1. 1 Food and Drug Administration Cardiovascular and Renal Drugs Advisory Committee Levitra® Tablets (NDA 21-400) (vardenafil HCl) May 29, 2003

2. 2 Introduction Mary E. Taylor, MPH Bayer Pharmaceuticals Corporation Vice President, Regulatory Affairs North America

3. 3 Agenda

4. 4 Consultants

5. 5 Levitra® Tablets (vardenafil HCl)  Proposed Indication: Levitra is indicated for the treatment of erectile dysfunction defined as the consistent or recurrent inability to attain and/or maintain a penile erection sufficient for sexual performance.  Dosage and Administration: 5, 10, 20 mg (starting dose 10 mg) may be titrated up or down

6. 6 Regulatory History  NDA submitted September 2001  Approvable letter received July 23, 2002  Application is currently under review  Approved in 34 countries including the UK, Germany, and 13 other EU countries; Australia; New Zealand; and several Latin American countries

7. 7 Timeline 199819992000200120022003 12/97 EU Guidance 3/01 Health Canada 11/02 FDA Concept Paper 2/02 ICH Safety Pharmacology QT Interval Regulatory Activities Phase III 3/03 European Launch 7/02 Approvable Action 5/03 Advisory Committee 9/01 Levitra NDA Submitted Vardenafil Development

8. 8 Cardiovascular & Renal Drugs Advisory Committee Topics  Clinical trial design for the assessment of QT/QTc prolongation  Approaches to the correction of the QT interval for drugs that affect heart rate  The risk of cardiac arrhythmia associated with different degrees of QT/QTc prolongation

9. 9 Assessment of the QT/QTc Effect of Vardenafil Thomas P. Segerson, MD Vice President Medical and Scientific Affairs Bayer Canada

10. 10 Agenda  Background information on vardenafil  Pharmacology and mechanism of action  Efficacy and adverse event profile  Human pharmacokinetics  Vardenafil data relevant to QT/QTc assessment  Preclinical effects  Clinical pharmacology  Phase III clinical studies  Study to rigorously evaluate the QT/QTc effect of vardenafil

11. 11 Vardenafil: Pharmacology and Mechanism of Action  Vardenafil is a potent PDE5 (phosphodiesterase type 5) inhibitor (IC 50 ~1 nM).  Vardenafil is highly specific for the type 5 PDE isoenzyme, inhibition of which leads to cyclic guanosine monophosphate (cGMP) accumulation and corpus cavernosum smooth muscle relaxation.  Transient effects of vardenafil on BP and HR are consistent with the distribution of PDEs in vascular tissue.

12. 12 Vardenafil Efficacy Data in General and ‘Resistant to Treatment’ ED Populations † International Index of Erectile Function Mean EF Domain † Score Change NA Pivotal Study 100249 Treatment Group 8.2 7.4 5.2 1.8 0 2 4 6 8 Placebo5 mg10 mg20 mg * * * 7.8 5.9 1.4 0 2 4 6 8 Placebo10 mg20 mg * * * p <0.01 vs placebo Diabetes Study 100250

13. 13 Frequent Adverse Events* in Placebo- Controlled Phase III Trials *  2% and more frequent with vardenafil than placebo

14. 14 Concentration at 24h 1 - 2% C max Pharmacokinetic Profile of Vardenafil after Single 20 mg Oral Dose in Men Elimination: Hepatic 91-95% Renal 2-6% Study 10118, n = 24 mean

15. 15 Human Pharmacokinetics of Vardenafil and Metabolites Peak concentration of metabolites  50% of vardenafil M1-glucuronide M1 M4M5 14 C study (10079), n=4 M1, M4 and M5 are deethylation/ demethylation products of vardenafil metabolism vardenafil

16. 16 Pharmacokinetic Interaction of Vardenafil with Ritonavir vardenafil 5mg vardenafil 5mg & ritonavir* vardenafil 80mg *interaction assessed on 10th day of ritonavir 600 mg BID dosing C max ( ng/ml) Study 100535

17. 17  In vitro evaluation showed an IC 50 of 30  M for vardenafil, and 47  M for sildenafil for inhibition of hERG potassium channel, at least 1000-fold above free concentration after maximum clinical dose*  No QTc prolongation found in vivo in Beagle dogs:  preclinical model as per guideline  pattern of vardenafil metabolites similar to human  safety pharmacology studies up to 10 mg/kg in anesthetized and conscious Beagle dogs  Tested concentrations 100-fold greater than the human exposure (Cmax) to vardenafil after 20 mg and 10-fold greater than exposure to M1 and M4 metabolites Preclinical QT Data *Sildenafil 100 mg (NDA #20-885 SBA), Vardenafil 20 mg (Study 100196)

