A 1 ARIFLO ® (cilomilast) Tablets, 15 mg September 5, 2003 NDA 21-573 Pulmonary - Allergy Drugs...

A A 11

ARIFLOARIFLO®® (cilomilast) Tablets, 15 mg (cilomilast) Tablets, 15 mg

September 5, 2003September 5, 2003

NDA 21-573NDA 21-573

Pulmonary - Allergy Drugs Pulmonary - Allergy Drugs Advisory Committee MeetingAdvisory Committee Meeting

A A 22

ARIFLOARIFLO®® (cilomilast) (cilomilast)Tablets, 15 mgTablets, 15 mg

David Wheadon, M.D.David Wheadon, M.D.Senior Vice President Senior Vice President

Regulatory Affairs Regulatory Affairs GlaxoSmithKlineGlaxoSmithKline

A A 33

Chronic ObstructiveChronic ObstructivePulmonary DiseasePulmonary Disease

EmphysemaEmphysema Chronic BronchitisChronic Bronchitis

A A 44

Impact of COPD in the USImpact of COPD in the US

• Affects an estimated 24 million AmericansAffects an estimated 24 million Americans11

• Annual cost $32.1 billion in 2002Annual cost $32.1 billion in 200222

– $18 billion in direct healthcare costs$18 billion in direct healthcare costs– $14.1 billion in indirect morbidity and mortality $14.1 billion in indirect morbidity and mortality

costscosts

• The fourth leading cause of The fourth leading cause of deathdeath33

– 123,974 deaths in 2001123,974 deaths in 2001

1. Mannino DM, 1. Mannino DM, et al.et al. MMWRMMWR 2002; 51(No. SS06):1-16. 2002; 51(No. SS06):1-16.2. NHLBI, 2. NHLBI, Morbidity and Mortality Chartbook on Cardiovascular, Lung and Blood Diseases, Morbidity and Mortality Chartbook on Cardiovascular, Lung and Blood Diseases,

2002.2002. 3. CDC, 3. CDC, National Vital Statistics ReportsNational Vital Statistics Reports, Vol. 51, No. 5, March 14, 2003., Vol. 51, No. 5, March 14, 2003.

A A 55

Mannino DM, Mannino DM, et al.et al. MMWR, MMWR, 2002; 51(SS06):1-16. 2002; 51(SS06):1-16. Pastor PN, Pastor PN, et al.et al. National Center for Health StatisticsNational Center for Health Statistics, 2002, 2002

COPD Mortality is IncreasingCOPD Mortality is Increasing

-48.0%

-19.9%

-6.9% -6.9%

25.5%

-50

-40

-30

-20

-10

0

10

20

30

40

50

Per

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HIV

CAD

Stroke Cancer

COPD

Percent change in age-adjusted death rates in theUS over 10 years (1990-2000)

A A 66

Prognosis in Chronic Prognosis in Chronic Obstructive Pulmonary DiseaseObstructive Pulmonary Disease

% S

urv

ival

% S

urv

ival

YearsYears

NormalsNormals>> 50% Predicted 50% Predicted40-49% Predicted40-49% Predicted30-39% Predicted30-39% Predicted<30% Predicted<30% Predicted

100100

9090

8080

7070

6060

00 11 22 33

FEVFEV11

Anthonisen N, Anthonisen N, Am Rev Respir DisAm Rev Respir Dis 1986; 133(1):14-20 1986; 133(1):14-20

A A 77

Unmet Medical NeedUnmet Medical Need

• Limited treatment optionsLimited treatment options

• Only bronchodilators are approved for Only bronchodilators are approved for COPD COPD – Address only bronchoconstriction Address only bronchoconstriction

• Smoking cessation is the only Smoking cessation is the only intervention known to reduce the rate of intervention known to reduce the rate of decline of FEVdecline of FEV11

A A 88

COPD is a Complex DiseaseCOPD is a Complex Disease

Progressive Loss of Lung Progressive Loss of Lung FunctionFunction

Reduced Quality of LifeReduced Quality of LifeExacerbationsExacerbations

MortalityMortality

Broncho-Broncho-

constrictionconstriction

InflammationInflammation

StructuralStructural

ChangesChangesAirflow Airflow

Limitation & Limitation &

HyperinflationHyperinflation

A A 99

Ariflo:Ariflo:Second Generation PDE4 InhibitorSecond Generation PDE4 Inhibitor• Highly Selective PDE4 Highly Selective PDE4

inhibitorinhibitor

– 100% bioavailability 100% bioavailability – Low plasma variabilityLow plasma variability– Low potential for drug Low potential for drug

interactionsinteractions– Improved safety profileImproved safety profile

• Tablet administered orally Tablet administered orally twice a day twice a day

• Ariflo is an important new Ariflo is an important new option for the treatment of option for the treatment of COPDCOPD

OO

CNCN

COOHCOOH

HHHH33COCO

A A 1010

Theophylline:Theophylline:Non-Selective PDE InhibitorNon-Selective PDE Inhibitor

• Pharmacological activityPharmacological activity– MethylxanthineMethylxanthine– Non-selective PDE inhibitorNon-selective PDE inhibitor– Adverse effects may be related to PDE3 inhibitionAdverse effects may be related to PDE3 inhibition– Effects on other pharmacological pathwaysEffects on other pharmacological pathways

(i.e., adenosine receptor antagonism)(i.e., adenosine receptor antagonism)

• Unpredictable pharmacokinetic profileUnpredictable pharmacokinetic profile– Drug and food interactions Drug and food interactions – Wide blood level variation (i.e., elderly, smokers)Wide blood level variation (i.e., elderly, smokers)– Need for blood level monitoringNeed for blood level monitoring

A A 1111

Phase III Development ProgramPhase III Development Program

Study/RegionStudy/Region DurationDuration

2 Pivotal NA2 Pivotal NA 24 weeks24 weeks

2 Pivotal EU2 Pivotal EU 24 weeks24 weeks

1 Cardiovascular Safety NA1 Cardiovascular Safety NA 12 weeks12 weeks

1 Induced sputum NA1 Induced sputum NA 12 weeks12 weeks

1 Lung biopsy EU1 Lung biopsy EU 12 weeks12 weeks

1 Lung volume NA1 Lung volume NA 12 weeks12 weeks

1 Open-Label Extension NA1 Open-Label Extension NA 12-36 months12-36 months

1 Open-Label Extension EU1 Open-Label Extension EU 12-36 months12-36 months

Exposure to Ariflo from above studies represents nearly 3,000 patient yearsExposure to Ariflo from above studies represents nearly 3,000 patient years

A A 1212

Poorly Reversible Population Poorly Reversible Population Studied in Ariflo Clinical StudiesStudied in Ariflo Clinical Studies

AsthmaAsthma COPDCOPD

Fully Reversible Fully Reversible Lung FunctionLung Function

Fixed Fixed Airways Airways DiseaseDisease

Reversibility

A A 1313

Proposed IndicationProposed Indication

ARIFLOARIFLO®® is indicated for the maintenance of is indicated for the maintenance of lung function (FEVlung function (FEV11) in patients with chronic ) in patients with chronic

obstructive pulmonary disease (COPD) who obstructive pulmonary disease (COPD) who are poorly responsive to albuterol (increase are poorly responsive to albuterol (increase in FEVin FEV11 of of <<15% or 15% or << 200 mL). 200 mL).

A A 1414

Order of GSK PresentationOrder of GSK Presentation

• Rationale for the Use Rationale for the Use of Ariflo in COPDof Ariflo in COPD

–Dr. Katharine KnobilDr. Katharine Knobil

Order of GSK PresentationOrder of GSK Presentation

–Dr. David WheadonDr. David Wheadon• Conclusion and Q&AConclusion and Q&A

–Dr. Katharine KnobilDr. Katharine Knobil• Efficacy Data from Efficacy Data from Ariflo Clinical ProgramAriflo Clinical Program

–Dr. Kathy RickardDr. Kathy Rickard• Safety of ArifloSafety of Ariflo

–Dr. Frank SciurbaDr. Frank Sciurba• Assessment of Outcome in Assessment of Outcome in COPDCOPD

A A 1616

Rationale for theRationale for theUse of Ariflo in COPDUse of Ariflo in COPD

Katharine Knobil, M.D.Katharine Knobil, M.D.Senior Director Senior Director

Respiratory Clinical Development and Medical AffairsRespiratory Clinical Development and Medical Affairs

GlaxoSmithKlineGlaxoSmithKline

A A 1717

COPD is a Complex DiseaseCOPD is a Complex Disease

Progressive Loss of Lung Progressive Loss of Lung FunctionFunction

Reduced Quality of LifeReduced Quality of LifeExacerbationsExacerbations

MortalityMortality

Broncho-Broncho-

constrictionconstriction

InflammationInflammation

StructuralStructural

ChangesChangesAirflow Airflow

Limitation & Limitation &

HyperinflationHyperinflation

A A 1818

Inflammatory Cells in COPDInflammatory Cells in COPD

Adapted from Retamales I, Adapted from Retamales I, et al.et al. Am J Respir Crit Care MedAm J Respir Crit Care Med 2001; 164:469-473. 2001; 164:469-473.

