1. Pulmonary-Allergy Drugs Advisory Committee September 6, 2002 Pulmonary-Allergy Drugs Advisory Committee NDA 21-395 Spiriva ® (tiotropium bromide) Inhalation Powder Eugene J. Sullivan, MD FCCP Medical Officer Division of Pulmonary and Allergy Drug Products NDA 21-395 Spiriva ® (tiotropium bromide) Inhalation Powder Eugene J. Sullivan, MD FCCP Medical Officer Division of Pulmonary and Allergy Drug Products

2. Pulmonary-Allergy Drugs Advisory Committee September 6, 2002 2 OutlineOutline Background PK/PD characteristics Overview of P3 clinical program Safety findings Efficacy findings –Bronchodilator efficacy –Dyspnea efficacy –Other efficacy findings Summary Background PK/PD characteristics Overview of P3 clinical program Safety findings Efficacy findings –Bronchodilator efficacy –Dyspnea efficacy –Other efficacy findings Summary

3. Pulmonary-Allergy Drugs Advisory Committee September 6, 2002 3 Background: COPD Indication Proposed Indication for tiotropium: “treatment of bronchospasm and dyspnea associated with COPD” No drugs approved in the US carry an Indication for the treatment of specific symptoms of COPD, or for the “treatment of COPD” Proposed Indication for tiotropium: “treatment of bronchospasm and dyspnea associated with COPD” No drugs approved in the US carry an Indication for the treatment of specific symptoms of COPD, or for the “treatment of COPD”

4. Pulmonary-Allergy Drugs Advisory Committee September 6, 2002 4 Background: COPD Indication Currently approved drugs : –“treatment of bronchospasm associated with COPD” Distinction: treatment of bronchospasm vs. treatment of the disease FEV 1 –direct measure of bronchospasm –“surrogate” measure of the disease itself (a constellation of physical signs and symptoms, physiologic processes, and histopathologic features) Currently approved drugs : –“treatment of bronchospasm associated with COPD” Distinction: treatment of bronchospasm vs. treatment of the disease FEV 1 –direct measure of bronchospasm –“surrogate” measure of the disease itself (a constellation of physical signs and symptoms, physiologic processes, and histopathologic features)

5. Pulmonary-Allergy Drugs Advisory Committee September 6, 2002 5 Background: COPD Indication Presumed clinical benefit of bronchodilators –approved based on spirometry, but clinically detectable benefit is presumed –“as-needed” use of the bronchodilator albuterol reflects bronchodilator-mediated symptom benefit Presumed clinical benefit of bronchodilators –approved based on spirometry, but clinically detectable benefit is presumed –“as-needed” use of the bronchodilator albuterol reflects bronchodilator-mediated symptom benefit

6. Pulmonary-Allergy Drugs Advisory Committee September 6, 2002 6 Background: COPD Efficacy Variables Primary: Measure of bronchodilation –Usually FEV 1 After chronic use (for maintenance drugs) Peak FEV 1, FEV 1 -Time Curve AUC Secondary (supportive) –Other spirometry variables –“Rescue” albuterol use –Peak flow –Six-minute walk test –Exacerbations, Patient-Reported Outcomes, etc. Primary: Measure of bronchodilation –Usually FEV 1 After chronic use (for maintenance drugs) Peak FEV 1, FEV 1 -Time Curve AUC Secondary (supportive) –Other spirometry variables –“Rescue” albuterol use –Peak flow –Six-minute walk test –Exacerbations, Patient-Reported Outcomes, etc.

