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Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

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Page 1: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs
Page 2: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

Introduction and Overview

Burkhard Blank, M.D.

Senior Vice President

Medical and Regulatory Affairs

Page 3: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

COPD

• Increasing prevalence worldwide

• Fourth leading cause of death in the US

• Further increase in prevalence and mortality predicted

Page 4: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

COPD

• Progressive limitation of airflow

• Most patients seek medical attention because of dyspnea

• Typically dyspnea progresses and eventually limits everyday activities

Page 5: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

COPD

• Smoking cessation has been shown to change the progression of the disease

• In the US bronchodilators are the only approved pharmacologic principle

Page 6: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

Spiriva® Clinical Development Program

• 4,124 subjects

• Phase 3 included 2,663 patients in six pivotal studies - three replicate pairs

• One-year vs. placebo

• One-year vs. ipratropium

• Six-month vs. placebo and salmeterol

Page 7: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

Spiriva® Phase 3

• Primary endpoints for efficacy

• Bronchodilation: trough FEV1 in all studies

• Dyspnea relief: as co-primary in six-month studies

• Safety

Page 8: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

Major Topics for Today

• 24-hour bronchodilation

• Relief of dyspnea• Use of validated instrument

• Clinically meaningful response

• Safety profile• Cardiovascular adverse events

Page 9: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

24-hour Bronchodilation

• Trough FEV1 as primary endpoint

• Consistency of findings across pivotal studies

• Supported by secondary spirometric data

Page 10: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

Relief of Dyspnea

• BDI/TDI chosen as an appropriate instrument

• Improvement over placebo shown in both pivotal studies

• Supportive evidence from the other four Phase 3 studies

Page 11: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

Safety Profile

• Large patient numbers and patient exposure

• Adverse events reflect anticholinergic pharmacology

• No association with life threatening events

Page 12: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

Proposed Indication

SPIRIVA® (tiotropium) is indicated for the long-term, once-daily, maintenance treatment of bronchospasm and dyspnea associated with Chronic Obstructive Pulmonary Disease (COPD) including chronic bronchitis and emphysema.

Page 13: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

Presentation Overview

24-Hour BronchodilationBernd Disse, M.D., Ph.D.Therapeutic Area HeadRespiratory Diseases

Measurement of DyspneaP. Jones, M.D., Ph.D.Professor of Respiratory MedicineDepartment of PhysiologySt. George’s Hospital Medical Center

Relief of DyspneaT. Witek, Dr. P.H.Vice President and HeadRespiratory Development & Operations

Safety S. Kesten, M.D. Medical Director International SPIRIVA® Program

Clinical Perspective J. Donohue, M.D.

Professor of Medicine and Director Clinical Group Pulmonary Division University of North Carolina

Conclusions B. Blank, M.D.

Senior Vice PresidentMedical and Regulatory Affairs

Page 14: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

Consultants

J. Donohue, M.D.

Professor of Medicine and Director, Clinical Group Pulmonary Division University of North Carolina

P. Jones, M.D., Ph.D.

Professor of Respiratory Medicine Department of PhysiologySt. George’s Hospital Medical School

D. Mahler, M.D.

Chief of PulmonaryCritical Care Medicine SchoolDartmouth Hitchcock Medical Center

E. Prystowsky, M.D.

Director, Clinical ElectrophysiologySt. Vincent Hospital, Indianapolis, INConsulting Professor of MedicineDuke University Medical Center, Durham, NC

Page 15: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs
Page 16: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

Bernd Disse, M.D., Ph.D.

Therapeutic Area Head Respiratory Diseases

Bronchodilator Efficacy in COPD

Page 17: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

SPIRIVA® (tiotropium) Bronchodilator Efficacy in COPD

• Preclinical and clinical pharmacology

• Long-term Phase 3 studies

• Patients

• Spirometry (primary endpoint)

• Subgroup analysis

• Secondary endpoints, supportive information

• Summary and conclusion

Page 18: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

Anticholinergics: From Ipratropium to Tiotropium

• Ipratropium

• Standard anticholinergic bronchodilator with established safety record, q.i.d administration

• Tiotropium

• KD at M3: 10 pM vs. 200 pM for ipratropium

• Long duration of action

• Most likely due to slow dissociation from M3-receptors

Page 19: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

Tiotropium Phase 2

• Single-dose study in COPD patients (10-160 µg) established

pharmacodynamic duration of action exceeding 24 hours

• Multiple-dose (4-week treatment, 4.5 - 36 µg, placebo)

allowed to select 18 µg for Phase 3

• Approaching pharmacodynamic plateau for FEV1

• Increasing tendency for dry mouth with 36 µg

Page 20: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

Delivered Dose: 10 µg

Dose Deposited in the Lungs

3.6 µg

Fine Particles(20% of nominal

dose)OropharyngealDeposited Dose

6.4 µg

Coarse Particles

Mucociliary Clearance

AbsorptionFrom Lungs:

90-100%

Systemic Dose3.5 µg

0.15 µg=3.65 µg

Oral Bioavailability:2-3 %

Topical (Inhalative) Selectivity ofN-quaternary Anticholinergics

HandiHaler®:18 µg

Nominal Dose

Page 21: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

Clinical Pharmacokinetics

Metabolism: 25 % (CYP 2D6, 3A4), including ester cleavage

Urine : 75 % (parent compound)

Bioavailability: 19.5 % by dry powder inhalationPlasma conc.: trough: 3-4 pg/mL, C max,ss: 15-20 pg/mL

CLR(i.v.) : 669 mL/min

ClCR: 50-80 30-50 < 30 [mL/min]

and AUC0-4h: +39% +81% +94% = AUC increase plateauing

t½ : 5-6 days

Page 22: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

SPIRIVA® (tiotropium) Bronchodilator Efficacy in COPD

• Preclinical and clinical pharmacology

• Long-term Phase 3 studies

• Patients

• Spirometry (primary endpoint)

• Subgroup analysis

• Secondary endpoints, supportive information

• Summary and conclusion

Page 23: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

Proposed Indication

SPIRIVA® (tiotropium) is indicated for the

long-term, once-daily, maintenance treatment

of bronchospasm and dyspnea associated with

Chronic Obstructive Pulmonary Disease (COPD)

including chronic bronchitis and emphysema

Page 24: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

Long-term Phase 3 Studies

Randomized, double-blind, double-dummy (if applicable), parallel groupTreatment: 18g tiotropium DPI once-a-day

114/115 122A/122B 130/137

N per study 470/451 288/247 623/584

Duration One-Year One-Year Six-Month

Placebo PlaceboComparator

Ipratropium 40µg MDIfour-times-daily

Salmeterol 50µg MDItwice-daily

Page 25: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

Clinical Program: Patient Selection

• Clinical diagnosis of COPD and exclusion of patients with history of asthma, allergic rhinitis, atopy (eosinophils 600/mm3)

• FEV1 65% of predicted normal, FEV1 70% of FVC

• Age 40 years and smoker >10 pack-years

Page 26: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

Clinical Program: Exclusion Criteria

• Not able to participate in long-term trial as judged by investigator (significant other disease),