18. 18 ECG Evaluation in Vardenafil NDA Clinical Pharmacology Program  Paired ECGs were obtained in 6 placebo-controlled studies as part of standard safety assessment of doses up to 80 mg  These studies were not designed specifically to detect a QT/QTc effect  Equivocal changes on QT/QTc were observed with no obvious dose relationship

19. 19 Incidence of Clinical Adverse Events Which May be a Potential Signal for Ventricular Arrhythmia in Placebo-Controlled Phase III Studies No events of TdP reported in clinical trials with vardenafil

20. 20 All Cause Mortality in Clinical Trials Nine deaths in patients before receiving study treatment Seven deaths in completed phase II/III studies*  1 of 1351 on placebo (0.07%)  1 of 164 on sildenafil (0.61%)  4 of 4814 on vardenafil (0.08%)  1 randomized to vardenafil but did not take drug No deaths on vardenafil were assessed as being related to vardenafil treatment. *As of January 2003

21. 21 Study 10929/011: Effect of Vardenafil on QT/QTc Interval  Goal of study to define effects of vardenafil on QT/QTc interval:  At therapeutic doses  At supratherapeutic doses  At plasma concentrations following maximal potential interaction with CYP 3A4 inhibitors  Study design discussed and agreed with FDA  Performed by Clinical Pharmacology and Statistics, GSK Pharmaceuticals

22. 22 Study 10929/011: Objectives and Design Primary Objective: Exclude a greater than 10 msec change from baseline 1-hour post-dose on QTcF interval compared to placebo after vardenafil 80 mg Secondary Objectives: change from baseline of QT/QTc versus placebo at T max maximal change from baseline of QT/QTc versus placebo over 4 hr Design : Six-way crossover, single-dose, placebo-controlled study. D oses evaluated, period of evaluation, positive control, statistical analysis all agreed with FDA. Treatments: Vardenafil 80 mg Vardenafil 10 mg Moxifloxacin 400 mg Sildenafil 400 mg Sildenafil 50 mg Placebo

23. 23 Study 10929/011 Methodology  59 healthy subjects, age range 45-60 years  QT interval determined by a validated central laboratory blinded to treatment; manual digital measurements of 3 beat average in Lead II  End of T-wave identified by return to baseline (or, if not possible, tangent method)  Subjects were non-ambulatory, supine, fasting

24. 24 Study 10929/011 Procedures Time (h) Dose Baseline Study 10929/011 6 ECGs at each timepoint one minute apart

25. 25 QTraw, HR, and QTcF Mean Change from Baseline (SE) 1 hour after Placebo Study 10929/011; n=58

26. 26 Placebo-Subtracted Mean Change from Baseline (90% CI) for QTraw, HR and QTcF at 1 Hour Study 10929/011; n=58

27. 27 Individually Corrected QT: QTci  Alternative to fixed approach to heart rate correction (Fridericia, Bazett)  Correction based on each subject’s RR-QT relationship  Based on placebo and baseline data (n = 138 per subject)  Two approaches  Linear relationship, QTci = QT + slope(1-RR)  Non-linear relationship, QTciX = QT/(RR) x  Same analyses performed as for QTcF Study 10929/011

28. 28 Placebo-Subtracted Mean Change from Baseline for QTcF and QTci* at 1 hour (Point Estimates of Treatment Effect and 90% CI ) vardenafil 80 mg 10 mg sildenafil 400 mg 50 mg moxifloxacin 400 mg QTcF (msec)QTci (msec) Study 10929/011; n=58 * linear relationship

29. 29 Placebo-Subtracted Mean Change from Baseline for QTcF and QTci* (msec) at 1 Hour Post-Dose Study 10929/011; n=58 * linear relationship

30. 30 Placebo-Subtracted Mean Change from Baseline for QTcF at 1 Hour, T max, and Maximum QTcF Study 10929/011; n=58

31. 31  No QTraw value  500 msec  No QTcF value  450 msec  No change in QTcF  60 msec  Only one subject (sildenafil 400 mg) with mean QTcF change  30 msec at any time point (average of 6 ECGs) QT/QTc Outlier Analysis Study 10929/011; n=59

32. 32 Observed & Population Predicted QTcF versus Vardenafil Plasma Concentration

33. 33 Summary  In clinical trials, vardenafil has been shown to be safe and effective for the treatment of erectile dysfunction in men.  Preclinical studies with vardenafil do not predict QT/QTc prolongation or arrhythmia at clinically relevant concentrations.  In the clinical development program, there was no evidence of TdP.

