# Presentation: 768411

## Pulmonary - Allergy Drugs Advisory Committee Meeting

**January 17, 2002**
**FLOVENT® DISKUS® NDA 20-833**
**ADVAIR DISKUS® NDA 21-077**

## FLOVENT® DISKUS® and ADVAIR DISKUS®

**David Wheadon, MD**
**Senior Vice President, Regulatory Affairs**
**GlaxoSmithKline**

## sNDAs forFLOVENT DISKUS and ADVAIR DISKUS

**INDICATION****	**
**	****Long term, twice-daily maintenance treatment of Chronic Obstructive Pulmonary Disease (including emphysema and chronic bronchitis)**

## SEREVENT®(salmeterol xinafoate)

**Serevent Inhalation Aerosol approved for COPD, 1998**
**Approval sought for Serevent Diskus for  the maintenance treatment of bronchospasm associated with COPD**

## FLOVENT(fluticasone propionate)

**Currently Approved in US for maintenance treatment of asthma**
**Approved for COPD in 67 countries outside US**
**Worldwide exposure estimate - 14.4 million patient years**
**Approval sought for Flovent Diskus for maintenance treatment of COPD at doses of 250mcg and 500mcg BID**

## ADVAIR DISKUS(fluticasone propionate andsalmeterol inhalation powder)

**Currently approved for maintenance treatment of asthma**
**Worldwide exposure estimate - 1.4 million patient years**
**Approval sought for maintenance treatment of COPD at doses of 250/50mcg and 500/50mcg BID**

## Impact of COPD in the US

**2****National Center for Health Statistics, National Health Interview Survey, 1998. Information cited in: American Lung Association, trends in Chronic bronchitis and Emphysema: Morbidity and Mortality, December,  2000.**** **
**3****Murray CJL and Lopez AD, eds. *****The Global Burden of Disease*****. Vol. 1. 1996:362. **

**Impact of COPD in the US**

**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**
**114,000 deaths in 1998****2**
**Third leading cause of death by 2020****3**
**Annual cost >$30 billion****2**
**$14.7 billion in direct healthcare costs**
**$15.7 billion in indirect healthcare costs**

## Global Initiative for ChronicObstructiveLungDisease

**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 2001. NIH publication 2701A.**

## Clinical Effects of ICS in COPD

**Reference****	****N****	****Duration****	****Treatment/Day****	****Outcome**
**Nishimura et al., 1999****	****30****	****4 w****	****BDP 3000mcg****	******** FEV1, ******** Sx**
**O’Brien et al., 2001 ****	****24****	****6 w****	****BDP 1500mcg****	****FEV1 preserved**
**Thompson et al., 1992 ****	****30****	****6 w****	****BDP 1000mcg****	******** FEV1, ******** bronchitis**
**Weiner et al., 1995****	****30****	****6 w****	****BUD 800mcg****	******** FEV1, ******** prn med **
**Weiner et al., 1999****	****168****	****6 w****	****BUD 1600mcg****	******** FEV1, ******** prn med **
**Auffarth et al., 1991****	****21****	****8 w****	****BUD 1600mcg****	******** dyspnea**
**Kerstjens et al., 1993****	****39****	****12 w****	****BDP 800mcg****	******** FEV1**
**Dompeling et al., 1992****	****28****	****52 w****	****BDP 800mcg****	******** PEF, ******** Sx**
**Paggiaro et al., 1998****	****281****	**** 24 w****	****FP 1000mcg****	******** FEV1, ******** exac**
**ISOLDE, 2000****	****751****	****3 Y****	****FP 1000mcg****	******** FEV1, ******** QoL, ******** exac**
**Euroscope, 1999****	****1277****	****3 Y****	****BUD 800mcg****	******** FEV1, ******** exac**
**Lung Health II, 2000****	****1116****	****3 Y****	****TAA 1200mcg****	******** Sx , ******** exac**
**Sin & Tu, 2001****	****22620****	****	****Varied ****	******** morbidity, mortality**

## Current Use of ICS for COPD:Prescription Data from July 2001

**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)**
**72% prescribed an ICS**
**57% prescribed an ICS + a maintenance  bronchodilator**
**17% prescribed Advair**

**Source: NDC Health, July 2001**

## SUMMARY

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

## Order of GSK Presentation

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

## Slide 13

## Scientific and Clinical Rationale

**Malcolm Johnson, PhD**
**Global Director of Respiratory Science**
**GlaxoSmithKline**

## Pathology of COPD

**Structural **
**Changes**

**Airway****Obstruction**

**Pathology of COPD**

## Pathophysiological Features of COPD

**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**

## Do inhaled corticosteroids reduce inflammation in COPD?

Are inhaled corticosteroids effective treatment for COPD?