• Recent respiratory tract infection within six weeks prior to study

• Daytime oxygen, pulmonary rehab, thoracotomy

• Recent history of MI, cardiac arrhythmia requiring treatment, hospitalization for heart failure

• Significant abnormal laboratory finding

• Known prostatic hypertrophy, bladder neck obstruction, narrow-angle glaucoma

Page 27: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

Selected Co-Morbidities of Phase 3 Study Population

• Cardiovascular diseases, total 42 - 67%• Hypertension 14 - 35%

• Arrhythmias 5.0 - 12%

• Coronary artery disease 2.2 - 12%

• Myocardial infarction in history 6.2 - 7.1%

• Neurologic and psychiatric disease 21 - 57%• Depression 1.7 – 21%

• Renal/urinary tract disease 13 - 33%• Prostatic hypertrophy + micturition disturbance 1.7 - 11%

• Metabolic/endocrine disease 10 - 28%• Diabetes 3.9 - 7.3%

• Hyperlipidemia 3.0 – 16%

Page 28: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

One-YearPlacebo

Controlled

One-YearIpratropiumControlled

Six-MonthPlacebo & Salmeterol

Controlled

N = 921 N = 535 N = 1207

% Males 65 85 76

Race: % Caucasian 94 100 99

Age: Mean

(range)

65

(39-87)

64

(41-82)

64

(39-87)

Smoking History(pack years)

61 34 44

Duration of COPD:Mean

8 11 10

FEV1 (L): Mean

(Range)

1.02

(0.29 - 2.63)

1.23

(0.29 - 2.45)

1.09

(0.26 - 2.51)

FEV1 % Pred: Mean 39 43 41

FEV1/FVC (%): Mean 46 46 42

Demographics and Baseline Characteristics

Page 29: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

Long-term Studies: Endpoints

One-Year Studies Six-Month Studies

Trough FEV1* At 13 weeks At 24 weeks

Dyspnea At 24 weeks

* Mean of PFTs at 1 hour and at 5 min before morning administration Reflects drug activity at the end-of-dosing-interval

Secondary Endpoints:• Time course FEV1 and FVC, PEFR (at home)

• Shuttle Walking Test (Six-month studies)• Symptom Scores, albuterol use• Exacerbations of COPD, patient reported outcomes

Primary Endpoint:

Page 30: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

SPIRIVA® (tiotropium) Bronchodilator Efficacy in COPD

• Preclinical and clinical pharmacology

• Long-term Phase 3 studies

• Patients

• Spirometry (primary endpoint)

• Subgroup analysis

• Secondary endpoints, supportive information

• Summary and conclusion

Page 31: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

30min 1 h 2 h 3 hTime After Administration

-1 h -5min0.95

1.00

1.05

1.10

1.15

1.20

1.25

FE

V1

(Lit

ers)

Day 344

Day 344

Day 8

Day 8Day 1

Day 1

Day 92

Day 92

Study 114: FEV1 -Time Profile vs. Placebo

dose

TioPbo

Page 32: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

1.2

1.25

1.3

1.35

1.4

1.45

1.5

1.55

-1h -5min 30min 1h 2h 3h 4h 5h 6h

Time After Administration

FE

V1

(Lit

er)

1.15

Day 1

Day 1Day 8

Day 8Day 364

Day 364

Study 122A: FEV1 -Time Profile vs. Ipratropium

dose

TioIb

Page 33: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

1.00

1.05

1.10

1.15

1.20

1.25

1.30

1.35

-1h -10min 30min 1h 2h 3h 4h 6h 8h 10h 12hTime After Administration

FE

V1

(Lit

er)

Study 130: FEV1 -Time Profile vs. Placebo and Salmeterol

dose

Day 1

Day 1

Day 15

Day 15

Day 169

Day 169

TioPbo

Day 1Day 15

Day 169

Sal

Page 34: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

-1h -10min 30min 1h 2h 3hTime after administration

1.05

1.10

1.15

1.20

1.25

1.30

1.35

1.40

FE

V1

(Lit

er)

Study 137: FEV1 -Time Profile vs. Placebo and Salmeterol

dose

Day 15

Day 15

Day 169

Day 169

Day 1

Day 1

Day 15

Day 169

Day 1

TioPboSal

Page 35: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

Magnitude of Spirometric Improvements

Study #Tiotropium

114 115 130 137Salmeterol

130 137

Peak* [L] 0.22 0.21 0.25 0.19 0.16 0.13

Trough* [L]%Baseline

0.1616%

0.1515%

0.1413%

0.109%

0.088%

0.087%

* FEV1-response from baseline compared to placebo at end of study

%Baseline 22% 21% 24% 17% 15% 12%

Page 36: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

Efficacy in Subgroups

• Age 40-64 / 65 to 74 / 75 years• Gender male / female• Smoking status ex-smoker /current-smoker• Severity of disease FEV1< 35 / 35 to 49 / 50 %• Previous Atrovent use user / non-user

• Concomitant medication:• Inhaled steroids user / non-user• Theophylline user / non-user

• Tiotropium was similarly effective in all subgroups based on subgroup analysis in combined replicate studies

Page 37: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

SPIRIVA® (tiotropium) Bronchodilator Efficacy in COPD

• Preclinical and clinical pharmacology

• Long-term Phase 3 studies

• Patients

• Spirometry (primary endpoint)

• Subgroup analysis

• Secondary endpoints, supportive information

• Summary and conclusion

Page 38: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

Combined data of studies 114/115nominal p<0.0001 for each time point in individual studies

Peak and Trough FVC Response Over One-Year vs. Placebo

Trough

Day

Peak

Day

00.10.20.30.40.50.60.70.8

1 8 50 92 176 260 344

F

VC

(L

ite

r)

290mL

440mL

00.10.20.30.40.50.60.70.8

1 8 50 92 176 260 344

F

VC

(L

ite

r)Tio (n=518)

Pbo (n=328)

Page 39: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

Mean Morning and Evening Peak Flow Rate (L/Min) for the One-Year Placebo-Controlled Studies

Morning Peak Flow

PPPP

TTTTTTT

TTTTTT

TTTTTTTTTTTTT

TTTTTTTTTTTTTTTTTTTTTTT

PPPPPPPPPPPPPP

PPPPPPPPPPPPP

PPPPPPPPPPPPPPPPPPP

T

250

240

230

220

210

200

190

0

PEFR(L/m)

0 8 16 24 32 40 48 56Week

Combined Studies 114/115

Evening Peak Flow

PT

TTTTTTT

TTTTTTTTTTTTTTTTT

TTTTTTTTTTTTTTTTTTTTTTTTT

PPPPPPPPPPPP

PPPPPPPPPPPPPPPPPPPPPPPPPPPPPP

PPPPPPP

Week

T T TP P P

Tio (N=507)Pbo (N=332)

T T TP P P

Tio (N=479)Pbo (N=311)

250

240

230

220

210

200

190

0

PEFR(L/m)