Calhoun WJ, et al. Calhoun WJ, et al. Am J Respir Crit Care MedAm J Respir Crit Care Med 2001; 165:730b-731b. 2001; 165:730b-731b.

Cel

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88

**

*

**

*p<0.01 vs control and mild*p<0.01 vs control and mild

A A 1919

Airway CD8+ T-cellAirway CD8+ T-cellCorrelation with Airflow LimitationCorrelation with Airflow Limitation

Adapted from Saetta M, Adapted from Saetta M, et al. Am J Respir Crit Care Medet al. Am J Respir Crit Care Med 1998; 157:822-826 1998; 157:822-826

CD

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(c

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CD

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22 ))

FEVFEV11 (% predicted) (% predicted)

10001000

0000 1101105050 7070 9090

400400

200200

800800

600600

6060 8080 100100

pp= 0.01= 0.01rho = -0.63rho = -0.63

A A 2020

A New Target for Treating COPDA New Target for Treating COPDCells Expressing PDE4Cells Expressing PDE4

NeutrophilNeutrophilMacrophageMacrophageCD8CD8++ T-Cell T-Cell EosinophilEosinophil EpitheliumEpitheliumMast cellMast cell

Mucus GlandMucus GlandAirwayAirway

Smooth Muscle Smooth Muscle

EndotheliumEndotheliumFibroblastsFibroblastsPDE4PDE4

A A 2121

Cyclic AMPCyclic AMPATPATP

Adenyl cyclaseAdenyl cyclase

Inhibition of Inhibition of Fibrosis/RemodelingFibrosis/Remodeling

Epithelial CellsEpithelial CellsFibroblastsFibroblasts

Smooth Muscle Smooth Muscle RelaxationRelaxation

PDE4PDE4

5'-AMP5'-AMP

Anti-InflammatoryAnti-InflammatoryCD8+ T cellsCD8+ T cellsMacrophagesMacrophagesNeutrophilsNeutrophils

ArifloAriflo

A Novel Approach to Treating COPD: A Novel Approach to Treating COPD: PDE4 InhibitorsPDE4 Inhibitors

A A 2222

Cilomilast Attenuates Fibroblast Cilomilast Attenuates Fibroblast ActivityActivity

In vitroIn vitro, cilomilast inhibited:, cilomilast inhibited:

• Release of MMP-1 and Release of MMP-1 and MMP-9 from fibroblastsMMP-9 from fibroblasts

• Activation of MMP-1 and Activation of MMP-1 and MMP-9 MMP-9

• Degradation of collagen Degradation of collagen by fibroblastsby fibroblasts

• Suggests potential of Suggests potential of PDE4 inhibitors to affect PDE4 inhibitors to affect remodelingremodeling

Kohyama T, Kohyama T, et al. Am J Respir Cell Mol Biolet al. Am J Respir Cell Mol Biol 2002; 27:487-494. 2002; 27:487-494.

Alveolar Wall DestructionAlveolar Wall Destruction

A A 2323

Cilomilast Attenuates Release of Cilomilast Attenuates Release of Chemoattractants for Human NeutrophilsChemoattractants for Human Neutrophils

Adapted from Profita M, Adapted from Profita M, et al.et al. ThoraxThorax 2003; 58:573-579 2003; 58:573-579

Bronchial Epithelial Cells Sputum Cells

Neu

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Neu

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00BaselineBaseline CilomilastCilomilast

(1 (1 M)M)

100100

300300

200200

400400

00BaselineBaseline CilomilastCilomilast

(1 (1 M)M)

100100

300300

200200

P<0.006P<0.008

Cells obtained from patients with COPD by bronchoscopy and sputum inductionCells obtained from patients with COPD by bronchoscopy and sputum induction

A A 2424

Study 076: Ariflo Decreased Study 076: Ariflo Decreased Macrophages in Bronchial BiopsiesMacrophages in Bronchial Biopsies

-75

-50

-25

0

25

50

Ch

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Placebo Ariflo

Difference from placebo: p=0.005

A A 2525

Study 076: Ariflo Decreased CD-8+ Study 076: Ariflo Decreased CD-8+ Lymphocytes in Bronchial BiopsiesLymphocytes in Bronchial Biopsies

-250

-200

-150

-100

-50

0

50

100

150

Ch

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Placebo Ariflo


A A 2626

BronchoconstrictionBronchoconstriction

Mediator Release From Pro-inflammatory CellsMediator Release From Pro-inflammatory Cells Influx of Inflammatory CellsInflux of Inflammatory Cells

Edema and AdhesionEdema and Adhesion

Mucus HypersecretionMucus Hypersecretion



EndotheliumEndothelium

Airway RemodellingAirway Remodelling

FibroblastsFibroblastsARIFLOARIFLO


Potential Therapeutic Benefits of ArifloPotential Therapeutic Benefits of Ariflo

A A 2828

Ariflo Clinical Ariflo Clinical Development ProgramDevelopment Program

Katharine Knobil, M.DKatharine Knobil, M.D..

Senior Director Senior Director Respiratory Clinical Development and Medical AffairsRespiratory Clinical Development and Medical Affairs


Efficacy DataEfficacy Data

A A 2929

Phase III Development Plan Phase III Development Plan Pivotal StudiesPivotal Studies

StudyStudy Abbreviated TitleAbbreviated Title LocLoc PatientsPatients Study DurationStudy Duration

039039 Pivotal Phase IIIPivotal Phase III NANA 647647 24 weeks24 weeks

156156 Pivotal Phase III Pivotal Phase III NANA 825825 24 weeks24 weeks

091091 Pivotal Phase III Pivotal Phase III EUEU 711711 24 weeks24 weeks

042042 Pivotal Phase III Pivotal Phase III EUEU 700700 24 weeks24 weeks

A A 3030

Phase III Development Plan Phase III Development Plan Supporting StudiesSupporting Studies

StudyStudy Abbreviated TitleAbbreviated Title LocLoc PatientsPatients Study DurationStudy Duration

110110 Induced Sputum Induced Sputum NANA 6565 12 weeks12 weeks

076076 Lung Biopsy Lung Biopsy EUEU 5959 12 weeks12 weeks

168168 Cardiovascular Safety Cardiovascular Safety NANA 282282 12 weeks12 weeks

041041 Long-term Safety Long-term Safety NANA 355355 up to 3 yearsup to 3 years

040040 Long-term Safety Long-term Safety EUEU 723723 up to 3 yearsup to 3 years

111111 Static Lung Volumes Static Lung Volumes NANA 156156 12 weeks12 weeks

A A 3131

Study Design: Pivotal StudiesStudy Design: Pivotal Studies

4 weeks4 weeks 24 weeks24 weeks

Ariflo 15mg BID Ariflo 15mg BID

PRNPRNalbuterolalbuterol Placebo BID Placebo BID

PlaceboPlaceboRun-inRun-in

A A 3232

Key Inclusion CriteriaKey Inclusion Criteria

• COPD diagnosisCOPD diagnosis

• 40-80 years old40-80 years old

• >> 10 pack year history of smoking 10 pack year history of smoking

• Symptoms*Symptoms*

*except NA Study 156*except NA Study 156

A A 3333

Key Inclusion CriteriaKey Inclusion Criteria

Lung Function Lung Function

• FEVFEV11 (post albuterol): 30 - 70% predicted (post albuterol): 30 - 70% predicted

• FEVFEV11/FVC (pre albuterol): /FVC (pre albuterol): <<70% predicted70% predicted

• Poorly reversible to albuterolPoorly reversible to albuterol– << 15% or 15% or << 200ml 200ml

A A 3434

Response to Albuterol in COPD Response to Albuterol in COPD Clinical Development ProgramsClinical Development Programs

1. COMBIVENT Inhalation Aerosol Study Group, 1. COMBIVENT Inhalation Aerosol Study Group, ChestChest 1994; 105:1411-1419. 2. Mahler D, 1994; 105:1411-1419. 2. Mahler D, et al. Chestet al. Chest 1999; 115:957-965. 3. Rennard S, 1999; 115:957-965. 3. Rennard S, et al. Am J Respir Crit Care Medet al. Am J Respir Crit Care Med 2001; 163:1087-1092. 4. Mahler D, 2001; 163:1087-1092. 4. Mahler D, et al. Am J Respir Crit Care Medet al. Am J Respir Crit Care Med 2002; 166:1084-1091. 5. Hanania NA, 2002; 166:1084-1091. 5. Hanania NA, et al. Chestet al. Chest 2003 2003 In Press.In Press.

