Safety of Foradil

1
Safety of Foradil
4

• Gregory P. Geba, MD, MPH
• Vice President US Head RDI
• Clinical Development and Medical Affairs
• Novartis

2
Key Points of Presentation

• We will describe
• Pharmacologic differences that exist between
  formoterol and salmeterol
• Phase IV trial 2307 examining asthma-related
  serious AEs in adolescents and adults
• Integrated clinical trial database
• Postmarketing adverse event data
• The totality of the evidence does not elevate
  concern for a safety signal for Foradil and
  continues to support the favorable benefit/risk
  profile of Foradil

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Chemical Structures
Formoterol
Salmeterol
4
Pharmacologic Differences ß2 Receptor Binding
for Formoterol DiffersFrom Salmeterol

• Both molecules bind to the ß2 adrenergic receptor
  active site, however
• Prolonged salmeterol activity depends on binding
  with an exosite
• Prolonged activity of formoterol is independent
  of exosite binding
• Mutation in the exosite region (Ile 164) could
  affect duration of action of salmeterol

Green SA, et al. J Biol Chem. 199627124029-24035
.
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Pharmacologic DifferencesAdvantages of Full vs
Partial Agonism

• Formoterol is a full agonist at the ß2 adrenergic
  receptor salmeterol is a partial agonist
• In isolated human bronchi, pre-incubation with
  formoterol or salmeterol results in
• Decreased relaxant effect of isoprenaline by
  salmeterol
• Maintained relaxant effect of isoprenaline by
  formoterol
• Potential implications
• Partial agonist may act as an antagonist to
  rescue medication

Molimar M, et al. Eur Respir J. 199811583-588.
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Phase IV Trial 2307 Examining Asthma-Related
Serious AEs
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US Pivotal Studies Possible Safety Signal for
Asthma-Related Serious AEs With High Dose Foradil?
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FDA BD
Patients, n/N () Patients, n/N () Patients, n/N () Patients, n/N ()
Foradil 12 µg bid Foradil 24 µg bid Albuterol Placebo
Study 040 (N 541) Study 040 (N 541) Study 040 (N 541) Study 040 (N 541)
0/136 (0) 4/135 (3.0) 2/134 (1.5) 0/136 (0)
Study 041 (N 554) Study 041 (N 554) Study 041 (N 554) Study 041 (N 554)
1/139 (0.7) 5/136 (3.7) 0/138 (0) 2/141 (1.4)
Study 049 (N 518) Study 049 (N 518) Study 049 (N 518) Study 049 (N 518)
8/171 (4.7) 11/171 (6.4) NA 0/176 (0)
Adults and adolescents 12 yr. Children 5 -
12 yr.
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Pivotal Studies and Phase IV 2307 Similar
Characteristics of Patient Populations
Study Study
Characteristic 2307 040, 041
Trial duration, wk 16 12
Age, yr 38 34.3
Baseline FEV1, predicted 68 64
Black, 12 7
Concomitant ICS use, 57.8 47.3
Targeted reversibility, Actual reversibility, 12 23 15 35
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Protocol 2307 Was Specifically Designed to
Examine Asthma-Related Serious AEs
1 DV
2307 CSR P20 , F 3-1

• Adolescents and adults were followed for up to 16
  wk whether or not they discontinued early

Study treatment
Run-in
Wk
2
0
4
8
12
16
Studydrug

• Formoterol 12 µg bid or
• Formoterol 24 µg bid or
• Placebo bid or
• Open-label formoterol 12 µg bid 2 rescue
  dosesof formoterol 12 µg

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Primary Outcome Data for Study 2307
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FDA BD
Patients, n () Patients, n () Patients, n () Patients, n ()
Formoterol12 µg bidn 527 Formoterol 12 µg bid 12 µg bid prnn 517 Formoterol24 µg bidn 527 Placebon 514
Serious asthma-related AEs 5 (0.9) 1 (0.2) 2 (0.4) 1 (0.2)
After FDA review 3 (0.6) 1 (0.2) 2 (0.4) 1 (0.2)
2 non-asthma-related cases removed by the FDA.
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Primary Outcome Data With 95 CI in Study 2307
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padac stats slides jt.ppt

• 95 CI for primary endpoint (percent of patients
  experiencing an asthma-related serious AE)

Foradil 12 µg
Foradil 24 µg
Foradil 12 µg 12 µg prn
All Foradil
Placebo
0
0.5
1
1.5
2
Estimate (95 CI)
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Conclusions Very Low Event Ratesin Study 2307

• Observed event rate was 10 of expected
• Absolute differences between groupswere very
  small
• Higher serious AE rate in higher dose Foradil
  arm, previously observed in adolescents and
  adults in 040 and 041, was not observed in 2307

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Pooled Foradil Clinical Trial Database Supports
Foradil Safety
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Safety Analysis of Integrated Foradil Clinical
Trial Database
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• Death, all cause or asthma related
• All controlled trials and uncontrolled trials in
  Aerolizer and Certihaler database irrespective
  of duration
• Asthma-related AEs
• All controlled trials 4 wk duration through
  2004were analyzed