0 8 16 24 32 40 48 56

Page 40: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

Exacerbations of COPD

• Evaluation retrospective and of exploratory nature in combined replicate one-year studies

• Prespecified secondary endpoint for combined analysis of replicate studies in six-month studies

Definition:Physician defined COPD exacerbation, or a complex of COPD related symptoms (i.e. cough, wheeze, dyspnea or sputum production), lasting at least three days and reported as adverse event

Page 41: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

0

0.5

0.6

0.7

0.8

0.9

1.0

0 50 100 150 200 250 300 350

Tiotropium (n = 550)

Placebo (n = 371)

Days on Treatment

Pro

bab

ility

of

No

Exa

cerb

atio

n

Time to first COPD exacerbation, nominal p=0.011 (log rank test) n.s. in individual studies 114/115

COPD Exacerbation Combined Replicate Studies vs. Placebo, 114/115

Page 42: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

0

0.5

0.6

0.7

0.8

0.9

1.0

0 50 100 150 200 250 300 350

Tiotropium (n = 356)

Ipratropium (n = 179)

Days on Treatment

Pro

bab

ility

of

No

Exa

cerb

atio

n

Vincken W et al. Eur Respir J (2002)

Time to first COPD exacerbation, nominal p=0.008 (log rank test) n.s. in study 122A alone

COPD Exacerbation Combined Replicate Studies vs. Ipratropium, 122A/122B

Page 43: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

Time to first COPD exacerbation, nominal p=0.005, tiotropium vs. pbo (log rank test)

0

0.5

0.6

0.7

0.8

0.9

1

0 30 60 90 120 150 180

Tio (n = 402)

Sal (n = 405)

Pbo (n = 400)

Days

Pro

bab

ility

of

No

Exa

cerb

atio

n

COPD Exacerbation Combined Replicate Studies vs. Placebo/Salmeterol 130/137

Page 44: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

Symptoms – distress due to respiratory symptomsActivity – disturbance of physical activities and

mobility caused by dyspneaImpacts – psycho-social effects of the disease Total score – overall health status

Decreasing scores indicate improvement Score change of 4 clinically meaningful

Health Status:St. George’s Respiratory Questionnaire (SGRQ)

Domains:

Disease-specific instrument

Page 45: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

SGRQ Total Score in One-Year Placebo-Controlled Studies

114 115Score

P P P

PP

PT

T TT T T

50

49

48

47

46

45

44

43

4241

40

1 50 92 176 260 344Test Day

PP P P

PP

T

50

49

48

47

46

45

44

43

4241

40

1 50 92 176 260 344Test Day

TT T

TT

Score

TioPbo

3.4

4.1

* ** **

*****

*****

* p < 0.05, ** p < 0.01, *** p < 0.001 (nominal p values)

Page 46: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

Summary and Conclusion

• Secondary endpoints and exploratory analyses show improvements of

• related lung-function measures (FVC, PEFR)

• exacerbations

• health status (approaching predefined clinical significance)

• Tiotropium once-daily provides sustained improvement of spirometric measures for 24 hours

• Improvements were maintained over one year, with no evidenceof tachyphylaxis

Page 47: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs
Page 48: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

Quantification of Dyspnea

Paul Jones M.D., Ph.D.

Professor of Respiratory MedicineSt. George’s Hospital Medical School

London

Page 49: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

This Presentation

• Measurement of breathlessness

• Validation of BDI & TDI

• Identification of clinically significant threshold

Page 50: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

Dyspnea

• Principal symptom of COPD

• Multiple causes of dyspnea in COPD

– Expiratory airflow limitation

– Static lung volume

– Dynamic hyperinflation

• Dyspnea should be measured directly

Page 51: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

Dyspnea (a Sensation) Must Be Related to a Known Level of Stimulus

In laboratory tests:

• Work Rate

• Minute Ventilation

• Oxygen Consumption

Page 52: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

Reference Points for Dyspnea in Daily Life

1. Strenuous exercise

2. Walking up hills

3. Normal pace on level

4. Slow pace on level

5. Washing & dressing

Page 53: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

Reference Points for Dyspnea in Daily Life

1. Strenuous exercise

2. Walking up hills

3. Normal pace on level

4. Slow pace on level

5. Washing & dressing

MRC/ATS grading system for dyspnea

Page 54: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

Reference Points for Dyspnea in Daily Life

1. Strenuous exercise

2. Walking up hills

3. Normal pace on level

4. Slow pace on level

5. Washing & dressing

MRC/ATS grading system for dyspnea

DecreasingMetabolicDemand

Page 55: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

Multifactorial Relationship between Dyspnea and Activity

• Activities causing dyspnea

• Activities more difficult because of dyspnea

• Activities prevented by dyspnea

Page 56: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

BDI & TDI: Construction

• Functional Impairment– Activities limited by dyspnea

• Magnitude of Task– Level of activity causing dyspnea

• Magnitude of effort– Level of effort causing dyspnea

Page 57: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

• Baseline Dyspnea Index (BDI)• Cross-sectional • Between patients• Discriminative

• Transitional Dyspnea Index (TDI)• Grounded on BDI• Longitudinal• Within patients• Evaluative

Characteristics of BDI & TDI

Page 58: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

Testing Validity of BDI - Psychometrics

Internal consistency (Cronbach alpha) 1 0.80

Inter-rater reliability (Weighted Kappa) 1,2 0.72 - 0.88

Test-retest reliability consistency (r value) 1 0.76

1 Eakin et al Int J Behavioral Med 1995; 2: 118-342 Mahler et al Chest 1988; 93: 580-6

Page 59: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

Do BDI & TDI Measure Dyspnea ?

Test whether they relate to:

– Physiological impairment

– Other measures of dyspnea

– Health status

Page 60: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

r - values

FEV1 1-2 0.40 - 0.41

1 Mahler et al Chest 1988; 93: 580-6 2 Eakin et al Int J Behavioral Med 1995; 2: 118-34

BDI: Correlation With Measures of COPD Severity

Page 61: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

r - values

FEV1 1-2 0.40 - 0.41

6-minute walk 1-3 0.48 - 0.75

1 Mahler et al Chest 1988; 93: 580-6 2 Eakin et al Int J Behavioral Med 1995; 2: 118-343 Guyatt et al. Br J Chron Dis 1985; 38: 517-24

BDI: Correlation With Measures of COPD Severity

Page 62: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

r - values

FEV1 1-2 0.40 - 0.41

6-minute walk 1-3 0.48 - 0.75

ATS Dyspnea, OCD, SOBQ 1-2 0.52 - 0.74

1 Mahler et al Chest 1988; 93: 580-6 2 Eakin et al Int J Behavioral Med 1995; 2: 118-343 Guyatt et al. Br J Chron Dis 1985; 38: 517-24

