ARIFLO cilomilast Tablets, 15 mg

1
ARIFLO (cilomilast) Tablets, 15 mg
NDA 21-573Pulmonary - Allergy Drugs Advisory
Committee Meeting

• September 5, 2003

2
ARIFLO (cilomilast)Tablets, 15 mg

• David Wheadon, M.D.
• Senior Vice President
• Regulatory Affairs
• GlaxoSmithKline

3
Chronic ObstructivePulmonary Disease
Emphysema
Chronic Bronchitis
4
Impact of COPD in the US

• Affects an estimated 24 million Americans1
• Annual cost 32.1 billion in 20022
• 18 billion in direct healthcare costs
• 14.1 billion in indirect morbidity and mortality
  costs
• The fourth leading cause of death3
• 123,974 deaths in 2001

1. Mannino DM, et al. MMWR 2002 51(No.
SS06)1-16. 2. NHLBI, Morbidity and Mortality
Chartbook on Cardiovascular, Lung and Blood
Diseases, 2002. 3. CDC, National Vital
Statistics Reports, Vol. 51, No. 5, March 14,
2003.
5
COPD Mortality is Increasing
Percent change in age-adjusted death rates in
theUS over 10 years (1990-2000)
Mannino DM, et al. MMWR, 2002 51(SS06)1-16.
Pastor PN, et al. National Center for Health
Statistics, 2002
6
Prognosis in Chronic Obstructive Pulmonary Disease
Anthonisen N, Am Rev Respir Dis 1986 133(1)14-20
7
Unmet Medical Need

• Limited treatment options
• Only bronchodilators are approved for COPD
• Address only bronchoconstriction
• Smoking cessation is the only intervention known
  to reduce the rate of decline of FEV1

8
COPD is a Complex Disease
9
ArifloSecond Generation PDE4 Inhibitor

• Highly Selective PDE4 inhibitor
• 100 bioavailability
• Low plasma variability
• Low potential for drug interactions
• Improved safety profile
• Tablet administered orally twice a day
• Ariflo is an important new option for the
  treatment of COPD

10
TheophyllineNon-Selective PDE Inhibitor

• Pharmacological activity
• Methylxanthine
• Non-selective PDE inhibitor
• Adverse effects may be related to PDE3 inhibition
• Effects on other pharmacological pathways(i.e.,
  adenosine receptor antagonism)
• Unpredictable pharmacokinetic profile
• Drug and food interactions
• Wide blood level variation (i.e., elderly,
  smokers)
• Need for blood level monitoring

11
Phase III Development Program

• Study/Region Duration
• 2 Pivotal NA 24 weeks
• 2 Pivotal EU 24 weeks
• 1 Cardiovascular Safety NA 12 weeks
• 1 Induced sputum NA 12 weeks
• 1 Lung biopsy EU 12 weeks
• 1 Lung volume NA 12 weeks
• 1 Open-Label Extension NA 12-36 months
• 1 Open-Label Extension EU 12-36 months

Exposure to Ariflo from above studies represents
nearly 3,000 patient years
12
Poorly Reversible Population Studied in Ariflo
Clinical Studies
13
Proposed Indication

• ARIFLO is indicated for the maintenance of lung
  function (FEV1) in patients with chronic
  obstructive pulmonary disease (COPD) who are
  poorly responsive to albuterol (increase in FEV1
  of lt15 or lt 200 mL).

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Order of GSK Presentation
Order of GSK Presentation

• Rationale for the Use of Ariflo in COPD

• Dr. Katharine Knobil

• Efficacy Data from Ariflo Clinical Program

• Dr. Katharine Knobil

• Dr. Kathy Rickard

• Safety of Ariflo

• Dr. Frank Sciurba

• Assessment of Outcome in COPD

• Dr. David Wheadon

• Conclusion and QA

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Rationale for theUse of Ariflo in COPD

• Katharine Knobil, M.D.
• Senior Director
• Respiratory Clinical Development and Medical
  Affairs
• GlaxoSmithKline

