A 1 Pulmonary-Allergy Drugs Advisory Committee Meeting July 13, 2005 Safety of Long-acting Beta 2 -Agonists

A 2 Long-Acting Beta 2 -Agonist Salmeterol C. Elaine Jones, PhD. Vice President Respiratory Regulatory Affairs GlaxoSmithKline

A 3 Burden of Asthma in the US Affected an estimated 20 million Americans in Affected an estimated 20 million Americans in Significant morbidity and mortality Significant morbidity and mortality – 484,000 hospitalizations in – 4,261 deaths in Risk factors for asthma-related mortality Risk factors for asthma-related mortality – Over-use of rescue medication – Under-use of ICS – Disease severity – Delay in seeking care – Ethnic origin – Gender – Age – Substance Abuse – Pollution 1 National Center for Health Statistics website,

A 4 Salmeterol Approval History First approved in the United Kingdom, 1990 First approved in the United Kingdom, 1990 Approved in over 100 countries Approved in over 100 countries COPD Asthma ADVAIR DISKUS ® SEREVENT ® DISKUS ® SEREVENT ® Inhalation Aerosol US Approval History

A 5 Salmeterol Exposure Worldwide exposure estimated to be 45.2 million patient-years Worldwide exposure estimated to be 45.2 million patient-years – 24.3 million patient-years for salmeterol – 20.9 million patient-years for salmeterol administered with fluticasone propionate in a single device

A 6 NHLBI Asthma Treatment Guidelines Severity Class Step 4 Severe Persistent Step 3 Moderate Persistent Step 2 Mild Persistent Step 1 Mild Intermittent Symptoms Continual Daily >2/week but <1x/day  2 days/week Daily Medications Preferred treatment: High-dose ICS + LABA Preferred treatment: Low-to-medium dose ICS + LABA Preferred treatment: Low-dose ICS No daily medication needed FEV 1  60% >60% - <80%  80%  80% LABA = Long-Acting Beta-Agonist Guidelines for the Diagnosis and Management of Asthma—Update on Selected Topics NIH, NHLBI. June NIH publication no

A 7 Salmeterol for the Treatment of Asthma Established as an important pharmacologic therapy Established as an important pharmacologic therapy Extensive clinical experience Extensive clinical experience Exhibits a favorable benefit to risk profile Exhibits a favorable benefit to risk profile

A 8 Salmeterol Review Katharine Knobil, M.D. Vice President Respiratory Clinical Development GlaxoSmithKline

A 9 Salmeterol Review Asthma Benefits of salmeterol Benefits of salmeterol Safety of salmeterol Safety of salmeterol – Post-marketing safety surveillance studies – Epidemiology studies Ongoing Studies Ongoing Studies Summary Summary

A 10 Beta 2 -Agonists: Albuterol and Salmeterol CHCH 2 NH-C OH HOH 2 C HO CH 3 Albuterol Salmeterol OCH 2 CH 2 NHCH 2 CH 2 CHCH 2 OH HOH 2 C HO

A 11 Improvement in FEV 1 Treatment Day 1 Percent Predicted FEV 1 Salmeterol 42mcg (n=184) Albuterol 180mcg (n=185) Placebo (n=187) Hours Second albuterol dose Percent Predicted FEV 1 Treatment Week 12 (Day 84) Hours Salmeterol 42mcg (n=152) Albuterol 180mcg (n=152) Placebo (n=150) Second albuterol dose Pearlman et al. NEJM 1992;327: D’Alonzo et al. JAMA 1994;271(18):

A 12 Maintenance of Bronchodilator Effect Salmeterol Diskus 50mcg BID (n=176) Placebo (n=176) 12 Hr FEV 1 AUC BL (Liter Hours) Day 1Week 8Week 20Week *p<0.001 vs. placebo Kemp et al. J Allergy Clin Immunol 1999;104: * * * *

A 13 Reduction in Symptom Scores † p<0.05 Salmeterol vs Placebo ‡ p<0.05 Salmeterol vs Albuterol QID Pearlman et al. NEJM 1992;327: D’Alonzo et al. JAMA 1994;271(18): Salmeterol 42mcg BID (n=184) Albuterol 180mcg QID (n=185) Placebo (n=187) Percent Change from Baseline Chest Tightness Shortness of Breath WheezingCough † ‡ ‡