**Are inhaled corticosteroids effective treatment for COPD?**

**Inhaled Corticosteroids**

## Anti-Inflammatory Effects of ICS in COPD

**Reference****	****N****	****Duration****	****Treatment/Day****	****Outcome**
**Balbi****	****8****	**** 6 w ****	****BDP 1500mcg****	******** BAL neutrophils, IL-8 ****et al., 2000****	****	****	**** ****	**** and MPO**
**Confalonieri****	****24****	****8 w****	****BDP 1500mcg****	******** Sputum neutrophils ****et al., 1998****	****	****	**
**Llewellyn-Jones****	****17****	****8 w****	****FP 1500mcg****	******** Sputum neutrophil ****et al., 1996****	****	****	**** ****	**** chemotactic activity**
**Thompson****	****30****	****6 w****	****BDP 1000mcg****	****Improvement in bronchial ****et al., 1992****	****	****	****	****cell counts and epithelial ****	****	****	****	****	****lining fluid proteins**
**Yildiz****	****18****	**** 8 w****	****FP 1500mcg****	******** Sputum neutrophils****et al., 2000****	****	****	****	****	**
**Hattotuwa****	****37****	****12 w****	****FP 1000mcg****	******** Biopsy CD8+/CD4+ ****et al., 1999, 2000****	****	****	****	****Tcell ratio and mast cells**
**Verhoeven****	****20****	****24 w****	****FP 1000mcg****	******** Biopsy CD8+ Tcells and ****et al., 1999****	****	****	****	**** eosinophils**** **
**Keatings****	****13****	****2 w****	****BUD 1600mcg****	****No change in total and ****et al.,1996****	****	****	****	****differential cell counts or ****	****	****	****	****   ****	****TNF********, ECP, EPO and  MPO**
**Culpitt****	****13****	****4 w****	****FP 1000mcg****	****No change in sputum ****et al., 1999****	****	****	****	****neutrophils, IL-8 or SLPI**
**O’Brien****	****5****	****6 w****	****BDP 400mcg ****	****No change in sputum ****et al., 2001****	****	****	**** ****	****neutrophils**

## Fluticasone Propionate Reduces Total Cell Counts and Neutrophils in the Sputum of COPD Patients

**Yildiz et al. *****Respiration*****. 2000; 67:71-76.**

**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**

## ICS (FP) Reduces Inflammation 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**

**ICS (FP) Positive Effect**

**?**

**ICS (FP) Reduces Inflammation in COPD**

## Do inhaled corticosteroids reduce inflammation in COPD?

Are inhaled corticosteroids effective treatment for COPD?