11 2,3,4,52,3,4,5 4,54,5

A A 3535

Key Exclusion CriteriaKey Exclusion Criteria

• Clinical diagnosis of asthmaClinical diagnosis of asthma

• FEVFEV11 variability >20% from Screening to variability >20% from Screening to

BaselineBaseline

• Exacerbation or oral steroid Exacerbation or oral steroid administration during run-in periodadministration during run-in period

A A 3636

Efficacy AssessmentsEfficacy AssessmentsCo-Primary EndpointsCo-Primary Endpoints

• Change from baseline in FEVChange from baseline in FEV1 1 – Measured in AM prior to the next dose Measured in AM prior to the next dose

(trough)(trough)

• Change from baseline in total score of Change from baseline in total score of the St. George’s Respiratory the St. George’s Respiratory Questionnaire (SGRQ) Questionnaire (SGRQ) – A health-related quality of life instrumentA health-related quality of life instrument

A A 3737

Efficacy AssessmentsEfficacy Assessments Secondary EndpointsSecondary Endpoints

• Change from baseline in FVCChange from baseline in FVC

• COPD ExacerbationsCOPD Exacerbations

• Post exercise breathlessnessPost exercise breathlessness(Borg scale)(Borg scale)

• Summary symptom score Summary symptom score – Not collected in NA study 156Not collected in NA study 156

• 6-Minute walk6-Minute walk

A A 3838

Baseline CharacteristicsBaseline Characteristics

NANA EU EU

039 039 156 156 042042 091091n=647n=647 n=825n=825 n=700n=700 n=711n=711

AgeAge 65.365.3 64.564.5 64.664.6 62.862.8

Female (%)Female (%) 3838 4141 2020 1414

Race % (W/B)Race % (W/B) 93/393/3 93/693/6 99/099/0 98/098/0

Active smokers (%)Active smokers (%) 4545 4646 4343 3838

FEVFEV11 (% Predicted) (% Predicted) 49.749.7 50.250.2 49.049.0 50.350.3

2 reversibility (% 2 reversibility (% )) 7.37.3 8.68.6 5.15.1 5.05.0

DLCO (% Predicted)DLCO (% Predicted) 58.558.5 55.355.3 70.870.8 70.070.0

Chronic Bronchitis (%)Chronic Bronchitis (%) 61.561.5 37.537.5 80.180.1 89.689.6

A A 3939

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WeekWeek

-0.1

-0.08

-0.06

-0.04

-0.02

0

0.02

0.04

0.06

0.08

0.1

0 2 4 8 12 16 20 24 AVG24

WKS

EP

Placebo

Ariflo

P<0.001P=0.002

Ariflo Maintains FEVAriflo Maintains FEV11

NA Study 039NA Study 039

A A 4040

P<0.001P<0.001

Ariflo: Consistent Treatment EffectAriflo: Consistent Treatment EffectM

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-0.1-0.1

-0.08-0.08

-0.06-0.06

-0.04-0.04

-0.02-0.02

00

0.020.02

0.040.04

0.060.06

0.080.08

0.10.1

00 22 44 88 1212 1616 2020 2424 AVGAVG2424

WKSWKS

EPEP

PlaceboPlaceboArifloAriflo

P=0.013P=0.013P=0.024P=0.024


-0.1-0.1

-0.08-0.08

-0.06-0.06

-0.04-0.04

-0.02-0.02

00

0.020.02

0.040.04

0.060.06

0.080.08

0.10.1

00 22 44 88 1212 1616 2020 2424 AVGAVG2424

WKSWKS

EPEP


P=0.146P=0.146

WeekWeek

P=0.055P=0.055

EU Study 091EU Study 091

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-0.06-0.06

-0.04-0.04

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0.040.04

0.060.06

0.080.08

0.10.1

00 22 44 88 1212 1616 2020 2424 AVGAVG2424

WKSWKS

EPEP

PlaceboPlacebo

WeekWeek

P=0.050P=0.050

P=0.044P=0.044

EU Study 042EU Study 042

-0.1-0.1

-0.08-0.08

-0.06-0.06

-0.04-0.04

-0.02-0.02

00

0.020.02

0.040.04

0.060.06

0.080.08

0.10.1

00 22 44 88 1212 1616 2020 2424 AVGAVG2424

WKSWKS

EPEP

PlaceboPlaceboArifloArifloArifloAriflo

A A 4141

Decline in Lung Function in Long-term COPD StudiesDecline in Lung Function in Long-term COPD Studies

Follow-up, yearFollow-up, year

2.752.75

2.702.70

2.652.65

2.602.60

2.552.55

2.502.50

2.452.45

Me

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Screen 2Screen 2 11 22 33 44 55

FE

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)

MonthMonth

1.501.50

1.451.45

1.401.40

1.351.35

1.301.30

1.251.25

1.201.20-3-3 00 33 66 99 1212 1515 1818 2121 2424 2727 3030 3333 3636

7575

FE

VF

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MonthMonth-6-6 -3-3 00 33 66 99 1212 1515 1818 2121 2424 2727 3030 3333 3636

-225-225

5050252500

-25-25-50-50-75-75

-100-100-125-125-150-150-175-175-200-200 M

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PlaceboPlacebo

MonthMonth00 33 66 99 1212 1515 1818 2121 2424 2727 3030 3333 3636

-0.25-0.25

00

-0.05-0.05

-0.10-0.10

-0.15-0.15

-0.20-0.20

PlaceboPlacebo

Lung Health StudyLung Health Study ISOLDEISOLDE

EUROSCOPEUROSCOP Copenhagen CityCopenhagen City

PlaceboPlacebo

2.802.80

SmokingSmokingInterventionIntervention

FPFP

BudesonideBudesonide

BudesonideBudesonide

A A 4242

Health-Related Quality of LifeHealth-Related Quality of LifeSt. George’s Respiratory QuestionnaireSt. George’s Respiratory Questionnaire

• Disease-specific (respiratory disease)Disease-specific (respiratory disease)

• Measures the impact of COPD on quality of lifeMeasures the impact of COPD on quality of life

• Components of SGRQComponents of SGRQ– Symptoms Symptoms – Activity Activity – Impact Impact

• Decrease in score indicates improvement in Decrease in score indicates improvement in QOL QOL – Change of -4.0 is a clinically meaningful Change of -4.0 is a clinically meaningful

improvementimprovement

A A 4343

Ariflo Significantly ImprovesAriflo Significantly ImprovesQuality of LifeQuality of Life

-1.3

0.4

-3.7-3.2

-4

-3.5

-3

-2.5

-2

-1.5

-1

-0.5

0

0.5

1

Placebo

Ariflo

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Improvement Improvement in patient’s in patient’s

QOLQOL

-4.1-4.1p<0.0001p<0.0001

Difference from Difference from placeboplacebo

-1.9-1.9p=0.017p=0.017

NA Study 039NA Study 039 NA Study 156NA Study 156

A A 4444

Change From Baseline In Total SGRQ Change From Baseline In Total SGRQ Scores Averaged Over 24 WeeksScores Averaged Over 24 Weeks

-2.3

-4.9

-1.3

-2.7

-4.2

-3.2

-3.7

-6

-5

-4

-3

-2

-1

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Improvement Improvement in patient’s in patient’s

QOLQOL

NA Study 039NA Study 039 NA Study 156NA Study 156 EU Study 042EU Study 042 EU Study 091EU Study 091

0.40.4

A A 4545

Ariflo Pivotal ResultsAriflo Pivotal ResultsSecondary EndpointsSecondary Endpoints