A 14 Salmeterol, 50mcg BID + BDP, 200mcg BID (n=220) BDP, 500mcg BID + Placebo (n=206) Weeks Change in PEF (Liters/min) *** p< ** p< 0.01 * p< 0.05 ** * *** Improvement in Lung Function vs. Increased-Dose Inhaled Corticosteroids Greening et al. Lancet 1994;344:219-24

A 15 Reduction in Exacerbations p < 0.05 vs. FP Time to First Exacerbation (weeks) Probability of No Exacerbation Salmeterol + FP 88mcg BID (n=467) FP 220mcg BID (n=458) Matz et al. J Allergy Clin Immunol 2001;107:

A 16 Improvement in Quality of Life LimitationFunctionExposureSymptoms Mean Change in AQLQ ActivityAsthmaEmotionalEnvironmentGlobal score Salmeterol 42mcg BID (n=240) Placebo (n=234) AQLQ = Asthma Quality of Life Questionnaire *p  0.005, salmeterol vs. placebo for all assessments Lockey et al. Chest 1999;115: * * * * *

A 17 Post-Marketing Surveillance Studies

A 18 Salmeterol MDI 42mcg BID + Usual Care (n=16,787) Requirement for regular bronchodilator No run-in 69% concurrent ICS Albuterol MDI 180mcg QID + Usual Care (n=8,393) Day 0 Visit 1 Week 4Week 8Week 16 Serevent Nationwide Surveillance Study (SNS) Castle et al. Br Med J 1993:306; :1

A 19 Outcome Salmeterol (n=16,787) Albuterol (n=8393) Relative Risk (P value) Asthma-related Deaths12 (0.07%)2 (0.02%)3.0 (P=0.105) Asthma-related Hospitalizations 193 (1.15%)102 (1.22%)0.95 (P=0.651) Asthma-related Withdrawals488 (2.91%)318 (3.79%)0.77 (P=0.0002) All Serious Events & Withdrawals4272 (25.5%)2209 (26.3%)0.97 (P=0.200) SNS Results Castle et al. Br Med J 1993:306;

A 20 Salmeterol MDI 42mcg BID + Usual Care (n=13,176) No inhaled long- acting beta 2 -agonist > 12 years of age Placebo MDI BID + Usual Care (n=13,179) Clinic Visit 28 week treatment period Phone contact every 4 weeks 28 week supply of study medication provided R SMART Salmeterol Multicenter Asthma Research Trial Nelson et al. Chest 2005 (In Press)

A 21 SMART Study Endpoints Primary Endpoint Primary Endpoint – Combined respiratory-related deaths or life- threatening experiences (intubation and ventilation) – Target sample size increased from 30,000 to 60,000 patients Key Secondary Endpoints Key Secondary Endpoints – Respiratory-related deaths – Combined asthma-related deaths or life-threatening experiences – Asthma-related deaths

A 22 Phone contacts, spontaneous reports Case Reports of Serious Adverse Events MMRC DSMB Study oversight Interim analysis Recommendations to GSK Adjudication of Serious Adverse Events from SMART MMRC= Mortality and Morbidity Review Committee DSMB= Data Safety Monitoring Board MMRC reviewed all events: Determined if respiratory- and/or asthma-related Unrelated Unlikely related Possibly related Almost certainly related

A 23 SMART Interim Analysis SMART did not reach predetermined stopping criteria at the interim analysis SMART did not reach predetermined stopping criteria at the interim analysis DSMB recommended DSMB recommended – Timely completion (within two years) If this was not possible: – Discontinuation of study and rapid dissemination of the interim results SMART was discontinued due to difficulties in enrollment and findings in African American patients SMART was discontinued due to difficulties in enrollment and findings in African American patients

A 24 Salmeterol (n=13,176) Placebo (n=13,179) Age, mean Sex, n (%) Female Male 8334 (64) 4703 (36) 8337 (64) 4686 (36) Ethnic Origin, n (%) Caucasian African American Hispanic Asian Other 9281 (71) 2366 (18) 996 (8) 173 (1) 230 (2) 9361 (72) 2319 (18) 999 (8) 149 (1) 224 (2) Baseline Characteristics Peak Expiratory Flow (% Predicted)