17
COPD is a Complex Disease
18
Inflammatory Cells in COPD



plt0.01 vs control and mild
Adapted from Retamales I, et al. Am J Respir Crit
Care Med 2001 164469-473. Calhoun WJ, et al.
Am J Respir Crit Care Med 2001 165730b-731b.
19
Airway CD8 T-cellCorrelation with Airflow
Limitation
Adapted from Saetta M, et al. Am J Respir Crit
Care Med 1998 157822-826
20
A New Target for Treating COPDCells Expressing
PDE4
21
A Novel Approach to Treating COPD PDE4 Inhibitors
Adenyl cyclase
Cyclic AMP
ATP
22
Cilomilast Attenuates Fibroblast Activity

• In vitro, cilomilast inhibited
• Release of MMP-1 and MMP-9 from fibroblasts
• Activation of MMP-1 and MMP-9
• Degradation of collagen by fibroblasts
• Suggests potential of PDE4 inhibitors to affect
  remodeling

Alveolar Wall Destruction
Kohyama T, et al. Am J Respir Cell Mol Biol 2002
27487-494.
23
Cilomilast Attenuates Release of
Chemoattractants for Human Neutrophils
Bronchial Epithelial Cells
Sputum Cells
400
400
Plt0.006
Plt0.008
300
300
Neutrophils per high power field
200
200
100
100
0
0
Cilomilast(1 ?M)
Cilomilast(1 ?M)
Baseline
Baseline
Cells obtained from patients with COPD by
bronchoscopy and sputum induction
Adapted from Profita M, et al. Thorax 2003
58573-579
24
Study 076 Ariflo Decreased Macrophages in
Bronchial Biopsies
25
Study 076 Ariflo Decreased CD-8 Lymphocytes in
Bronchial Biopsies
26
Potential Therapeutic Benefits of Ariflo
27
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Ariflo Clinical Development Program
Efficacy Data

• Katharine Knobil, M.D.
• Senior Director
• Respiratory Clinical Development and Medical
  Affairs
• GlaxoSmithKline

29
Phase III Development Plan Pivotal Studies

• Study Abbreviated Title Loc Patients Study
  Duration
• 039 Pivotal Phase III NA 647 24 weeks
• 156 Pivotal Phase III NA 825 24 weeks
• 091 Pivotal Phase III EU 711 24 weeks
• 042 Pivotal Phase III EU 700 24 weeks

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Phase III Development Plan Supporting Studies

• Study Abbreviated Title Loc Patients Study
  Duration
• 110 Induced Sputum NA 65 12 weeks
• 076 Lung Biopsy EU 59 12 weeks
• 168 Cardiovascular Safety NA 282 12 weeks
• 041 Long-term Safety NA 355 up to 3 years
• 040 Long-term Safety EU 723 up to 3 years
• 111 Static Lung Volumes NA 156 12 weeks

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Study Design Pivotal Studies
Ariflo 15mg BID
PlaceboRun-in
PRNalbuterol
Placebo BID
4 weeks
24 weeks
32
Key Inclusion Criteria

• COPD diagnosis
• 40-80 years old
• gt 10 pack year history of smoking
• Symptoms

except NA Study 156
33
Key Inclusion Criteria

• Lung Function
• FEV1 (post albuterol) 30 - 70 predicted
• FEV1/FVC (pre albuterol) lt70 predicted
• Poorly reversible to albuterol
• lt 15 or lt 200ml

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Response to Albuterol in COPD Clinical
Development Programs
1. COMBIVENT Inhalation Aerosol Study Group,
Chest 1994 1051411-1419. 2. Mahler D, et al.
Chest 1999 115957-965. 3. Rennard S, et al. Am
J Respir Crit Care Med 2001 1631087-1092. 4.
Mahler D, et al. Am J Respir Crit Care Med 2002
1661084-1091. 5. Hanania NA, et al. Chest 2003
In Press.
35
Key Exclusion Criteria

• Clinical diagnosis of asthma
• FEV1 variability gt20 from Screening to Baseline
• Exacerbation or oral steroid administration
  during run-in period

