A 1 Pulmonary - Allergy Drugs Advisory Committee Meeting January 17, 2002 FLOVENT® DISKUS® NDA ADVAIR DISKUS® NDA

A 2 FLOVENT® DISKUS® and ADVAIR DISKUS® David Wheadon, MD Senior Vice President, Regulatory Affairs GlaxoSmithKline

A 3 sNDAs for FLOVENT DISKUS and ADVAIR DISKUS INDICATION Long term, twice-daily maintenance treatment of Chronic Obstructive Pulmonary Disease (including emphysema and chronic bronchitis)

A 4 SEREVENT® (salmeterol xinafoate) Serevent Inhalation Aerosol approved for COPD, 1998 Serevent Inhalation Aerosol approved for COPD, 1998 Approval sought for Serevent Diskus for the maintenance treatment of bronchospasm associated with COPD Approval sought for Serevent Diskus for the maintenance treatment of bronchospasm associated with COPD

A 5 FLOVENT (fluticasone propionate) Currently Approved in US for maintenance treatment of asthma Currently Approved in US for maintenance treatment of asthma Approved for COPD in 67 countries outside US Approved for COPD in 67 countries outside US Worldwide exposure estimate million patient years Worldwide exposure estimate million patient years Approval sought for Flovent Diskus for maintenance treatment of COPD at doses of 250mcg and 500mcg BID Approval sought for Flovent Diskus for maintenance treatment of COPD at doses of 250mcg and 500mcg BID

A 6 ADVAIR DISKUS (fluticasone propionate and salmeterol inhalation powder) Currently approved for maintenance treatment of asthma Currently approved for maintenance treatment of asthma Worldwide exposure estimate million patient years Worldwide exposure estimate million patient years Approval sought for maintenance treatment of COPD at doses of 250/50mcg and 500/50mcg BID Approval sought for maintenance treatment of COPD at doses of 250/50mcg and 500/50mcg BID

A 7 1 Data on file (analysis of NHANES III data), GlaxoSmithKline. 2 National Center for Health Statistics, National Health Interview Survey, Information cited in: American Lung Association, trends in Chronic bronchitis and Emphysema: Morbidity and Mortality, December, Murray CJL and Lopez AD, eds. The Global Burden of Disease. Vol :362. Impact of COPD in the US Affects an estimated 21.7 million Americans 1 Affects an estimated 21.7 million Americans 1 – 6.5 Million Diagnosed – 4.3 Million Treated With Prescription Medications The fourth leading cause of death 2 The fourth leading cause of death 2 – 114,000 deaths in – Third leading cause of death by Annual cost >$30 billion 2 Annual cost >$30 billion 2 – $14.7 billion in direct healthcare costs – $15.7 billion in indirect healthcare costs

A 8 G lobal Initiative for Chronic O bstructive L ung D isease Global Initiative for Chronic Obstructive Lung Disease. Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease: NHLBI/WHO Workshop Report. Bethesda, Md: National Heart, Lung, and Blood Institute, National Institutes of Health; March NIH publication 2701A.

A 9 Clinical Effects of ICS in COPD ReferenceNDurationTreatment/DayOutcome Nishimura et al., wBDP 3000mcg  FEV1,  Sx O’Brien et al., wBDP 1500mcgFEV1 preserved Thompson et al., wBDP 1000mcg  FEV1,  bronchitis Weiner et al., wBUD 800mcg  FEV1,  prn med Weiner et al., wBUD 1600mcg  FEV1,  prn med Auffarth et al., wBUD 1600mcg  dyspnea Kerstjens et al., wBDP 800mcg  FEV1 Dompeling et al., wBDP 800mcg  PEF,  Sx Paggiaro et al., wFP 1000mcg  FEV1,  exac ISOLDE, YFP 1000mcg  FEV1,  QoL,  exac Euroscope, YBUD 800mcg  FEV1,  exac Lung Health II, YTAA 1200mcg  Sx,  exac Sin & Tu, Varied  morbidity, mortality

A 10 Current Use of ICS for COPD: Prescription Data from July % of all COPD patients were prescribed ICS therapy 40% of all COPD patients were prescribed ICS therapy 46% of all patients prescribed 2 or more COPD maintenance medications (any medication other than albuterol) 46% of all patients prescribed 2 or more COPD maintenance medications (any medication other than albuterol) – 72% prescribed an ICS – 57% prescribed an ICS + a maintenance bronchodilator – 17% prescribed Advair Source: NDC Health, July 2001

A 11 SUMMARY COPD is a serious public health issue COPD is a serious public health issue Considerable unmet medical needs Considerable unmet medical needs New treatment options are needed New treatment options are needed

A 12 Order of GSK Presentation Scientific and Clinical Rationale Scientific and Clinical Rationale – Dr. Malcolm Johnson (15 minutes) Clinician’s Perspective Clinician’s Perspective – Dr. James Donohue (15 minutes) Clinical Efficacy and Safety Clinical Efficacy and Safety – Dr. Tushar Shah (45 minutes) Conclusion and Q & A Conclusion and Q & A – Dr. David Wheadon

A 14 Scientific and Clinical Rationale Malcolm Johnson, PhD Global Director of Respiratory Science GlaxoSmithKline