StudyStudy 039039 156156 091091 042042

MeasureMeasure NANA NANA EUEU EUEU

FVCFVC TT TT

6-minute Walk6-minute Walk —— — — —— ——

Symptom ScoreSymptom Score —— N/A N/A ——

Post-exercise Post-exercise T T TT TT BreathlessnessBreathlessness

COPD ExacerbationsCOPD Exacerbations —— ——

= P <0.05 versus placebo= P <0.05 versus placebo— — = P >0.2 versus placebo= P >0.2 versus placeboT = 0.05 T = 0.05 << P P << 0.2 in favor of Ariflo 0.2 in favor of Ariflo

A A 4646

Percent of Patients Exacerbation-FreePercent of Patients Exacerbation-Free

50

55

60

65

70

75

80

85

90

95

100

0 50 100 150 200

50

55

60

65

70

75

80

85

90

95

100

0 50 100 150 200

50

55

60

65

70

75

80

85

90

95

100

0 50 100 150 200

50

55

60

65

70

75

80

85

90

95

100

0 50 100 150 200

NA Study 156NA Study 156No symptoms No symptoms required at entryrequired at entry

P=0.2113P=0.2113

P=0.0094P=0.0094

NA Study 039NA Study 039 P=0.0037P=0.0037

Per

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DaysDays

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DaysDays


A A 4747

Supporting StudiesSupporting Studies

A A 4848

Long Term Extension StudiesLong Term Extension Studies

• Evaluate long term safety and tolerabilityEvaluate long term safety and tolerability

• Further evaluate FEVFurther evaluate FEV11 over time over time

• Open-Label Extension of the pivotal studiesOpen-Label Extension of the pivotal studies– Subjects from NA Study 039 were eligible to enter Subjects from NA Study 039 were eligible to enter

Study 041Study 041– Subjects from EU Studies 042 and 091 were Subjects from EU Studies 042 and 091 were

eligible to enter Study 040eligible to enter Study 040

• Concomitant COPD medication use allowed Concomitant COPD medication use allowed

A A 4949

Study 041

Long-Term Extension Long-Term Extension NA Study 041: FEVNA Study 041: FEV11

Week

EP

Study 039

A A 5050

Long-Term Extension Long-Term Extension EU Study 040: FEVEU Study 040: FEV11

Week

Studies 042, 091 Study 040

A A 5151

Patient with COPDPatient with COPDNormal Chest X-rayNormal Chest X-ray

Physiology of HyperinflationPhysiology of Hyperinflation

A A 5252

Lit

ers

Lit

ers

88

66

44

22

00

TotalTotalLungLung

CapacityCapacity

TidalTidalVolumeVolume

Functional Functional ResidualResidualCapacityCapacity ResidualResidual

VolumeVolume

NormalNormal

ResidualResidualVolumeVolume

Functional Functional ResidualResidualCapacityCapacity

COPDCOPD

TotalTotalLungLung

CapacityCapacity TidalTidalVolumeVolume

Physiology of HyperinflationPhysiology of Hyperinflation

A A 5353

Study 111: Static Lung VolumesStudy 111: Static Lung Volumes

4 weeks4 weeks 12 weeks12 weeks

Ariflo 15mg BID (n=79) Ariflo 15mg BID (n=79)

PRNPRNalbuterolalbuterol Placebo BID (n=77)Placebo BID (n=77)

PlaceboPlaceboRun-inRun-in

A A 5454

Change From Baseline In Pre-albuterol Change From Baseline In Pre-albuterol Volume Of Trapped Gas (D)Volume Of Trapped Gas (D)

Difference from placebo = -180 ml (week 12), -140 ml (EP)Difference from placebo = -180 ml (week 12), -140 ml (EP)

D = TLCD = TLCboxbox – TLC – TLChehe

WEEKWEEK

0.50.5

0.40.4

0.30.3

0.20.2

0.10.1

0.00.0

-0.1-0.1

-0.2-0.2

-0.3-0.3

-0.4-0.4

-0.5-0.5

-0.6-0.6

00 2 4 8 12 EP 2 4 8 12 EP

PlaceboPlacebo

ArifloAriflo

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A A 5555

Ariflo Reduces Residual Volume Ariflo Reduces Residual Volume

Difference from placebo at Endpoint = -390mlDifference from placebo at Endpoint = -390ml

Ch

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Ch

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WeeksWeeks

A A 5656

Ariflo Reduces Functional Ariflo Reduces Functional Residual Capacity Residual Capacity


Ch

ang

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FR

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L)

Ch

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FR

C (

L)

WeeksWeeks

P=0.022

A A 5757

Can Ariflo be Compared to Can Ariflo be Compared to Theophylline?Theophylline?

• No comparable studies of similar designNo comparable studies of similar design– Small numbers of patients (8 to 60 patients)Small numbers of patients (8 to 60 patients)11

– Short duration (1 day to 8 weeks)Short duration (1 day to 8 weeks)– Criteria for reversibility vary between studiesCriteria for reversibility vary between studies

• Non-selective PDE inhibitorNon-selective PDE inhibitor– Primarily bronchodilator effectPrimarily bronchodilator effect– Predominantly due to inhibition of PDE3Predominantly due to inhibition of PDE322

– Weak activity at PDE4Weak activity at PDE433

11Ram FSF, Ram FSF, et al. Cochrane Database of Systematic Reviewset al. Cochrane Database of Systematic Reviews 2003. 2003.2 2 TheolairTheolair®® Prescribing Information Prescribing Information33Howell, Howell, et al. J Pharmacol. Exp. Ther.et al. J Pharmacol. Exp. Ther. 1993; 264: 609-615. 1993; 264: 609-615.

A A 5858

Can Ariflo be Compared to Can Ariflo be Compared to Theophylline?Theophylline?

ZuWallack RL, ZuWallack RL, et al. Chestet al. Chest 2001; 119:1661-1670. 2001; 119:1661-1670.

Data on file, Data on file, GlaxoSmithKline (SLGA4020/21).GlaxoSmithKline (SLGA4020/21).

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HourHour HourHour

Day 1Day 1 Week 12Week 12

-0.1-0.1

-0.05-0.05

00

0.050.05

0.10.1

0.150.15

0.20.2

0.250.25

0.30.3

0.350.35

00 11 22 33 44 55 66 77 88 99 1010 1111 1212

ITTITT

-0.1-0.1

-0.05-0.05

00

0.050.05

0.10.1

0.150.15

0.20.2

0.250.25

0.30.3

0.350.35

00 11 22 33 44 55 66 77 88 99 1010 1111 1212

ITTITTNon-reversibleNon-reversible Non-reversibleNon-reversible

A A 5959

Efficacy SummaryEfficacy SummaryCo-Primary EndpointsCo-Primary Endpoints

FEVFEV11::

• Maintenance of FEVMaintenance of FEV11 over 24 weeks with over 24 weeks with statistically significant benefit over placebo in statistically significant benefit over placebo in both NA pivotal studiesboth NA pivotal studies

• Magnitude of effect consistent across NA and EU Magnitude of effect consistent across NA and EU studiesstudies

SGRQ:SGRQ:

• Significant improvement in health-related quality Significant improvement in health-related quality of life versus placebo in both NA studiesof life versus placebo in both NA studies

• Consistent improvement from baseline in Ariflo Consistent improvement from baseline in Ariflo groups across NA and EU studiesgroups across NA and EU studies

A A 6060

Efficacy SummaryEfficacy SummarySupporting DataSupporting Data

• Decrease in relative risk of moderate to Decrease in relative risk of moderate to severe exacerbations in Studies 039 severe exacerbations in Studies 039 and 091and 091

• Maintenance of FEVMaintenance of FEV11 observed in the observed in the

long term studies for up to 84 weeks long term studies for up to 84 weeks

• Substantial reduction in hyperinflationSubstantial reduction in hyperinflation

A A 6161

Efficacy ConclusionsEfficacy Conclusions

• COPD is a complex and progressive COPD is a complex and progressive diseasedisease

• Poorly reversible populationPoorly reversible population

– Difficult to treat, more rapid decline in Difficult to treat, more rapid decline in FEVFEV11

• Ariflo targets inflammation specific to Ariflo targets inflammation specific to COPDCOPD

• Efficacy data support proposed indicationEfficacy data support proposed indication

A A 6363

Safety of ArifloSafety of Ariflo

Kathy Rickard, M.D.Kathy Rickard, M.D.