36
Efficacy AssessmentsCo-Primary Endpoints

• Change from baseline in FEV1
• Measured in AM prior to the next dose (trough)
• Change from baseline in total score of the St.
  Georges Respiratory Questionnaire (SGRQ)
• A health-related quality of life instrument

37
Efficacy Assessments Secondary Endpoints

• Change from baseline in FVC
• COPD Exacerbations
• Post exercise breathlessness(Borg scale)
• Summary symptom score
• Not collected in NA study 156
• 6-Minute walk

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Baseline Characteristics
NA EU 039 156
042 091 n647 n825 n700 n711 Age 65.3 64.5 64
.6 62.8 Female () 38 41 20 14 Race
(W/B) 93/3 93/6 99/0 98/0 Active smokers
() 45 46 43 38 FEV1 ( Predicted) 49.7 50.2 49.0
50.3 ?2 reversibility ( ?) 7.3 8.6 5.1 5.0 DLCO
( Predicted) 58.5 55.3 70.8 70.0 Chronic
Bronchitis () 61.5 37.5 80.1 89.6
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Ariflo Maintains FEV1NA Study 039
40
Ariflo Consistent Treatment Effect
Plt0.001
41
Decline in Lung Function in Long-term COPD Studies
42
Health-Related Quality of LifeSt. Georges
Respiratory Questionnaire

• Disease-specific (respiratory disease)
• Measures the impact of COPD on quality of life
• Components of SGRQ
• Symptoms
• Activity
• Impact
• Decrease in score indicates improvement in QOL
• Change of -4.0 is a clinically meaningful
  improvement

43
Ariflo Significantly ImprovesQuality of Life
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Change From Baseline In Total SGRQ Scores
Averaged Over 24 Weeks
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Ariflo Pivotal ResultsSecondary Endpoints
Study 039 156 091 042 Measure NA NA EU EU FVC
? ? T T 6-minute Walk
Symptom Score N/A ? Post-exercise
? T T T Breathlessness COPD Exacerbations
? ?
? P lt0.05 versus placebo P gt0.2 versus
placebo T 0.05 lt P lt 0.2 in favor of Ariflo
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Percent of Patients Exacerbation-Free
47
Supporting Studies
48
Long Term Extension Studies

• Evaluate long term safety and tolerability
• Further evaluate FEV1 over time
• Open-Label Extension of the pivotal studies
• Subjects from NA Study 039 were eligible to enter
  Study 041
• Subjects from EU Studies 042 and 091 were
  eligible to enter Study 040
• Concomitant COPD medication use allowed

49
Long-Term Extension NA Study 041 FEV1
Study 041
Study 039
EP
Week
50
Long-Term Extension EU Study 040 FEV1
Studies 042, 091
Study 040
Week
51
Physiology of Hyperinflation


Normal Chest X-ray
Patient with COPD
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Physiology of Hyperinflation
53
Study 111 Static Lung Volumes
Ariflo 15mg BID (n79)
PlaceboRun-in
PRNalbuterol
Placebo BID (n77)
4 weeks
12 weeks
54
Change From Baseline In Pre-albuterol Volume Of
Trapped Gas (D)
D TLCbox TLChe
Difference from placebo -180 ml (week 12), -140
ml (EP)
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Ariflo Reduces Residual Volume
56
Ariflo Reduces Functional Residual Capacity
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Can Ariflo be Compared to Theophylline?

• No comparable studies of similar design
• Small numbers of patients (8 to 60 patients)1
• Short duration (1 day to 8 weeks)
• Criteria for reversibility vary between studies
• Non-selective PDE inhibitor
• Primarily bronchodilator effect
• Predominantly due to inhibition of PDE32
• Weak activity at PDE43

1Ram FSF, et al. Cochrane Database of Systematic
Reviews 2003. 2 Theolair Prescribing
Information 3Howell, et al. J Pharmacol. Exp.
Ther. 1993 264 609-615.
58
Can Ariflo be Compared to Theophylline?
Change from Baseline in FEV1 (L)
ZuWallack RL, et al. Chest 2001
1191661-1670. Data on file, GlaxoSmithKline
(SLGA4020/21).
59
Efficacy SummaryCo-Primary Endpoints