A 25 Asthma Medications at Baseline SalmeterolPlacebo Concurrent Medications, n (%) n=13,176 n=13,179 Subjects using asthma medications at Baseline12,715 (97)12,660 (96) Subjects with no asthma medications at Baseline461 (3)519 (4) Inhaled or oral beta 2 -agonists (excluding inhaled LABAs)12,059 (92)12,043 (91) Inhaled corticosteroids6127 (47)6138 (47) Methylxanthines1766 (13)1767 (13) Leukotriene modifiers1437 (11)1402 (11)

A 26 Baseline Asthma Characteristics in Caucasians and African Americans Caucasian (n=18,642) African American (n=4685) Peak expiratory flow (% predicted) 85%78% Baseline ICS Use49%38% Nocturnal symptoms present 57% 64% 6%15%1 hospitalization last 12 months  30%44% 1 hospitalization lifetime  4%8% 1 intubation for asthma lifetime  59%72% 1 ER visit lifetime  22%41% 1 ER visit last 12 months 

A 27 SMART Results All Patients and Ethnic Subgroups RR (95% CI)SAL nPLA n1° Endpoint 7.26 (0.89, 58.94) (1.68,14.45) (0.83, 18.26) (0.70, 48.37) (0.55, 2.14) (0.94, 5.56) (1.54, 10.90) (0.62, 1.76)2928 Asthma Death Asthma Death or Life Threatening Experience Respiratory Death 4.37 (1.25, 15.34) (1.01, 2.89) (1.06, 4.41)2411 Respiratory Death or Life Threatening Experience 1.40 (0.91, 2.14)5036 TotalN=13176 N=13179 CaucasianN=9281N=9361 African AmericanN=2366N= ° Endpoints

A 28 Total N=13176 N=13179 ICSN=6127N=6138 Non-ICSN=7049N=7041 RR (95% CI)SAL nPLA n1° Endpoint Asthma Death Asthma Death or Life Threatening Experience Respiratory Death or Life Threatening Experience SMART Results All Patients and by ICS Use at Baseline (1.10, 5.22) (0.88, 5.94) (0.87, 2.93) (0.30, 6.04) (0.60, 2.58) (0.69, 5.86) (0.66, 2.23) (1.25, 15.34) (1.01, 2.89) (1.06, 4.41) (0.91, 2.14)5036 Respiratory Death 2° Endpoints.125

A 29 RR (95% CI)SAL nPLA n Asthma Death Asthma Death or Life Threatening Experience Respiratory Death or Life Threatening Experience SMART Results Ethnic Subgroups by ICS Use at Baseline African American ICS (SAL N=906, PLA N=785) African American Non-ICS (SAL N=1460, PLA N=1444) Cauc. ICS (SAL N=4586, PLA N=4637) Cauc. Non-ICS (SAL N=4695, PLA N=4724) (0.82, 11.11) (1.25, 25.26) (0.60, 2.60) (0.42, 1.84) (0.33, 29.92) (0.52, 37.89) (0.70, 7.42) (0.60, 8.93) (0.82, 11.11) (1.34, 81.58) (0.63, 4.17) (0.24, 1.90) (0.33, 29.92) (0.06, 15.35)11 Respiratory Death 2° Endpoints 1° Endpoint

A 30 SMART Summary More events occurred in patients receiving salmeterol More events occurred in patients receiving salmeterol – Suggestion of higher risk in African Americans – Suggestion of higher risk in patients not reporting ICS use at baseline Low number of events prevents definitive conclusions Low number of events prevents definitive conclusions No clear explanation from these data No clear explanation from these data

A 31 Dissemination of SMART Results Two ‘Dear Health Care Professional’ Letters Two ‘Dear Health Care Professional’ Letters – On the day SMART was stopped – When the labels were updated Labeling Revisions Labeling Revisions – Boxed warning added; Clinical Trials and Warnings sections updated for Serevent and Advair – Updated with final results

A 32 WARNING: Data from a large placebo-controlled US study that compared the safety of salmeterol (SEREVENT ® Inhalation Aerosol) or placebo added to usual asthma therapy showed a small but significant increase in asthma-related deaths in patients receiving salmeterol (13 deaths out of 13,176 patients treated for 28 weeks) versus those on placebo (3 of 13,179) (see WARNINGS in complete Prescribing Information). Important Safety Information

