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 BackgroundBackground: Jon Villaume, PhD, Sanofi-Synthelabo PharmacokineticsPharmacokinetics: Jim Oppermann, PhD, Sanofi-Synthelabo ECG studiesECG studies: Wocjiech Zareba, MD, PhD, University of Rochester ConclusionsConclusions: 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, PhD Senior Vice President Drug Safety Evaluation Sanofi-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 Steady state is reached after a single dose Individual and mean (SD) trough levels observed over 5 days of repeated administration (10 mg OD)

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 Dose: 10 mg C max (ng/mL) Mean (S.D.) AUC 0-24 (ng.h/mL) Mean (S.D.) C trough (ng/mL) Mean (S.D.) Single dose (N=58)13.5 (6.8)172 (79)3.5 (2.0) Repeated dose (N=42)13.6 (5.6)194 (75)3.2 (1.6) Ratio Estimate Repeated vs single dose [90% CI] 1.03 [ ] 1.15 [ ] 0.97 [ ] 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 14 C 1 hour after oral administration of 14 C-alfuzosin in man Alfuzosin is the major circulating compound. Major metabolites are glucuronide conjugates. Glucuronides of Alfuzosin & O-Desmethyl Alfuzosin Alfuzosin 0.0 min50.0 min

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

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 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  C max x 2.3 :  AUC X 3 Time (hours) Alfuzosin concentration (ng/mL) LOQ Alfuzosin alone Alfuzosin + ketoconazole Mean ± SD

27 Factors that Increase Exposure to Alfuzosin Alfuzosin: Special Populations/Interaction Fold-increase Repeated dose vs. single dose With Ketoconazole 400 mg Moderate Severe Hepatic impairment Renal impairment Age > 75 yrs C max AUC With Diltiazem Dose 40 mg

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

29 Predicted C max 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 Trials Methods and Results Wojciech Zareba, MD, PhD Associate Professor of Cardiology University of Rochester, Rochester, NY

32 Alfuzosin ECG Trials Overview Heart rate increase and impact on QT interval assessment Holter Bin Method Study designs Results

33 Heart Rate Changes with Alfuzosin Alfuzosin 10 mg Alfuzosin 40 mg Moxifloxacin 400 mg  HR (bpm) Mean* Subjects with  HR >15 bpm 7%33%9% *HR differences vs. placebo – Study 5105

34 Methods for QT Interval Correction Traditional QT correction formulae Bazett QTcB (QTcB = QT/RR 1/2 ) Fridericia QTcF (QTcF = QT/RR 1/3 ) Study-population based QTcN: regression modeling (QTcN = QT/RR B ) Individual subject-specific QTcNi: regression modeling (QTcNi = QT/RR Bi )

35 Heart Rate QT (msec) QTcB (msec) QTcF (msec) QTcNi (msec) 60 (bpm) (bpm) (bpm) QT Correction for Changing Heart Rate Typical subject in study 5105 (QTcNi=QT/RR 0.24 ) 24 ms over-correction

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

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

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 Holter Bin Method Individual QT/RR Relationship QT (msec) Placebo QT = Ai*RR Bi Drug QT 800 QT 1000 QT 1200 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 – Results Study 4532 – Results Holter Bin Method Treatment QT 1000 change from placebo (msec) 95% CIp Alfuzosin 10 mg ; Alfuzosin 20 mg ; Alfuzosin 40 mg ;

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 QT 1000 –Change in QT at RR bin with the largest number 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 (QT 800, …, QT 1200 )

47 Holter Bin Method Time Window Time (hours) Alfuzosin concentration (ng/mL) Moxifloxacin concentration (ng/mL) Alfuzosin 10 mg Alfuzosin 40 mg Moxifloxacin 400 mg Holter Period

48 Power Considerations More than 80% power to detect a moxifloxacin  QTcB as small as 5 msec (to confirm assay sensitivity) Needs N=45 subjects Provides more than 80% power to detect a 3 msec  QT 1000 for 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 Endpoint Difference vs. placebo (msec) 95% CIp HolterQT ; IndividualQTcNi ; PopulationQTcN ; Traditional QTcF ; QTcB ; Heart Rate  HR 1.5 bpm >15 bpm9%