• FEV1
• Maintenance of FEV1 over 24 weeks with
  statistically significant benefit over placebo in
  both NA pivotal studies
• Magnitude of effect consistent across NA and EU
  studies
• SGRQ
• Significant improvement in health-related quality
  of life versus placebo in both NA studies
• Consistent improvement from baseline in Ariflo
  groups across NA and EU studies

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Efficacy SummarySupporting Data

• Decrease in relative risk of moderate to severe
  exacerbations in Studies 039 and 091
• Maintenance of FEV1 observed in the long term
  studies for up to 84 weeks
• Substantial reduction in hyperinflation

61
Efficacy Conclusions

• COPD is a complex and progressive disease
• Poorly reversible population
• Difficult to treat, more rapid decline in FEV1
• Ariflo targets inflammation specific to COPD
• Efficacy data support proposed indication

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Safety of Ariflo

• Kathy Rickard, M.D.
• Vice President
• Respiratory Clinical Development and Medical
  Affairs
• GlaxoSmithKline

64
Safety Overview

• Phase I II studies
• Over 50 studies including clinical pharmacology
  and dose ranging
• Phase III studies
• Adverse events
• Gastrointestinal Safety
• Cardiovascular Safety
• Long term safety up to 3 years

65
Safety Exposure

• 3,445 patients in all Phase III COPD studies
• 2,119 Ariflo 1,326 placebo
• 2,883 patients in the pivotal 24-week COPD
  studies
• 1,792 Ariflo 1,091 placebo
• Over 1,000 patients in long-term extension
  studies
• Nearly 3,000 patient-years of exposure to Ariflo

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COPD 24-week Studies AEs
All Randomized
Patients Placebo Ariflo n1091 n1792 Adverse
Experience Total 76.9 78.3 COPD
36.2 30.4 Nausea 5.0 15.7 Diarrhea 7.9 14.4 Abdom
inal Pain 7.1 11.7 Upper Respiratory Tract
infection 10.3 8.8 Headache 7.0 8.2 Dyspepsia 2.5
6.8 Vomiting 1.6 6.1 Injury 5.0 5.4 Coughing 5.3 3
.5
Includes adverse experiences reported for gt5
of patients in either of the treatment groups
67
COPD 24-week StudiesWithdrawal Due to AEs

All Randomized Patients Placebo
Ariflo Adverse Experience n1091 n1792 To
tal 11.7 17.5 Nausea 0.5 5.1 Abdominal
Pain 0.7 4.3 Diarrhea 0.6 3.6 COPD 3.8 2.2 Vomitin
g 0.3 1.4 Dyspepsia 0.1 1.0 Dizziness 0.2 0.9 Hea
dache 0.1 0.9 Flatulence 0.1 0.5
Includes adverse experiences reported for gt0.5
of patients in either of the treatment groups
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Rationale for Extensive GI Monitoring

• Class-related GI adverse events
• Medial necrosis in rat mesenteric arteries seen
  at gt30mg/kg/day
• Not observed in primates
• No intestinal ischemia observed
• Medial necrosis also seen with theophylline and
  caffeine in rodents
• No association of mesenteric ischemia over
  decades of use in humans

Collins JJ, et al. Fundam Appl Toxicol 1988
11472-484. Johansson S, Acta Pathol Microbiol
Scand 1981 89185-191.
69
Extensive GI Safety Monitoring

• Physical exams
• Laboratory assessments
• Orthostatic vital signs
• Fecal occult blood tests
• GI adverse events of concern
• Any GI adverse event that interfered with
  patients daily activities

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Extensive GI Safety Monitoring

• Patients who completed study
• 6 fecal occult blood tests
• 10 sets of laboratory evaluations
• 13 sets of vital signs
• 4 sets of orthostatic vital signs