7. Pulmonary-Allergy Drugs Advisory Committee September 6, 2002 7 Background: Tiotropium P3 Primary Efficacy Variables All studies: –Change from baseline in “trough” (pre-dose) FEV 1 Two studies: –Change from baseline in “trough” (pre-dose) FEV 1 and –Transitional Dyspnea Index (TDI) All studies: –Change from baseline in “trough” (pre-dose) FEV 1 Two studies: –Change from baseline in “trough” (pre-dose) FEV 1 and –Transitional Dyspnea Index (TDI)

8. Pulmonary-Allergy Drugs Advisory Committee September 6, 2002 8 OutlineOutline Background PK/PD characteristics Overview of P3 clinical program Safety findings Efficacy findings –Bronchodilator efficacy –Dyspnea efficacy –Other efficacy findings Summary Background PK/PD characteristics Overview of P3 clinical program Safety findings Efficacy findings –Bronchodilator efficacy –Dyspnea efficacy –Other efficacy findings Summary

9. Pulmonary-Allergy Drugs Advisory Committee September 6, 2002 9 PK/PD Characteristics Bioavailability of tiotropium –Oral ingestion 2-3% –Oral inhalation 19.5% Single dose PK (oral inhalation): –C max = 5 minutes –Detectable in blood for 2-4 hours –Prolonged urinary excretion detectable in urine for 25 days after a dose of 108mcg Volume of distribution: 32 liters/kg Bioavailability of tiotropium –Oral ingestion 2-3% –Oral inhalation 19.5% Single dose PK (oral inhalation): –C max = 5 minutes –Detectable in blood for 2-4 hours –Prolonged urinary excretion detectable in urine for 25 days after a dose of 108mcg Volume of distribution: 32 liters/kg

10. Pulmonary-Allergy Drugs Advisory Committee September 6, 2002 10 PK/PD Characteristics Elimination: –74% eliminated in urine as parent compound 44% by 4 hours, 54% by 24 hours, 61% by 96 hours active renal secretion (renal clearance > creatinine clearance) –Fate of remaining 26% not well established non-enzymatic hydrolysis hepatic metabolism (CYP2D6 and CYP 3A4) Elimination: –74% eliminated in urine as parent compound 44% by 4 hours, 54% by 24 hours, 61% by 96 hours active renal secretion (renal clearance > creatinine clearance) –Fate of remaining 26% not well established non-enzymatic hydrolysis hepatic metabolism (CYP2D6 and CYP 3A4)

11. Pulmonary-Allergy Drugs Advisory Committee September 6, 2002 11 PK/PD Characteristics Terminal elimination half-life = 5-6 days Multiple-dose accumulation: 2-3 fold –suggests effective T1/2= 24-36 hours PK characteristics are indicative of extensive tissue binding, with slow release back into circulation –large volume of distribution and long terminal elimination half-life Terminal elimination half-life = 5-6 days Multiple-dose accumulation: 2-3 fold –suggests effective T1/2= 24-36 hours PK characteristics are indicative of extensive tissue binding, with slow release back into circulation –large volume of distribution and long terminal elimination half-life

12. Pulmonary-Allergy Drugs Advisory Committee September 6, 2002 12 PK/PD Characteristics Pharmacodynamic effect increases with multiple daily dosing –Spirometry data from Phase 3 studies –Separate “sub-study” of one of the Phase 3 studies (122A, ipratropium-controlled) N= 28 six-hour, serial spirometry on Days 1, 2, 3, 8, and 50 –Maximum (“steady state”) effect is achieved by Day 8 Pharmacodynamic effect increases with multiple daily dosing –Spirometry data from Phase 3 studies –Separate “sub-study” of one of the Phase 3 studies (122A, ipratropium-controlled) N= 28 six-hour, serial spirometry on Days 1, 2, 3, 8, and 50 –Maximum (“steady state”) effect is achieved by Day 8

13. Pulmonary-Allergy Drugs Advisory Committee September 6, 2002 13 PD Effect Increases with Multiple Dosing Phase 3, one-year, placebo-controlled studies:

14. Pulmonary-Allergy Drugs Advisory Committee September 6, 2002 14 PD Effect Increases with Multiple Dosing PD Effect Increases with Multiple Dosing Onset of Steady State “Sub-study” Daily AM PEFR reached maximum effect at Day 6

