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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.

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pulmonary allergy drugs advisory committee meeting

Pulmonary - Allergy Drugs Advisory Committee Meeting

January 17, 2002

FLOVENT® DISKUS® NDA 20-833

ADVAIR DISKUS® NDA 21-077

flovent diskus and advair diskus

FLOVENT® DISKUS® and ADVAIR DISKUS®

David Wheadon, MD

Senior Vice President, Regulatory Affairs

GlaxoSmithKline

sndas for flovent diskus and advair diskus
sNDAs forFLOVENT 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®(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
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
ADVAIR DISKUS(fluticasone propionate andsalmeterol 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
Impact of COPD in the US
  • Affects an estimated 21.7 million Americans1
    • 6.5 Million Diagnosed
    • 4.3 Million Treated With Prescription Medications
  • The fourth leading cause of death2
    • 114,000 deaths in 19982
    • Third leading cause of death by 20203
  • Annual cost >$30 billion2
    • $14.7 billion in direct healthcare costs
    • $15.7 billion in indirect healthcare costs

1Data on file (analysis of NHANES III data), GlaxoSmithKline.

2National 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.

3Murray CJL and Lopez AD, eds. The Global Burden of Disease. Vol. 1. 1996:362.

g lobal initiative for chronic o bstructive l ung d isease

GlobalInitiative for ChronicObstructiveLungDisease

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
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
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
SUMMARY
  • COPD is a serious public health issue
  • Considerable unmet medical needs
  • New treatment options are needed
order of gsk presentation
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
scientific and clinical rationale

Scientific and Clinical Rationale

Malcolm Johnson, PhD

Global Director of Respiratory Science

GlaxoSmithKline

pathology of copd
Pathology of COPD

Inflammation

AirwayObstruction

Structural

Changes

pathophysiological features of copd
Pathophysiological Features of COPD

Airway

Obstruction

StructuralChanges

Inflammation

Increased Neutrophils,macrophages,

CD8+ lymphocytes.

Elevated IL-8, TNFa

Protease/anti-proteaseimbalance

Alveolar destruction

Collagen deposition

Glandular hypertrophy

Airway fibrosis

Smooth muscle contraction

Increased cholinergic tone

Loss of elastic recoil

Symptoms

 FEV1

Exacerbations

inhaled corticosteroids
Do inhaled corticosteroids reduce inflammation in COPD?

Are inhaled corticosteroids effective treatment for COPD?

Inhaled Corticosteroids
anti inflammatory effects of ics in copd
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 neutrophilset 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
Fluticasone Propionate Reduces Total Cell Counts and Neutrophils in the Sputum of COPD Patients

Neutrophils

Total Cell Counts

*

x106 cells/g

*

percent

Placebo

FP 1500 mcg/day

*

P<0.05

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

ics fp reduces inflammation in copd
ICS (FP) Reduces Inflammation in COPD

Airway

Obstruction

StructuralChanges

Inflammation

ICS (FP) Positive Effect

?

Increased Neutrophils,macrophages,

CD8+ lymphocytes.

Elevated IL-8, TNFa

Protease/anti-proteaseimbalance

Alveolar destruction

Collagen deposition

Glandular hypertrophy

Airway fibrosis

Smooth muscle contraction

Increased cholinergic tone

Loss of elastic recoil

Symptoms

 FEV1

Exacerbations

inhaled corticosteroids21
Do inhaled corticosteroids reduce inflammation in COPD?

Are inhaled corticosteroids effective treatment for COPD?

