • Needs N=45 subjects • Provides more than 80% power to detect a 3 msec DQT1000for any of the treatment groups

49. Alfuzosin ECG Trials • Heart rate increase and impact on QT interval assessment • Holter Bin Method • Study designs • Results

50. Moxifloxacin Results