**Are inhaled corticosteroids effective treatment for COPD?**

**Inhaled Corticosteroids**

## Clinical Effects of ICS in COPD

**Reference****	****N****	****Duration****	****Treatment/Day****	****Outcome**
**Nishimura et al., 1999****	****30****	****4 w****	****BDP 3000mcg****	******** FEV****1, ******** Sx**
**O’Brien et al., 2001 ****	****24****	****6 w****	****BDP 1500mcg****	****FEV****1**** preserved**
**Thompson et al., 1992 ****	****30****	****6 w****	****BDP 1000mcg****	******** FEV****1, ******** bronchitis**
**Weiner et al., 1995****	****30****	****6 w****	****BUD 800mcg****	******** FEV****1, ******** prn med **
**Weiner et al., 1999****	****168****	****6 w****	****BUD 1600mcg****	******** FEV****1****, ******** prn med **
**Auffarth et al., 1991****	****21****	****8 w****	****BUD 1600mcg****	******** dyspnea**
**Kerstjens et al., 1993****	****39****	****12 w****	****BDP 800mcg****	******** FEV****1**
**Dompeling et al., 1992****	****28****	****52 w****	****BDP 800mcg****	******** PEF, ******** Sx**
**Paggiaro et al., 1998****	****281****	**** 24 w****	****FP 1000mcg****	******** FEV****1****, ******** exac**
**ISOLDE, 2000****	****751****	****3 Y****	****FP 1000mcg****	******** FEV****1****, ******** QoL, ******** exac**
**Euroscope, 1999****	****1277****	****3 Y****	****BUD 800mcg****	******** FEV****1****,**** ******** exac**
**Lung Health II, 2000****	****1116****	****3 Y****	****TAA 1200mcg****	******** Sx , ******** exac**
**Sin & Tu, 2001****	****22620****	****	****Varied ****	******** morbidity, mortality**
**Keatings et al., 1999****	****   13****	****2 w****	****BUD 1600mcg ****	**** No ******** PFT, Sx, prn med**
**Culpitt et al., 1999****	****   13****	****4 w ****	****FP 1000mcg****	**** No ******** PFT, Sx**
**Engel et al., 1989****	****   18****	****12 w****	****BUD 800mcg****	**** No ******** PFT, Sx****Watson et al., 1992****	****   14****	****12 w****	****BUD 1200mcg ****	**** No ******** PFT, Sx**
**Bourbeau et al., 1998****	****   79****	****28 w****	****BUD 1600mcg****	**** No ******** PFT, Sx, QoL**
**Copenhagen City, 1996  290****	****3 Y****	****BUD 800mcg****	**** No ******** PFT, Sx, exac**

## Reduced Risk of Mortality and Repeat Hospitalization with Inhaled Corticosteroids

**Reduced Risk of Mortality and Repeat Hospitalization with Inhaled Corticosteroids**

**Adapted from Sin DD, Tu JV.  *****Am J Respir Crit Care Med***** 2001;164:580-584**

## Fluticasone Propionate Significantly Improves Pre-dose FEV1 in COPD

**Week**

****** ****FEV****1**** (L)**

**P<0.01**

**P<0.02**

**Paggiaro et al. *****Lancet.***** 1998; 351:773-780.**

**Fluticasone Propionate Significantly Improves Pre-dose FEV****1**** in COPD**

## 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: worsening of COPD symptoms requiring changes to normal treatment**
**Exacerbation severity:**
**Mild: ****	****	****patient self-managed at home**
**Moderate:****	****patient treated by a physician**
**Severe: ****	****	****patient hospitalized**
**Multiple exacerbations requiring OCS were allowed**

**Paggiaro et al. *****Lancet.***** 1998; 351:773-780.**

## Fluticasone Propionate Reduces Moderate/Severe Exacerbations in COPD

**Treatment Group**

**	****Fluticasone**
**Placebo ****	****propionate**
**(n=139) ****	****(n=142)**

**Number of exacerbations*******
**Total****	****111****	****76**
**Number of Patients with one or more****exacerbations**
**Total ****	****51****	****45**
**Mild****	****  7 (14%)****	****17 (38%)‡**
**Moderate/severe****	****44 (86%)****	**** 27 (60%) ‡**

- * Each patient may have experienced more than one exacerbation. ‡ *p*<0.001.