Inhaled Corticosteroids
clinical effects of ics in copd22
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

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, SxWatson 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

slide23

1.0

0.9

0.8

0.7

0.6

0.5

ICS associated with a 26% lower relative risk for all-cause mortality and repeat hospitalization

Inhaled Corticosteroids

COPD Hospitalization Free Survival

No Inhaled Corticosteroids

0 2 4 6 8 10 12

Months After Discharge

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 fev 1 in copd
Fluticasone Propionate Significantly Improves Pre-dose FEV1 in COPD

P<0.01

P<0.02

 FEV1 (L)

Week

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

collection of exacerbation data in paggiaro et al 1998
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
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 moreexacerbations

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
Inhaled Steroids in Obstructive Lung Disease in Europe (ISOLDE)

FP MDI 500mcg BID

Corticosteroid

Withdrawal

PlaceboRun-in

Placebo BID

2 Months

3 yrs

N = 751

Reversibility <10% predicted

Mean FEV1 50% at baseline

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

fp improves post bronchodilator fev 1 response in copd isolde study

1.5

*

*

*

FP 500µg BID (n=376)

*

1.4

*

Post-bronchodilator FEV1

1.3

Placebo BID (n=375)

1.2

-3

0

3

6

9

12

15

18

21

24

27

30

33

36

Time (months)

*p<0.001

FP Improves Post-bronchodilator FEV1 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
FP Reduces Median Annual Exacerbation Rate: ISOLDE Study

1.32

*p=0.026

O.99*

Exacerbations/patient/year

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

Regression Analysis

12

10

8

6

4

2

0

P = 0.004

Placebo

Fluticasone propionate

Change

in Total

Score

Threshold of

clinical significance

0 6 12 18 24 30 36

Time (months)

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

An increase in score reflects a decrease in quality of life.

*St George’s Respiratory Questionnaire

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

ics fp reduces inflammation in copd31
ICS (FP) Reduces Inflammation in COPD

Airway

Obstruction

StructuralChanges

Inflammation

ICS (FP) Positive Effect

?

Increased Neutrophils,macrophages,

CD8+ lymphocytes.

Elevated IL-8, TNFa

Protease/anti-proteaseimbalance

Alveolar destruction

Collagen deposition

Glandular hypertrophy

Airway fibrosis

Smooth muscle contraction

Increased cholinergic tone

Loss of elastic recoil

 Symptoms

 FEV1

 Exacerbations

salmeterol is a long acting bronchodilator in copd

0.4

0.3

0.2

0.1

0

Salmeterol Day 1Salmeterol Day 84Placebo

*

*

*

*

*

 FEV1(L)

*

*

*

*

0 1 2 3 4 5 6 7 8 9 10 11 12 13

Time (hours)

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
Salmeterol Reduces Airway Obstruction in COPD

Airway

Obstruction

StructuralChanges

Inflammation

Salmeterol Positive Effect

Increased Neutrophils,macrophages,

CD8+ lymphocytes.

Elevated IL-8, TNFa

Protease/anti-proteaseimbalance

Alveolar destruction

Collagen deposition

Glandular hypertrophy

Airway fibrosis

Smooth muscle contraction

Increased cholinergic tone

Loss of elastic recoil

Symptoms

 FEV1

Exacerbations

combined effects of salmeterol and fp in copd
Combined Effects of Salmeterol and FP in COPD

Salmeterol+FP

?

Airway

Obstruction

StructuralChanges

Inflammation

Increased Neutrophils,macrophages,

CD8+ lymphocytes.

Elevated IL-8, TNFa

Protease/anti-proteaseimbalance

Smooth muscle contraction

Increased cholinergic tone

Loss of elastic recoil

Alveolar destruction

Collagen deposition

Glandular hypertrophy

Airway fibrosis

 Symptoms

 FEV1

 Exacerbations

slide36

Corticosteroids Increase RespiratoryMucosal Beta2-receptors

*

0.45

0.40

0.35

0.30

beta2-receptor/actin ratio

0.25

0.20

0.15

0.10

p<0.04

*

0.05

0

Baseline

BDP

100mcg for 3 days

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 fromAirway Smooth Muscle Cells

IL8 (pg/ml)

*P <0.01

(0.1 µM)

(0.1 µM)

(1 µM)

Adapted from Pang L, and Knox AJ. Am J Respir Cell Mol Biol. 2000; 23: 79-85.

