Title: Safety of Foradil
1Safety of Foradil
4
- Gregory P. Geba, MD, MPH
- Vice President US Head RDI
- Clinical Development and Medical Affairs
- Novartis
2Key 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
3Chemical Structures
Formoterol
Salmeterol
4Pharmacologic 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
.
5Pharmacologic 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.
6Phase IV Trial 2307 Examining Asthma-Related
Serious AEs
7US Pivotal Studies Possible Safety Signal for
Asthma-Related Serious AEs With High Dose Foradil?
14
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.
8Pivotal 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
9Protocol 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
10Primary Outcome Data for Study 2307
14
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.
11Primary Outcome Data With 95 CI in Study 2307
7
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)
12Conclusions 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
13Pooled Foradil Clinical Trial Database Supports
Foradil Safety
14Safety Analysis of Integrated Foradil Clinical
Trial Database
4
- 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
15Randomized 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
16Uncontrolled 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
17Significant Asthma Exacerbations
4
- 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.
18More 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.
19More 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.
20Foradil 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.
21Significant Asthma ExacerbationsConclusion
4
- Significant asthma exacerbations with Foradil
were lower than or similar to placebo
22Review of Postmarketing Mortality Data
4
23Postmarketing AnalysisCharacteristics and
Limitations
4
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.
24Analysis of FDA Adverse Events Reporting System
(AERS)
4
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.
25FDA AERS AE and Death Reports for Formoterol Were
Low
4
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.
26Overall 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
27Overall 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