BDI: Correlation With Measures of COPD Severity

Page 63: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

r - values

FEV1 1-2 0.40 - 0.41

6-minute walk 1-3 0.48 - 0.75

ATS Dyspnea, OCD, SOBQ 1-2 0.52 - 0.74

CRQ, SGRQ 4 0.58 - 0.73

1 Mahler et al Chest 1988; 93: 580-6 2 Eakin et al Int J Behavioral Med 1995; 2: 118-343 Guyatt et al. Br J Chron Dis 1985; 38: 517-244 Hajiro et al Am J Respir Crit Care Med 1998; 157: 785-90

BDI: Correlation With Measures of COPD Severity

Page 64: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

r - values

FEV1 1-2 0.40 - 0.41

6-minute walk 1-3 0.48 - 0.75

ATS Dyspnea, OCD, SOBQ 1-2 0.52 - 0.74

CRQ, SGRQ 4 0.58 - 0.73

SF-36, QWB 2 0.50 - 0.91

1 Mahler et al Chest 1988; 93: 580-6 2 Eakin et al Int J Behavioral Med 1995; 2: 118-343 Guyatt et al. Br J Chron Dis 1985; 38: 517-244 Hajiro et al Am J Respir Crit Care Med 1998; 157: 785-90

BDI: Correlation With Measures of COPD Severity

Page 65: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

TDI: Inter-Rater Reliability

Weighted Kappa = 0.83

Eakin et al Int J Behavioral Med 1995; 2: 118-34

Page 66: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

TDI: Correlates of Change

TDI Focal vs ∆ CRQ Dyspnea r = 0.59

1 Guyatt, et al. J Clin Epidemiol 1999; 52: 187-192

Changes following pulmonary rehabilitation 1

Page 67: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

TDI: Correlates of Change

TDI Focal vs ∆ CRQ Dyspnea r = 0.59

1 Guyatt, et al. J Clin Epidemiol 1999; 52: 187-192

2 Aaron, et al. Chest 2002; 121: 688-696

Changes following pulmonary rehabilitation 1

Recovery from a COPD exacerbation 2

TDI Focal vs. CRQ Dyspnea r = 0.78TDI Focal vs. FEV1 r = 0.46

Page 68: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

Clinical Significance

Page 69: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

“The smallest difference in score which patients perceive as beneficial and would mandate, in the absence of troublesome side effects and excessive cost, a change in the patient’s management”

Jaeschke and Guyatt. Measurement of health status: ascertaining the minimal clinically important difference. Controlled Clinical Trials 1989; 10:407-415

Clinical Significance - Humanistic Approach

Page 70: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

-3Major Deterioration. Has deteriorated two grades or greater from baseline status.

-2Moderate Deterioration. Has deteriorated at least one grade but fewer than two grades from baseline status.

-1Minor Deterioration. Has deteriorated less than one grade from baseline. Patient with distinct deterioration within grade, but has not changed grades.

0No Change. No change from baseline.

+1 Minor Improvement. Has improved less than one grade from baseline. Patient with distinct improvement within grade, but has not changed grades.

+2 Moderate Improvement. Has improved at least one grade but fewer than two grades from baseline.

+3 Major Improvement. Has improved two grades or greater from baseline

ZFurther Impairment for Reasons Other than Shortness of Breath. Patient has reduced exertional capacity, but not related to shortness of breath. For example, musculoskeletal problem or chest pain.

Clinically Meaningful Change:Magnitude of Task

+1 unit change

A patient who was dyspneic Walking on the level or even when washing

Now only becomes dyspneicWalking up a gradual hill or carrying light load on the level

Page 71: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

1. Strenuous Exercise

2. On hills

3. Normal pace on level

4. Slow pace on level

5. Wash/dress

ATS Dyspnea Grading (Abbreviated)

Page 72: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

1. Strenuous Exercise

2. On hills

3. Normal pace on level

4. Slow pace on level

5. Wash/dress

ATS Dyspnea Grading (Abbreviated)

Page 73: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

1. Strenuous Exercise

2. On hills

3. Normal pace on level

4. Slow pace on level

5. Wash/dress

ATS Dyspnea Grading (Abbreviated)

Page 74: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

Dyspnea - As Measured by BDI & TDI

• Reliable measurement properties

• Scores are valid estimates of dyspnea

• Clinical significance can be attached to scores

Page 75: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs
Page 76: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

Dyspnea and Related Measures

Theodore J. Witek Jr., Dr.P.H.

Vice President and Head Respiratory Development & Operations

Page 77: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

Dyspnea

SPIRIVA® (tiotropium) is indicated for the long-term,

once-daily, maintenance treatment of bronchospasm

and dyspnea associated with Chronic Obstructive Pulmonary

Disease (COPD) including chronic bronchitis and emphysema.

• Assessing dyspnea in clinical trials

• Application of BDI/TDI in our program

• Response of TDI and related measures to Tiotropium

Page 78: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

Dyspnea Assessments in Clinical Trials

• Long-term assessments particularly important in chronic disease maintenance treatment

• Instrument needs to be practical for multi-center and multi-national programs

• Dyspnea assessment needs to be in context of clinic visit

• Supportive assessments should be included to assist in determining validity and consistency

Page 79: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

Key Protocol Elements

• TDI evaluations performed at clinic visit (e.g. Days 57, 113, and 169)

• TDI assessments reference the BDI scores measured at baseline visit

• TDI completed after SGRQ and prior to post-dose PFTs

Page 80: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

BDI TDI

Grade Axis Grade

0 to +4 Functional impairment -3 to +3

0 to +4 Magnitude of task -3 to +3

0 to +4 Magnitude of effort -3 to +3

0 to +12 Focal Score -9 to +9

Domains of BDI and TDI

• Performance of daily activities and occupation

• Severity or difficulty of physical activities

• Degree of exertional effort

Page 81: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

Frequency Distribution of BDI Focal Score

BDI Focal Score

% o

f P

atie

nts

0

5

10

15

20

25

30

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

0.44 0.55

2.76

8.069.05

11.59

2.431.10

6.62

27.04

20.20

8.72

1.43

Source: Studies 114 and 115

BDI=6 May describe a patient who…

• Abandoned at least one activity due to shortness of breath• Becomes short of breath with an average task such as walking

up a gradual hill• Becomes short of breath with moderate effort, tasks performed

with occasional pauses and requiring longer to complete thanan average person

Page 82: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

Improvements in Dyspnea with Tiotropium

• Two studies: TDI primary endpoint (responder analysis)

• Four studies: TDI secondary endpoint (means)

• TDI improvements

• Supportive endpoints

• Consistency - across time and across studies

Page 83: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

TDI: Responder Analysis vs. Population Mean

• Responder analysis:• Proportion of patients achieving meaningful response

• One unit change: meaningful effect inherent in the instrument

• Responder analysis reflects individual patient benefit from baseline

• Analysis of means:• Reflects overall population change

• A positive and statistically significant delta vs. placebo indicates overall benefit

Page 84: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

Study 130

Pbo (n=148)Tio (n=184)

TDI Responders

* p < 0.05 vs. placeboco-primary endpoint

0

10

20

30

40

50

60

70

57 113 169

Test Day

Pe

rce

nt

of

Pa

tien

ts (

%)