rationale for combining fp with salmeterol
Rationale for CombiningFP with Salmeterol
  • Fluticasone propionate is an effective inhaled anti-inflammatory corticosteroid with clinical benefit in COPD.
  • Salmeterol is a long-acting b2-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.
clinician s perspective

Clinician’s Perspective

James F. Donohue, MD

Chief, Pulmonary and Critical Care MedicineUniversity of North Carolina, Chapel Hill

overview
Overview
  • Diagnosis of COPD
  • Evaluating treatment effects in COPD
    • FEV1
    • Other measures
  • GOLD guidelines
  • Clinician’s Perspective
diagnosis of copd
Diagnosis of COPD
  • Clinically based on:
    • Smoking history
    • Age
    • Symptoms
    • Persistent airflow obstruction (spirometry)
      • FEV1 post bronchodilator < 80% predicted
      • FEV1 / FVC < 70%
  • The presence of reversibility does not exclude a diagnosis of COPD
bronchodilator response in copd intermittent positive pressure breathing trial ippb
Bronchodilator Response in COPDIntermittent Positive Pressure Breathing Trial (IPPB)
  • Evaluated the BD response to inhaled isoproteronol in 985 subjects with COPD (asthma excluded)
  • Pre and post- bronchodilator FEV1 evaluated every 3 months for 3 yrs.
  • Key demographics:
    • Age: 60.9
    • Male: 79%
    • Smoking Status:
      • 54 pack yrs
      • 40% current smokers
    • FEV1 (% predicted): 36 %

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

bronchodilator response in copd ippb trial
Bronchodilator Response in COPD IPPB Trial
  • 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

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

Anthonisen, et al. Am Rev Respir Dis, 1986;133:814-819.

demographic and reversibility data from clinical trials in copd
Demographic and Reversibility Data from Clinical Trials in COPD

Salmeterol Combivent Formoterol

(n=816) (n=1067) (n=780)

Age 63 64 63

% male 68 69 75

Pack yr 63 na 42

FEV1 L (% pred) 1.25 (40) 0.99 (36) 1.3 (45)

% Pts Rev 62 68-73 42

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.

efficacy measures used to assess treatment response in copd
Efficacy Measures Used to Assess Treatment Response in COPD
  • Spirometry (FEV1)
    • Objective, reproducible
    • Diagnostic and prognostic
  • Other Measures
    • Health Status (QOL)
    • Symptoms
    • Exacerbations
slide47

FEV1 Response withCombivent® on Day 85

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

 FEV1 (%)

Postdose (hours)

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

other efficacy measures observed with combivent
Other Efficacy Measures Observed with Combivent

Ipratropium + Albuterol Ipratropium Albuterol

Measure (n=173) (n=176) (n=165)

CRDQ (QOL)nsns ns

Physician Global nsnsnsEvaluation

Symptom Score nsnsns

PEFR ns ns ns

ns = not significant compared to baseline and/or components

CRDQ = Chronic Respiratory Index Questionnaire

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

other efficacy measures observed with serevent mdi
Other Efficacy Measures Observed with Serevent MDI

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

— = p>0.05 salmeterol vs. placebo

*Am. J. Respir. Crit. Care Med. 2001;163:1087-1092

**Chest 1999;115:957-965.

g lobal initiative for chronic o bstructive l ung d isease50

GlobalInitiative for ChronicObstructiveLungDisease

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
GOLD: Recommendations for ICS Use

Severity

Symptoms

Spirometry

Treatment

At RiskStage 0

+/- Chronic cough,

sputum

Normal

Education, avoidance

risk factors,

flu vaccine

MildStage I

FEV1 / FVC < 70%

Short-acting 2-

adrenergic PRN

+/- Chronic cough,

sputum

FEV1 > 80%

predicted

FEV1 / FVC < 70% FEV1 30% - 80% predicted

Reg Bronchodilator

Consider ICS

Rehabilitation

ModerateStage II A & B

+/- Chronic cough, sputum,

dyspnea

SevereStage III

+/- Cough, sputum,

dyspnea

FEV1 / FVC < 70%

FEV1 < 30% or

FEV1 < 50% with

respiratory failure,

cor pulmonale

Reg Bronchodilator

Consider ICS

Rehabilitation

LT Oxygen

Surgery

a physician s perspective on treatment of copd
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
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
overview of clinical program