**Paggiaro et al. *****Lancet.***** 1998; 351:773-780.**

## Inhaled Steroids in Obstructive Lung Disease in Europe (ISOLDE)

**3 yrs**

**FP MDI 500mcg BID**

**Corticosteroid**
**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;320:1297-1303.**

**Inhaled Steroids in Obstructive Lung Disease in Europe (ISOLDE)**

## FP Improves Post-bronchodilator FEV1 Response in COPD: ISOLDE Study

**FP Improves Post-bronchodilator FEV****1**** Response in COPD: ISOLDE Study**

**Adapted from Burge PS et al. *****Br Med J*****. 2000;320:1297-1303.**

## FP Reduces Median Annual Exacerbation Rate: ISOLDE Study

**1.32**

**O.99***

- *p=0.026

**Burge PS et al., *****Br Med J.***** 2000;320:1297-1303**

- Exacerbations/patient/year

## FP Slows the Decline in Quality of Life as Measured by SGRQ*: ISOLDE Study

***St George’s Respiratory Questionnaire **
**Burge PS et al. *****Br Med J******.***** 2000;320:1297-1303.**

**FP Slows the Decline in Quality of Life as Measured by SGRQ*: ISOLDE Study**

## ICS (FP) Reduces Inflammation in COPD

**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**

## Salmeterol in COPD

## Salmeterol is a Long-Acting Bronchodilator in COPD

********P *****< .001 salmeterol vs placebo.**
**Adapted from Mahler DA et al. *****Chest*****. 1999;115:957-965.**

## 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**

**Salmeterol Positive  Effect**** **

## 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**

**?**

## Corticosteroids Increase RespiratoryMucosal Beta2-receptors

**Corticosteroids Increase Respiratory****Mucosal Beta****2****-receptors**

**0**

**0.05**

**0.10**

**0.15**

**0.20**

**0.25**

**0.30**

**0.35**

**0.40**

**0.45**

**Baseline**

**BDP**
**100mcg for 3 days**

**beta****2****-receptor/actin ratio**

**p<0.04**

*****

**Baraniuk et al *****AJRCCM***** 155: 704-710(1997)**

*****

## Salmeterol Potentiates the Effect of FP on TNF-induced IL8 Release fromAirway Smooth Muscle Cells

**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)**

## Rationale for CombiningFP with Salmeterol

**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.**
**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.**

## Slide 39

## Clinician’s Perspective

**James F. Donohue, MD**
**Chief, Pulmonary and Critical Care Medicine****University of North Carolina, Chapel Hill**

## Overview

**Diagnosis of COPD**
**Evaluating treatment effects in COPD**
**FEV****1**** **
**Other measures **
**GOLD guidelines**
**Clinician’s Perspective**

## Diagnosis of COPD

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

## Bronchodilator Response in COPDIntermittent Positive Pressure Breathing Trial (IPPB)

**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. **
**Key demographics:**
**Age: 60.9**
**Male: 79%**
**Smoking Status:**
**54 pack yrs**
**40% current smokers**
**FEV****1**** (% predicted): 36 %**

**Anthonisen, et al.  *****Am Rev Respir Dis*****, 1986;133:14-20.**

## Approximately half of the subjects were reversible at screening (>12% increase in FEV1 over baseline)
In subjects non-reversible at screening (<10% increase in FEV1)
30% of these subjects had a >15% increase in FEV1 at each subsequent test day
68% of these subjects had a >15% increase in FEV1 on at least one of the 7 follow-up test days

**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;133:814-819.**

***Annals of Internal Medicine,***** 1983;99:612-620.**

**Bronchodilator Response in COPD**** IPPB Trial**

## Demographic and Reversibility Data from Clinical Trials in COPD

**Data on file: SLGA 4004, SLGA 4005, *****Chest *****1994; 105:1411-1419.**
***Chest***** 1999; 115;966-971.**
***Am J Respir Crit Care Med.***** Vol 165. p. 778-784, 2001.**

**	****Salmeterol****	****Combivent****	****Formoterol**
**	****(n=816)****	****(n=1067)****	****(n=780)**
**Age****	****63****	****64****	****63**
**% male****	****68****	****69****	****75**
**Pack yr****	****63****	****na****	****42 **
**FEV****1**** L (% pred) ****	****1.25 (40)****	****0.99 (36)****	****1.3 (45)**
**% Pts Rev****	****62****	****68-73****	****42**

## Efficacy Measures Used to Assess Treatment Response in COPD 

**Spirometry (FEV****1****)**
**Objective, reproducible **
**Diagnostic and prognostic **
**Other Measures**
**Health Status (QOL)**
**Symptoms**
**Exacerbations**