** *

Page 85: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

TDI Responders

0

10

20

30

40

50

60

70

57 113 169

Test Day

Pe

rce

nt

of

Pa

tien

ts (

%)

** *

* p < 0.05 vs. placeboco-primary endpoint

Study 130Tio (n=184)

Sal (n=179)Pbo (n=148)

Page 86: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

TDI RespondersStudy 137

Tio (n=164)

Pbo (n=161)

0

10

20

30

40

50

60

70

57 113 169

Test Day

Per

cen

t o

f P

atie

nts

(%

)

* * *

* p < 0.05 vs. placebo

Page 87: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

TDI Responders

Study 137Tio (n=164)

Sal (n=161)

Pbo (n=161)

* p < 0.05 vs. placebo

0

10

20

30

40

50

60

70

57 113 169

Test Day

Per

cen

t o

f P

atie

nts

(%

)

* * ** * *

Page 88: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

T

T

PP

Mean TDI Focal Score Over Six-Months

-1.2

-0.9

-0.6

-0.3

0.0

0.3

0.6

0.9

1.2

57 113 169

* * *

P

P

T

=

1.0

2p

< 0

.05

T

*nominal p<0.05 vs placebo

Me

an

TD

I F

oc

al

Sc

ore

Imp

rov

em

en

t

57 113 169

* **

PP

TT

=

1.2

1p

< 0

.05

Study 130 Study 137

Tio (n=164)

P

T

Sal (n=161) S

SS S

SS

S

* **

Pbo (n=161)

Page 89: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

Percent of TDI Responders(Placebo-Controlled, Supportive Studies)

Tio (n=258)

Pbo (n=171)

Tio (n=249)

Pbo (n=154)

*nominal p 0.05 vs. placebo

**

010203040506070

50 92 176 260 344Day

Per

cen

t o

f P

ati

en

ts (

%)

010

203040506070

50 92 176 260 344Day

Per

cen

t o

f P

ati

en

ts (

%)

** * *

* * * **

Study 114

Study 115

Page 90: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

Percent of TDI Responders(Ipratropium-Controlled, Supportive Studies)

0

10

20

30

40

50

60

70

8 50 92 182 273 364

Pe

rce

nt

of

Pa

tie

nts

(%

)

Tio (n=172)

IB (n=85)

Day

0

10

20

30

40

50

60

70

8 50 92 182 273 364Day

Pe

rce

nt

of

Pa

tie

nts

(%

)

Tio (n=148)

IB (n=67)

*nominal p 0.05 vs. ipratropium

*

* **

Study 122A

Study 122B

Page 91: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

50 92 176 260 344

Score

-0.4-0.20.00.20.4

0.60.81.01.21.41.6

Test Day

TT

TT T

P P

P PP

Tio (n=248)Pbo (n=154)

50 92 176 260 344

Score

-0.4-0.20.00.20.40.60.81.01.21.41.6

Test Day

P

P PP P

Tio (n=258)Pbo (n=171)

Mean TDI Focal Score (One-Year Placebo-Controlled Studies)

TT

TT

T

Study 114 Study 115

nominal p<0.05 vs. placebo (all days) nominal p<0.001 vs. placebo (all days)

PT

PT

Page 92: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

8 50 92 182 273 364

Score

-0.8-0.6-0.4-0.20.00.20.40.60.81.01.21.41.6

Test Day8 50 92 182 273 364

Score

-0.8-0.6-0.4-0.20.00.20.40.60.81.01.21.41.6

Test Day

Tio (n=148)IB (n=67)

Tio (n=172)IB (n=85)

Mean TDI Focal Score (One-Year Ipratropium-Controlled Studies)

Study 122A Study 122B

nominal p<0.05 vs. ipratropium (days 8, 182, 273, 364) nominal p<0.05 vs. ipratropium (all days)

Page 93: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

Dyspnea Score

S

1 57 113 1690.8

1.0

1.2

1.4

1.6

1.8

Test Day

Tio (N=203) Pbo (N=180)Sal (N=204)

T

TT

T

TT T

T

S

S S SS S

P

P

PP P P P

Shortnessof BreathScore

Study 130 Study 137

S S S

SP

1 57 113 1690.8

1.0

1.2

1.4

1.6

1.8

Test Day

T

T TT

TS S SS

PP P

PP P

P

Shortnessof BreathScore

TT

T

TIO vs. PBO nominal p<0.001 (all days) TIO vs. PBO nominal p<0.05 (days 1, 57)

PT

S

Tio (N=185)

Pbo (N=186)Sal (N=187)

PT

S

Page 94: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

P

Dyspnea Score

PP

1 50 92 176 260 3441.0

1.2

1.4

1.6

1.8

2.0

Test Day

T

T T TT T T

TT T T T

T T TT T TP

PP P P

P P

P

PP P

PP P P

P

Tio (N=258)

Pbo (N=160)

Shortnessof BreathScore

Shortnessof BreathScoreTio (N=275)

Pbo (N=184)

P

1 50 92 176 260 3441.0

1.2

1.4

1.6

1.8

2.0

Test Day

T

T T T T TT

TT T T

T TT

TT T TP P P P

PP

P

P

PP P

PP

PP

P

Study 114 Study 115

TIO vs. PBO nominal p<0.05 (all days) TIO vs. PBO nominal p<0.05 (except days 113, 134)

PT

P

T

Page 95: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

S

SS

SP

S

SP

1 57 113 169 1 57 113 169

Score

4.14.24.34.44.54.64.74.84.95.05.1

Test Day

T

TT

T

T TT

S SS S S

P

P PP

PP

P

Tio (N=203)Sal (N=204)Pbo (N=180)

T T TS S SP P P

Tio (N=185)Sal (N=187)Pbo (N=186)

T T TS S SP P P

Score

4.14.24.34.44.54.64.74.84.95.05.1

Test Day

T

TT

T TT

S TS S S

S

PP P

P P PP

Study 130 Study 137

Mean Score; Physician’s Global Evaluation (Six-Month Studies)

T

T

TIO vs. PBO nominal p<0.001 (all days) TIO vs. PBO nominal p<0.05 (days 1, 57, 113)

Page 96: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

P

1 50 92 176 260 344

Score

4.0

4.4

4.8

5.2

5.6

6.0

Test Day

T

T TT T T

T TT T T T

P P P P PP P P

P P P

Tio (N=275)Pbo (N=184)

T T TP P P

Study 114

P

1 50 92 176 260 344

Score

4.0

4.4

4.8

5.2

5.6

6.0

Test Day

T

TT T T T T T

T T T T

PP P P P P

P P P P P

Tio (N=259)Pbo (N=161)

T T TP P P

Study 115

Mean Score; Physician’s Global Evaluation (One-Year Placebo-Controlled Studies)

TIO vs. PBO nominal p<0.001 (all days) TIO vs. PBO nominal p<0.05 (all days)