A 15 Inflammation Structural Changes Airway Obstruction Pathology of COPD

A 16 Airway Obstruction Inflammation Structural Changes Smooth muscle contraction Increased cholinergic tone Loss of elastic recoil Increased Neutrophils, macrophages, CD8+ lymphocytes. Elevated IL-8, TNF  Protease/anti- protease imbalance Alveolar destruction Collagen deposition Glandular hypertrophy Airway fibrosis Symptoms  FEV 1 Exacerbations Pathophysiological Features of COPD

A 17 Do inhaled corticosteroids reduce inflammation in COPD? Are inhaled corticosteroids effective treatment for COPD? Inhaled Corticosteroids

A 18 Anti-Inflammatory Effects of ICS in COPD ReferenceNDurationTreatment/DayOutcome Balbi8 6 w BDP 1500mcg  BAL neutrophils, IL-8 et al., 2000 and MPO Confalonieri248 wBDP 1500mcg  Sputum neutrophils et al., 1998 Llewellyn-Jones178 wFP 1500mcg  Sputum neutrophil et al., 1996 chemotactic activity Thompson306 wBDP 1000mcgImprovement in bronchial et al., 1992cell counts and epithelial lining fluid proteins Yildiz18 8 wFP 1500mcg  Sputum neutrophils et al., 2000 Hattotuwa3712 wFP 1000mcg  Biopsy CD8+/CD4+ et al., 1999, 2000Tcell ratio and mast cells Verhoeven2024 wFP 1000mcg  Biopsy CD8+ Tcells and et al., 1999 eosinophils Verhoeven2024 wFP 1000mcg  Biopsy CD8+ Tcells and et al., 1999 eosinophils Keatings132 wBUD 1600mcgNo change in total and et al.,1996differential cell counts or TNF , ECP, EPO and MPO Culpitt134 wFP 1000mcgNo change in sputum et al., 1999neutrophils, IL-8 or SLPI O’Brien56 wBDP 400mcg No change in sputum et al., 2001 neutrophils

A 19 Yildiz et al. Respiration. 2000; 67: Placebo FP 1500 mcg/day * * * P<0.05 x10 6 cells/g percent Fluticasone Propionate Reduces Total Cell Counts and Neutrophils in the Sputum of COPD Patients Total Cell Counts Neutrophils

A 20 Airway Obstruction Inflammation Structural Changes Smooth muscle contraction Increased cholinergic tone Loss of elastic recoil Increased Neutrophils, macrophages, CD8+ lymphocytes. Elevated IL-8, TNF  Protease/anti- protease imbalance Alveolar destruction Collagen deposition Glandular hypertrophy Airway fibrosis Symptoms  FEV 1 Exacerbations ICS (FP) Positive Effect ? ICS (FP) Reduces Inflammation in COPD

A 21 Do inhaled corticosteroids reduce inflammation in COPD? Are inhaled corticosteroids effective treatment for COPD? Inhaled Corticosteroids

A 22 Clinical Effects of ICS in COPD ReferenceNDurationTreatment/DayOutcome Nishimura et al., wBDP 3000mcg  FEV 1,  Sx O’Brien et al., wBDP 1500mcgFEV 1 preserved Thompson et al., wBDP 1000mcg  FEV 1,  bronchitis Weiner et al., wBUD 800mcg  FEV 1,  prn med Weiner et al., wBUD 1600mcg  FEV 1,  prn med Auffarth et al., wBUD 1600mcg  dyspnea Kerstjens et al., wBDP 800mcg  FEV 1 Dompeling et al., wBDP 800mcg  PEF,  Sx Paggiaro et al., wFP 1000mcg  FEV 1,  exac ISOLDE, YFP 1000mcg  FEV 1,  QoL,  exac Euroscope, YBUD 800mcg  FEV 1,  exac Lung Health II, YTAA 1200mcg  Sx,  exac Sin & Tu, Varied  morbidity, mortality Keatings et al., wBUD 1600mcg No  PFT, Sx, prn med Culpitt et al., w FP 1000mcg No  PFT, Sx Engel et al., wBUD 800mcg No  PFT, Sx Watson et al., wBUD 1200mcg No  PFT, Sx Bourbeau et al., wBUD 1600mcg No  PFT, Sx, QoL Copenhagen City, YBUD 800mcg No  PFT, Sx, exac

A 23 Reduced Risk of Mortality and Repeat Hospitalization with Inhaled Corticosteroids Adapted from Sin DD, Tu JV. Am J Respir Crit Care Med 2001;164: Inhaled Corticosteroids No Inhaled Corticosteroids COPD Hospitalization Free Survival Months After Discharge ICS associated with a 26% lower relative risk for all-cause mortality and repeat hospitalization

A 24 Week  FEV 1 (L) P<0.01 P<0.02 Paggiaro et al. Lancet. 1998; 351: Fluticasone Propionate Significantly Improves Pre-dose FEV 1 in COPD

A 25 Collection of Exacerbation Data in Paggiaro et al., 1998 Exacerbation history: at least 1/ year (treated by physician or hospital) for previous 3 years Exacerbation history: at least 1/ year (treated by physician or hospital) for previous 3 years Exacerbation: worsening of COPD symptoms requiring changes to normal treatment Exacerbation: worsening of COPD symptoms requiring changes to normal treatment Exacerbation severity: Exacerbation severity: – Mild: patient self-managed at home – Moderate:patient treated by a physician – Severe: patient hospitalized Multiple exacerbations requiring OCS were allowed Multiple exacerbations requiring OCS were allowed Paggiaro et al. Lancet. 1998; 351:

A 26 Fluticasone Propionate Reduces Moderate/Severe Exacerbations in COPD Treatment Group Fluticasone Placebo propionate (n=139) (n=142) Number of exacerbations* Total11176 Number of Patients with one or more exacerbations Total 5145 Mild 7 (14%)17 (38%)‡ Moderate/severe44 (86%) 27 (60%) ‡ * Each patient may have experienced more than one exacerbation. ‡ p< Paggiaro et al. Lancet. 1998; 351:

A 27 2 Months 3 yrs FP MDI 500mcg BID Corticostero id Withdrawal Placebo BID Placebo Run-in N = 751 Reversibility <10% predicted Mean FEV 1 50% at baseline Burge PS et al. Br Med J. 2000;320: Inhaled Steroids in Obstructive Lung Disease in Europe (ISOLDE)

A 28 *p< Time (months) Post-bronchodilator FEV 1 FP 500µg BID (n=376) Placebo BID (n=375) * * * * * FP Improves Post-bronchodilator FEV 1 Response in COPD: ISOLDE Study Adapted from Burge PS et al. Br Med J. 2000;320:

A 29 FP Reduces Median Annual Exacerbation Rate: ISOLDE Study O.99* *p=0.026 Burge PS et al., Br Med J. 2000;320: Exacerbations/patient/year

A 30 An increase in score reflects a decrease in quality of life. *St George’s Respiratory Questionnaire Burge PS et al. Br Med J. 2000;320: FP Slows the Decline in Quality of Life as Measured by SGRQ*: ISOLDE Study Change in Total Score Placebo Fluticasone propionate Threshold of clinical significance Time (months) Regression Analysis P = 0.004

A 31 Airway Obstruction Inflammation Structural Changes Smooth muscle contraction Increased cholinergic tone Loss of elastic recoil Increased Neutrophils, macrophages, CD8+ lymphocytes. Elevated IL-8, TNF  Protease/anti- protease imbalance Alveolar destruction Collagen deposition Glandular hypertrophy Airway fibrosis  Symptoms  FEV 1  Exacerbations ? ICS (FP) Reduces Inflammation in COPD ICS (FP) Positive Effect

A 32 Salmeterol in COPD

A 33 Salmeterol is a Long-Acting Bronchodilator in COPD *P <.001 salmeterol vs placebo. Adapted from Mahler DA et al. Chest. 1999;115: * * * * * * * Time (hours)  FEV 1 (L) Salmeterol Day 1 Salmeterol Day 84 Placebo * *

A 34 Salmeterol Reduces Airway Obstruction in COPD Airway Obstruction Inflammation Structural Changes Smooth muscle contraction Increased cholinergic tone Loss of elastic recoil Increased Neutrophils, macrophages, CD8+ lymphocytes. Elevated IL-8, TNF  Protease/anti- protease imbalance Alveolar destruction Collagen deposition Glandular hypertrophy Airway fibrosis Symptoms  FEV 1 Exacerbations Salmeter ol Positive Effect

A 35 Combined Effects of Salmeterol and FP in COPD Salmeterol + FP Airway Obstruction Inflammation Structural Changes Smooth muscle contraction Increased cholinergic tone Loss of elastic recoil Increased Neutrophils, macrophages, CD8+ lymphocytes. Elevated IL-8, TNF  Protease/anti-protease imbalance Alveolar destruction Collagen deposition Glandular hypertrophy Airway fibrosis  Symptoms  FEV 1  Exacerbations ?

A 36 Corticosteroids Increase Respiratory Mucosal Beta 2 -receptors Baseline BDP 100mcg for 3 days beta 2 -receptor/actin ratio p<0.04 * Baraniuk et al AJRCCM 155: (1997) *

A 37 Adapted from Pang L, and Knox AJ. Am J Respir Cell Mol Biol. 2000; 23: Salmeterol Potentiates the Effect of FP on TNF  -induced IL8 Release from Airway Smooth Muscle Cells IL8 (pg/ml)  (0.1 µM)(1 µM) *P <0.01 (0.1 µM)

A 38 Rationale for Combining FP with Salmeterol Fluticasone propionate is an effective inhaled anti-inflammatory corticosteroid with clinical benefit in COPD. Fluticasone propionate is an effective inhaled anti-inflammatory corticosteroid with clinical benefit in COPD. Salmeterol is a long-acting  2-adrenoceptor agonist with demonstrated efficacy in COPD. Salmeterol is a long-acting  2-adrenoceptor agonist with demonstrated efficacy in COPD. Each molecule influences a different aspect of COPD pathophysiology, so together they provide a broad therapeutic cover. Each molecule influences a different aspect of COPD pathophysiology, so together they provide a broad therapeutic cover. There is some evidence of interaction between these molecules which may be important in improving the overall efficacy of the combination. There is some evidence of interaction between these molecules which may be important in improving the overall efficacy of the combination.