## FEV1 Response withCombivent® on Day 85

**FEV****1**** Response with****Combivent****® ****on Day 85**

**Combivent is a registered trademark of Boehringer Ingelheim.****Bone R et al. *****Chest.***** 1994;105:1411-1419.**

****** ****FEV****1 ****(%)**

**Ipratropium + Albuterol (n = 173)****Albuterol (n = 165)****Ipratropium (n = 176)**

## Other Efficacy Measures Observed with Combivent

**CRDQ = Chronic Respiratory Index Questionnaire**

**Other Efficacy Measures Observed with Combivent**

**	****Ipratropium + Albuterol****	****Ipratropium****	****Albuterol**
**Measure ****	****  (n=173)****	****(n=176)****	****(n=165)****	**
**CRDQ ****(QOL)****	****ns****	****ns****	****ns**
**Physician Global****	**** ****ns**** ****	****ns****	**** ****ns**** ****Evaluation  ****	**
**Symptom Score****	****ns****	****ns****	****ns**** ****	**
**PEFR****	****ns****	****ns****	****ns **

**Bone R et al. *****Chest******.***** 1994;105:1411-1419.**

## 	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.	—	 

** — **** ****=  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;163:1087-1092**
*****Chest *****1999;115:957-965.**

**Other Efficacy Measures Observed with Serevent MDI**

## Global Initiative for ChronicObstructiveLungDisease

**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 2001. NIH publication 2701A.**

## GOLD: Recommendations for ICS Use

**Symptoms**

**Spirometry**

**Treatment**

** ****At Risk**** ****Stage 0**

**+/- Chronic cough,**
**sputum**

**Normal**

**Education, 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 Physician’s Perspective on Treatment of COPD

**Smoking cessation**
**Bronchodilator therapy alone is not adequate in many patients **
**Use of ICS in COPD**

## CONCLUSIONS

**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**
**Guidelines support use of ICS in patients with moderate to severe COPD**

## Slide 54

## Overview ofClinical Program

**Tushar Shah, MD****Vice President****Respiratory Clinical Development**

## Topics of Presentation

**Review results of clinical program designed in consultation with FDA**
**Primary objectives**** **
**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**
**Review long-term safety data with FP**

## Definitions

**FSC =****	**_**F**_**luticasone propionate and ****	****	****	**_**S**_**almeterol **_**C**_**ombination product**
**FSC 500/50****	****=****	****ADVAIR 500**
**FSC 250/50****	****=****	****ADVAIR 250**

## Overview of Clinical Program

**FLTA3025****	****FP 500****	****24 weeks**
**N=640****	****FP 250**
**	****Placebo**
**	**
**SFCA3006****	****FSC 500/50****	****24 weeks**
**N=691****	****FP 500**
**	****SAL 50 **
**	****Placebo**
**	**
**SFCA3007****	****FSC 250/50****	****24 weeks**
**N=723****	****FP 250**
**	****SAL 50**
**	****Placebo****	**

## Study Design: FLTA3025

## Study Design: SFCA3006

**2 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**

## 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**

## Key Inclusion Criteria

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

## Key Exclusion Criteria

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

## Primary Efficacy Measures 

**Pre-dose FEV****1**** **
**FP vs. Placebo**
**FSC vs. SAL (contribution of FP)**** **
**2 hour post-dose FEV****1**
**FSC vs. FP (contribution of SAL)**

## Secondary Efficacy Measures

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

## Primary Analysis

**Endpoint was used to account for patient withdrawals**** **
**Endpoint =****	****Last post-baseline ****	****	****	****observation**

## Patient Demography and Baseline Characteristics Were Similar Across Treatment Groups

**Patient Demography and Baseline Characteristics Were Similar Across Treatment Groups**

**	****	****	****	****	****FSC250/****	****FSC500/**
**	****Placebo****	****SAL50****	****FP250****	****FP500****	****50****	****50**
**Variable ****	****n=572****	****n=337****	****n=399****	****n=386****	****n=178****	****n=165**
**Age (yrs)****	****65****	****64****	****65****	****64****	****63****	****62**
**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****	****63****	****63****	****61****	****60****	****60****	****62**
**Prev ICS****	****27%****	****25%****	****29%****	****28%****	****23%****	****28%**
**FEV****1 ****% pred****	****42%****	****41%****	****41%****	****41%****	****41%****	**** 41%**
**BD resp. (% pts rev)****	****57%****	****53%****	****57%****	****55%****	****56%****	****53%**
**Emphysema %****	****75%****	****72%****	****73%****	****74%****	****71%****	****75%**