51 Alfuzosin 10 mg Results Endpoint Difference vs. placebo (msec) 95% CIp HolterQT ; IndividualQTcNi ; PopulationQTcN ; Traditional QTcF ; QTcB ; Heart Rate  HR 1.5 bpm >15 bpm7%

52 Alfuzosin 40 mg Results Endpoint Difference vs. placebo (msec) 95% CIp HolterQT ; IndividualQTcNi ; PopulationQTcN ; Traditional QTcF ; QTcB ; Heart Rate  HR 3.7 bpm >15 bpm33%

53 Holter Endpoints  QT (msec) Mean difference vs. placebo

54 QT Changes at Various RR Intervals RR (msec)  QT (msec) HR (bpm)

55 Study 5105 – ECG Outliers No subject with QTcF, QTcN or QTcNi >450 msec or change >60 msec 7 subjects with QTcB >450 msec –2 placebo, 1 alfuzosin 10 mg, 3 alfuzosin 40 mg, 1 moxifloxacin –maximum 458 msec 4 subjects with  QTcB >60 msec –1 alfuzosin 10 mg, 3 alfuzosin 40 mg Alfuzosin outlier values are associated with a substantial HR increase vs. baseline

56 Delta QTcNi at the Highest Concentrations Concentration (ng/mL) _ Delta QTcNi (msec) Placebo Alfuzosin 10mg Alfuzosin 40mg n= 1470 Slope = Intercept = … …...

57 Study 5105 using Holter Bin approach had the required assay sensitivity. With therapeutic dose of moxifloxacin 400 mg: Holter Bin Method documented a 7 msec increase in QT QTc correction methods resulted in 9-12 msec increase. Study 5105: Summary Assay Sensitivity

58 Study 5105: Summary Alfuzosin Results At therapeutic dose of 10 mg, alfuzosin did not produce significant changes in QT At 4 times the therapeutic dose, alfuzosin produced a mean QT 1000 change of 2.9 msec, less than half what is observed with moxifloxacin administered at therapeutic dose. Whatever the dose, no clinically relevant QT/QTc changes were observed.

59 Summary and Conclusions Jeremy Ruskin, M.D. Director, Cardiac Arrhythmia Service Massachussetts General Hospital

60 Outline Limitations of Correction Formulae Adequacy of Study 5105 Study Design Results of ECG Studies Pharmacovigilance Safety Margin Conclusions

61 Limitations of Correction Formulae N=495 observations slope = Int.= N=495 observations slope = Int.= N=495 observations slope = Int.= N=495 observations slope = Int.= RR(msec) QTcB (msec) QTcN (msec) QTcNi (msec) QTcF (msec)

62 Holter Bin Method Avoids need for heart rate correction Correlates closely with QTcNi Limited experience in drug trials

63 Adequacy of Study Design Four-fold dose range Exposures exceeded those seen with maximum metabolic inhibition or in patients with renal impairment Moxifloxacin control for assay sensitivity Internal validation of Holter Bin Method

64 Fold Increase in Exposure Fold increase

65 Study 5105 QT/QTc Results Method Alfuzosin 10 mg (msec) Alfuzosin 40 mg (msec) Moxifloxacin 400 mg (msec) QT 1000 Holter Bin QTcNi QTcN

66 Changes in QT 1000 msec

67 Outlier Analysis No outliers (QTc >450 msec or  QTc >60 msec) with any correction method except Bazett All QTcB outliers occurred in association with significant increases in HR No outliers (QTc >500 msec) in any study with any method No QT/QTc greater than 440 msec by any correction method in subjects with concentrations > 5x therapeutic

68 Post Marketing Experience No report of torsades de pointe in over 1.35 billion estimated therapy days (estimated 3.7 million patient years)

69 Comparison of Inhibition of HERG Potassium Currents by Various Drugs Drug

70 Comparison of Therapeutic Concentrations and HERG IC 50 ng/ml

71 ng/ml Comparison of Therapeutic Concentrations and HERG IC 50

72 Terfenadine Change in QTcB msec non-peak

73 Conclusions: QT Interval Effects of Alfuzosin Well characterized Small (<5 msec) effect size Approximately half the effect of moxifloxacin No outliers No torsades de pointe