34. 34 Summary (continued)  A QT/QTc study of vardenafil 10 and 80 mg conducted in accordance with current regulatory guidance demonstrated a 4-10 msec mean maximum QTc prolongation.  Vardenafil shortened uncorrected QT duration compared to placebo, whereas moxifloxacin lengthened it.  Vardenafil concentrations achieved cover the range following strong metabolic inhibition.  The relationship between corrected QT values and vardenafil doses/concentrations is very shallow (2 msec increment with 8-fold increase in dose).  Vardenafil effect on the QT/QTc interval is similar to that of sildenafil, an approved drug in the same class.

35. 35 QT/QTc Study Design, Heart Rate Correction & Risk of Cardiac Arrhythmia Joel Morganroth, MD Clinical Professor of Medicine University of Pennsylvania Chief Scientist eResearchTechnology

36. 36 Agenda  QT/QTc study design issues  QT correction factor analysis  Clinical relevance of 5 to 10 msec QTc effect

37. 37 FDA-Health Canada Preliminary Concept Paper: November 2002 The document recommends:  Robust and valid determination of cardiac risk (QT/QTc duration) using a validated ECG laboratory with specific design recommendations  All bioactive compounds should undergo a “definitive” Phase I QT/QTc assessment

38. 38 What are the design issues in a “definitive” Phase I QT/QTc trial that should be considered in light of the marked spontaneous variability in QTc duration?

39. 39 Managing Sources of QTc Variability  Sample size: usually need >30 per arm to detect small QTc effect with adequate power [used 59]  Frequency of baseline and on-therapy ECGs to cover maximum concentration of parent and metabolites; diurnal variation [n=18 at baseline and 30 on each therapy at the same time of day]  ECG measurement precision: digital process with manual method in a validated core ECG laboratory [done]  Population: male and female volunteers [all men due to therapeutic use; age 45-60 yrs]  Conditions of the ECG recording (e.g., subjects resting, supine, ECG taken before blood sampling) [done]

40. 40 Other Aspects of QT/QTc Trial Design  Dose ranging (at least 2 doses, one of which is an appropriate multiple of the recommended dose) - no need to study metabolic inhibitors if supratherapeutic dose meets theoretical maximum exposure  [1x and 8x recommended starting clinical dose]  Control groups: placebo (interpret spontaneous variability) and positive (assay sensitivity)  [both done]  Correction of QT (Fridericia, population, individual, Bazett)  [Fridericia and individual reported]  Statistical plan: placebo-corrected, central tendency and outlier analyses  [all done]

41. 41 Drug-Specific Factors to Consider in the Design of a QT/QTc Study  Pharmacokinetics  to ensure observation period covers C max of parent and metabolites [4-hour sampling appropriate]  to ensure no carryover effects in a crossover trial [PK of parent and metabolites appropriate for crossover]  Therapeutic use  single- vs multiple-dose study [single-dose trial appropriate]  Heart rate effects of drug  consider special procedures for heart rate correction when drug increases heart rate [QTci analysis done]

42. 42 “The traditionally used Bazett’s formula for correction of the measured QT interval for variations in heart rates (QTc = QT/RR 0.50 ) has limitations for drugs that significantly increase the heart rate.” “Although none of the 30 or so formulae available is entirely satisfactory, the Fridericia correction (QTc =QT/RR 0.33 ), or preferably a study-specific derived formula (QTc =QT/RR x ), may be more appropriate.” Shah Fundamental & Clinical Pharmacology (2002) 16: 147–156. What Correction Formula Should be Used to Derive QTc from Heart Rate and QT?

43. 43 Which Correction Formula Should be Used to Derive QTc from Heart Rate and QT?  FDA-Health Canada concept paper, November 2002:  “...heart rate corrections using individual patient data have been proposed, applying regression analysis techniques to obtain individual pretherapy QT/RR interval data over a range of heart rates, then looking for a change in regression line with treatment.”  Practical limitations of this approach:  heart rate range at baseline  Need for 50-100 ECGs off therapy [combine baselines and placebo in crossover trials]

44. 44 Placebo-Subtracted Mean Change from Baseline for QTcF and QTci* at 1 hour (Point Estimates of Treatment Effect and 90% CI ) vardenafil 80 mg 10 mg sildenafil 400 mg 50 mg moxifloxacin 400 mg QTcF (msec)QTci (msec) Study 10929/011; n=58 * linear relationship

45. 45 Placebo-Subtracted Mean Change from Baseline for QTc (msec) at 1 hr Post-Dose Study 10929/011;n=58

46. 46 Population QTc vs HR: Bazett’s and Fredericia Note: data plotted is baseline and placebo data only

47. 47 Population QTc vs HR: Fredericia and Individual Note: data plotted is baseline and placebo data only

48. 48 Individual QTc vs HR relationships: Fridericia and Individual Note: Data represents fitted linear relationship for baseline and placebo data only

49. 49 Individual QTci.2 vs HR Relationships N = 59 Patients  Analysis conducted by FDA biostatistician  Individual correction (linear) based on baseline data only (n = 108 vs. 138 ECGs)  QTci.2/HR relationship: applied to both baseline and placebo data  Thus, “The more data used the better the QTci”