## FLOVENTEFFICACY RESULTS

## FLOVENT

**Primary Efficacy Measure**
**Pre-dose FEV****1**** **
**FP vs. Placebo**

## FLTA3025: Dose-Related Increases in Pre-Dose FEV1 Were Seen with FP Treatment vs. Placebo

*******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%)**

## SFCA3006: Significantly Greater Improvement in Pre-Dose FEV1 Seen with FP500 vs. Placebo

**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)**

*****

## SFCA3007: Significantly Greater Improvements in Pre-Dose FEV1 Seen with FP250 vs. Placebo

**SFCA3007: Significantly Greater Improvements in Pre-Dose FEV****1**** Seen with FP250 vs. Placebo**

**Endpoint**

****** ****FEV****1**** (ml)**

*****

**(1%)**

**(11%)**

## SFCA3007: Additional Evidence of Improvements in Pre-Dose FEV1 with FP250

**SFCA3007: Additional Evidence of Improvements in Pre-Dose FEV****1**** with FP250**

**Endpoint**

**(1%)**

**(11%)**

**(17%)**

**(9%)**

****** ****FEV****1**** (ml)**

*****

## Change in Pre-dose FEV1 (mL) for FP at Endpoint in Reversible/Non-Reversible Patients

## Greater Improvements Seen for Most Secondary Efficacy Measures with FP vs 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 **

**	****FLTA3025****	****SFCA3007****	****FLTA3025****	****SFCA3006**
**Measure ****	****FP250****	****FP250****	****FP500****	****FP500**
**TDI ****(dyspnea)****	****—****	**** — ****	****  ******** ****	**
**CRDQ ****(QOL)****	**** ********	**** ****	****  ******** ****	**** ****—**
**CBSQ ****(cough/sputum)****	**** ****—**** ****	**** ****	**** ****—**** ****	**** ****—**
**PEF****	**** ********	**** ********	****  ******** ****	****  ******
**NT awakenings****	****  ******** ****	****  ******** ****	****  ******** ****	****  ******
**Ventolin use****	****  ******** ****	**** ****— ****	****  ******** ****	****  ******
**Time to COPD exac.****	**** ****— ****	**** — ****	**** — ****	**** —**

***

***

***

***

## FLOVENT EFFICACY SUMMARY

**Significantly greater improvements in primary efficacy measure (pre-dose FEV****1****)**
**Magnitude of improvement related to reversibility**
**Secondary efficacy measures supportive**
**Suggestion of dose response**

## ADVAIREFFICACY RESULTS

## ADVAIR

**Primary Efficacy Measure**
**Pre-dose FEV****1**** **
**FSC vs. SAL (contribution of FP)**

## SFCA3006: Significantly Greater Improvement in Pre-Dose FEV1 Seen with FSC500/50 vs. SAL50

**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**

*****

## SFCA3006: Significantly Greater Improvement in Pre-Dose FEV1 Seen with FSC500/50 vs. SAL50

**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)**

## SFCA3007: Significantly Greater Improvements in Pre-Dose FEV1 Seen with FSC250/50 vs. SAL50

**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)**

*****

## SFCA3007: Significantly Greater Improvements in Pre-Dose FEV1 Seen with FSC250/50 vs. SAL50

**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)**

## ADVAIR

**Primary Efficacy Measure**
**2 hour post-dose FEV****1**
**FSC vs. FP (contribution of SAL)**

## SFCA3006: Significantly Greater Improvements in Post-Dose FEV1 Seen with FSC500/50 vs. FP500 

**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)**

## SFCA3006: Significantly Greater Improvements in Post-Dose FEV1 Seen with FSC500/50 vs. FP500 

**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)**

## SFCA3007: Significantly Greater Improvements in Post-Dose FEV1 Seen with FSC250/50 vs. FP250 

****** ****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**

*****

## SFCA3007: Significantly Greater Improvements in Post-Dose FEV1 Seen with FSC250/50 vs. FP250 

****** ****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**

*****

## Change in FEV1 (mL) for FSC at Endpoint in Reversible/Non-Reversible patients

**	****PLA****	**** SAL****	****FP****	****FSC250/50****	****PLA****	****SAL****	****FP****	****FSC500/50**
**Pre-dose**
**Rev.****	****-15****	****141****	****138****	****196****	****-1****	****132****	****123****	****191**
**Non-Rev.****	****19****	****26****	****74****	****126****	****-8****	****80****	****93****	****116**
**2 hr****Post-dose**
**Rev.****	****46****	****262****	****179****	****328****	****29****	****287****	****161****	****319**
**Non-Rev.****	****71****	****119****	****107****	****221****	****28****	****175****	****111****	****195**