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COPD 24-week StudiesGIAEs of Concern
All Randomized
Patients Placebo Ariflo Adverse
Experience n1091 n1792 (Preferred
term) Total 4.8 12.9 Abdominal
Pain 2.6 5.9 Diarrhea 2.1 5.2 Nausea 0.6 4.3 Vomit
ing 0.5 2.9 Dyspepsia 0.3 1.6 Melena 0.8 0.9 Flatu
lence 0.2 0.9
Includes adverse experiences reported for gt0.5
of patients in either of the treatment groups
72
Cumulative Incidence of GI Adverse Events of
Concern in Pivotal Studies
73
Fecal Occult Blood Testing in the Pivotal Studies

• 
  All Randomized Patients
• Placebo Ariflo
• n1091 n1792
• Total
• Tested 788 1256
• Positive n () 12 (1.5) 27 (2.2)
• GIAEs of Concern n52 n231
• Tested 42 205
• Positive n () 5 (11.9) 16 (7.8)

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Reports of Bowel Ischemia in the Clinical Program

• Placebo Ariflo
• Pivotal Trials
• Cases 2 0
• Person-Years Exposed 444 683
• Incidence Rate per 1000 py 4.5 0
• Long Term Extension
• Cases Not Applicable 3
• Person-Years Exposed 1800
• Incidence Rate per 1000 py 1.7
• Total
• Cases 2 3
• Person-Years Exposed 444 2483
• Incidence Rate per 1000 py 4.5 1.2
• pyperson years

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Incidence of Serious Adverse Events in Pivotal
Studies

All Randomized Patients Placebo
Ariflo n1091 n1792 Serious Adverse Event n
() Total 96 (8.8) 104 (5.8) Gastrointestinal
body system 12 (1.1) 10 (0.6) Cardiovascular
body system 28 (2.6) 20
(1.1) Respiratory body system 31 (2.8) 30
(1.7)
Includes events reported for cardiovascular
general, heart rate and rhythm, and myocardial,
endocardial, pericardial valve body systems.
76
GI Safety SummaryNo Evidence of Bowel Ischemia

• Mesenteric vasculopathy occurred only in rodents
• No evidence of bowel ischemia in animals,
  including rats
• Extensive GI safety monitoring demonstrated no
  serious GI effects
• Incidence of bowel ischemia was comparable
  between Ariflo and placebo

77
Extensive Cardiovascular Safety Monitoring

• CV safety issues with non-selective PDE
  inhibitors
• Myocardial necrosis at high, lethal doses
  (gt80mg/kg/day) in rat toxicity studies
• CV Safety (vital signs, ECGs, Holters)

Whitehurst VE, et al. Toxicology 1996
100113-121.
78
Extensive Cardiovascular Safety Monitoring

• gt70,000 ECGs
• gt68,000 ECGs in patients with COPD
• gt6,000 ECGs at Cmax
• gt1,000 Holters
• 24-hour Holter monitoring in over 400 patients

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Extensive ECG Monitoring Revealed No Safety
Issues with Ariflo
All Randomized
Patients Placebo Ariflo New Onset ECG
Abnormalities n1091 n1792 Sinus
Bradycardia 13.6 14.4 Q-T Interval
Increased 12.4 12.3 T-wave Abnormal
NOS 13.0 9.5 Premature Atrial Contractions
NOS 10.3 9.0 Intraventicular Block
NOS 6.2 8.1 S-T Changes Nonspecific 9.4 8.1 Poor
R-wave Progression 9.0 7.6 Sinus
Tachycardia 5.8 6.0 PVCs NOS 2.8 5.7 Sinus
Arrhythmia 7.1 5.6 Left Atrial Hypertrophy (P
mitrale) 5.8 4.9 PVCs Unifocal 7.2 4.6
gt5 of patients in any treatment group
80
QTc Interval Similar Between Treatment Groups

All Randomized Patients
Placebo Ariflo
n1091 n1792 Mean QTc (msec) Baseline
424 425 Change from Baseline at EP
0.1 -0.4 QTc Increases from baseline at any
time-point Patients with 30-60msec change
144 (18.6) 212 (17.3) Patients with
gt60msec change 23 (3.0) 21
(1.7)
Bazetts correction in patients with a normal
QTc at Baseline
81
New Onset Cardiac Events24-Hour Holter
Monitoring