15. Pulmonary-Allergy Drugs Advisory Committee September 6, 2002 15 OutlineOutline Background PK/PD characteristics Overview of P3 clinical program Safety findings Efficacy findings –Bronchodilator efficacy –Dyspnea efficacy –Other efficacy findings Summary Background PK/PD characteristics Overview of P3 clinical program Safety findings Efficacy findings –Bronchodilator efficacy –Dyspnea efficacy –Other efficacy findings Summary

16. Pulmonary-Allergy Drugs Advisory Committee September 6, 2002 16 Phase 3 Clinical Program

17. Pulmonary-Allergy Drugs Advisory Committee September 6, 2002 17 Phase 3: Patients Studied Inclusion Criteria: –age  40 years –smoking history > 10 pack-years –FEV1  60% or 65% predicted –FEV1  70% of FVC Exclusion Criteria: –h/o asthma, allergic rhinitis, or atopy –elevated blood eosinophil count –significant disease other than COPD –symptomatic prostatic hypertrophy or bladder outlet obstruction –narrow angle glaucoma –MI (1 year), cardiac arrhythmia requiring drug treatment, or hospitalization for heart failure (3 years) Inclusion Criteria: –age  40 years –smoking history > 10 pack-years –FEV1  60% or 65% predicted –FEV1  70% of FVC Exclusion Criteria: –h/o asthma, allergic rhinitis, or atopy –elevated blood eosinophil count –significant disease other than COPD –symptomatic prostatic hypertrophy or bladder outlet obstruction –narrow angle glaucoma –MI (1 year), cardiac arrhythmia requiring drug treatment, or hospitalization for heart failure (3 years)

18. Pulmonary-Allergy Drugs Advisory Committee September 6, 2002 18 Phase 3: Demographic and Baseline Features

19. Pulmonary-Allergy Drugs Advisory Committee September 6, 2002 19 OutlineOutline Background PK/PD characteristics Overview of P3 clinical program Safety findings Efficacy findings –Bronchodilator efficacy –Dyspnea efficacy –Other efficacy findings Summary Background PK/PD characteristics Overview of P3 clinical program Safety findings Efficacy findings –Bronchodilator efficacy –Dyspnea efficacy –Other efficacy findings Summary

20. Pulmonary-Allergy Drugs Advisory Committee September 6, 2002 20 Safety Database 1308 patients exposed in P3 Phase 3 Safety Evaluations: –adverse events –vital signs –physical examination –clinical labs –ECGs (timing not specified) 1308 patients exposed in P3 Phase 3 Safety Evaluations: –adverse events –vital signs –physical examination –clinical labs –ECGs (timing not specified)

21. Pulmonary-Allergy Drugs Advisory Committee September 6, 2002 21 Safety Database Additional Safety Data (Phase 2) –timed ECGs (multiple dose study, up to 44mcg QD) –Holter monitors (n=72 patients, pre- and on- treatment) Additional Safety Data (Phase 2) –timed ECGs (multiple dose study, up to 44mcg QD) –Holter monitors (n=72 patients, pre- and on- treatment)

22. Pulmonary-Allergy Drugs Advisory Committee September 6, 2002 22 Safety Database Focus on one-year, placebo-controlled studies Median exposure 10 days longer for tiotropium patients (338 days) than for placebo patients (328 days). Focus on one-year, placebo-controlled studies Median exposure 10 days longer for tiotropium patients (338 days) than for placebo patients (328 days).

23. Pulmonary-Allergy Drugs Advisory Committee September 6, 2002 23 Adverse Events with Tiotropium (One-year, placebo-controlled studies) Gastrointestinal: –dry mouth (16% vs. 2.7%) –dyspepsia (5.8% vs. 4.6%) –abdominal pain (4.7% vs. 3.0%) –constipation (3.5% vs. 1.6%) –vomiting (3.5% vs. 2.4%) Gastrointestinal: –dry mouth (16% vs. 2.7%) –dyspepsia (5.8% vs. 4.6%) –abdominal pain (4.7% vs. 3.0%) –constipation (3.5% vs. 1.6%) –vomiting (3.5% vs. 2.4%)