**Change in FEV****1**** (mL) for FSC at Endpoint in Reversible/Non-Reversible patients**

**SFCA3007**

**SFCA3006**

## 	SFCA3007	SFCA3007	SFCA3006	SFCA3006
Measure 	SAL50	FP250	SAL50	FP500
TDI (dyspnea)	  	 — 	—	
CRDQ (QOL)	—	 	—	—
CBSQ (cough/sputum)	 — 	 	 — 	—
PEF	 	 	   	  
NT awakenings	 — 	   	  	  
Ventolin use	   	—	   	  
Time to COPD exac.	—	—	—	—

**Measure ****	****SAL50****	****FP250****	****SAL50****	****FP500**
**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**

***

***

***

***

## Greater Improvements Seen for Almost All Secondary Efficacy Measures with FSC vs. Placebo 

**	****SFCA3007****	****SFCA3006**
**Measure ****	****FSC250/50****	****FSC500/50**
**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**

***

***

***

***

***

***

***

## SFCA3006: Significantly Greater Improvement in TDI Score Seen with FSC500/50 vs. SAL50 and PLA 

**†****P<0.001 vs SAL**

**SFCA3006: Significantly Greater Improvement in TDI Score Seen with FSC500/50 vs. SAL50 and PLA **

**Endpoint**

**TDI Score**

*****

**,†**

*****

## Treatment with FSC250/50 Led to Greater Increase in AM PEF Within 1 Day

**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**

*****

**,†**

*****

*****

## ADVAIR EFFICACY SUMMARY

**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**
**Advair 250/50 and 500/50 provide similar benefits**

## SAFETY RESULTSFlovent / Advair

## Safety Exposure

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

## Adverse Events Occurred at Similar Frequency Across Treatment Groups

**	****PLA****	****SAL50****	****FP250****	****FP500 ****	**** FSC250/50 ****	****FSC500/50****	****n=576****	****n=341****	****n=399****	****n=391****	****n=178****	****n=169**
**Mean Exposure****	****129****	****139****	****136****	****132****	****141****	****138 ****(days)**
**Patients with ****	****69****	****68****	****74****	****80****	****70****	****78****AE (%)****	**
**Patients withdrawn ****	****6****	****4****	****6****	****11****	****5****	****7****due to AE (%)**
**Patients with ****	****6****	****4****	****6****	****7****	****4****	****5****SAE (%)**
**Deaths****	****4****	****0****	****0****	****0****	****0****	****0**

## Similar Adverse Events of Special Interest Except for Expected Topical Effects of ICS

**Adverse Events****	****n=576****	****n=341****	****n=399****	****n=391****	****n=178****	****n=169**
**Candidiasis****	****1%****	****2%****	****7%****	****13%****	****11%****	****11%**
**Throat Irritation****	****6%****	****7%****	****9%****	****9%****	****8%****	****11%**
**Hoarseness /****	****1%****	****<1%****	****5%****	****5%****	****5%****	****3%****Dysphonia**
**Fractures****	****2%****	****<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**

## Comparable Incidence of Pneumonia Across Treatment Groups

**Pneumonia****	****n=576****	****n=341****	****n=399****	****n=391****	****n=178****	****n=169**
**Adverse Events****	**** 7 ****	**** 2 ****	****  7 ****	****  10 ****	****0****	****2****	****(1.2%)****	**** (0.6%)****	**** (1.8%)****	**** (2.6%)****	****	****(1.2%)**
**Serious Adverse****	****3****	**** 2****	****5****	****7****	****0****	****2****Events****	**** (0.5%)****	**** (0.6%)****	**** (1.3%)****	**** (1.8%)****	****	**** (1.2%)**

**Comparable Incidence of Pneumonia Across Treatment Groups**

## HPA Axis Monitoring(Performed in a Subset of Patients)

**12 hour unstimulated cortisol profile in FLTA3025 (n=86)**
**In SFCA3006 and SFCA3007 (n=359)**
**Morning cortisol concentrations**
**Short ACTH stimulation test**