New Onset n () Cardiac Event
Placebo Ariflo Atrial
Fibrillation 0 2 (0.7) Atrial Flutter 0 1
(0.4) First Degree AV Block 5 (3.6) 6
(2.2) Mobitz Type 1 0 2 (0.7) Mobitz Type 2 2
(1.4) 1 (0.4) Sinus Bradycardia 12 (12.2) 29
(15.1) Sinus Pause 6 (4.3) 4 (1.5) Supraventricul
ar Tachycardia 29 (46.8) 65 (45.5) Non-Sustained
VT 11 (8.3) 23 (8.7)
82
Incidence of Serious Adverse Events in Pivotal
Studies

All Randomized Patients Placebo
Ariflo n1091 n1792 Serious Adverse Event n
() Total 96 (8.8) 104 (5.8) Gastrointestin
al body system 12 (1.1) 10 (0.6) Cardiovascula
r body system 28 (2.6) 20 (1.1)
Respiratory body system 31 (2.8) 30 (1.7)
Includes events reported for cardiovascular
general, heart rate and rhythm, and myocardial,
endocardial, pericardial valve body systems.
83
Serious Adverse Events with Fatal Outcome in the
Pivotal Studies

• Placebo Ariflo
• n1091 n1792
• Fatal SAEs 5 (0.5) 7 (0.4)

None were considered related to treatment.
84
Safety Data from Long Term Extension Studies

• Greater than 1,000 patients for up to 3 years
• Over 25,000 ECGs performed
• Safety data similar to pivotal trials
• No cardiovascular safety issues identified
• No gastrointestinal safety issues identified

85
Additional Safety AssessmentsClinical
Pharmacology Studies

• Male reproductive
• Neuroendocrine
• Drug-drug interactions

86
Male Reproductive System

• Nonclinical studies with Ariflo showed testicular
  degeneration in rats and rabbits, but not in mice
  or primates
• Ariflo 15mg BID or placebo was administered to
  100 healthy, young male subjects for 12 weeks
• No evidence of a clinically significant effect on
  sperm number, motility, or morphology in humans

87
Neuroendocrine System

• Adrenocortical hypertrophy in rats
• Stimulation of the HPA-axis is well-recognized
  response of rats to PDE inhibitors
• Mammary tumors at high dose in mice associated
  with pseudopregnancy
• No evidence of an effect on prolactin, ACTH,
  serum or urinary cortisol levels in humans

Kumari M, et al. Brit J Pharmacol 1997
121459-468. Law LW, Proc Soc Exp Biol Med 1941
48486-487.
88
Interaction Studies

• No evidence of interactions
• Albuterol, ipratropium, theophylline,
  prednisolone, warfarin, and digoxin
• Smoking
• No effect on bioavailability with
  magnesium-aluminum-dimethicone antacid or food
• Potential for increased GI intolerance
• Co-administration with erythromycin
• Severe hepatic impairment
• Severe renal impairment

89
Ariflo Safety Conclusions

• Extensive safety data with exposure to Ariflo up
  to 3 years
• For patients with GI adverse events, most
  occurred early and were mild to moderate in
  intensity
• Serious AEs, including GI, were infrequent and
  similar between treatment groups
• No evidence of an increased risk of
  cardiovascular events

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Assessment of Outcome in COPD

• Frank Sciurba, MD
• Associate Professor of Medicine
• Division of Pulmonary, Allergy and Critical Care
  Medicine University of Pittsburgh

92
The Face of Chronic Obstructive Pulmonary Disease
(COPD)
Chronic Bronchitis
Emphysema
93
Health Care Utilization and Mortality Due to
Exacerbations
Connors AF, et al. Am J Respir Crit Care Med.
1996154959-967
94
No single parameter in patients with COPD is
sufficient to be considered the gold standard to
assess outcome.
A. Fishman, 1994
95
Clinical Research in COPDNeeds and Opportunities

• NHLBI Workshop Summary
• What measures of disease status are useful
  indices therapeutic benefit?
• What can be done to promote the development and
  testing of novel agents for the treatment of
  COPD? efforts that may reduce these barriers
  exploration of alternative outcome measures

