# Presentation: 867528

## Food and Drug AdministrationCardiovascular and Renal DrugsAdvisory Committee

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

## Introduction

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

## Agenda

## Consultants

## 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

## 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

## Timeline

- 1998

- 1999

- 2000

- 2001

- 2002

- 2003

## 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

## Assessment of the QT/QTc Effect of Vardenafil

- Thomas P. Segerson, MD
- Vice President
- Medical and Scientific Affairs
- Bayer Canada

## 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

## 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.

## 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**

**Placebo**

**5 mg**

**10 mg**

**20 mg**

- *

- *

- *

*******p <0.01 vs placebo**

- Diabetes Study 100250

## Frequent Adverse Events* in Placebo-Controlled Phase III Trials

- *  2% and more frequent with vardenafil than placebo

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

- 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*

- mean

## Human Pharmacokinetics of Vardenafil and Metabolites

**Human Pharmacokinetics of ****Vardenafil and Metabolites**

- Peak concentration of metabolites  50% of vardenafil

*M1-glucuronide*

*M1*

*M4*

*M5*

*14**C study (10079), n=4*

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

*vardenafil*

## Pharmacokinetic Interaction of Vardenafil with Ritonavir

- vardenafil 5mg

- vardenafil 5mg & ritonavir*

- vardenafil 80mg

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

- Cmax (ng/ml)

*Study 100535*

## Preclinical QT Data

- 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)*

## 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

## Incidence of Clinical Adverse Events Which May be a Potential Signal for Ventricular Arrhythmia in Placebo-Controlled Phase III Studies

**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 *

## 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*

## 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

## 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.

## 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

## Study 10929/011 Procedures

- Time (h)

- Dose

- Baseline

*Study 10929/011*

- 6 ECGs at each timepoint one minute apart

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

*Study 10929/011; n=58*

## Placebo-Subtracted Mean Change from Baseline (90% CI) for QTraw, HR and QTcF at 1 Hour

*Study 10929/011; n=58*

## 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*

## 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

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

*Study 10929/011; n=58*

*****linear relationship

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

*Study 10929/011; n=58*

## 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)

- 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*

## Observed & Population Predicted QTcF versus Vardenafil Plasma Concentration

## 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.

## 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.

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

- Joel Morganroth, MD
- Clinical Professor of Medicine
- University of Pennsylvania
- Chief Scientist
- eResearchTechnology

## Agenda

**QT/QTc study design issues**
**QT correction factor analysis**
**Clinical relevance of 5 to 10 msec QTc effect**

## 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

## 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?

## 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]

## 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]

## 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]

## What Correction Formula Should be Used 

- 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?**

## 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]

## 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

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

*Study 10929/011;n=58*

## Population QTc  vs HR: Bazett’s and Fredericia

- Note: data plotted is baseline and placebo data only

## Population QTc  vs HR: Fredericia and Individual

- Note: data plotted is baseline and placebo data only

## Individual QTc  vs HR relationships: Fridericia and Individual 

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

## 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”

## 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

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

## 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)

## 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

## 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)

## Terfenadine

- Mean change in QTc across the 12-hour dosing interval*a*:
- 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, 1993*
*b** Honig, et al., JAMA 269: 1513-1518, 1993*

## 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

## Moxifloxacin Cardiac Safety: Post-Marketing Surveillance

- 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**

## 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)

## 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 database
- bUsage data from IMS

## 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 TdP
_**5 - 10 msec**_		_**no clear risk**_
- 10 - 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

## 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

## 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

## Slide 63