Overview ofClinical Program

Tushar Shah, MDVice PresidentRespiratory Clinical Development

topics of presentation
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
Definitions
  • FSC = Fluticasone propionate and Salmeterol Combination product
    • FSC 500/50 = ADVAIR 500
    • FSC 250/50 = ADVAIR 250
overview of clinical program58
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

FP 500mcg BID (n=218)

PRNalbuterol

FP 250mcg BID (n=216)

PlaceboRun-in

Placebo BID (n=206)

2 weeks

24 weeks

Study Design: FLTA3025
study design sfca3006
Study Design: SFCA3006

FSC 500/50mcg BID (n=169)

FP 500mcg BID (n=173)

PRNalbuterol

SAL 50mcg BID (n=164)

PlaceboRun-in

Placebo BID (n=185)

2 weeks

24 weeks

study design sfca3007
Study Design: SFCA3007

FSC 250/50mcg BID (n=178)

FP 250mcg BID (n=183)

PRNalbuterol

SAL 50mcg BID (n=177)

PlaceboRun-in

Placebo BID (n=185)

2 weeks

24 weeks

key inclusion criteria
Key Inclusion Criteria
  • COPD as defined by ATS
  • Age 40 years
  • Current or ex-smoker (20 pack years)
  • Pre-bronchodilator FEV1<65% predicted
  • FEV1/FVC 70%
  • Dyspnea and symptoms of chronic bronchitis
key exclusion criteria
Key Exclusion Criteria
  • Current diagnosis of asthma
  • Use of systemic corticosteroids or high dose ICS for 6 weeks prior toscreening visit
  • Need for long-term oxygen therapy
  • COPD exacerbation during run-in
primary efficacy measures
Primary Efficacy Measures
  • Pre-dose FEV1
    • FP vs. Placebo
    • FSC vs. SAL (contribution of FP)
  • 2 hour post-dose FEV1
    • FSC vs. FP (contribution of SAL)
secondary efficacy measures
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
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%

FEV1 % 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
FLOVENT

Primary Efficacy Measure

  • Pre-dose FEV1
    • FP vs. Placebo
flta3025 dose related increases in pre dose fev 1 were seen with fp treatment vs placebo
FLTA3025: Dose-Related Increases in Pre-Dose FEV1 Were Seen with FP Treatment vs. Placebo

*

(8%)

 FEV1 (ml)

(5%)

(2%)

Endpoint

*P=0.010 vs PLA

sfca3006 significantly greater improvement in pre dose fev 1 seen with fp500 vs placebo
SFCA3006: Significantly Greater Improvement in Pre-Dose FEV1 Seen with FP500 vs. Placebo

*

(11%)

 FEV1 (ml)

(2%)

Endpoint

*P<0.001 vs PLA

sfca3007 significantly greater improvements in pre dose fev 1 seen with fp250 vs placebo
SFCA3007: Significantly Greater Improvements in Pre-Dose FEV1 Seen with FP250 vs. Placebo

*

(11%)

 FEV1 (ml)

(1%)

Endpoint

*P<0.001 vs PLA

sfca3007 additional evidence of improvements in pre dose fev 1 with fp250
SFCA3007: Additional Evidence of Improvements in Pre-Dose FEV1 with FP250

*

(17%)

(11%)

(9%)

 FEV1 (ml)

(1%)

Endpoint

*P=0.012 vs SAL

change in pre dose fev 1 ml for fp at endpoint in reversible non reversible patients

FLTA3025SFCA3007 SFCA3006

PLA FP250 FP500 PLA FP250 PLA FP500

Rev. 29 70 93 -15 138 -1 123

Non-Rev -17 -15 21 19 74 -8 93

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
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. — — — —