A 40 Clinician’s Perspective James F. Donohue, MD Chief, Pulmonary and Critical Care Medicine University of North Carolina, Chapel Hill

A 41 Overview Diagnosis of COPD Diagnosis of COPD Evaluating treatment effects in COPD Evaluating treatment effects in COPD – FEV 1 – Other measures GOLD guidelines GOLD guidelines Clinician’s Perspective Clinician’s Perspective

A 42 Diagnosis of COPD Clinically based on: Clinically based on: – Smoking history – Age – Symptoms – Persistent airflow obstruction (spirometry) FEV 1 post bronchodilator < 80% predicted FEV 1 post bronchodilator < 80% predicted FEV 1 / FVC < 70% FEV 1 / FVC < 70% The presence of reversibility does not exclude a diagnosis of COPD The presence of reversibility does not exclude a diagnosis of COPD

A 43 Bronchodilator Response in COPD Intermittent Positive Pressure Breathing Trial (IPPB) Evaluated the BD response to inhaled isoproteronol in 985 subjects with COPD (asthma excluded) Evaluated the BD response to inhaled isoproteronol in 985 subjects with COPD (asthma excluded) Pre and post- bronchodilator FEV 1 evaluated every 3 months for 3 yrs. Pre and post- bronchodilator FEV 1 evaluated every 3 months for 3 yrs. Key demographics: Key demographics: – Age: 60.9 – Male: 79% – Smoking Status: 54 pack yrs 54 pack yrs 40% current smokers 40% current smokers – FEV 1 (% predicted): 36 % Anthonisen, et al. Am Rev Respir Dis, 1986;133:14-20.

A 44 Approximately half of the subjects were reversible at screening (>12% increase in FEV 1 over baseline) Approximately half of the subjects were reversible at screening (>12% increase in FEV 1 over baseline) In subjects non-reversible at screening (<10% increase in FEV 1 ) In subjects non-reversible at screening (<10% increase in FEV 1 ) – 30% of these subjects had a >15% increase in FEV 1 at each subsequent test day – 68% of these subjects had a >15% increase in FEV 1 on at least one of the 7 follow-up test days Anthonisen, et al. Am Rev Respir Dis, 1986;133: Annals of Internal Medicine, 1983;99: Bronchodilator Response in COPD IPPB Trial

A 45 Demographic and Reversibility Data from Clinical Trials in COPD Data on file: SLGA 4004, SLGA 4005, Chest 1994; 105: Chest 1999; 115; Am J Respir Crit Care Med. Vol 165. p , SalmeterolCombiventFormoterol (n=816)(n=1067)(n=780) Age % male Pack yr63na42 FEV 1 L (% pred) 1.25 (40)0.99 (36)1.3 (45) % Pts Rev

A 46 Efficacy Measures Used to Assess Treatment Response in COPD Spirometry (FEV 1 ) Spirometry (FEV 1 ) – Objective, reproducible – Diagnostic and prognostic Other Measures Other Measures – Health Status (QOL) – Symptoms – Exacerbations

A 47 Postdose (hours) FEV 1 Response with Combivent ® on Day 85 Combivent is a registered trademark of Boehringer Ingelheim. Bone R et al. Chest. 1994;105:  FEV 1 (%) Ipratropium + Albuterol (n = 173) Albuterol (n = 165) Ipratropium (n = 176)

A 48 ns= not significant compared to baseline and/or components CRDQ = Chronic Respiratory Index Questionnaire Other Efficacy Measures Observed with Combivent Ipratropium + AlbuterolIpratropiumAlbuterol Measure (n=173)(n=176)(n=165) CRDQ (QOL) nsnsns Physician Global ns ns ns Evaluation Symptom Scorensnsns PEFRnsnsns Bone R et al. Chest. 1994;105:

A 49  = p≤0.05 salmeterol vs. placebo — = p>0.05 salmeterol vs. placebo Rennard et al.*Mahler et al.** Measure (n=405)(n=411) PEF   NT Awakenings   Ventolin use   TDI (Dyspnea) — — CRDQ—— Diary Symptoms—— Borg Dyspnea—— Six min walk—— COPD exac. (% pts)—— Time to first exac.—  *Am. J. Respir. Crit. Care Med. 2001;163: **Chest 1999;115: Other Efficacy Measures Observed with Serevent MDI

A 50 G lobal Initiative for Chronic O bstructive L ung D isease Global Initiative for Chronic Obstructive Lung Disease. Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease: NHLBI/WHO Workshop Report. Bethesda, Md: National Heart, Lung, and Blood Institute, National Institutes of Health; March NIH publication 2701A.