A 33 Dissemination of SMART Results Two ‘Dear Health Care Professional’ Letters Two ‘Dear Health Care Professional’ Letters – On the day SMART was stopped – When the labels were updated Labeling Revisions Labeling Revisions – Boxed warning added; Clinical Trials and Warnings sections updated for Serevent and Advair – Updated with final results Publications Publications – Abstract at American College of Chest Physicians – Manuscript accepted for publication by Chest

A 34 Epidemiology Studies

A 35 Epidemiology Studies Strengths Strengths – Utilization of comprehensive medical and pharmacy databases – Identification of a greater number of events Limitations Limitations – Assignment of treatment is not random – Potential confounding by differences in baseline characteristics

A 36 Studies of Severe Asthma Outcomes and Salmeterol Meier. Thorax 1997;52:612-7 (n=16,919) 2 Lanes et al. Am J Respir Crit Care Med 1998;158: (n=6533) 3 Williams et al. Thorax 1998;53:7-13 (n= 233) 4 Anderson et al. BMJ 2005;330: (n=1064) Resp Death Theo Resp Death Ipra ER Hosp ICU ICU Asthma Death Relative Risk Theo Usual Care

A 37 Ongoing Studies to Help Address SMART Findings Studies in African Americans Exacerbations in African American Subjects Exacerbations in African American Subjects – 1 year duration, 460 subjects – FP/salmeterol vs. FP Epidemiology study of African Americans and Caucasians Epidemiology study of African Americans and Caucasians – Medicaid data from 7 states, 1995 to 1999 – Association of asthma-related prescription medication use and asthma morbidity and mortality

A 38 Ongoing Studies to Help Address SMART Findings Studies Including Genetic Evaluations Response by beta 2 -receptor genotype Response by beta 2 -receptor genotype – 38-week duration, 540 subjects – FP/salmeterol vs. salmeterol Beta 2 -receptor and glucocorticoid pathway polymorphisms and clinical response Beta 2 -receptor and glucocorticoid pathway polymorphisms and clinical response – 1000 subjects from completed clinical trials – FP/salmeterol vs. salmeterol vs. FP

A 39 Ongoing Studies in Patients with COPD Mortality in patients with COPD Mortality in patients with COPD – 3-year duration, 6200 subjects – FP/salmeterol, salmeterol, FP vs. placebo COPD Exacerbations COPD Exacerbations – Two 1-year studies, 740 subjects each – FP/salmeterol vs. salmeterol

A 40 Benefit to Risk Summary Asthma is a serious disease with significant morbidity and mortality Asthma is a serious disease with significant morbidity and mortality Salmeterol provides substantial therapeutic benefits Salmeterol provides substantial therapeutic benefits – Improves lung function and asthma-related quality of life – Reduces symptoms, use of rescue medication, and exacerbations – Endorsed by evidenced-based treatment guidelines Salmeterol and serious asthma-related events Salmeterol and serious asthma-related events – Association observed in SNS and SMART – No association observed in epidemiology studies

A 41 Benefit to Risk Summary Prescribing information provides guidance on use of salmeterol Prescribing information provides guidance on use of salmeterol – Should not be used to treat acute symptoms – Is not a substitute for inhaled or oral corticosteroids – Consideration should be given to adding anti- inflammatory agents (e.g. corticosteroids) – Should not be initiated in patients with significantly worsening or acutely deteriorating asthma Incorporation of SNS and SMART results Incorporation of SNS and SMART results

A 42 Benefit to Risk Summary Salmeterol is an important therapeutic option Salmeterol is an important therapeutic option – Remains a valuable medication – Improves the level of care Favorable benefit to risk profile Favorable benefit to risk profile

A 43 External Experts Professor Richard Beasley, MBChB, DM, FRCP Professor Richard Beasley, MBChB, DM, FRCP – Director of the Medical Research Institute of New Zealand Eugene Bleecker, M.D. Eugene Bleecker, M.D. – Professor of Medicine and Section Head Pulmonary, Critical Care, Allergy and Immunologic Diseases at Wake Forest University Health Sciences – Co-Director, Center for Human Genomics George O’Connor, M.D., M.S. George O’Connor, M.D., M.S. – Professor of Medicine Division of Pulmonary and Critical Care Medicine Boston University School of Medicine – Director, Adult Asthma Program, Boston Medical Center