*

*

*

*

  • = statistically significantly different than placebo
  • = P≤0.05, FP vs. Placebo

— = P>0.05, FP vs. Placebo

flovent efficacy summary
FLOVENT EFFICACY SUMMARY
  • Significantly greater improvements in primary efficacy measure (pre-dose FEV1)
    • Magnitude of improvement related to reversibility
  • Secondary efficacy measures supportive
  • Suggestion of dose response
advair
ADVAIR

Primary Efficacy Measure

  • Pre-dose FEV1
    • FSC vs. SAL (contribution of FP)
sfca3006 significantly greater improvement in pre dose fev 1 seen with fsc500 50 vs sal50
SFCA3006: Significantly Greater Improvement in Pre-Dose FEV1 Seen with FSC500/50 vs. SAL50

*

(15%)

(10%)

 FEV1 (ml)

Endpoint

*P=0.012 vs SAL

sfca3006 significantly greater improvement in pre dose fev 1 seen with fsc500 50 vs sal5080
SFCA3006: Significantly Greater Improvement in Pre-Dose FEV1 Seen with FSC500/50 vs. SAL50

*

(15%)

(11%)

(10%)

 FEV1 (ml)

(2%)

Endpoint

*P=0.012 vs SAL

sfca3007 significantly greater improvements in pre dose fev 1 seen with fsc250 50 vs sal50
SFCA3007: Significantly Greater Improvements in Pre-Dose FEV1 Seen with FSC250/50 vs. SAL50

*

(17%)

(9%)

 FEV1 (ml)

Endpoint

*P=0.012 vs SAL

sfca3007 significantly greater improvements in pre dose fev 1 seen with fsc250 50 vs sal5082
SFCA3007: Significantly Greater Improvements in Pre-Dose FEV1 Seen with FSC250/50 vs. SAL50

*

(17%)

(11%)

(9%)

 FEV1 (ml)

(1%)

Endpoint

*P=0.012 vs SAL

advair83
ADVAIR

Primary Efficacy Measure

  • 2 hour post-dose FEV1
    • FSC vs. FP (contribution of SAL)
sfca3006 significantly greater improvements in post dose fev 1 seen with fsc500 50 vs fp500
SFCA3006: Significantly Greater Improvements in Post-Dose FEV1 Seen with FSC500/50 vs. FP500

*

(24%)

(13%)

 FEV1 (ml)

Endpoint

*P<0.001 vs FP

sfca3006 significantly greater improvements in post dose fev 1 seen with fsc500 50 vs fp50085
SFCA3006: Significantly Greater Improvements in Post-Dose FEV1 Seen with FSC500/50 vs. FP500

*

(24%)

(22%)

(13%)

 FEV1 (ml)

(4%)

Endpoint

*P<0.001 vs FP

sfca3007 significantly greater improvements in post dose fev 1 seen with fsc250 50 vs fp250
SFCA3007: Significantly Greater Improvements in Post-Dose FEV1 Seen with FSC250/50 vs. FP250

*

(27%)

(14%)

 FEV1 (ml)

Endpoint

*P<0.001 vs FP

sfca3007 significantly greater improvements in post dose fev 1 seen with fsc250 50 vs fp25087
SFCA3007: Significantly Greater Improvements in Post-Dose FEV1 Seen with FSC250/50 vs. FP250

*

(27%)

(19%)

(14%)

 FEV1 (ml)

(6%)

Endpoint

*P<0.001 vs FP

change in fev 1 ml for fsc at endpoint in reversible non reversible patients
Change in FEV1 (mL) for FSC at Endpoint in Reversible/Non-Reversible patients

SFCA3007

SFCA3006

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 hrPost-dose

Rev. 46 262 179 328 29 287 161 319

Non-Rev. 71 119 107 221 28 175 111 195

similar improvements seen in secondary efficacy measures for fp and sal vs pla
Similar Improvements Seen in Secondary Efficacy Measures for FP and SAL vs. PLA