A 51 SeveritySymptomsSpirometryTreatment At Risk Stage 0 +/- Chronic cough, sputum NormalEducation, avoidance risk factors, flu vaccine Mild Stage I +/- Chronic cough, sputum FEV 1 / FVC < 70% FEV 1 > 80% predicted Short-acting  2 - adrenergic PRN Moderate Stage II A & B +/- Chronic cough, sputum, dyspnea Reg Bronchodilator Consider ICS Rehabilitation Severe Stage III +/- Cough, sputum, dyspnea Reg Bronchodilator Consider ICS Rehabilitation LT Oxygen Surgery FEV 1 / FVC < 70% FEV 1 < 30% or FEV 1 < 50% with respiratory failure, cor pulmonale FEV 1 / FVC < 70% FEV 1 30% - 80% predicted GOLD: Recommendations for ICS Use

A 52 A Physician’s Perspective on Treatment of COPD Smoking cessation Smoking cessation Bronchodilator therapy alone is not adequate in many patients Bronchodilator therapy alone is not adequate in many patients Use of ICS in COPD Use of ICS in COPD

A 53 CONCLUSIONS Diagnosis of COPD is based on several clinical parameters Diagnosis of COPD is based on several clinical parameters – A large proportion of patients with COPD are reversible Small magnitude of response on efficacy measures are usually observed Small magnitude of response on efficacy measures are usually observed Guidelines support use of ICS in patients with moderate to severe COPD Guidelines support use of ICS in patients with moderate to severe COPD

A 55 Overview of Clinical Program Tushar Shah, MD Vice President Respiratory Clinical Development

A 56 Topics of Presentation Review results of clinical program designed in consultation with FDA Review results of clinical program designed in consultation with FDA – Primary objectives FLOVENT DISKUS: Greater efficacy compared to placebo with no significant safety concerns FLOVENT DISKUS: Greater efficacy compared to placebo with no significant safety concerns ADVAIR DISKUS: Greater efficacy compared to fluticasone propionate (FP) and salmeterol alone with no significant safety concerns ADVAIR DISKUS: Greater efficacy compared to fluticasone propionate (FP) and salmeterol alone with no significant safety concerns Review long-term safety data with FP Review long-term safety data with FP

A 57 Definitions FSC =Fluticasone propionate and Salmeterol Combination product FSC =Fluticasone propionate and Salmeterol Combination product – FSC 500/50=ADVAIR 500 – FSC 250/50=ADVAIR 250

A 58 Overview of Clinical Program FLTA3025FP weeks N=640FP 250 Placebo SFCA3006FSC 500/5024 weeks N=691FP 500 SAL 50 Placebo SFCA3007FSC 250/5024 weeks N=723FP 250 SAL 50 Placebo

A 59 Study Design: FLTA weeks 24 weeks FP 500mcg BID (n=218) FP 250mcg BID (n=216) PRN albuterol Placebo BID (n=206) Placebo Run-in

A 60 Study Design: SFCA weeks Placebo BID (n=185) FSC 500/50mcg BID (n=169) FP 500mcg BID (n=173) SAL 50mcg BID (n=164) 24 weeks Placebo Run-in PRN albuterol

A 61 Study Design: SFCA3007 Placebo BID (n=185) FSC 250/50mcg BID (n=178) FP 250mcg BID (n=183) SAL 50mcg BID (n=177) 2 weeks 24 weeks Placebo Run-in PRN albuterol

A 62 Key Inclusion Criteria COPD as defined by ATS COPD as defined by ATS Age  40 years Age  40 years Current or ex-smoker (  20 pack years) Current or ex-smoker (  20 pack years) Pre-bronchodilator FEV 1 <65% predicted Pre-bronchodilator FEV 1 <65% predicted FEV 1 /FVC  70% FEV 1 /FVC  70% Dyspnea and symptoms of chronic bronchitis Dyspnea and symptoms of chronic bronchitis

A 63 Key Exclusion Criteria Current diagnosis of asthma Current diagnosis of asthma Use of systemic corticosteroids or high dose ICS for 6 weeks prior to screening visit Use of systemic corticosteroids or high dose ICS for 6 weeks prior to screening visit Need for long-term oxygen therapy Need for long-term oxygen therapy COPD exacerbation during run-in COPD exacerbation during run-in

A 64 Primary Efficacy Measures Pre-dose FEV 1 Pre-dose FEV 1 – FP vs. Placebo – FSC vs. SAL (contribution of FP) 2 hour post-dose FEV 1 2 hour post-dose FEV 1 – FSC vs. FP (contribution of SAL)

A 65 Secondary Efficacy Measures Transition Dyspnea Index (TDI) Transition Dyspnea Index (TDI) Chronic Respiratory Disease Questionnaire (CRDQ) Chronic Respiratory Disease Questionnaire (CRDQ) Chronic Bronchitis Symptoms Questionnaire (CBSQ) Chronic Bronchitis Symptoms Questionnaire (CBSQ) Diary Card (AM PEF, Ventolin use and nighttime awakenings) Diary Card (AM PEF, Ventolin use and nighttime awakenings) Time to first COPD exacerbation Time to first COPD exacerbation

A 66 Primary Analysis Endpoint was used to account for patient withdrawals Endpoint was used to account for patient withdrawals Endpoint =Last post-baseline observation Endpoint =Last post-baseline observation

A 67 Patient Demography and Baseline Characteristics Were Similar Across Treatment Groups FSC250/FSC500/ PlaceboSAL50FP250FP Variable n=572n=337n=399n=386n=178n=165 Age (yrs) Gender (% male)70%61%69%64%61%62% Race (% white)94%94%93%94%96%95% Curr Smoker %48%49%46%47%43%46% Pack years Prev ICS27%25%29%28%23%28% FEV 1 % pred42%41%41%41%41% 41% BD resp. (% pts rev)57%53%57%55%56%53% Emphysema %75%72%73%74%71%75%

