Food and Drug Administration Cardiovascular and Renal Drugs Advisory Committee

1
Food and Drug AdministrationCardiovascular and
Renal DrugsAdvisory 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
Agenda
4
Consultants
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
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 Vardenafil

• Thomas P. Segerson, MD
• Vice President
• Medical 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
NA Pivotal Study 100249
Diabetes Study 100250


8.2
7.4
8

5.2
Mean EF Domain Score Change
6
4
1.8
2
0
Placebo
5 mg
10 mg
20 mg
Treatment Group
International Index of Erectile Function
p lt0.01 vs placebo
13
Frequent Adverse Events in Placebo-Controlled
Phase III Trials
? 2 and more frequent with vardenafil than
placebo
14
Pharmacokinetic Profile of Vardenafil after
Single 20 mg Oral Dose in Men

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

Concentration at 24h1 - 2 Cmax
mean
Study 10118, n 24
15
Human Pharmacokinetics of Vardenafil and
Metabolites
M1, M4 and M5 are deethylation/ demethylation
products of vardenafilmetabolism
Peak concentration of metabolites ? 50 of
vardenafil
vardenafil
M1-glucuronide
M4
M5
M1
14C study (10079), n4
16
Pharmacokinetic Interaction of Vardenafil with
Ritonavir
Cmax (ng/ml)
interaction assessed on 10th day of ritonavir
600 mg BID dosing
vardenafil 5mg
vardenafil 5mg ritonavir
vardenafil 80mg
Study 100535
17
Preclinical QT Data

• In vitro evaluation showed an IC50 of 30 mM for
  vardenafil, and 47 mM 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

Sildenafil 100 mg (NDA 20-885 SBA), Vardenafil
20 mg (Study 100196)
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
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
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
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
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.

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
Study 10929/011 Procedures
Dose
Time (h)
6 ECGs at each timepoint one minute apart
Baseline
Study 10929/011
25
QTraw , HR, and QTcF Mean Change from Baseline
(SE) 1 hour after Placebo
Study 10929/011 n58
26
Placebo-Subtracted Mean Change from Baseline (90
CI) for QTraw, HR and QTcF at 1 Hour
Study 10929/011 n58
27
Individually Corrected QT QTci

• Alternative to fixed approach to heart rate
  correction (Fridericia, Bazett)
• Correction based on each subjects 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)
80 mg
vardenafil
10 mg
400 mg
sildenafil
50 mg
moxifloxacin 400 mg
QTcF (msec)
QTci (msec)
Study 10929/011 n58
linear relationship
29
Placebo-Subtracted Mean Change from Baseline for
QTcF and QTci (msec) at 1 Hour Post-Dose
Study 10929/011 n58
linear relationship
30
Placebo-Subtracted Mean Change from Baseline for
QTcF at 1 Hour, Tmax, and Maximum QTcF
Study 10929/011 n58
31
QT/QTc Outlier Analysis

• 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)

Study 10929/011 n59
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.

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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
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 gt30 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 n18 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

• Pharmacokinetics
• to 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 drug
• consider special procedures for heart rate
  correction when drug increases heart rate QTci
  analysis done

42
What Correction Formula Should be Used to Derive
QTc from Heart Rate and QT?
The traditionally used Bazetts formula for
correction of the 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
147156.
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)
80 mg
vardenafil
10 mg
400 mg
sildenafil
50 mg
moxifloxacin 400 mg
QTcF (msec)
QTci (msec)
Study 10929/011 n58
linear relationship
45
Placebo-Subtracted Mean Change from Baseline for
QTc (msec) at 1 hr Post-Dose
Study 10929/011n58
46
Population QTc vs HR Bazetts and Fredericia
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
48
Individual QTc vs HR relationships Fridericia
and Individual
Note Data represents fitted linear relationship
for baseline and placebo data only
49
Individual QTci.2 vs HR Relationships

• 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

N 59 Patients
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
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(contd)

• 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 gt 500 msec
• No subjects on vardenafil and only 1 subject in
  sildenafil group with gt 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 7226B-32B,
1993 b 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
Moxifloxacin Cardiac Safety Post-Marketing
Surveillance

• 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

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) N12 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)
• Usageb
• 38.7 million sildenafil prescriptions written
  worldwide from April 1998 to December 2002
• aSpontaneous reports from FDA Adverse Event
  Reporting System database
• bUsage 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
• lt 5 msec no TdP
• 5 - 10 msec no clear risk
• 10 - 20 msec some concern
• gt 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 Vardenafils 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
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