## No Clinically Significant Difference in HPA Axis Results Between FSC and Individual Agents or Placebo

**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 short ACTH stimulation tests was similar across all treatment groups**

## SUMMARY OF SAFETY RESULTS

**Flovent Diskus**
**Flovent was well tolerated**
**No clinically relevant safety concerns identified compared to placebo**** **
**Advair Diskus**
**Advair was well tolerated **
**No difference in safety results between Advair and individual agents and/or placebo**

## Long-term Safety Data with FP

**Comparison of systemic exposure between patients with asthma and COPD**
**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**

## 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)**

## Clinical Studies Examining BMD and/or Ophthalmic Effects of FP inPatients with Asthma

**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**
**FP versus BDP (3 trials)**
**FP versus budesonide (2 trials)**

## 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).**

## No Evidence of Cataracts orGlaucoma was Seen with FP versus Placebo Treatment

**No posterior subcapsular cataracts**** **
**No diagnosis of glaucoma**

## BMD Results from Clinical Trials Comparing FP MDI vs. Other ICS

**Treatment Groups**
**(mcg BID)****	****BMD Results****	****Reference**
**FP 250, 375, or 500****	****FP: ******** at all BMD sites  assessed****	****Pauwels, 1998**
**      ****versus****	****BDP: ******** at femoral neck; trochanter;**
**BDP 500, 750, or 1000****	****Ward’s triangle **
**	**
**FP 500 versus BDP 1000****	****FP: No vertebral trabecular bone decline****	****Egan,  1999**
**	****BDP: ******** Vertebral trabecular bone**
**	****FP and BDP: ******** at spine; femoral neck**
**FP 200 versus BDP 400****	****FP: ******** at lumbar spine****	****Medici, 2000**
**FP 375 versus BDP 750****	****BDP: ******** at lumbar spine **
**FP 500 versus BUD 800****	****FP and BUD: ******** at lumbar spine; trochanter****	****Hughes, 1999**
**	****FP: ******** at femoral neck **
**	****BUD: ******** at femoral neck**
**	**
**FP 250 versus BUD 400****	****FP and BUD: ******** at all BMD sites assessed****	****Harmanci, 1999**

## ISOLDE: Adverse Events of Special Interest 

**	****n=370****	****n=372**
**Mean Exposure (days)**** ****	****748****	****824**
**Adverse Events**
**Fractures****	****17 (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 **

## SummaryLong-term Safety Data with FP

**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**

## Proposed Dosage and Administration Recommendations

**For Flovent Diskus: ****The starting dosage is 250mcg 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.**

## CONCLUSIONS

**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**

## Slide 112

## Summary Remarks

**David Wheadon, MD**
**Senior Vice President, Regulatory Affairs**
**GlaxoSmithKline**

## COPD is a Significant Public Health Problem in the US

**0**

**0.5**

**1.0**

**1.5**

**2.0**

**2.5**

**3.0**

**Proportion of 1965 Mortality Rate **

**1965 - 1998**

**1965 - 1998**

**1965 - 1998**

**1965 - 1998**

**1965 - 1998**

**–****59%**

**–****64%**

**–****35%**

**+163%**

**–****7%**

**Coronary**
**Heart**
**Disease**

**Stroke**

**Other CVD**

**COPD**

**All Other**
**Causes**

**COPD is a Significant Public Health Problem in the US**

## Current Therapeutic Managementof COPD

**COPD remains under diagnosed and under treated **
**Bronchodilators are the only approved treatments**
**Additional treatment options are needed**

## 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**

**?**

## Advair Diskus / Flovent Diskus

**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**

## Pulmonary - Allergy Drugs Advisory Committee Meeting

**January 17, 2002**
**FLOVENT® DISKUS® NDA 20-833**
**ADVAIR DISKUS® NDA 21-077**

## External Experts

**Professor Romain Pauwels, M.D.**
**Professor of Respiratory Medicine at University of Gent, Belgium**
**Jonathon D Adachi, M.D.**
**Professor of Medicine at McMaster University, Hamilton, Ontario**

## Slide 120