24. Pulmonary-Allergy Drugs Advisory Committee September 6, 2002 24 Adverse Events with Tiotropium (One-year, placebo-controlled studies) Respiratory System: –upper respiratory tract infection (41.1% vs. 37.2%) –epistaxis (3.6% vs. 1.9%) –pharyngitis (8.9% vs. 7.3%) –sinusitis (11.3% vs. 9.4%) Chest pain (6.9% vs. 4.6%) Rash (4.2% vs. 2.2%) Urinary Tract Infection (7.3% vs. 5.1%) Respiratory System: –upper respiratory tract infection (41.1% vs. 37.2%) –epistaxis (3.6% vs. 1.9%) –pharyngitis (8.9% vs. 7.3%) –sinusitis (11.3% vs. 9.4%) Chest pain (6.9% vs. 4.6%) Rash (4.2% vs. 2.2%) Urinary Tract Infection (7.3% vs. 5.1%)

25. Pulmonary-Allergy Drugs Advisory Committee September 6, 2002 25 Adverse Events with Tiotropium (Six-month studies) Fewer differences between tiotropium and placebo. AEs more common in tiotropium: –Dry mouth (8.2% vs. 2.3%) –Upper Respiratory Tract Infection (19.4%vs. 16%) –Pharyngitis (4.5% vs. 3.0%) –Sinusitis (3.2% vs. 2.5%) –Influenza-like symptoms (6.7% vs. 4%) Fewer differences between tiotropium and placebo. AEs more common in tiotropium: –Dry mouth (8.2% vs. 2.3%) –Upper Respiratory Tract Infection (19.4%vs. 16%) –Pharyngitis (4.5% vs. 3.0%) –Sinusitis (3.2% vs. 2.5%) –Influenza-like symptoms (6.7% vs. 4%)

26. Pulmonary-Allergy Drugs Advisory Committee September 6, 2002 26 Safety Interactions with Tiotropium (One-year, placebo-controlled studies) Age (  60, 61-70,  71): –Dry Mouth: 11%, 16%, 21% (Pbo values: 3%, 1.9%, 3.5%) –Constipation: 2%, 2.8%, 6% (Pbo values: 3%, 0.6%, 1.7%) –Urinary Tract Infection: 3.3%, 5.2%, 12% (Pbo values: 2%, 3.9%, 6.1%) Gender: –Dry Mouth: women 23%, men 13% (Pbo values: 2.9% and 2.6%) Age (  60, 61-70,  71): –Dry Mouth: 11%, 16%, 21% (Pbo values: 3%, 1.9%, 3.5%) –Constipation: 2%, 2.8%, 6% (Pbo values: 3%, 0.6%, 1.7%) –Urinary Tract Infection: 3.3%, 5.2%, 12% (Pbo values: 2%, 3.9%, 6.1%) Gender: –Dry Mouth: women 23%, men 13% (Pbo values: 2.9% and 2.6%)

27. Pulmonary-Allergy Drugs Advisory Committee September 6, 2002 27 Other Safety Observations (One-year, placebo-controlled studies) Urinary Retention: –4 patients, all treated with tiotropium –all required Foley catheter; three were started on medication for BPH following the event “Micturation disorder” or “micturation frequency” –6 (1.1%) tiotropium patients vs. 0 placebo patients Urinary Retention: –4 patients, all treated with tiotropium –all required Foley catheter; three were started on medication for BPH following the event “Micturation disorder” or “micturation frequency” –6 (1.1%) tiotropium patients vs. 0 placebo patients

28. Pulmonary-Allergy Drugs Advisory Committee September 6, 2002 28 Other Safety Observations (One-year, placebo-controlled studies) Constipation: –one patient treated with tiotropium was hospitalized with fecal impaction “Diabetes mellitus”, “diabetes mellitus aggravated,” or “hyperglycemia” –14 (2.5%) tiotropium patients vs. 1 (0.3%) placebo patients Constipation: –one patient treated with tiotropium was hospitalized with fecal impaction “Diabetes mellitus”, “diabetes mellitus aggravated,” or “hyperglycemia” –14 (2.5%) tiotropium patients vs. 1 (0.3%) placebo patients