Page 97: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

PPPPP PP

SSSS

SSSS

SSSSSSS

SSSSSSS

S

SP

SP

SSSSSSSSSS

SSSS

SSS

SSSSS

SS

Week

Puffs

2.02.22.42.62.83.03.23.43.63.84.04.24.44.6

0 4 8 12 16 20 24

T

TT T

T TT T TT T T T TT T TT TT T T T T T

PPP

PPPPPPPPPPPP

PPP

PPPPPP

T T TS S SP P P

Tio (N=181)Sal (N=184)Pbo (N=187)

Week

Puffs

2.02.22.42.62.83.03.23.43.63.84.04.24.44.6

0 4 8 12 16 20 24

T

TT T

TT T T

T T T T T T TTT T

T TT TTT

T

PPPPPPP PPPPPPP

PP P

Study 130 Study 137

Mean Number of Daily Doses of Albuterol -(Six-Month Studies)

P

Tio (N=203)Sal (N=208)Pbo (N=176)

T T TS S SP P P

TIO vs. PBO nominal p<0.01 (all weeks) TIO vs. PBO nominal p<0.05 (week 1 only)

Page 98: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

Tio (N=276)Pbo (N=186)

T T TP P P

P

Doses

2.42.62.83.03.23.43.63.84.04.24.4

Week0 8 16 24 32 40 48 56

T

TTTT

TTTTTTTTTT

TTTTTTTTTTT

TTTTTT

TTTTTTTTTTTTT

TTTTTPPPPPPP

PPPPPPPPPP

PPPPPPPP

PPPPPPPPPP

PPPPPPPPPPPPPP

Study 114Tio (N=267)Pbo (N=166)

T T TP P P

P

Doses

2.42.62.83.03.23.43.63.84.04.24.4

Week0 8 16 24 32 40 48 56

T

TTTTTTTT

TTTTTTTTTTTTT

TTTTT

TTTTTT

TTTTTTTTTTTTTTTTTP

P

PPPPPPPPPPP

PPPPPP

PPPP

PPPPPPPPP

PPPPPPP

PPPPPPPPPP

Study 115

Mean Number of Daily Doses of Albuterol -(One-Year Studies)

TIO vs. PBO nominal p<0.002 (all weeks) TIO vs. PBO nominal p<0.01 (all weeks)

Page 99: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

Consistency of Tiotropium Benefit

Dyspnea Symptom Score

SGRQ Total Score

Physician Global

Albuterol Use

Endpoint

FEV1 Trough

TDI % Responders

TDI Mean vs. Placebo

114 115 130 137

0.0001 0.0001 0.0001 0.0001

0.0024 0.0001

0.0001 0.0001

0.0049 0.0232

0.0134 0.0021

0.0002 0.0003 0.0001

0.0021 0.0006 0.0374 0.0388

0.0001 0.0264 0.0001

0.0010 0.0010 0.0001

0.6937

0.9683

0.3480

nominal p-value vs. placebo at end of study

p-value vs. placebo at end of study

Page 100: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

The Effect of Tiotropium on Dyspnea

Summary

• Utilization of a validated instrument

• Prespecification of primary endpoint

• Statistical significance observed in two independent studies

• Proportion with meaningful change supported by mean responses

• Dyspnea response reflected in related measures

Page 101: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

Proposed Indication

Given the importance of dyspnea as a

COPD symptom and given our demonstration

of dyspnea relief, we believe that dyspnea

should be included as an indication for use.

Page 102: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs
Page 103: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

SPIRIVA® (tiotropium)

Clinical Safety Evaluation

Steven Kesten, M.D.

Medical DirectorInternational SPIRIVA® Program

Page 104: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

Tiotropium: Safety

• Extensive clinical safety evaluation

• Large patient experience

• Long-term exposure

• Clinical safety profile similar to ipratropium

• Fifteen years experience in the US

Page 105: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

Experience With Ipratropium

Cardiovascular: palpitations, tachycardia, SVT, atrial fibrillation

Gastrointestinal: dry mouth, constipation

Genitourinary: urinary retention, urinary difficulty

Opthalmologic: blurred vision, worsening of narrow-angle glaucoma, acute eye pain, mydriasis

Page 106: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

Healthy Volunteers

Single Dosing Inhaled Tiotropium• 160 g (n=6)

• no effect on vital signs, ECG, pupillometry, salivary secretions• 282 g (n=6)

• no effect on vital signs, ECG, pupillometry, salivary secretions

Multiple Dosing Inhaled Tiotropium• 70.4 g (n=11), 140.8 g (n=12), 7 days treatment• decreased salivary secretions, dry mouth [7/11 for 70.4 g,

12/12 for 140.8 g]• no effect on vital signs, ECG, pupillometry

Page 107: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

COPD Experience

Tiotropium Patients

1,723*

Short-Term Studies Long-Term Studies414 1,308

61 353Single-Dose Multiple-Dose

906 402One-Year Six-Month

*one patient discontinued after placebo, before tiotropium

Page 108: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

COPD: Clinical Safety Evaluation

Clinical Adverse Event Reporting

Supporting Measures

• Physical examination and vital signs

• Lung function

• Laboratory evaluations

• Characterization studies

• Electrocardiograms

Page 109: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

COPD: Electrocardiographic Evaluation

ECG Profiling:• 12 lead ECGs + 2 minute rhythm strips: multi-dose, dose-ranging• 134 patients, 4 weeks (2,198 ECGs on tiotropium)

Holter monitoring:• 72 patients, 6 weeks

Long-Term Studies:• 12 lead ECGs: long-term studies• placebo-controlled: 550 patients (1,809 ECGs on tiotropium)• ipratropium-controlled: 371 patients (1,225 ECGs on tiotropium)• six-month studies: 402 patients (390 ECGs on tiotropium)

Total ECGs on Tiotropium: 5,622

Page 110: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

Placebo 4.5 g 9 g 18 g 36 g

Total Patients Treated 35 34 33 33 34

Total with Changes 20 24 22 23 16

Borderline PR Interval 1 0 1 0 0First Degree A-V Block 1 1 0 1 0

Atrial Fibrillation 0 0 1 0 0

Sinus Arrhythmia 0 0 0 0 1

Sinus Tachycardia 1 0 0 1 0

Consistent with Ventricular Tachycardia 0 1 0 0 0

Repetitive Premature Systoles 1 2 0 2 0

Multiforme Premature Systoles 0 4 2 1 2

Premature Systoles, Ventricular 9 11 7 10 8

Premature Systoles, Atrial 10 10 10 10 6Sinus Arrest or Sino-atrial Block 0 2 2 0 0

Ectopic Atrial Rhythm 2 0 2 1 0

Borderline QT Interval 1 0 0 1 0

ECG Profiling: Changes in ECG During Multi-dose Dose-Ranging Study

Page 111: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

ECG Results: One-Year Placebo-Controlled Studies

Maximum HR (bpm)

101-105 106-110 111-120 121-130Tiotropium 6 2 3 1Placebo 2 2 1 1

Tiotropium Placebo

Number of Patients 518 343

Number of ECGs 1,758 1,108

Abnormal Rhythm 9.0% 10.1%

Heart Rate

Mean change (bpm) 0 0Mean maximum change (bpm) 7 6Percent with bradycardia events 0.2% 0.3%Percent with tachycardia events 2.3% 1.7% Number of patients with single event 10/12 6/6