A 68 FLOVENT EFFICACY RESULTS

A 69 FLOVENT Primary Efficacy Measure Pre-dose FEV 1 Pre-dose FEV 1 – FP vs. Placebo

A 70 * P=0.010 vs PLA FLTA3025: Dose-Related Increases in Pre-Dose FEV 1 Were Seen with FP Treatment vs. Placebo * Endpoint (8%) (5%)  FEV 1 (ml) (2%)

A 71 SFCA3006: Significantly Greater Improvement in Pre-Dose FEV 1 Seen with FP500 vs. Placebo Endpoint (2% ) (11% ) *P<0.001 vs PLA  FEV 1 (ml) *

A 72 *P<0.001 vs PLA SFCA3007: Significantly Greater Improvements in Pre-Dose FEV 1 Seen with FP250 vs. Placebo Endpoint  FEV 1 (ml) * (1%) (11%)

A 73 *P=0.012 vs SAL SFCA3007: Additional Evidence of Improvements in Pre-Dose FEV 1 with FP250 Endpoint (1%) (11%) (17%) (9%)  FEV 1 (ml) *

A 74 Change in Pre-dose FEV 1 (mL) for FP at Endpoint in Reversible/Non-Reversible Patients FLTA3025 SFCA3007 SFCA3006 PLAFP250FP500PLAFP250PLAFP500 Rev Non-Rev

A 75 = statistically significantly different than placebo  = P≤0.05, FP vs. Placebo — = P>0.05, FP vs. Placebo Greater Improvements Seen for Most Secondary Efficacy Measures with FP vs Placebo FLTA3025SFCA3007FLTA3025SFCA3006 Measure FP250FP250FP500FP500 TDI (dyspnea) — —  CRDQ (QOL)   — CBSQ (cough/sputum) — — — PEF     NT awakenings     Ventolin use  —   Time to COPD exac. — — — — * * * *

A 76 FLOVENT EFFICACY SUMMARY Significantly greater improvements in primary efficacy measure (pre- dose FEV 1 ) Significantly greater improvements in primary efficacy measure (pre- dose FEV 1 ) – Magnitude of improvement related to reversibility Secondary efficacy measures supportive Secondary efficacy measures supportive Suggestion of dose response Suggestion of dose response

A 77 ADVAIR EFFICACY RESULTS

A 78 ADVAIR Primary Efficacy Measure Pre-dose FEV 1 Pre-dose FEV 1 – FSC vs. SAL (contribution of FP)

A 79 SFCA3006: Significantly Greater Improvement in Pre-Dose FEV 1 Seen with FSC500/50 vs. SAL50  FEV 1 (ml) Endpoint (15%) (10%) *P=0.012 vs SAL *

A 80 SFCA3006: Significantly Greater Improvement in Pre-Dose FEV 1 Seen with FSC500/50 vs. SAL50 Endpoint (15%) (2% ) (11% ) (10%) *P=0.012 vs SAL *  FEV 1 (ml)

A 81 SFCA3007: Significantly Greater Improvements in Pre-Dose FEV 1 Seen with FSC250/50 vs. SAL50 Endpoint (17%) (9%) *P=0.012 vs SAL  FEV 1 (ml) *

A 82 SFCA3007: Significantly Greater Improvements in Pre-Dose FEV 1 Seen with FSC250/50 vs. SAL50 Endpoint (1%) (11%) (17%) (9%) * *P=0.012 vs SAL  FEV 1 (ml)

A 83 ADVAIR Primary Efficacy Measure 2 hour post-dose FEV 1 2 hour post-dose FEV 1 – FSC vs. FP (contribution of SAL)

A 84 SFCA3006: Significantly Greater Improvements in Post-Dose FEV 1 Seen with FSC500/50 vs. FP500 Endpoint (13%) (24% ) *P<0.001 vs FP *  FEV 1 (ml)

A 85 SFCA3006: Significantly Greater Improvements in Post-Dose FEV 1 Seen with FSC500/50 vs. FP500 Endpoint (4%) (13%) (22% ) (24% ) *P<0.001 vs FP *  FEV 1 (ml)

A 86  FEV 1 (ml) SFCA3007: Significantly Greater Improvements in Post-Dose FEV 1 Seen with FSC250/50 vs. FP250 Endpoint (14% ) (27% ) *P<0.001 vs FP *

A 87  FEV 1 (ml) SFCA3007: Significantly Greater Improvements in Post-Dose FEV 1 Seen with FSC250/50 vs. FP250 Endpoint (6%) (14% ) (19% ) (27% ) *P<0.001 vs FP *

A 88 PLA SALFPFSC250/50PLASALFPFSC500/50 Pre-dose Rev Non-Rev hr Post-dose Rev Non-Rev Change in FEV 1 (mL) for FSC at Endpoint in Reversible/Non-Reversible patients SFCA3007SFCA3006

A 89 SFCA3007SFCA3007SFCA3006SFCA3006 Measure SAL50FP250SAL50FP500 TDI (dyspnea)  — — CRDQ (QOL) — —— CBSQ (cough/sputum) — — — PEF     NT awakenings —    Ventolin use  —   Time to COPD exac.———— Similar Improvements Seen in Secondary Efficacy Measures for FP and SAL vs. PLA = statistically significantly different than placebo  = P≤0.05, FP vs. Placebo — = P>0.05, FP vs. Placebo * * * *