29. Pulmonary-Allergy Drugs Advisory Committee September 6, 2002 29 Other Safety Observations (One-year, placebo-controlled studies) Cardiovascular Effects –“Heart Rate and Rhythm Disorders”: AEs: 24 (4.4%) tiotropium patients vs. 8 (2.2%) placebo patients SAEs: 1.3% tiotropium patients vs. 0.5%placebo patients (signal not seen in ipratropium-controlled studies) –No safety signal on ECGs Cardiovascular Effects –“Heart Rate and Rhythm Disorders”: AEs: 24 (4.4%) tiotropium patients vs. 8 (2.2%) placebo patients SAEs: 1.3% tiotropium patients vs. 0.5%placebo patients (signal not seen in ipratropium-controlled studies) –No safety signal on ECGs

30. Pulmonary-Allergy Drugs Advisory Committee September 6, 2002 30 Other Safety Observations (One-year studies) Deaths –One-year studies: –incidence of death similar in all groups –placebo-controlled: 5/7 tiotropium deaths were attributable to cardiac ischemia or arrhythmia (compared with 1/7 placebo deaths) –ipratropium-controlled: deaths due to MI = 3/9 tiotropium deaths, 0/3 ipratropium deaths Deaths –One-year studies: –incidence of death similar in all groups –placebo-controlled: 5/7 tiotropium deaths were attributable to cardiac ischemia or arrhythmia (compared with 1/7 placebo deaths) –ipratropium-controlled: deaths due to MI = 3/9 tiotropium deaths, 0/3 ipratropium deaths

31. Pulmonary-Allergy Drugs Advisory Committee September 6, 2002 31 Other Safety Observations Phase 2 Study: –No safety signal on Holter monitors N=72 patients, pre- and on-treatment –compared with n = 284 patients during five, 24-hour periods described in Serevent MDI label One subject developed a four-fold increase in ventricular ectopy on-treatment (tiotropium). Phase 2 Study: –No safety signal on Holter monitors N=72 patients, pre- and on-treatment –compared with n = 284 patients during five, 24-hour periods described in Serevent MDI label One subject developed a four-fold increase in ventricular ectopy on-treatment (tiotropium).

32. Pulmonary-Allergy Drugs Advisory Committee September 6, 2002 32 Adverse Events with Tiotropium (One-year, ipratropium-controlled studies) EventTiotropium Ipratropium Chest Pain 5.3%2.2% Dry Mouth 12.1%6.1% Dyspepsia 1.4%0.6% Moniliasis 2.8%1.7% Pharyngitis 6.5%2.8% Sinusitis 3.4%2.2% URTI 43%34.6% UTI 3.9%2.2% EventTiotropium Ipratropium Chest Pain 5.3%2.2% Dry Mouth 12.1%6.1% Dyspepsia 1.4%0.6% Moniliasis 2.8%1.7% Pharyngitis 6.5%2.8% Sinusitis 3.4%2.2% URTI 43%34.6% UTI 3.9%2.2%

33. Pulmonary-Allergy Drugs Advisory Committee September 6, 2002 33 OutlineOutline Background PK/PD characteristics Overview of P3 clinical program Safety findings Efficacy findings –Bronchodilator efficacy –Dyspnea efficacy –Other efficacy findings Summary Background PK/PD characteristics Overview of P3 clinical program Safety findings Efficacy findings –Bronchodilator efficacy –Dyspnea efficacy –Other efficacy findings Summary

34. Pulmonary-Allergy Drugs Advisory Committee September 6, 2002 34 OutlineOutline Background PK/PD characteristics Overview of P3 clinical program Safety findings Efficacy findings –Bronchodilator efficacy –Dyspnea efficacy –Other efficacy findings Summary Background PK/PD characteristics Overview of P3 clinical program Safety findings Efficacy findings –Bronchodilator efficacy –Dyspnea efficacy –Other efficacy findings Summary

