# Presentation: 530028

## Safety of Foradil®

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

**4**

## 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**

## Chemical Structures

**Formoterol**

**Salmeterol**

## Pharmacologic Differences: β2 Receptor Binding for Formoterol DiffersFrom Salmeterol

**Both molecules bind to the β****2**** 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. *****1996;271:24029-24035. **

## Pharmacologic Differences:Advantages of Full vs Partial Agonism

**Formoterol is a full agonist at the ****β****2**** 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.***** 1998;11:583-588.**

## Phase IV Trial 2307 Examining Asthma-Related Serious AEs

## US Pivotal Studies Possible Safety Signal for Asthma-Related Serious AEs With High Dose Foradil?

- FDA BD

- 14

| Patients, n/N (%) |  |  |  |
| --- | --- | --- | --- |
| Foradil 12 μg bid | Foradil 24 μg bid | Albuterol | Placebo |
| Study 040† (N = 541) |  |  |  |
| 0/136 (0) | 4/135 (3.0) | 2/134 (1.5) | 0/136 (0) |
| Study 041† (N = 554) |  |  |  |
| 1/139 (0.7) | 5/136 (3.7) | 0/138 (0) | 2/141 (1.4) |
| 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.**

## Pivotal Studies and Phase IV 2307: Similar Characteristics of Patient Populations

|  | 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 |

## Protocol 2307 Was Specifically Designed to Examine Asthma-Related Serious AEs

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

**2307 CSR P20 , F 3-1**

**1 DV**

**Wk**

**–****2**

**0**

**4**

**8**

**12**

**16**

**Study treatment**

**Run-in**

**Study****drug**

**Formoterol 12 μg bid *****or***
**Formoterol 24 μg bid *****or***
**Placebo bid *****or***
**Open-label formoterol 12 μg bid + ≤ 2 rescue doses****of formoterol 12 μg**

## Primary Outcome Data for Study 2307 

|  | Patients, n (%) |  |  |  |
| --- | --- | --- | --- | --- |
|  | Formoterol12 μg bidn = 527 | Formoterol 12 μg bid + 12 μg bid prnn = 517 | Formoterol24 μg bidn = 527 | Placebon = 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)

 |

- FDA BD

- 14

**† ****2 non-asthma-related cases removed by the FDA.**

## Primary Outcome Data With 95% CI in Study 2307

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

**7**

**padac stats slides – jt.ppt**

| Foradil 12 μg |
| --- |
| Foradil 24 μg |
| Foradil 12 μg + 12 μg prn |
| All Foradil  |
| Placebo |

**Estimate (95% CI)**

**0**

**0.5**

**1**

**1.5**

**2**

## Conclusions: Very Low Event Ratesin Study 2307

**Observed event rate was 10% of expected**
**Absolute differences between groups****were 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**

## Pooled Foradil Clinical Trial Database Supports Foradil Safety

## Safety Analysis of Integrated Foradil Clinical Trial Database

**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 2004****were 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 |

**4**

## Randomized Controlled Trials:1 Asthma-Related Death in 1600 Patient-Yr

**572**

**242**

**1610**

**Total exposure, patient-yr**

**Placebo****n = 2446**

**Albuterol****n = 1238**

**Formoterol****all doses****n = 5907 **

**Asthma-related deaths**

**Foradil BB 09_jun_05 final draft T 3-3**

**4**

## Uncontrolled Trials: 5 Asthma-Related Deaths in 1240 patient-years

**1240**

**Total exposure, patient-yr**

**Formoterol****all doses****n = 2783 **

**Asthma-related deaths**

**Foradil BB 09_jun_05 final draft  T 3-3**

**4**

## Significant Asthma Exacerbations†

**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)**

**4**

**† ****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.**

## More Asthma-Related Discontinuationsin Placebo Group Multiple-Dose, Placebo-Controlled Trials ≥ 4 Wk

|  |  | Formoterol |  |  |  |  |
| --- | --- | --- | --- | --- | --- | --- |
|  |  | All doses | 20/24 μgtdd | 48 μgtdd | Placebo | Albuterol |
| All patients | N%n/100 yr | 37682.17.1 | 19481.75.6 | 11562.98.8 | 18633.210.7 | 6302.18.1 |

**Foradil BB 09_jun_05 final draft T 3-6**

**4**

**ICS = Inhaled corticosteroids; tdd= Total daily dose.**

## More Asthma-Related Serious AEsin Formoterol GroupsMultiple-Dose, Placebo-Controlled Trials ≥ 4 Wk 

|  |  | Formoterol |  |  |  |  |
| --- | --- | --- | --- | --- | --- | --- |
|  |  | All doses | 20/24 μg tdd | 48 μg tdd | Placebo | Albuterol |
| All patients | N%n/100 yr | 37681.13.9 | 19480.93.5 | 11561.95.6 | 18630.30.9 | 6300.63.1 |

**ICS = Inhaled corticosteroids; tdd = Total daily dose.**

**Foradil BB 09_jun_05 final draft T 3-5**

**4**

## Foradil: Lower or Similar Rates of Significant Asthma Exacerbations Compared With PlaceboMultiple-Dose, Placebo-Controlled Trials ≥ 4 Wk

|  |  | Formoterol |  |  |  |  |
| --- | --- | --- | --- | --- | --- | --- |
|  |  | Alldoses | 20/24 μgtdd | 48 μgtdd | Placebo | Albuterol |
| All patients | N%n/100 yr | 37682.58.7 | 19482.07.1 | 11563.5
10.9 | 18633.210.9 | 6302.29.4 |

**Foradil BB 09_jun_05 final draft T 3-4**

**Significant asthma exacerbations defined as asthma-related serious AEs or premature discontinuations because of an asthma-related AE.**
**tdd = Total daily dose.**

**4**

## Significant Asthma ExacerbationsConclusion

**Significant asthma exacerbations with Foradil****®**** were lower than or similar to placebo**

**4**

## Review of Postmarketing Mortality Data

**4**

## Postmarketing AnalysisCharacteristics and Limitations 

**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**

**Foradil BB 09_jun_05 final draft P 42**

**† ****Heeley E, et al. *****Lancet.***** 2001;358:1872-1873.****‡ Strom BL, *****JAMA***** 2004;192:2643-2646.**
**§ de Graaf L, et al. *****Pharm World Sci*****. 2003;25:260-263.**
**¶ Hartnell NR, Wilson JP *****Pharmacotherapy***** 2004;24:743-749.**

**4**

## Analysis of FDA Adverse Events Reporting System (AERS)

**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 100,000****person-yr **

**Foradil BB 09_jun_05 final draft P 36**

**4**

**† ****Strom BL. *****JAMA***** 2004;192:2643-2646.**

## FDA AERS AE and Death Reports for Formoterol Were Low

| Drug | AE reportsof death†, n | Total AEreports, n | Reportingproportion(per 100 AE) | AE reportsof death‡, n | Person yrof exposure§ | Reporting rateper 100,000person yr‡ |
| --- | --- | --- | --- | --- | --- | --- |
| Formoterol | 139 | 1252 | 11.1 | 139 | 13,119,893
 | 1.05 |
| Salmeterol | 1182 | 16,064 | 7.4 | 1182 | 45,000,000 | 2.48 |

**Foradil BB 09_jun_05 final draft T 4-1**

**4**

**† ****FDA AERS database up to Dec. 31, 2004.**
**‡ ****Data on exposure and reports of death: 1994 – 2004.**
**§ Based on kg sold. **

## 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 Foradil****high-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**

## 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**