50. 50 QTc Statistical Reporting Issues  Central tendency  Mean change  Mean maximal change  Categorical analysis looking for outliers  % of patients (not observations) with:  a change from baseline of 30-60 msec (sensitive) and  60 msec (specific)  new value  500 msec  new abnormal T-U waves

51. 51 Number of ECGs with Changes from Baseline 30-60 msec in QTci

52. 52 Results of the Vardenafil QT/QTc Study I consider the trial to be valid and the results reliable  Placebo and the positive control, moxifloxacin, behaved as anticipated in the study  placebo = 0 msec; moxifloxacin = 8 msec  Vardenafil 10 and 80 mg produced 4 -10 msec change from baseline at 1 hr and at T max, using QTcF or QTci  Shallow dose response (8x starting dose)

53. 53 Results of the Vardenafil QT/QTc Study (cont’d)  QT/QTc effects comparable to sildenafil  Vardenafil and sildenafil shortened uncorrected QT duration compared to placebo, whereas moxifloxacin lengthened it  Outliers  None  60 msec  No new > 500 msec  No subjects on vardenafil and only 1 subject in sildenafil group with > 30 msec change

54. 54 Clinical Relevance of a Drug-Induced QT/QTc Effect: Risk Assessment  Experience with other compounds  terfenadine, cisapride, ziprasadone...  moxifloxacin  Post-marketing surveillance data  moxifloxacin PMS data  sildenafil PMS data (similar QT/QTc effect and same therapeutic class)  Regulatory opinions  FDA-Health Canada concept paper  Medicines Control Agency (EMEA/CPMP)

55. 55 Terfenadine  Mean change in QTc across the 12-hour dosing interval a : 6 msec  Mean change in QTc at T max (mean maximum change) a : 18 msec  Mean change in the presence of a metabolic inhibitor (ketoconazole) b : up to 82 msec a Morganroth, et al., Am J Cardiol 72:26B-32B, 1993 b Honig, et al., JAMA 269: 1513-1518, 1993

56. 56 Moxifloxacin  hERG channel blockade at concentrations approaching clinical concentrations  Mean maximum QTc effect = 6-10 msec increase (400 mg PO) and a doubling of the effect with 800 mg PO  Minimal effect on heart rate  Prolongs both QT and QTc

57. 57 Two post-marketing observational studies (n ~ 55,000)  No cases of Torsades de Pointes  No signal of cardiac arrhythmia or a QT interval prolongation-related cardiac rhythm disorder Moxifloxacin Cardiac Safety: Post-Marketing Surveillance

58. 58 Moxifloxacin Spontaneous Reports of Torsades de Pointes as of May 7, 2003 Moxifloxacin (19 million patients; 8-day average prescription; 416,000 patient-years): N=12 TdP Oral: 4 US, 4 Europe IV: 3 US and 1 Europe All 12 cases showed marked confounders except 2 oral (1 with no clinical data) Rate of TdP on oral moxifloxacin in US 4 per 7.7 million patients Comparable to other antibiotics (Brinker FDA)

59. 59 Sildenafil FDA AERS Data Torsades de Pointes: No cases reported a from launch to December 15, 2002 (data lock) Usage: b 38.7 million sildenafil prescriptions written worldwide from April 1998 to December 2002 a Spontaneous reports from FDA Adverse Event Reporting System database b Usage data from IMS

60. 60 What Does a 5 to 10 msec QTc Increase Mean?  FDA concept paper notes importance of magnitude of mean maximal QT/QTc effect: < 5 msecno TdP 5 - 10 msecno clear risk 10 - 20 msecsome concern > 20 msecsubstantially increased likelihood of being proarrhythmic  QT is a surrogate. There is good evidence (dofetilide, sotalol, terfenadine) that the size of the effect relates to risk of TdP, but there could be other properties that mitigate or enhance risk. - Robert Temple, January 2003, Shady Grove Meeting

61. 61 Additional Considerations in the Assessment of the Clinical Relevance of Vardenafil’s QTc Effect  The drug is indicated for use in males (risk of drug- induced TdP lower in males)  Single dose, used intermittently  Shallow dose response for QTc effects  Vardenafil tends to increase heart rate

62. 62 Conclusions: About Vardenafil  In a definitive QT/QTc trial, vardenafil and sildenafil showed comparable maximum QTci effects on cardiac repolarization of about 5 msec over an 8x dose range  This magnitude is generally considered by regulatory authorities as not associated with TdP  No clinically significant outliers with vardenafil  Post-marketing surveillance data for sildenafil provides no reports of TdP  Thus, the QTc effect of vardenafil should not pose a cardiac safety concern

63. 63