Foradil patients, n Median exposure,days/patient
Controlled 5907 89
Uncontrolled 2783 75
Trials 4 wk duration
Controlled 5048 94
Placebo-controlled 3768 94
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Randomized Controlled Trials1 Asthma-Related
Death in 1600 Patient-Yr
4
Foradil BB 09_jun_05 final draft T 3-3
Placebon 2446
Albuteroln 1238
Formoterolall dosesn 5907
Asthma-related deaths
572
242
1610
Total exposure, patient-yr
16
Uncontrolled Trials 5 Asthma-Related Deaths in
1240 patient-years
4
Foradil BB 09_jun_05 final draft T 3-3
Formoterolall dosesn 2783
Asthma-related deaths
1240
Total exposure, patient-yr
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Significant Asthma Exacerbations
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• Asthma-related AEs which were meaningful enough
  to prompt patient discontinuation whether a
  serious AE or not
• Asthma-related AEs reported as serious with or
  without discontinuation (serious AEs)

Pooled endpoint defined on p 31 Section IV FDA
Briefing Book. Predefined terms included
asthma, dyspnea, bronchospasm, chest discomfort,
cough, wheezing, dyspnea exacerbated, status
asthmaticus, respiratory distress, acute
respiratory failure, hypoxia. All AEs were
reported regardless of causality.
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More Asthma-Related Discontinuationsin Placebo
Group Multiple-Dose, Placebo-Controlled Trials
4 Wk
4
Foradil BB 09_jun_05 final draft T 3-6
Formoterol Formoterol Formoterol
All doses 20/24 µgtdd 48 µgtdd Placebo Albuterol
All patients Nn/100 yr 37682.17.1 19481.75.6 11562.98.8 18633.210.7 6302.18.1
ICS Inhaled corticosteroids tdd Total daily
dose.
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More Asthma-Related Serious AEsin Formoterol
GroupsMultiple-Dose, Placebo-Controlled Trials
4 Wk
4
Foradil BB 09_jun_05 final draft T 3-5
Formoterol Formoterol Formoterol
All doses 20/24 µg tdd 48 µg tdd Placebo Albuterol
All patients Nn/100 yr 37681.13.9 19480.93.5 11561.95.6 18630.30.9 6300.63.1
ICS Inhaled corticosteroids tdd Total daily
dose.
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Foradil Lower or Similar Rates of Significant
Asthma Exacerbations Compared With
PlaceboMultiple-Dose, Placebo-Controlled Trials
4 Wk
4
Foradil BB 09_jun_05 final draft T 3-4
Formoterol Formoterol Formoterol
Alldoses 20/24 µgtdd 48 µgtdd Placebo Albuterol
All patients Nn/100 yr 37682.58.7 19482.07.1 11563.5 10.9 18633.210.9 6302.29.4
Significant asthma exacerbations defined as
asthma-related serious AEs or premature
discontinuations because of an asthma-related
AE. tdd Total daily dose.
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Significant Asthma ExacerbationsConclusion
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• Significant asthma exacerbations with Foradil
  were lower than or similar to placebo

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Review of Postmarketing Mortality Data
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Postmarketing AnalysisCharacteristics and
Limitations
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Foradil BB 09_jun_05 final draft P 42

• Spontaneous reporting of adverse-drug reactions
  (ADR) remains the most common method available
  for monitoring safety of marketed drugs
• Useful for monitoring for safety signals
• Main limitations
• Substantial percentage of ADRs not reported
• Other potential biases
• Targeting drug to lower- or higher-risk patients
  may alter ADR occurrence
• Notoriety bias
• Time on the market, drug familiarity, and other
  influences
• ADR of interest is the disease itself

Heeley E, et al. Lancet. 20013581872-1873.
Strom BL, JAMA 20041922643-2646. de Graaf L,
et al. Pharm World Sci. 200325260-263.
Hartnell NR, Wilson JP Pharmacotherapy
200424743-749.
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Analysis of FDA Adverse Events Reporting System
(AERS)
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Foradil BB 09_jun_05 final draft P 36

• FDA AERS database was searched for all reports
  of death and/or outcome of death for formoterol
  or salmeterol
• Reporting rates for AEs and deaths decrease with
  time postcommercialization
• Reporting rate
• Reports through 2004 with case definition on drug
  X exposure on drug X per 100,000person-yr

Strom BL. JAMA 20041922643-2646.
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FDA AERS AE and Death Reports for Formoterol Were
Low
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Foradil BB 09_jun_05 final draft T 4-1
Drug AE reportsof death, n Total AEreports, n Reportingproportion(per 100 AE) AE reportsof death, n Person yrof exposure Reporting rateper 100,000person yr
Formoterol 139 1252 11.1 139 13,119,893 1.05
Salmeterol 1182 16,064 7.4 1182 45,000,000 2.48
FDA AERS database up to Dec. 31, 2004. Data
on exposure and reports of death 1994 2004.
Based on kg sold.
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Overall Conclusions (1)

• Well-described pharmacologic differences exist
  between formoterol and salmeterol
• In pivotal trials conducted for US registration,
  a potential safety signal emerged in the
  Foradilhigh-dose group, leading to the approval
  of the 12 µg dose only and to postmarketing
  asthma safety study 2307
• Study 2307 examined asthma-related serious AEs in
  adolescents and adults and did not provide
  evidence of a safety signal for Foradil at any
  dose

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Overall Conclusions (2)

• An analysis of the pooled Foradil clinical trial
  database, and a review of postmarketing adverse
  event data, does not provide evidence of a safety
  signal for Foradil
• The totality of the evidence does not elevate
  concern for a safety signal and continues to
  support the favorable benefit/risk profile of
  Foradil in the treatment of asthma