Vice President Vice President

Respiratory Clinical Development and Medical AffairsRespiratory Clinical Development and Medical Affairs


A A 6464

Safety OverviewSafety Overview

• Phase I & II studiesPhase I & II studies– Over 50 studies including clinical Over 50 studies including clinical

pharmacology and dose rangingpharmacology and dose ranging

• Phase III studiesPhase III studies

– Adverse eventsAdverse events– Gastrointestinal Safety Gastrointestinal Safety – Cardiovascular Safety Cardiovascular Safety – Long term safety up to 3 yearsLong term safety up to 3 years

A A 6565

Safety Exposure Safety Exposure

• 3,445 patients in all Phase III COPD 3,445 patients in all Phase III COPD studies studies – 2,119 Ariflo; 1,326 placebo2,119 Ariflo; 1,326 placebo

• 2,883 patients in the pivotal 24-week 2,883 patients in the pivotal 24-week COPD studiesCOPD studies– 1,792 Ariflo; 1,091 placebo1,792 Ariflo; 1,091 placebo

• Over 1,000 patients in long-term Over 1,000 patients in long-term extension studiesextension studies– Nearly 3,000 patient-years of exposure to Nearly 3,000 patient-years of exposure to

ArifloAriflo

A A 6666

All Randomized PatientsAll Randomized PatientsPlacebo Placebo ArifloAriflon=1091n=1091 n=1792n=1792

Adverse Experience* Adverse Experience* %% %%

TotalTotal 76.976.9 78.378.3COPD COPD 36.236.2 30.430.4NauseaNausea 5.05.0 15.715.7DiarrheaDiarrhea 7.97.9 14.414.4Abdominal PainAbdominal Pain 7.17.1 11.711.7Upper Respiratory Tract infectionUpper Respiratory Tract infection 10.310.3 8.88.8HeadacheHeadache 7.07.0 8.28.2DyspepsiaDyspepsia 2.52.5 6.86.8VomitingVomiting 1.61.6 6.16.1InjuryInjury 5.05.0 5.45.4CoughingCoughing 5.35.3 3.53.5

COPD 24-week Studies: AEsCOPD 24-week Studies: AEs

* Includes adverse experiences reported for * Includes adverse experiences reported for >>5% of patients in either of the treatment groups5% of patients in either of the treatment groups

A A 6767

COPD 24-week Studies:COPD 24-week Studies:Withdrawal Due to AEsWithdrawal Due to AEs

All Randomized PatientsAll Randomized PatientsPlacebo Placebo ArifloAriflo

Adverse Experience*Adverse Experience* n=1091n=1091 n=1792n=1792%% %%

TotalTotal 11.711.7 17.517.5NauseaNausea 0.50.5 5.15.1Abdominal PainAbdominal Pain 0.70.7 4.34.3DiarrheaDiarrhea 0.60.6 3.63.6COPDCOPD 3.83.8 2.22.2VomitingVomiting 0.30.3 1.41.4Dyspepsia Dyspepsia 0.10.1 1.01.0DizzinessDizziness 0.20.2 0.90.9HeadacheHeadache 0.10.1 0.90.9FlatulenceFlatulence 0.10.1 0.50.5

* Includes adverse experiences reported for * Includes adverse experiences reported for >>0.5% of patients in either of the treatment 0.5% of patients in either of the treatment groupsgroups

A A 6868

Rationale for Extensive GI Rationale for Extensive GI MonitoringMonitoring

• Class-related GI adverse eventsClass-related GI adverse events

• Medial necrosis in rat mesenteric arteries Medial necrosis in rat mesenteric arteries seen at seen at >>30mg/kg/day 30mg/kg/day – Not observed in primatesNot observed in primates– No intestinal ischemia observed No intestinal ischemia observed

• Medial necrosis also seen with theophylline Medial necrosis also seen with theophylline and caffeine in rodentsand caffeine in rodents– No association of mesenteric ischemia over No association of mesenteric ischemia over

decades of use in humansdecades of use in humans

Collins JJ, Collins JJ, et al. Fundam Appl Toxicolet al. Fundam Appl Toxicol 1988; 11:472-484. 1988; 11:472-484. Johansson S, Johansson S, Acta Pathol Microbiol ScandActa Pathol Microbiol Scand 1981; 89:185-191. 1981; 89:185-191.

A A 6969

Extensive GI Safety Monitoring Extensive GI Safety Monitoring

• Physical examsPhysical exams

• Laboratory assessmentsLaboratory assessments

• Orthostatic vital signsOrthostatic vital signs

• Fecal occult blood testsFecal occult blood tests

• GI adverse events of concernGI adverse events of concern– Any GI adverse event that interfered with Any GI adverse event that interfered with

patient’s daily activitiespatient’s daily activities

A A 7070

Extensive GI Safety Monitoring Extensive GI Safety Monitoring

• Patients who completed study:Patients who completed study:

– 6 fecal occult blood tests6 fecal occult blood tests– 10 sets of laboratory evaluations10 sets of laboratory evaluations– 13 sets of vital signs13 sets of vital signs– 4 sets of orthostatic vital signs4 sets of orthostatic vital signs

A A 7171

COPD 24-week Studies:COPD 24-week Studies:GIAEs of ConcernGIAEs of Concern

All Randomized PatientsAll Randomized PatientsPlacebo Placebo ArifloAriflo

Adverse Experience*Adverse Experience* n=1091n=1091 n=1792n=1792(Preferred term)(Preferred term) %% %%

TotalTotal 4.84.8 12.912.9Abdominal PainAbdominal Pain 2.62.6 5.95.9DiarrheaDiarrhea 2.12.1 5.25.2NauseaNausea 0.60.6 4.34.3VomitingVomiting 0.50.5 2.92.9DyspepsiaDyspepsia 0.30.3 1.61.6MelenaMelena 0.80.8 0.90.9FlatulenceFlatulence 0.20.2 0.90.9

* Includes adverse experiences reported for * Includes adverse experiences reported for >>0.5% of patients in either of the treatment groups0.5% of patients in either of the treatment groups

A A 7272

Cumulative Incidence of GI Adverse Cumulative Incidence of GI Adverse Events of Concern in Pivotal StudiesEvents of Concern in Pivotal Studies

00

55

1010

2020

2525

00 3030 9090 120120 180180 210210

Study DayStudy Day

% o

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ArifloAriflo

PlaceboPlacebo

1515

1501506060141477 2121

A A 7373

Fecal Occult Blood Testing in the Fecal Occult Blood Testing in the Pivotal StudiesPivotal Studies

All Randomized PatientsAll Randomized Patients

Placebo Placebo ArifloAriflo

n=1091n=1091 n=1792n=1792

Total Total

# Tested# Tested 788788 12561256 # Positive n (%)# Positive n (%) 12 (1.5%)12 (1.5%) 27 (2.2%)27 (2.2%)

GIAEs of ConcernGIAEs of Concern n=52 n=52 n=231n=231

# Tested# Tested 4242 205205

# Positive n (%)# Positive n (%) 5 (11.9%)5 (11.9%) 16 (7.8%)16 (7.8%)

A A 7474

Reports of Bowel Ischemia in the Reports of Bowel Ischemia in the Clinical ProgramClinical Program

PlaceboPlacebo ArifloAriflo

Pivotal TrialsPivotal Trials# Cases# Cases 22 00Person-Years ExposedPerson-Years Exposed 444444 683683Incidence Rate per 1000 pyIncidence Rate per 1000 py 4.54.5 00

Long Term ExtensionLong Term Extension# Cases# Cases Not ApplicableNot Applicable 33Person-Years ExposedPerson-Years Exposed …… 18001800Incidence Rate per 1000 pyIncidence Rate per 1000 py …… 1.71.7

TotalTotal# Cases# Cases 22 33Person-Years ExposedPerson-Years Exposed 444444 24832483Incidence Rate per 1000 pyIncidence Rate per 1000 py 4.54.5 1.21.2

py=person yearspy=person years

A A 7575

Incidence of Serious Adverse Events Incidence of Serious Adverse Events in Pivotal Studiesin Pivotal Studies


Serious Adverse Event: n (%)Serious Adverse Event: n (%)

TotalTotal 96 (8.8%) 96 (8.8%) 104 (5.8%)104 (5.8%)

Gastrointestinal body system Gastrointestinal body system 12 (1.1%)12 (1.1%) 10 (0.6%) 10 (0.6%)

Cardiovascular body system* 28 (2.6%)Cardiovascular body system* 28 (2.6%) 20 (1.1%) 20 (1.1%)

Respiratory body systemRespiratory body system 31 (2.8%)31 (2.8%) 30 (1.7%) 30 (1.7%)

*Includes events reported for cardiovascular general, heart rate and rhythm, *Includes events reported for cardiovascular general, heart rate and rhythm, and myocardial, endocardial, pericardial valve body systems.and myocardial, endocardial, pericardial valve body systems.