Page 112: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

Short-Term Studies (< 6 weeks)

• Eight studies in COPD patients receiving capsules (n=414)

4.5 g 9 g 18 g 36 g 72 g

Number of patients 34 93 312 93 34

• Adverse events

• Overall, similar frequency to placebo

• Dry mouth - evidence of dose-response

• No relevant imbalances with other adverse events

• Serious adverse events: tiotropium - 5, placebo - 6

• Deaths: 3 (lymphoma 15 weeks post-study, MI 11 weeks post-study, respiratory failure)

Page 113: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

Long-Term Studies

Four One-Year Studies

TIO

356

IB

179

TIO

550

PBO

371

Two Six-Month Studies

TIO

402

PBO

400

SAL

405

906

1,308

Tiotropium Patients

Page 114: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

Adverse Event Profile: One-Year Studies

Total adverse events 495 90 338 91 318 89 162 91

Leading to disc. 53 10 50 14 35 10 22 12

Serious 99 18 78 21 57 16 46 26

Fatal 7 1 7 2 9 3 3 2

Total treated 550 100 371 100 356 100 179 100

Tio N %

PboN %

TioN %

IbN %

Page 115: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

Chest Pain 7 5 5 2Edema 5 4 3 5

GASTROINTESTINAL Abdominal Pain 5 3 6 6Constipation 4 2 1 1Dry Mouth 16 3 12 6Dyspepsia 6 5 1 1

RESISTANCEMECHANISM

Infection 4 3 1 3Moniliasis 4 2 3 2

BODY AS A WHOLE Accidents 13 11 5 8% % % %

Vomiting 1 24 2

MUSCULOSKELETAL Myalgia 4 3 4 3

Most Common Adverse Events: One-Year Studies

TioN=550

PboN=371

TioN=356

Ib N=179

Page 116: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

TioN=550

PboN=371

TioN=356

Ib N=179

RESPIRATORY SYSTEM - UPPER

Epistaxis 4 2 1 1Pharyngitis 9 7 7 3Rhinitis 6 5 3 2Sinusitis 11 9 3 2Upper RespiratoryTract Infection

41 37 43 35

URINARY SYSTEM Urinary Tract Infection 7 5 4 2

SKIN & APPENDAGE Rash 4 2 2 2

RESPIRATORY SYSTEM - LOWER

COPD Exacerbation 36% 40% 35% 48%Pneumonia 4 7 5 6

Most Common Adverse Events: One-Year Studies

Page 117: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

Tio Pbo Tio Ib

Total with serious adverse events 18.0% 21.0% 16.0% 25.7%

BODY AS A WHOLE Accidents 0.4 0.0 0.8 0.0

CARDIOVASCULAR Cardiac Failure 0.5 0.8 0.0 0.6Syncope 0.5 0.0 0.6 0.6

HEART RATE ANDRHYTHM

Atrial Fibrillation 0.4 0.3 0.0 1.1

Chest Pain 1.5 1.1 0.3 0.0Fall 0.0 0.5 0.0 0.0

GASTROINTESTINAL Abdominal Pain 0.0 0.5 0.3 0.0Diverticulitis 0.0 0.5 0.0 0.0GI Hemorrhage 0.4 0.5 0.0 0.0Pancreatitis 0.2 0.5 0.0 0.0

METABOLIC ANDNUTRITIONAL

Dehydration 0.9 0.0 0.0 0.0Diabetes MellitusAggravated

0.4 0.0 0.3 0.0

Hyperglycemia 0.4 0.0 0.0 0.0

N=550 N=371 N=356 N=179

Serious Adverse Events: One-Year Studies

Page 118: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

MYO, ENDOAND PERICARDIAL

Angina Pectoris 0.4 0.3 0.8 1.7Coronary ArteryDisorder

0.7 0.8 0.0 0.0

Myocardial Infarction 0.5 0.3 0.8 0.0

PLATELET BLEEDINGAND CLOTTING

Embolism Pulmonary 0.0 0.0 0.6 0.0

PSYCHIATRIC Manic Reaction 0.4 0.0 0.0 0.0

NEOPLASM Basal Cell Carcinoma 0.5 1.3 0.0 0.0Neoplasm Malignant 0.7 0.0 0.0 0.6Oral NeoplasmMalignant

0.0 0.5 0.0 0.0

Pulmonary Carcinoma 0.4 0.5 1.1 0.6Skin NeoplasmMalignant

0.2 0.8 0.0 0.0

REPRODUCTIVE, MALE

Prostatic Disorder 0.4 0.0 0.0 0.6

Tio Pbo Tio IbN=550 N=371 N=356 N=179

Serious Adverse Events: One-Year Studies (continued)

Page 119: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

RESPIRATORYSYSTEM - LOWER

COPD Exacerbation 5.8 8.1 6.5 11.7Dyspnea 0.0 0.3 0.0 1.1Pneumonia 2.4 3.8 1.7 2.2

RESISTANCEMECHANISM

Infection 0.4 0.0 0.0 0.0

Tio Pbo Tio IbN=550 N=371 N=356 N=179

VASCULAR CerebrovascularDisorder

0.7 0.3 0.3 0.6

Serious Adverse Events: One-Year Studies (continued)

Page 120: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

BODY AS A WHOLE 0.2 0.3 0.0 0.6CARDIOVASCULAR 0.2 0.3 0.0 0.0HEART RATE AND RHYTHM 0.4 0.0 0.0 0.0MYO, ENDO AND PERICARDIAL 0.5 0.3 0.8 0.6NEOPLASM 0.0 1.1 0.8 0.0PSYCHIATRIC 0.2 0.0 0.0 0.0PLATELET, BLEEDING AND CLOTTING 0.0 0.0 0.3 0.0RESISTANCE MECHANISM 0.0 0.0 0.3 0.0RESPIRATORY SYSTEM - LOWER 0.0 0.3 0.3 0.6URINARY SYSTEM 0.0 0.0 0.3 0.0VASCULAR EXTRACARDIAC 0.0 0.0 0.3 0.0WHITE CELL AND RESISTANCE 0.0 0.0 0.0 0.6

Fatal Adverse Events: One-Year Studies

Total with fatal adverse events 1.3% 1.9% 2.5% 1.7%

Tio Pbo Tio IbN=550 N=371 N=356 N=179

Page 121: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

Fatal Cardiovascular EventsOne-year Six-Month

Tio550

Pbo371

Tio356

Ib179

Tio402

Pbo400

Salm405

DEATHS TOTAL 7 7 9 3 1 5 6

CV DEATHS TOTAL 6 1 3 1 1 3 2body as a whole death 0 0 0 0 0 1 0

sudden death 1 0 0 0 0 0 1CV, general cardiac failure 1* 1t 0 0 0 0 1

cor pulmonale 0 1t 0 0 0 0 0heart rate & rhythm arrhythmia 1 0 0 0 0 0 0

cardiac arrest 1 0 0 0 0 2 0myo,endo,peric. aneurysm 0 0 0 1 1 0 0

cardiomyopathy 1* 0 0 0 0 0 0CAD 1 1 0 0 0 0 0MI 1 0 3 0 0 0 0

* t same patient

Page 122: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

Rationale• Reduce random error

Justification• Similar protocols and populations

• Similar patterns of response

Variables • Incidence rates (IR) per 100 person-years

• Rate differences (RD)