A 90 Greater Improvements Seen for Almost All Secondary Efficacy Measures with FSC vs. Placebo SFCA3007SFCA3006 Measure FSC250/50FSC500/50 TDI (dyspnea) CRDQ (QOL) CBSQ (cough/sputum) PEF   NT awakenings   Ventolin use   Time to COPD exac—— = statistically significantly different than placebo  = P≤0.05, FP vs. Placebo — = P>0.05, FP vs. Placebo * * * ** **

A 91 * P≤0.005 vs PLA † P<0.001 vs SAL SFCA3006: Significantly Greater Improvement in TDI Score Seen with FSC500/50 vs. SAL50 and PLA Endpoint TDI Score *,† *

A 92 Treatment with FSC250/50 Led to Greater Increase in AM PEF Within 1 Day  PEF (L/min) * P<0.001 vs PLA † P<0.001 FSC vs FP and SAL *,† * *

A 93 ADVAIR EFFICACY SUMMARY Significantly greater improvements in both trials on the primary efficacy measures Significantly greater improvements in both trials on the primary efficacy measures – Advair vs. salmeterol for pre-dose FEV 1 – Advair vs. FP for 2-hour post-dose FEV 1 – Magnitude of improvement related to reversibility Secondary efficacy measures supportive Secondary efficacy measures supportive Advair 250/50 and 500/50 provide similar benefits Advair 250/50 and 500/50 provide similar benefits

A 94 SAFETY RESULTS Flovent / Advair

A 95 Safety Exposure 2,054 Patients in clinical program 2,054 Patients in clinical program – 790 on FP – 347 on Advair Additional safety from 1298 COPD patients from non US studies evaluating FP Additional safety from 1298 COPD patients from non US studies evaluating FP Supported by extensive safety in asthma Supported by extensive safety in asthma

A 96 Adverse Events Occurred at Similar Frequency Across Treatment Groups PLASAL50FP250FP500 FSC250/50 FSC500/50n=576n=341n=399n=391n=178 n=169 Mean Exposure (days) Patients with AE (%) Patients withdrawn due to AE (%) Patients with SAE (%) Deaths400000

A 97 PLASAL50FP250FP500 FSC250/50 FSC500/50 Adverse Eventsn=576n=341n=399n=391n=178n=169 Candidiasis1%2%7%13%11%11% Throat Irritation6%7%9%9%8%11% Hoarseness /1%<1%5%5%5%3% Dysphonia Fractures2%<1%1%1%2%2% Cataracts<1%0%0%<1%0%0% Ocular Pressure<1%0%0%0%0%1% Disorders Similar Adverse Events of Special Interest Except for Expected Topical Effects of ICS

A 98 PLASAL50FP250FP500 FSC250/50 FSC500/50 Pneumonian=576n=341n=399n=391n=178n=169 Adverse Events (1.2%) (0.6%) (1.8%) (2.6%)(1.2%) Serious Adverse Events (0.5%) (0.6%) (1.3%) (1.8%) (1.2%) Comparable Incidence of Pneumonia Across Treatment Groups

A 99 HPA Axis Monitoring (Performed in a Subset of Patients) 12 hour unstimulated cortisol profile in FLTA3025 (n=86) 12 hour unstimulated cortisol profile in FLTA3025 (n=86) In SFCA3006 and SFCA3007 (n=359) In SFCA3006 and SFCA3007 (n=359) – Morning cortisol concentrations – Short ACTH stimulation test

A 100 No Clinically Significant Difference in HPA Axis Results Between FSC and Individual Agents or Placebo 12 hour unstimulated plasma cortisol profile 12 hour unstimulated plasma cortisol profile – FP250: 10% < placebo (N.S.) – FP500: 21% < placebo (p<0.05) The incidence of abnormal morning cortisol was similar across all treatment groups The incidence of abnormal morning cortisol was similar across all treatment groups The incidence of abnormal short ACTH stimulation tests was similar across all treatment groups The incidence of abnormal short ACTH stimulation tests was similar across all treatment groups

A 101 SUMMARY OF SAFETY RESULTS Flovent Diskus Flovent Diskus – Flovent was well tolerated – No clinically relevant safety concerns identified compared to placebo Advair Diskus Advair Diskus – Advair was well tolerated – No difference in safety results between Advair and individual agents and/or placebo

A 102 Long-term Safety Data with FP Comparison of systemic exposure between patients with asthma and COPD Comparison of systemic exposure between patients with asthma and COPD Clinical studies examining bone mineral density and ophthalmic effects in patients with asthma Clinical studies examining bone mineral density and ophthalmic effects in patients with asthma Incidence of fractures and ophthalmic AEs in a 3 year clinical study in patients with COPD Incidence of fractures and ophthalmic AEs in a 3 year clinical study in patients with COPD

A 103 The Range of Systemic Exposure with FP Diskus in COPD is Not Greater Than FP CFC MDI in Asthma Asthma Diskus 500mcg BID CFC MDI 440mcg BID COPD FP AUC last (pg*h/mL)

A 104 Clinical Studies Examining BMD and/or Ophthalmic Effects of FP in Patients with Asthma Two 2-year safety studies of FP vs placebo Two 2-year safety studies of FP vs placebo – FP 88mcg, FP 440mcg CFC MDI BID (FLTA3001) – FP 500mcg ROTADISK BID (FLTA3017) Comparator MDI studies Comparator MDI studies – FP versus BDP (3 trials) – FP versus budesonide (2 trials)

A 105 Mean Percent Change in Lumbar Spine BMD was Similar Between FP Groups Compared to Placebo Weeks Mean Percent Change from Baseline Data on File, GlaxoSmithKline (FLTA3001).