A A 7676

GI Safety SummaryGI Safety SummaryNo Evidence ofNo Evidence of Bowel IschemiaBowel Ischemia

• Mesenteric vasculopathy occurred only in Mesenteric vasculopathy occurred only in rodentsrodents

• No evidence of bowel ischemia in animals, No evidence of bowel ischemia in animals, including ratsincluding rats

• Extensive GI safety monitoring demonstrated Extensive GI safety monitoring demonstrated no serious GI effectsno serious GI effects

• Incidence of bowel ischemia was comparable Incidence of bowel ischemia was comparable between Ariflo and placebobetween Ariflo and placebo

A A 7777

Extensive Cardiovascular Safety Extensive Cardiovascular Safety Monitoring Monitoring

• CV safety issues with non-selective CV safety issues with non-selective PDE inhibitorsPDE inhibitors

• Myocardial necrosis at high, lethal Myocardial necrosis at high, lethal doses (doses (>>80mg/kg/day) in rat toxicity 80mg/kg/day) in rat toxicity studiesstudies

• CV Safety (vital signs, ECGs, Holters)CV Safety (vital signs, ECGs, Holters)

Whitehurst VE, Whitehurst VE, et al. Toxicologyet al. Toxicology 1996; 100:113-121. 1996; 100:113-121.

A A 7878

Extensive Cardiovascular Safety Extensive Cardiovascular Safety MonitoringMonitoring

• >70,000 ECGs >70,000 ECGs – >68,000 ECGs in patients with COPD>68,000 ECGs in patients with COPD

– >6,000 ECGs at C>6,000 ECGs at Cmaxmax

• >1,000 Holters>1,000 Holters– 24-hour Holter monitoring in over 400 24-hour Holter monitoring in over 400

patients patients

A A 7979

Extensive ECG Monitoring Revealed Extensive ECG Monitoring Revealed No Safety Issues with ArifloNo Safety Issues with Ariflo

*>5% of patients in any treatment group*>5% of patients in any treatment group

All Randomized PatientsAll Randomized PatientsPlacebo % Placebo % Ariflo %Ariflo %

New Onset ECG Abnormalities* New Onset ECG Abnormalities* n=1091n=1091 n=1792n=1792

Sinus BradycardiaSinus Bradycardia 13.613.6 14.414.4Q-T Interval IncreasedQ-T Interval Increased 12.412.4 12.312.3T-wave Abnormal NOST-wave Abnormal NOS 13.013.0 9.59.5Premature Atrial Contractions NOSPremature Atrial Contractions NOS 10.310.3 9.09.0Intraventicular Block NOSIntraventicular Block NOS 6.26.2 8.18.1S-T Changes NonspecificS-T Changes Nonspecific 9.49.4 8.18.1Poor R-wave ProgressionPoor R-wave Progression 9.09.0 7.67.6Sinus TachycardiaSinus Tachycardia 5.85.8 6.06.0PVCs NOSPVCs NOS 2.82.8 5.75.7Sinus ArrhythmiaSinus Arrhythmia 7.17.1 5.65.6Left Atrial Hypertrophy (P mitrale)Left Atrial Hypertrophy (P mitrale) 5.85.8 4.94.9PVCs UnifocalPVCs Unifocal 7.27.2 4.64.6

A A 8080

QTc Interval Similar Between QTc Interval Similar Between Treatment GroupsTreatment Groups

All Randomized PatientsAll Randomized Patients

Placebo Placebo ArifloAriflo n=1091n=1091 n=1792n=1792

Mean QTc* (msec)Mean QTc* (msec) BaselineBaseline 424 424 425425 Change from Baseline at EPChange from Baseline at EP 0.1 0.1 -0.4-0.4

QTc* Increases from baseline at any time-pointQTc* Increases from baseline at any time-point Patients with 30-60msec change**Patients with 30-60msec change** 144 (18.6%) 144 (18.6%) 212 (17.3%)212 (17.3%) Patients with >60msec change*Patients with >60msec change** 23 (3.0%)* 23 (3.0%) 21 (1.7%) 21 (1.7%)

*Bazett’s correction*Bazett’s correction

**in patients with a normal QTc at Baseline**in patients with a normal QTc at Baseline

A A 8181

New Onset Cardiac Events:New Onset Cardiac Events:24-Hour Holter Monitoring24-Hour Holter Monitoring

New Onset n (%)New Onset n (%)Cardiac Event Cardiac Event PlaceboPlacebo Ariflo Ariflo

Atrial FibrillationAtrial Fibrillation 00 2 (0.7)2 (0.7)

Atrial FlutterAtrial Flutter 00 1 (0.4)1 (0.4)

First Degree AV BlockFirst Degree AV Block 5 (3.6)5 (3.6) 6 (2.2)6 (2.2)

Mobitz Type 1Mobitz Type 1 00 2 (0.7)2 (0.7)

Mobitz Type 2Mobitz Type 2 2 (1.4)2 (1.4) 1 (0.4)1 (0.4)

Sinus BradycardiaSinus Bradycardia 12 (12.2)12 (12.2) 29 (15.1)29 (15.1)

Sinus PauseSinus Pause 6 (4.3)6 (4.3) 4 (1.5)4 (1.5)

Supraventricular TachycardiaSupraventricular Tachycardia 29 (46.8)29 (46.8) 65 (45.5)65 (45.5)

Non-Sustained VTNon-Sustained VT 11 (8.3)11 (8.3) 23 (8.7)23 (8.7)

A A 8282

Incidence of Serious Adverse Events Incidence of Serious Adverse Events in Pivotal Studiesin Pivotal Studies


Serious Adverse Event: n (%)Serious Adverse Event: n (%)

TotalTotal 96 (8.8%) 96 (8.8%) 104 (5.8%)104 (5.8%)

Gastrointestinal body system Gastrointestinal body system 12 (1.1%)12 (1.1%) 10 (0.6%)10 (0.6%)

Cardiovascular body system* Cardiovascular body system* 28 (2.6%)28 (2.6%) 20 (1.1%)20 (1.1%)

Respiratory body systemRespiratory body system 31 (2.8%)31 (2.8%) 30 (1.7%)30 (1.7%)

*Includes events reported for cardiovascular general, heart rate and rhythm, *Includes events reported for cardiovascular general, heart rate and rhythm, and myocardial, endocardial, pericardial valve body systems.and myocardial, endocardial, pericardial valve body systems.

A A 8383

Serious Adverse Events with Fatal Serious Adverse Events with Fatal Outcome in the Pivotal StudiesOutcome in the Pivotal Studies

PlaceboPlacebo ArifloAriflo

n=1091n=1091 n=1792n=1792

Fatal SAEs* Fatal SAEs* 5 (0.5%)5 (0.5%) 7 (0.4%)7 (0.4%)

*None were considered related to treatment.*None were considered related to treatment.

