1

Food and Drug AdministrationCardiovascular and Renal Drugs

Advisory Committee

Levitra® Tablets (NDA 21-400)(vardenafil HCl)May 29, 2003

2

Introduction

Mary E. Taylor, MPH Bayer Pharmaceuticals Corporation Vice President, Regulatory Affairs

North America

3

AgendaIntroduction Mary Taylor, MPH

Vice PresidentRegulatory Affairs North AmericaBayer Pharmaceuticals Corporation

Assessment of the QT/QTcEffect of Vardenafil

Thomas Segerson, MDVice PresidentMedical and Scientific AffairsBayer Canada

QT/QTc Study Design,Heart Rate Correction &Risk of Cardiac Arrhythmia

Joel Morganroth, MDClinical Professor of MedicineUniversity of PennsylvaniaChief ScientisteResearchTechnology

4

ConsultantsJoel Morganroth, MD Clinical Professor of Medicine

University of PennsylvaniaChief ScientisteResearchTechnology

John Camm, MD Professor of Clinical CardiologySt. George's HospitalLondon

Gerald Faich, MD Pharmaceutical Safety Assessments, Inc.

Gary Koch, PhD Professor of BiostatisticsUniversity of North Carolina

Udho Thadani, MD Professor of Medicine, Cardiovascular SectionUniversity of Oklahoma

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

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

Timeline

1998 1999 2000 2001 2002 2003

12/97 EUGuidance

3/01 HealthCanada

11/02 FDA Concept Paper

2/02 ICH SafetyPharmacology

QT Interval RegulatoryActivities

Phase III

3/03 EuropeanLaunch

7/02 Approvable Action

5/03 Advisory Committee

9/01 Levitra NDASubmitted

Vardenafil Development

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

Assessment of the QT/QTc Effect of

VardenafilThomas P. Segerson, MD

Vice PresidentMedical and Scientific Affairs

Bayer Canada

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

Vardenafil: Pharmacology and Mechanism of Action

Vardenafil is a potent PDE5 (phosphodiesterase type 5) inhibitor (IC50 ~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

Vardenafil Efficacy Data in General and ‘Resistant to Treatment’ ED Populations

†International Index of Erectile Function

Me

an

EF

Do

ma

in† S

core

Cha

nge NA Pivotal Study 100249

Treatment Group

8.27.4

5.2

1.8

0

2

4

6

8

Placebo 5 mg 10 mg 20 mg

*

**

7.8

5.9

1.4

0

2

4

6

8

Placebo 10 mg 20 mg

*

*

*p <0.01 vs placebo

Diabetes Study 100250

13

Frequent Adverse Events* in Placebo-Controlled Phase III Trials

Percentage of Patients with ReportedEvent

Adverse Event PlaceboN = 1199

(%)

VardenafilN = 2203

(%)Any Event 33 53Headache 4 15Flushing 1 11Rhinitis 3 9Dyspepsia 1 4Accidental Injury 2 3Sinusitis 1 3Flu Syndrome 2 3Dizziness 1 2Increased CK 1 2Nausea 1 2

* 2% and more frequent with vardenafil than placebo

14

Time (hrs)

0 6 12 18 24

vard

en

afil

co

nce

ntr

atio

n (

ng

/ml)

0

5

10

15

20

Concentration at 24h1 - 2% Cmax

Pharmacokinetic Profile of Vardenafil after Single 20 mg Oral Dose in Men

Elimination:• Hepatic 91-95%• Renal 2-6%

Study 10118, n = 24

mea

n

15

Time (h)

0 4 8 12 16

Co

nce

ntr

atio

n n

g/m

l

0.1

1

10

100

Human Pharmacokinetics of Vardenafil and Metabolites

Peak concentration of metabolites 50% of vardenafil

M1-glucuronide

M1M4M5

14C study (10079), n=4

M1, M4 and M5 are deethylation/ demethylation products of vardenafilmetabolism

vardenafil

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Pharmacokinetic Interaction of Vardenafil with Ritonavir

vardenafil 5mg

vardenafil 5mg &

ritonavir*

vardenafil

80mg

*interaction assessed on 10th day of ritonavir 600 mg BID dosing

Cm

ax (

ng/

ml)

Study 100535

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In vitro evaluation showed an IC50 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)

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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

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Placebon=1199 (%)

Vardenafiln=2203 (%)

Adverse Event

Syncope 1 (<0.1) 2 (<0.1)

Dizziness 11 (0.9) 48 (2.2)

Palpitations 3 (0.3) 11 (0.5)

Seizures(convulsions)

0 (0) 1 (<0.1)

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

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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

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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

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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 Tmax

• maximal change from baseline of QT/QTc versus placebo over 4 hr

Design: Six-way crossover, single-dose, placebo-controlled study. Doses 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

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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

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Study 10929/011 Procedures

Time (h)

Dose

Baseline

Study 10929/011

6 ECGs at each timepoint one minute apart

25

QTraw , HR, and QTcF Mean Change from Baseline (SE) 1 hour

after Placebo

Treatment QTraw

(msec)

HR

(bpm)

QTcF

(msec)

Placebo 6 (1.0) -3 (0.5) 0 (0.7)

Study 10929/011; n=58

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Placebo-Subtracted Mean Change from Baseline (90% CI) for QTraw, HR and

QTcF at 1 Hour

Treatment effect (90% CI)

Treatment QTraw(msec)

HR(bpm)

QTcF(msec)

80 mg vardenafil -2 (-4, 0) 6 (5, 7) 10 (8, 11)

