CS-1 Safety of Foradil ® Gregory P. Geba, MD, MPH Vice President – US Head RDI Clinical Development and Medical Affairs Novartis Gregory P. Geba, MD, MPH Vice President – US Head RDI Clinical Development and Medical Affairs Novartis 4

CS-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  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

CS-3 Chemical Structures HN OH N H O OH O O N H HO OH Formoterol Salmeterol

CS-4 Pharmacologic Differences: β 2 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  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:

CS-5 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  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:

CS-6 Phase IV Trial 2307 Examining Asthma-Related Serious AEs

CS-7 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 bidAlbuterolPlacebo 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)NA0/176 (0) † Adults and adolescents ≥ 12 yr. ‡ Children yr.

CS-8 Pivotal Studies and Phase IV 2307: Similar Characteristics of Patient Populations Study Characteristic , 041 Trial duration, wk1612 Age, yr Baseline FEV 1, % predicted6864 Black, %127 Concomitant ICS use, % Targeted reversibility, % Actual reversibility, % ≥ ≥ 15 35

CS-9 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 DVWk– Study treatmentRun-in Study drug Formoterol 12 µg bid orFormoterol 12 µg bid or Formoterol 24 µg bid orFormoterol 24 µg bid or Placebo bid orPlacebo bid or Open-label formoterol 12 µg bid + ≤ 2 rescue doses of formoterol 12 µgOpen-label formoterol 12 µg bid + ≤ 2 rescue doses of formoterol 12 µg

CS-10 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.

CS-11 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)

CS-12 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  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

CS-13 Pooled Foradil Clinical Trial Database Supports Foradil Safety

CS-14 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  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 Uncontrolled Trials ≥ 4 wk duration Controlled Placebo-controlled

CS-15 Randomized Controlled Trials: 1 Asthma-Related Death in 1600 Patient-Yr Total exposure, patient-yr Placebo n = 2446 Albuterol n = 1238 Formoterol all doses n = 5907 Asthma-related deaths 1 (0.04) (0.08) (0.02) 0.06 n (%) n/100 yr All-cause deaths 001 (0.02) 0.06 n (%) n/100 yr Asthma- related deaths Foradil BB 09_jun_05 final draft T 3-3 4

CS-16 Uncontrolled Trials: 5 Asthma-Related Deaths in 1240 patient-years 1240Total exposure, patient-yr Formoterol all doses n = 2783 Asthma-related deaths 5 (0.18) 0.40 n (%) n/100 yr Asthma-related deaths 14 (0.50) 1.13 n (%) n/100 yr All-cause deaths Foradil BB 09_jun_05 final draft T 3-3 4

CS-17 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)  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.

CS-18 More Asthma-Related Discontinuations in Placebo Group Multiple-Dose, Placebo-Controlled Trials ≥ 4 Wk Formoterol All doses 20/24 µg tdd 48 µg tddPlaceboAlbuterol All patientsN % n/100 yr Foradil BB 09_jun_05 final draft T ICS = Inhaled corticosteroids; tdd= Total daily dose.

CS-19 More Asthma-Related Serious AEs in Formoterol Groups Multiple-Dose, Placebo-Controlled Trials ≥ 4 Wk Formoterol All doses 20/24 µg tdd 48 µg tddPlaceboAlbuterol All patientsN % n/100 yr ICS = Inhaled corticosteroids; tdd = Total daily dose. Foradil BB 09_jun_05 final draft T 3-5 4

CS-20 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 tddPlaceboAlbuterol All patientsN % n/100 yr 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

CS-21 Significant Asthma Exacerbations Conclusion  Significant asthma exacerbations with Foradil ® were lower than or similar to placebo 4

CS-22 Review of Postmarketing Mortality Data 4

CS-23 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  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: ‡ Strom BL, JAMA 2004;192: § de Graaf L, et al. Pharm World Sci. 2003;25: ¶ Hartnell NR, Wilson JP Pharmacotherapy 2004;24:

CS-24 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  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:

CS-25 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 ,119, Salmeterol118216, ,000, Foradil BB 09_jun_05 final draft T † FDA AERS database up to Dec. 31, ‡ Data on exposure and reports of death: 1994 – § Based on kg sold.

CS-26 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  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

CS-27 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  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