A A 8484

Safety Data from Long Term Safety Data from Long Term Extension StudiesExtension Studies

• Greater than 1,000 patients for up to 3 yearsGreater than 1,000 patients for up to 3 years

• Over 25,000 ECGs performedOver 25,000 ECGs performed

• Safety data similar to pivotal trialsSafety data similar to pivotal trials– No cardiovascular safety issues identifiedNo cardiovascular safety issues identified– No gastrointestinal safety issues identifiedNo gastrointestinal safety issues identified

A A 8585

Additional Safety AssessmentsAdditional Safety AssessmentsClinical Pharmacology StudiesClinical Pharmacology Studies

• Male reproductiveMale reproductive

• NeuroendocrineNeuroendocrine

• Drug-drug interactionsDrug-drug interactions

A A 8686

Male Reproductive SystemMale Reproductive System

• Nonclinical studies with Ariflo showed Nonclinical studies with Ariflo showed testicular degeneration in rats and rabbits, testicular degeneration in rats and rabbits, but not in mice or primatesbut not in mice or primates

• Ariflo 15mg BID or placebo was administered Ariflo 15mg BID or placebo was administered to 100 healthy, young male subjects for 12 to 100 healthy, young male subjects for 12 weeksweeks

• No evidence of a clinically significant effect No evidence of a clinically significant effect on sperm number, motility, or morphology in on sperm number, motility, or morphology in humanshumans

A A 8787

Neuroendocrine SystemNeuroendocrine System

• Adrenocortical hypertrophy in ratsAdrenocortical hypertrophy in rats– Stimulation of the HPA-axis is well-recognized Stimulation of the HPA-axis is well-recognized

response of rats to PDE inhibitors response of rats to PDE inhibitors

• Mammary tumors at high dose in mice Mammary tumors at high dose in mice associated with pseudopregnancy associated with pseudopregnancy

• No evidence of an effect on prolactin, ACTH, No evidence of an effect on prolactin, ACTH, serum or urinary cortisol levels in humansserum or urinary cortisol levels in humans

Kumari M, Kumari M, et al. Brit J Pharmacolet al. Brit J Pharmacol 1997; 121:459-468. 1997; 121:459-468.Law LW, Law LW, Proc Soc Exp Biol MedProc Soc Exp Biol Med 1941; 48:486-487. 1941; 48:486-487.

A A 8888

Interaction StudiesInteraction Studies

• No evidence of interactions:No evidence of interactions:– Albuterol, ipratropium, theophylline, prednisolone, Albuterol, ipratropium, theophylline, prednisolone,

warfarin, and digoxinwarfarin, and digoxin– SmokingSmoking

• No effect on bioavailability with magnesium-No effect on bioavailability with magnesium-aluminum-dimethicone antacid or foodaluminum-dimethicone antacid or food

• Potential for increased GI intolerance Potential for increased GI intolerance – Co-administration with erythromycin Co-administration with erythromycin – Severe hepatic impairmentSevere hepatic impairment– Severe renal impairmentSevere renal impairment

A A 8989

Ariflo Safety ConclusionsAriflo Safety Conclusions

• Extensive safety data with exposure to Ariflo Extensive safety data with exposure to Ariflo up to 3 yearsup to 3 years

• For patients with GI adverse events, most For patients with GI adverse events, most occurred early and were mild to moderate in occurred early and were mild to moderate in intensityintensity

• Serious AEs, including GI, were infrequent Serious AEs, including GI, were infrequent and similar between treatment groupsand similar between treatment groups

• No evidence of an increased risk of No evidence of an increased risk of cardiovascular eventscardiovascular events

A A 9191

Assessment of Outcome in Assessment of Outcome in COPDCOPD

Frank Sciurba, MDFrank Sciurba, MDAssociate Professor of MedicineAssociate Professor of Medicine

Division of Pulmonary, Allergy and Critical Care Division of Pulmonary, Allergy and Critical Care

Medicine University of PittsburghMedicine University of Pittsburgh

A A 9292

The Face of Chronic Obstructive The Face of Chronic Obstructive Pulmonary Disease (COPD)Pulmonary Disease (COPD)

EmphysemaEmphysema ChronicChronic Bronchitis

A A 9393

0

10

20

30

40

50

60

HospitalStay

60 Days 180 Days 1 Year 2 Years

Mo

rtal

ity

(%)

Mo

rtal

ity

(%)

Median length of hospital stay: 9 daysMedian length of hospital stay: 9 daysMedian cost of hospitalization: $7,100Median cost of hospitalization: $7,100Readmission rate (6 months): 44%Readmission rate (6 months): 44%

Time After HospitalizationTime After Hospitalization

Connors AF, Connors AF, et al.et al. Am J Respir Crit Care MedAm J Respir Crit Care Med. 1996;154:959-967. 1996;154:959-967

Health Care Utilization and Health Care Utilization and Mortality Due to ExacerbationsMortality Due to Exacerbations

A A 9494

No single parameter in patients No single parameter in patients with COPD is sufficient to be with COPD is sufficient to be

considered the gold standard to considered the gold standard to assess outcome.assess outcome.

— — A. Fishman, 1994A. Fishman, 1994

A A 9595

Clinical Research in COPD:Clinical Research in COPD:Needs and OpportunitiesNeeds and Opportunities

• NHLBI Workshop SummaryNHLBI Workshop Summary

– What measures of disease status are useful What measures of disease status are useful indices therapeutic benefit?indices therapeutic benefit?

– What can be done to promote the development What can be done to promote the development and testing of novel agents for the treatment of and testing of novel agents for the treatment of COPD? efforts that may reduce these barriers …COPD? efforts that may reduce these barriers …exploration of alternative outcome measures”exploration of alternative outcome measures”

Croxton TL, Croxton TL, et al.et al. Am J Respir Crit Care Med Am J Respir Crit Care Med 2003; 167:1142.2003; 167:1142.

A A 9696

FEVFEV11: Advantages: Advantages

• On average reflects function and On average reflects function and prognosisprognosis

• Reproducible measureReproducible measure

• Responsiveness to various therapies Responsiveness to various therapies well establishedwell established

A A 9797

Prognosis in Chronic Prognosis in Chronic Obstructive Pulmonary DiseaseObstructive Pulmonary Disease

% S

urv

ival

% S

urv

ival

YearsYears

NormalsNormals>> 50% Predicted 50% Predicted40-49% Predicted40-49% Predicted30-39% Predicted30-39% Predicted<30% Predicted<30% Predicted

100100

9090

8080

7070

6060

00 11 22 33

FEVFEV11

Anthonisen N, Anthonisen N, Am Rev Respir DisAm Rev Respir Dis 1986; 133(1):14-20 1986; 133(1):14-20

A A 9898

FEVFEV11: Limitations: Limitations

• Marked Marked individualindividual variation in symptoms and variation in symptoms and disability independent of FEVdisability independent of FEV11

• Symptomatic and functional response to Symptomatic and functional response to therapy may be independent of FEVtherapy may be independent of FEV11

• May not reflect changes in important disease May not reflect changes in important disease activity which could lead to long term activity which could lead to long term functional decline or frequency of functional decline or frequency of exacerbationsexacerbations

A A 9999

SGRQ = St. George’s Respiratory QuestionnaireSGRQ = St. George’s Respiratory Questionnaire*Higher scores = worse quality of life*Higher scores = worse quality of lifeAdapted with permission from Jones PW. Adapted with permission from Jones PW. ChestChest 1995; 107(suppl): 187S-193S. 1995; 107(suppl): 187S-193S.

100100

9090

8080

7070

6060

5050

4040

3030

2020

1010

0000 2020 4040 6060 8080 100100 120120

FEVFEV11 (% predicted) (% predicted)

SGRQ SGRQ ScoreScore

r=0.30r=0.30P<0.001P<0.001

Normal Normal Means 2 SDMeans 2 SD

Correlation of Quality of Life Scores Correlation of Quality of Life Scores (SGRQ*) with FEV(SGRQ*) with FEV11 in Patients with COPD in Patients with COPD

A A 100100

Spirometric Changes with Spirometric Changes with Increasing Degrees of ObstructionIncreasing Degrees of Obstruction

00

11

22

33

44

55

66

77

00 11 22 33 44 55 66

SecondsSeconds

LitersLiters(BTPS)(BTPS)

A A 101101

Residual VolumeResidual Volume

ResidualResidualVolumeVolume (RV) (RV)

Normal PatternNormal PatternObstructive PatternObstructive Pattern

FunctionalFunctionalResidual Residual Capacity Capacity

(FRC)(FRC) FunctionalFunctionalResidualResidualCapacityCapacity

Vital Capacity Vital Capacity

Vital Vital Capacity Capacity

(VC)(VC)

A A 102102

Hyperinflation in EmphysemaHyperinflation in Emphysema

A A 103103

Lung and Chest Wall Forces at Lung and Chest Wall Forces at End-Expiration in COPD vs. NormalEnd-Expiration in COPD vs. Normal

NormalNormal

Adapted From O’Donnell.Adapted From O’Donnell.

Chest wall recoil remainsChest wall recoil remainsinward resulting in ainward resulting in athreshold load at the threshold load at the start of inspirationstart of inspiration

Flattened shortened Flattened shortened diaphragm muscle diaphragm muscle inefficient in force inefficient in force generationgeneration

COPDCOPD

A A 104104

A A 105105

Dynamic Lung Volume Regulation During Dynamic Lung Volume Regulation During Exertion in COPD Compared to NormalExertion in COPD Compared to Normal

O’Donnell. O’Donnell. ChestChest 2000; 117:42S-47S. 2000; 117:42S-47S.