35. Pulmonary-Allergy Drugs Advisory Committee September 6, 2002 35 Bronchodilator Efficacy: Studies 114 and 115 Trough FEV1 statistically superior on all other clinic visits (1, 7, 25, 37, and 49 weeks), with mean effect sizes of 0.11 - 0.16 liters. Tiotropium was also statistically superior to placebo on peak FEV1, and average FEV1 during the 3-hour serial spirometry performed on all clinic visits. Trough FEV1 statistically superior on all other clinic visits (1, 7, 25, 37, and 49 weeks), with mean effect sizes of 0.11 - 0.16 liters. Tiotropium was also statistically superior to placebo on peak FEV1, and average FEV1 during the 3-hour serial spirometry performed on all clinic visits.

36. Pulmonary-Allergy Drugs Advisory Committee September 6, 2002 36 Bronchodilator Efficacy: Studies 114 and 115 Peak FEV1 Data –Mean Peak FEV1 response was 0.24 liters on Day 1 and 0.25 - 0.31 liters on subsequent clinic visits. –On Day 1, the mean peak FEV1 at each time point (0.5, 1, 2, and 3 hours) was <0.20 liters –This is because patients reached their personal peak FEV1 at differing time points: Peak FEV1 Data –Mean Peak FEV1 response was 0.24 liters on Day 1 and 0.25 - 0.31 liters on subsequent clinic visits. –On Day 1, the mean peak FEV1 at each time point (0.5, 1, 2, and 3 hours) was <0.20 liters –This is because patients reached their personal peak FEV1 at differing time points:

37. Pulmonary-Allergy Drugs Advisory Committee September 6, 2002 37 Bronchodilator Efficacy: Studies 114 and 115 Tiotropium was statistically superior to placebo: –FVC response (trough, average, and peak) –AM and PM PEFR, for most weeks, with mean effect sizes of 8 - 31 liters/minute (morning) and 13 to 40 liters/minute (evening) Tiotropium was statistically superior to placebo: –FVC response (trough, average, and peak) –AM and PM PEFR, for most weeks, with mean effect sizes of 8 - 31 liters/minute (morning) and 13 to 40 liters/minute (evening)

38. Pulmonary-Allergy Drugs Advisory Committee September 6, 2002 38 Bronchodilator Efficacy: Studies 122A and 122B Primary Efficacy Endpoint: Trough FEV1 at 13 weeks –Note: Ipratropium not expected to show significant efficacy at this time point –Tiotropium was superior to ipratropium on this variable at all clinic visits, with mean effect sizes of 0.11 to 0.18 liters (over ipratropium) Primary Efficacy Endpoint: Trough FEV1 at 13 weeks –Note: Ipratropium not expected to show significant efficacy at this time point –Tiotropium was superior to ipratropium on this variable at all clinic visits, with mean effect sizes of 0.11 to 0.18 liters (over ipratropium)

39. Pulmonary-Allergy Drugs Advisory Committee September 6, 2002 39 Bronchodilator Efficacy: Studies 130 and 137 Trough FEV1 was statistically superior on all other clinic visits (Day 1, and Weeks 2, 8, and 16), with mean effect sizes of 0.11 - 0.15 liters. Tiotropium was also statistically superior to placebo on peak FEV1, and average FEV1 during the 12- or 3-hour serial spirometry performed on all clinic visits. Trough FEV1 was statistically superior on all other clinic visits (Day 1, and Weeks 2, 8, and 16), with mean effect sizes of 0.11 - 0.15 liters. Tiotropium was also statistically superior to placebo on peak FEV1, and average FEV1 during the 12- or 3-hour serial spirometry performed on all clinic visits.