A 106 No Evidence of Cataracts or Glaucoma was Seen with FP versus Placebo Treatment No posterior subcapsular cataracts No posterior subcapsular cataracts No diagnosis of glaucoma No diagnosis of glaucoma

A 107 BMD Results from Clinical Trials Comparing FP MDI vs. Other ICS Treatment Groups (mcg BID)BMD ResultsReference FP 250, 375, or 500FP:  at all BMD sites assessedPauwels, 1998 versusBDP:  at femoral neck; trochanter; versusBDP:  at femoral neck; trochanter; BDP 500, 750, or 1000Ward’s triangle FP 500 versus BDP 1000FP: No vertebral trabecular bone declineEgan, 1999 BDP:  Vertebral trabecular bone FP and BDP:  at spine; femoral neck FP 200 versus BDP 400FP:  at lumbar spineMedici, 2000 FP 375 versus BDP 750BDP:  at lumbar spine FP 500 versus BUD 800FP and BUD:  at lumbar spine; trochanterHughes, 1999 FP:  at femoral neck BUD:  at femoral neck FP 250 versus BUD 400FP and BUD:  at all BMD sites assessed Harmanci, 1999

A 108 Placebo BIDFP500mcg BID n=370n=372 Mean Exposure (days) Adverse Events Fractures17 (5%)9 (2%) Cataracts 7 (2%)5 (1%) Ocular Pressure Disorders 3 (<1%)6 (2%) Serious Adverse Events Fractures 7 (2%)4 (1%) ISOLDE: Adverse Events of Special Interest

A 109 Summary Long-term Safety Data with FP Exposure data allows extrapolation of safety data from asthma to COPD Exposure data allows extrapolation of safety data from asthma to COPD – Two 2-year placebo controlled FP studies showed no clinically relevant BMD or eye findings – FP vs BDP studies suggest not all ICS may have same predisposition to effect BMD No evidence of increased incidence of fractures and ophthalmic AEs over 3 years of FP treatment in COPD No evidence of increased incidence of fractures and ophthalmic AEs over 3 years of FP treatment in COPD

A 110 Proposed Dosage and Administration Recommendations For Flovent Diskus: The starting dosage is 250mcg twice daily For Flovent Diskus: The starting dosage is 250mcg twice daily For Advair Diskus: The starting dosage is 250/50mcg twice daily For Advair Diskus: The starting dosage is 250/50mcg twice daily For patients who do not respond adequately to the starting dose, increasing the dose to 500mcg for Flovent and 500/50 for Advair twice daily may provide additional control.

A 111 CONCLUSIONS Clinical programs achieved regulatory objectives Clinical programs achieved regulatory objectives – Flovent: greater improvement in primary efficacy measure with no safety issues – Advair: superiority over individual components in primary efficacy measures with a similar safety profile Long-term safety data provide further reassurance on the use of FP in treatment of COPD Long-term safety data provide further reassurance on the use of FP in treatment of COPD

A 113 Summary Remarks David Wheadon, MD Senior Vice President, Regulatory Affairs GlaxoSmithKline

A Proportion of 1965 Mortality Rate –59% –64% –35% +163% –7% Coronary Heart Disease Coronary Heart Disease Stroke Other CVD COPD All Other Causes All Other Causes COPD is a Significant Public Health Problem in the US

A 115 Current Therapeutic Management of COPD COPD remains under diagnosed and under treated COPD remains under diagnosed and under treated Bronchodilators are the only approved treatments Bronchodilators are the only approved treatments Additional treatment options are needed Additional treatment options are needed

A 116 Combined Effects of Salmeterol and FP in COPD Salmeterol + FP Airway Obstruction Inflammation Structural Changes Smooth muscle contraction Increased cholinergic tone Loss of elastic recoil Increased Neutrophils, macrophages, CD8+ lymphocytes. Elevated IL-8, TNF  Protease/anti-protease imbalance Alveolar destruction Collagen deposition Glandular hypertrophy Airway fibrosis  Symptoms  FEV 1  Exacerbations ?

A 117 Advair Diskus / Flovent Diskus Achieved objectives of clinical program Achieved objectives of clinical program – Flovent provided superior efficacy over placebo for primary measure – Advair provided superior efficacy over individual agents for primary measures – No significant safety issues identified

A 118 Pulmonary - Allergy Drugs Advisory Committee Meeting January 17, 2002 FLOVENT® DISKUS® NDA ADVAIR DISKUS® NDA

A 119 External Experts Professor Romain Pauwels, M.D. Professor Romain Pauwels, M.D. – Professor of Respiratory Medicine at University of Gent, Belgium Jonathon D Adachi, M.D. Jonathon D Adachi, M.D. – Professor of Medicine at McMaster University, Hamilton, Ontario