10 mg vardenafil -2 (-4, 0) 5 (4, 6) 8 (6, 9)

400 mg sildenafil -1 (-3, 1) 5 (4, 6) 9 (8, 11)

50 mg sildenafil -2 (-4, 0) 4 (3, 5) 6 (5, 8)

400 mg moxifloxacin 3 ( 1, 5) 2 (1, 3) 8 (6, 9)

Study 10929/011; n=58

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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

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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

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Placebo-Subtracted Mean Change from Baseline for QTcF and QTci* (msec) at 1

Hour Post-Dose

Treatment effect (90% CI)

Treatment QTcF(msec)

QTci(msec)

80 mg vardenafil 10 (8, 11) 6 (4, 7)

10 mg vardenafil 8 (6, 9) 4 (3, 6)

400 mg sildenafil 9 (8, 11) 5 (4, 7)

50 mg sildenafil 6 (5, 8) 4 (2, 5)

400 mg moxifloxacin 8 (6, 9) 7 (5, 8)

Study 10929/011; n=58*linear relationship

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Placebo-Subtracted Mean Change from Baseline for QTcF at 1 Hour, Tmax, and

Maximum QTcF

Treatment Effect (90%CI)

Treatment 1 hour Tmax Maximum QTcF

80 mg vardenafil 10 (8, 11) 9 (8, 11) 9 (7, 10)

10 mg vardenafil 8 (6, 9) 7 (5, 9) 6 (5, 7)

400 mg sildenafil 9 (8, 11) 6 (4, 7) 8 (7, 9)

50 mg sildenafil 6 (5, 8) 6 (5, 8) 5 (4, 6)

400 mg moxifloxacin 8 (6, 9) 8 (7, 10) 9 (7, 10)

Study 10929/011; n=58

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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

Observed & Population Predicted QTcF versus Vardenafil Plasma Concentration

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

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

QT/QTc Study Design, Heart Rate Correction & Risk of Cardiac

Arrhythmia

Joel Morganroth, MDClinical Professor of Medicine

University of PennsylvaniaChief Scientist

eResearchTechnology

36

Agenda

QT/QTc study design issues

QT correction factor analysis

Clinical relevance of 5 to 10 msec QTc effect

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

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

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

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

Drug-Specific Factors to Consider in the Design of a QT/QTc Study

Pharmacokineticsto ensure observation period covers Cmax 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 drugconsider special procedures for heart rate correction when drug

increases heart rate [QTci analysis done]

42

“The traditionally used Bazett’s formula for correction ofthe measured QT interval for variations in heart rates(QTc = QT/RR0.50) 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/RR0.33), or preferably a study-specific derived formula (QTc =QT/RRx), 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

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

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

Placebo-Subtracted Mean Change from Baseline for QTc (msec) at 1 hr Post-Dose

Treatment Effect (90% CI)

Treatment QTcF QTci(linear)

QTci(nonlinear)

10 mg vardenafil 8 (6,9) 4 (3,6) 4 (3,6)

80 mg vardenafil 10 (8,11) 6 (4,7) 6 (5,8)

50 mg sildenafil 6 (5,8) 4 (2,5) 4 (2,5)

400 mg sildenafil 9 (8,11) 5 (4,7) 6 (4,7)

400 mg moxifloxacin 8 (6,9) 7 (5,8) 7 (5,8)

Study 10929/011;n=58

46

Population QTc vs HR: Bazett’s and Fredericia

QTcB

HR (bpm)

QTc

(m

sec)

40 60 80 100

350

400

450

QTcF

HR (bpm)Q

Tc (

mse

c)

40 60 80 100

350

400

450

Note: data plotted is baseline and placebo data only

47

Population QTc vs HR: Fredericia and Individual

Note: data plotted is baseline and placebo data only

QTcF

HR (bpm)

QTc

(m

sec)

40 60 80 100

350

400

450

QTciX

HR (bpm)

QTc

(m

sec)

40 60 80 100

350

400

450

48

Individual QTc vs HR relationships: Fridericia and Individual

QTcF

HR (bpm)

QTc

(m

sec)

40 60 80 100

360

380

400

420

QTciX

HR (bpm)Q

Tc (

mse

c)40 60 80 100

360

380

400

420

Note: Data represents fitted linear relationship for baseline and placebo data only

49

Individual QTci.2 vs HR Relationships

QTci

HR (bpm)

QTc (

msec)

40 60 80 100

360

380

400

420

QTci.2

HR (bpm)Q

Tc (

msec)

40 60 80 100

360

380

400

420

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

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

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

Regimen

Frequency (%) V10 V80 S50 S400 M P Total

QTci 30<60 2

(0.11)

4

(0.23)

1

(0.06)

4

(0.23)

18

(1.03)

1

(0.06)

30

(0.29)

Total 1740 1740 1740 1740 1740 1740 10440

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 Tmax, using QTcF or QTci

Shallow dose response (8x starting dose)

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

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

Terfenadine Mean change in QTc across the 12-hour dosing intervala:

6 msec

Mean change in QTc at Tmax (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, 1993b Honig, et al., JAMA 269: 1513-1518, 1993

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

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

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

Sildenafil FDA AERS Data

Torsades de Pointes:

No cases reporteda from launch to December 15, 2002 (data lock)

Usage:b

38.7 million sildenafil prescriptions written worldwide from April 1998 to December 2002

aSpontaneous reports from FDA Adverse Event Reporting System databasebUsage data from IMS

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 msec no TdP5 - 10 msec no clear risk10 - 20 msec some concern> 20 msec substantially 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

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

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