40. Pulmonary-Allergy Drugs Advisory Committee September 6, 2002 40 Bronchodilator Efficacy: Studies 130 and 137 Tiotropium was statistically superior to placebo: –FVC response (trough, average, and peak) –AM and PM PEFR, with mean effect sizes of 14.9 - 27 liters/minute (morning) and 21 - 33 liters/minute (evening) Tiotropium was statistically superior to placebo: –FVC response (trough, average, and peak) –AM and PM PEFR, with mean effect sizes of 14.9 - 27 liters/minute (morning) and 21 - 33 liters/minute (evening)

41. Pulmonary-Allergy Drugs Advisory Committee September 6, 2002 41 OutlineOutline Background PK/PD characteristics Overview of P3 clinical program Safety findings Efficacy findings –Bronchodilator efficacy –Dyspnea efficacy –Other efficacy findings Summary Background PK/PD characteristics Overview of P3 clinical program Safety findings Efficacy findings –Bronchodilator efficacy –Dyspnea efficacy –Other efficacy findings Summary

42. Pulmonary-Allergy Drugs Advisory Committee September 6, 2002 42 Dyspnea Efficacy: Studies 130 and 137 TDI “responders” at 6 months (Co-primary Endpoint) StudyTiotropium PlaceboSalmeterol 130 42%** 26% 35% 137 45%* 33% 48%** *p<0.05 (placebo comparison) **p<0.01 (placebo comparison) [Responders defined as patients with TDI score  1] TDI “responders” at 6 months (Co-primary Endpoint) StudyTiotropium PlaceboSalmeterol 130 42%** 26% 35% 137 45%* 33% 48%** *p<0.05 (placebo comparison) **p<0.01 (placebo comparison) [Responders defined as patients with TDI score  1]

43. Pulmonary-Allergy Drugs Advisory Committee September 6, 2002 43 Exclusions from TDI Data Set

44. Pulmonary-Allergy Drugs Advisory Committee September 6, 2002 44 Dyspnea Efficacy: Studies 130 and 137 Number Needed to Treat (NNT) Analyses* StudyNNT 1306.45 1378.6 Combined7.5 *To achieve one “responder,” defined as TDI  1 Number Needed to Treat (NNT) Analyses* StudyNNT 1306.45 1378.6 Combined7.5 *To achieve one “responder,” defined as TDI  1

45. Pulmonary-Allergy Drugs Advisory Committee September 6, 2002 45 Dyspnea Efficacy: Studies 130 and 137 TDI “responders” at 8 and 16 weeks (Secondary Endpoints) 8 Weeks StudyTiotropiumPlaceboSalmeterol 130 40%* 24% 34% 137 44%* 31% 47%** 16 Weeks StudyTiotropiumPlaceboSalmeterol 130 43%* 27% 34% 137 42%* 30% 47%** * p<0.05 (placebo comparison) **p<0.01 (placebo comparison) TDI “responders” at 8 and 16 weeks (Secondary Endpoints) 8 Weeks StudyTiotropiumPlaceboSalmeterol 130 40%* 24% 34% 137 44%* 31% 47%** 16 Weeks StudyTiotropiumPlaceboSalmeterol 130 43%* 27% 34% 137 42%* 30% 47%** * p<0.05 (placebo comparison) **p<0.01 (placebo comparison)

46. Pulmonary-Allergy Drugs Advisory Committee September 6, 2002 46 Dyspnea Efficacy: TDI - Analyses of Mean Values Statistically Difference Superior  1 (Weeks) (Weeks) Study 130 8, 16, 24 (all) 8, 24 Study 137 8, 16, 24 (all)8, 16, 24 (all) Study 114 7, 13, 25, 37, 49 (all) 49 Study 115 7, 13, 25, 37, 49 (all) 37, 49 Study 122A* 1, 26, 39, 52 (not 7, 13) - Study 122B* 1,7,13,26,39,52 (all)1, 26, 29, 52 *comparison: ipratropium Statistically Difference Superior  1 (Weeks) (Weeks) Study 130 8, 16, 24 (all) 8, 24 Study 137 8, 16, 24 (all)8, 16, 24 (all) Study 114 7, 13, 25, 37, 49 (all) 49 Study 115 7, 13, 25, 37, 49 (all) 37, 49 Study 122A* 1, 26, 39, 52 (not 7, 13) - Study 122B* 1,7,13,26,39,52 (all)1, 26, 29, 52 *comparison: ipratropium