2020

EELVEELV

00 4040 6060 80804040

6060

8080

140140

120120

100100

% p

red

icte

d T

LC

% p

red

icte

d T

LC

TLCTLC

normalnormal

EELV (FRC)EELV (FRC)

TLCTLC

COPDCOPD

Ventilation (L/min)Ventilation (L/min)

A A 106106

Bronchodilator Responses in Patients Bronchodilator Responses in Patients with “Irreversible” Emphysemawith “Irreversible” Emphysema

Ch

ang

e fr

om

Bas

elin

e p

ost

-alb

ute

rol

Ch

ang

e fr

om

Bas

elin

e p

ost

-alb

ute

rol

(L)

(L)

*p<0.05*p<0.05

O’Donnell, DE. O’Donnell, DE. Eur Resp JEur Resp J 2001; 18:914-920. 2001; 18:914-920.

0.10*0.08*0.09*

-0.51*

-0.27*-0.37*-0.45*

-0.21*-0.31*

-1

-0.5

0

0.5

1FEV1

RV

FRC

All Patientsn=84

Moderaten=48

Severen=36

A A 107107

Number of Inflammatory CellsNumber of Inflammatory Cellsper mper m22 of Lung Surface Area of Lung Surface Area

Air SpaceAir Space TissueTissue

ControlControl MildMild SevereSevere ControlControl MildMild SevereSevere

NeutrophilsNeutrophils 2020 5050 300*300* 2424 2929 140* 140* (x10(x1088/m/m22))

MacrophagesMacrophages 270270 330330 4000*4000* 4.54.5 4.44.4 71*71*(x10(x1088/m/m22))

CD8+CD8+ 4040 4646 1400*1400* 3131 3434 250*250*(x10(x1088/m/m22))

*Different from Control and Mild (p <0.01) *Different from Control and Mild (p <0.01)

Retamales I, Retamales I, et al.et al. Am J Respir Crit Care MedAm J Respir Crit Care Med 2001; 164:469-473. 2001; 164:469-473.

Calhoun WJ,Calhoun WJ, et al. Am J Respir Crit Care Med et al. Am J Respir Crit Care Med 2001;2001; 165:730b-731b.165:730b-731b.

A A 108108

- S. Shapiro- S. Shapiro

The Cigarette Burns Out The Cigarette Burns Out But the Inflammation But the Inflammation

Rages OnRages On

A A 109109

Smoking Cessation: Anti-inflammatory ModelSmoking Cessation: Anti-inflammatory Model

Participants = 5887

Pre

dic

ted

FE

VP

red

icte

d F

EV

11 (%

) (

%)

Adapted from Anthonisen N, Adapted from Anthonisen N, et al.et al. JAMAJAMA. 1994;272:1497-1505. . 1994;272:1497-1505.

8282

8080

7878

7676

7474

7272

BL BL 1 1 22 33 44 55Annual VisitsAnnual Visits

QuittersQuittersSmokersSmokers

1516

38043804

1207

32643264

1067

28642864

972

25262526

910

22982298

A A 110110

Mea

n C

han

ge

fro

m B

asel

ine

Mea

n C

han

ge

fro

m B

asel

ine

in T

rou

gh

FE

Vin

Tro

ug

h F

EV

11 (L

) (

L)

WeekWeek

-0.1

-0.08

-0.06

-0.04

-0.02

0

0.02

0.04

0.06

0.08

0.1

0 2 4 8 12 16 20 24 AVG24

WKS

EP

Placebo

Ariflo

P<0.001P=0.002

Ariflo Maintains FEVAriflo Maintains FEV11


A A 111111

Ariflo Reduces Residual Volume Ariflo Reduces Residual Volume


Ch

ang

e in

Res

idu

al V

olu

me

(L)

Ch

ang

e in

Res

idu

al V

olu

me

(L)

WeeksWeeks

A A 112112

Study 076:Study 076:Ariflo Decreased Inflammatory Cells in Ariflo Decreased Inflammatory Cells in

Bronchial BiopsiesBronchial Biopsies

-75

-50

-25

0

25

50

Ch

an

ge

in s

ub

-ep

ith

elia

l m

ac

rop

ha

ge

s/a

rea

tis

su

e

Placebo Ariflo


-250

-200

-150

-100

-50

0

50

100

150

Ch

an

ge

in s

ub

-ep

ith

elia

l CD

8+

ly

mp

ho

cy

tes

/are

a t

iss

ue

Placebo Ariflo


A A 113113

ConclusionsConclusions

• Clinically relevant outcomes of novel anti-Clinically relevant outcomes of novel anti-inflammatory agents for COPDinflammatory agents for COPD

– Stabilization of FEVStabilization of FEV11

– Reduction in lung hyperinflationReduction in lung hyperinflation– Airway inflammationAirway inflammation

• FEVFEV11

– Useful measure of severity and outcome in COPDUseful measure of severity and outcome in COPD– May not reflect other clinically important May not reflect other clinically important

measures of lung hyperinflation and inflammatory measures of lung hyperinflation and inflammatory activityactivity

A A 115115

Summary RemarksSummary Remarks

David Wheadon, M.D.David Wheadon, M.D.

Senior Vice PresidentSenior Vice President

Regulatory Affairs Regulatory Affairs


A A 116116

COPD Mortality is IncreasingCOPD Mortality is Increasing

Mannino DM Mannino DM et al.et al. MMWR, MMWR, 2002: 51(SS06);1-16. 2002: 51(SS06);1-16. Pastor PN Pastor PN et al. National Center for Health Statisticset al. National Center for Health Statistics, 2002., 2002.

-48.0%

-19.9%

-6.9% -6.9%

25.5%

-50

-40

-30

-20

-10

0

10

20

30

40

50

Per

cen

t ch

ang

e

HIV

CAD

Stroke Cancer

COPD

Percent change in age-adjusted death rates in theUS over 10 years (1990-2000)

A A 117117

BronchoconstrictionBronchoconstriction

Mediator Release From Pro-inflammatory CellsMediator Release From Pro-inflammatory Cells Influx of Inflammatory CellsInflux of Inflammatory Cells

Edema and AdhesionEdema and Adhesion

Mucus HypersecretionMucus Hypersecretion



EndotheliumEndothelium

Airway RemodellingAirway Remodelling

FibroblastsFibroblastsARIFLOARIFLO


Potential Therapeutic Benefits of ArifloPotential Therapeutic Benefits of Ariflo

A A 118118

Ariflo:Ariflo:A New Treatment Option for COPDA New Treatment Option for COPD

• Achieved co-primary endpoints in both Achieved co-primary endpoints in both North American studiesNorth American studies

• No serious safety issuesNo serious safety issues

• Lack of interactionsLack of interactions

• Oral treatment may improve complianceOral treatment may improve compliance

A A 119119

External ExpertsExternal Experts

Loren Laine, M.D.Loren Laine, M.D.Chief, GI SectionChief, GI SectionL.A. County – U.S.C. Medical CenterL.A. County – U.S.C. Medical CenterProfessor of MedicineProfessor of MedicineUniversity of Southern California University of Southern California Medical SchoolMedical School

Christina Wang, M.D.Christina Wang, M.D.Program DirectorProgram DirectorGeneral Clinical Research CenterGeneral Clinical Research CenterHarbor-UCLA Medical CenterHarbor-UCLA Medical CenterProfessor of MedicineProfessor of MedicineDavid Geffen UCLADavid Geffen UCLASchool of MedicineSchool of Medicine

Jeremy N. Ruskin, M.D.Jeremy N. Ruskin, M.D.Director, Cardiac Arrhythmia ServiceDirector, Cardiac Arrhythmia ServiceMassachusetts General HospitalMassachusetts General HospitalAssociate Professor of MedicineAssociate Professor of MedicineHarvard Medical SchoolHarvard Medical School

Gary Koch, Ph.D.Gary Koch, Ph.D.Professor of BiostatisticsProfessor of BiostatisticsUniversity of North CarolinaUniversity of North Carolina

A 1 ARIFLO ® (cilomilast) Tablets, 15 mg September 5, 2003 NDA 21-573 Pulmonary - Allergy Drugs...

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