• RD = IR (tiotropium) - IR (placebo)

• P-values to assess statistical reliability

Adverse Events: Pooled Placebo-Controlled Studies

Page 123: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

Pooled Placebo-Controlled Studies

Four One-Year Studies

TIO

356

IB

179

TIO

550

PBO

371

Two Six-Month Studies

TIO

402

PBO

400

SAL

405

TIO

952

PBO

771

Pooled Placebo-Controlled Studies

906

1,308Tiotropium Patients

Page 124: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

679 pyrsTio

P-valueN Rate483 pyrs

Pbo

N Rate RD

Adverse Events: Pooled Placebo-Controlled Studies

HEART RATE AND RHYTHM

Tachycardia 8 2 0.77

Supraventricular Tachycardia 3 1 0.23

Arrhythmia 4 1 0.38 Atrial Fibrillation 7 3 0.41

Cardiac Arrest 1 2 -0.27 Palpitation 5 6 -0.51

0.181.19 0.41

0.44 0.21

0.59 0.201.03 0.62

0.15 0.410.74 1.25

0.57

0.380.49

0.450.40

MYO, ENDO AND PERICARDIAL

Angina Pectoris 9 3 0.71

Angina Pectoris Aggravated 2 0 0.29 CAD 4 4 -0.24

1.33 0.62

0.30 0.000.59 0.83

0.26

0.340.64

Myocardial Infarction 5 5 -0.300.74 1.04 0.60 Thrombosis Coronary 1 0 0.150.15 0 0.58

Page 125: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

Selected Adverse Events: Pooled Placebo-Controlled Studies

Tachycardia/SVT/Atrial fibrillation 18 6 1.432.68 1.25 0.10

679 pyrsTiotropium

RD P-valueN Rate483 pyrsPlacebo

N Rate

Angina/CAD/thrombosis coronary 16 7 0.932.38 1.45 0.28

Myocardial infarction 5 5 -0.300.74 1.04 0.60

Ischemic deaths 2 1 0.090.29 0.21 0.82

Arrhythmic deaths 3 3 -0.180.44 0.62 0.69

Cardiovascular deaths 7 5 0.001.03 1.03 0.98

Total deaths 8 12 -1.311.18 2.48 0.11

Page 126: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

679 pyrsTio

P-valueN Rate483 pyrs

Pbo

N Rate RD

RESPIRATORY SYSTEM - UPPER

Epistaxis 23 11 1.16 Laryngitis 7 1 0.83

Pharyngitis 67 39 1.99

Sinusitis 75 45 2.02

Upper Resp Tract Infection 304 202 6.18

0.273.46 2.300.101.03 0.21

0.2910.33 8.35

0.3211.70 9.69

0.2156.92 50.73

RESPIRATORY SYSTEM - LOWER

COPD Exacerbation 331 311 -23.44

Dyspnea 51 56 -4.31

<0.0161.06 84.51

0.027.68 11.99

GASTROINTESTINAL

Dry Mouth 121 19 16.22 <0.01 Constipation 23 8 1.78 0.07

20.23

3.444.02

1.67

Selected Adverse Events: Pooled Placebo-Controlled Studies

Page 127: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

679 pyrsTio

P-valueN Rate483 pyrs

Pbo

N Rate RD

URINARY SYSTEM

Micturition Disorders 4 0 0.59

Urinary Retention 5 0 0.74

Urinary Tract Infection 41 17 2.63

Cystitis 6 7 -0.57

0.120.59 0.00

0.070.74 0.00

0.056.21 3.57

0.380.89 1.46

VISUAL

Glaucoma 3 3 -0.18 0.690.44 0.62

Selected Adverse Events: Pooled Placebo-Controlled Studies

Page 128: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

Summary

• Safety data includes long-term studies of 1,308 tiotropium treated patients

• Events consistent with anticholinergic pharmacology• SVT, dry mouth, constipation, urinary tract disorders

• No associations of treatment with life-threatening events

• Tiotropium safety profile consistent with established inhaled anticholinergic therapy

Page 129: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs
Page 130: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

Clinical Perspective

Dr. James Donohue, M.D.

Professor & Chairman of Pulmonary Critical Care

UNC Pulmonary DivisionSchool of Medicine

Chapel Hill, NC

Page 131: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

Overview of COPD

• 32 million with COPD

• 17 million diagnosed

• 6 million on therapy

• Older patients with comorbidities

• Limited therapeutic options

Page 132: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

Based on Fletcher and Peto. Br Med J. 1977;1:1645-1648.*Average and range of FEV1 decline

FE

V1 (

% o

f va

lue

at a

ge

25)

Smokedregularly andsusceptible toits effects

Death

Never smoked or not susceptible to smoke*

Stoppedat 45

Stoppedat 65

25 50 75

Age (years)

0

25

50

75

100

Disability

Disease Progression

Page 133: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

Bronchodilation

• Clinical relevance of tiotropium bronchodilator effect

• Once-daily dosing

• Magnitude of effect: Trough, Peak, and Average

• Peak-to-trough differences in FEV1

• Consistent, sustained bronchodilation

• No evidence of tachyphylaxis on long-term treatment

Page 134: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

Dyspnea

• Challenges in demonstrating dyspnea relief in clinical studies

• Dyspnea is a highly complex subjective symptom

• Patients alter activity to avoid this unpleasant sensation

• Individual patients vary considerably in their evaluation

• Substantial placebo response

• Comorbidities complicate assessment of treatment benefit

• Drug effect must be robust to be consistently detected

Page 135: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

Dyspnea

• Clinical relevance of one-unit improvement in TDI focal score

• Clinical relevance of responder rate comparison to placebo

Page 136: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

Safety

• Substantial long-term exposure

• Representative COPD population with stable comorbidities

• Low incidence of adverse events consistent with inhaled anticholinergic side effects

Page 137: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

Conclusion

• Tiotropium represents a significant addition to the medical armamentarium

Page 138: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs
Page 139: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

Conclusions

Burkhard Blank, M.D.

Senior Vice PresidentMedical and Regulatory Affairs

Page 140: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

Major Topics for Today

• Safety profile• Cardiovascular adverse events

• 24-hour bronchodilation

• Relief of dyspnea• Use of validated instrument

• Clinically meaningful response

Page 141: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs

Proposed Indication

SPIRIVA® (tiotropium) is indicated for the long-term, once-daily, maintenance treatment of bronchospasm and dyspnea associated with Chronic Obstructive Pulmonary Disease (COPD) including chronic bronchitis and emphysema.

Page 142: Introduction and Overview Burkhard Blank, M.D. Senior Vice President Medical and Regulatory Affairs