Croxton TL, et al. Am J Respir Crit Care Med
2003 1671142.
96
FEV1 Advantages

• On average reflects function and prognosis
• Reproducible measure
• Responsiveness to various therapies well
  established

97
Prognosis in Chronic Obstructive Pulmonary Disease
Anthonisen N, Am Rev Respir Dis 1986 133(1)14-20
98
FEV1 Limitations

• Marked individual variation in symptoms and
  disability independent of FEV1
• Symptomatic and functional response to therapy
  may be independent of FEV1
• May not reflect changes in important disease
  activity which could lead to long term functional
  decline or frequency of exacerbations

99
Correlation of Quality of Life Scores (SGRQ)
with FEV1 in Patients with COPD
SGRQ St. Georges Respiratory
Questionnaire Higher scores worse quality of
life Adapted with permission from Jones PW. Chest
1995 107(suppl) 187S-193S.
100
Spirometric Changes with Increasing Degrees of
Obstruction
101
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102
Hyperinflation in Emphysema
103
Lung and Chest Wall Forces at End-Expiration in
COPD vs. Normal
104
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105
Dynamic Lung Volume Regulation During Exertion in
COPD Compared to Normal
ODonnell. Chest 2000 11742S-47S.
106
Bronchodilator Responses in Patients with
Irreversible Emphysema
Change from Baseline post-albuterol (L)
plt0.05 ODonnell, DE. Eur Resp J 2001
18914-920.
107
Number of Inflammatory Cellsper m2 of Lung
Surface Area

• Air Space Tissue
• Control Mild Severe Control Mild Severe
• Neutrophils 20 50 300 24 29 140 (x108/m2)
• Macrophages 270 330 4000 4.5 4.4 71(x108/m2)
• CD8 40 46 1400 31 34 250(x108/m2)

Different from Control and Mild (p lt0.01)
Retamales I, et al. Am J Respir Crit Care Med
2001 164469-473.
Calhoun WJ, et al. Am J Respir Crit Care Med
2001 165730b-731b.
108
The Cigarette Burns Out But the Inflammation
Rages On
- S. Shapiro
109
Smoking Cessation Anti-inflammatory Model
110
Ariflo Maintains FEV1NA Study 039
111
Ariflo Reduces Residual Volume
112
Study 076Ariflo Decreased Inflammatory Cells in
Bronchial Biopsies
113
Conclusions

• Clinically relevant outcomes of novel
  anti-inflammatory agents for COPD
• Stabilization of FEV1
• Reduction in lung hyperinflation
• Airway inflammation
• FEV1
• Useful measure of severity and outcome in COPD
• May not reflect other clinically important
  measures of lung hyperinflation and inflammatory
  activity

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Summary Remarks

• David Wheadon, M.D.
• Senior Vice President
• Regulatory Affairs
• GlaxoSmithKline

116
COPD Mortality is Increasing
Percent change in age-adjusted death rates in
theUS over 10 years (1990-2000)
Mannino DM et al. MMWR, 2002 51(SS06)1-16.
Pastor PN et al. National Center for Health
Statistics, 2002.
117
Potential Therapeutic Benefits of Ariflo
118
ArifloA New Treatment Option for COPD

• Achieved co-primary endpoints in both North
  American studies
• No serious safety issues
• Lack of interactions
• Oral treatment may improve compliance

119
External Experts

• Loren Laine, M.D.
• Chief, GI Section
• L.A. County U.S.C. Medical Center
• Professor of Medicine
• University of Southern California Medical School

Christina Wang, M.D. Program Director General
Clinical Research Center Harbor-UCLA Medical
CenterProfessor of Medicine David Geffen
UCLASchool of Medicine
Jeremy N. Ruskin, M.D. Director, Cardiac
Arrhythmia Service Massachusetts General
Hospital Associate Professor of Medicine Harvard
Medical School
Gary Koch, Ph.D. Professor of BiostatisticsUniver
sity of North Carolina
120
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