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. — — — —

*

*

*

*

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

,†

*

*

TDI Score

Endpoint

*P≤0.005 vs PLA

†P<0.001 vs SAL

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
ADVAIR EFFICACY SUMMARY
  • Significantly greater improvements in both trials on the primary efficacy measures
    • Advair vs. salmeterol for pre-dose FEV1
    • Advair vs. FP for 2-hour post-dose FEV1
    • Magnitude of improvement related to reversibility
  • Secondary efficacy measures supportive
  • Advair 250/50 and 500/50 provide similar benefits
safety exposure
Safety Exposure
  • 2,054 Patients in clinical program
    • 790 on FP
    • 347 on Advair
  • Additional safety from 1298 COPD patients from non US studiesevaluating FP
  • Supported by extensive safety in asthma
adverse events occurred at similar frequency across treatment groups
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 78AE (%)

Patients withdrawn 6 4 6 11 5 7due to AE (%)

Patients with 6 4 6 7 4 5SAE (%)

Deaths 4 0 0 0 0 0

similar adverse events of special interest except for expected topical effects of ics
Similar Adverse Events of Special Interest Except for Expected Topical Effects of ICS

PLA SAL50 FP250 FP500 FSC250/50 FSC500/50

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

comparable incidence of pneumonia across treatment groups
Comparable Incidence of Pneumonia Across Treatment Groups

PLA SAL50 FP250 FP500 FSC250/50 FSC500/50

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 2Events (0.5%) (0.6%) (1.3%) (1.8%) (1.2%)

hpa axis monitoring performed in a subset of patients
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
slide100
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
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
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
The Range of Systemic Exposure with FP Diskus in COPD is Not Greater Than FP CFC MDI in Asthma

Diskus 500mcg BID

CFC MDI 440mcg BID

FP AUClast (pg*h/mL)

Asthma

COPD

clinical studies examining bmd and or ophthalmic effects of fp in patients with asthma
Clinical Studies Examining BMD and/or Ophthalmic Effects of FP inPatients 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
Mean Percent Change in Lumbar Spine BMD was Similar Between FP Groups Compared to Placebo

Mean Percent Change from Baseline

Weeks

Data on File, GlaxoSmithKline (FLTA3001).

no evidence of cataracts or glaucoma was seen with fp versus placebo treatment
No Evidence of Cataracts orGlaucoma 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
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
ISOLDE: Adverse Events of Special Interest

Placebo BID FP500mcg BID

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%)

summary long term safety data with fp
SummaryLong-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
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.

conclusions111
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
summary remarks

Summary Remarks

David Wheadon, MD

Senior Vice President, Regulatory Affairs

GlaxoSmithKline

copd is a significant public health problem in the us
COPD is a Significant Public Health Problem in the US

Proportion of 1965 Mortality Rate

3.0

Coronary

Heart

Disease

Stroke

Other CVD

COPD

All Other

Causes

2.5

2.0

1.5

1.0

0.5

–59%

–64%

–35%

+163%

–7%

0

1965 - 1998

1965 - 1998

1965 - 1998

1965 - 1998

1965 - 1998

current therapeutic management of copd
Current Therapeutic Managementof 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 copd116
Combined Effects of Salmeterol and FP in COPD

Salmeterol+FP

?

Airway

Obstruction

StructuralChanges

Inflammation

Increased Neutrophils,macrophages,

CD8+ lymphocytes.

Elevated IL-8, TNFa

Protease/anti-proteaseimbalance

Smooth muscle contraction

Increased cholinergic tone

Loss of elastic recoil

Alveolar destruction

Collagen deposition

Glandular hypertrophy

Airway fibrosis

 Symptoms

 FEV1

 Exacerbations

advair diskus flovent diskus
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 meeting118

Pulmonary - Allergy Drugs Advisory Committee Meeting

January 17, 2002

FLOVENT® DISKUS® NDA 20-833

ADVAIR DISKUS® NDA 21-077

external experts
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