47. Pulmonary-Allergy Drugs Advisory Committee September 6, 2002 47 Dyspnea Efficacy: Shuttle Walk Test/ Borg Dyspnea Scale Studies 130 and 137 included a post-dose Shuttle Walk Test on Day 1, and Weeks 8, 16, and 25. Shuttle Walk Test (SWT): a standardized test in which patients walk at a steady pace on a 10- meter course until they are unable to maintain the required speed without becoming unduly breathless. The Modified Borg Dyspnea Scale was administered before and after each SWT. –Scale: ranges from 0 (“nothing at all”) to 10 (“maximal”) Studies 130 and 137 included a post-dose Shuttle Walk Test on Day 1, and Weeks 8, 16, and 25. Shuttle Walk Test (SWT): a standardized test in which patients walk at a steady pace on a 10- meter course until they are unable to maintain the required speed without becoming unduly breathless. The Modified Borg Dyspnea Scale was administered before and after each SWT. –Scale: ranges from 0 (“nothing at all”) to 10 (“maximal”)

48. Pulmonary-Allergy Drugs Advisory Committee September 6, 2002 48 Dyspnea Efficacy: Shuttle Walk Test/ Borg Dyspnea Scale SWT (Walking Distance) –No difference between groups in either study –Placebo numerically superior in 1 study –Walking distance did not increase during the study in any of the groups Modified Borg Dyspnea Scale –Study 130: No differences between tiotropium and placebo, except Week 8 (Difference: 0.24 pre-exercise, 0.32 post-exercise) –Study 137: No differences between tiotropium and placebo SWT (Walking Distance) –No difference between groups in either study –Placebo numerically superior in 1 study –Walking distance did not increase during the study in any of the groups Modified Borg Dyspnea Scale –Study 130: No differences between tiotropium and placebo, except Week 8 (Difference: 0.24 pre-exercise, 0.32 post-exercise) –Study 137: No differences between tiotropium and placebo

49. Pulmonary-Allergy Drugs Advisory Committee September 6, 2002 49 Dyspnea Efficacy: “COPD Symptom Score” Studies 130/137 and 114/115 Investigator’s assessment of the prior week Wheezing, Shortness of Breath, Coughing, and Tightness of Chest Each scored from 0-3 Results: Tiotropium statistically superior to placebo for “Shortness of Breath” at most visits Effect Size: 0.13 to 0.36 Interpretation: Uncertain significance (validation, effect size) Studies 130/137 and 114/115 Investigator’s assessment of the prior week Wheezing, Shortness of Breath, Coughing, and Tightness of Chest Each scored from 0-3 Results: Tiotropium statistically superior to placebo for “Shortness of Breath” at most visits Effect Size: 0.13 to 0.36 Interpretation: Uncertain significance (validation, effect size)

50. Pulmonary-Allergy Drugs Advisory Committee September 6, 2002 50 OutlineOutline Background PK/PD characteristics Overview of P3 clinical program Safety findings Efficacy findings –Bronchodilator efficacy –Dyspnea efficacy –Other efficacy findings Summary Background PK/PD characteristics Overview of P3 clinical program Safety findings Efficacy findings –Bronchodilator efficacy –Dyspnea efficacy –Other efficacy findings Summary

51. Pulmonary-Allergy Drugs Advisory Committee September 6, 2002 51 Other Efficacy Findings Studies 114 and 115 –Tiotropium was statistically superior to placebo: Physician’s Global Evaluation (effect size of 0.25 to 0.59 on a scale of 1-8) As-needed albuterol (5-6 fewer doses per week) –No consistent meaningful difference shown: COPD exacerbations or hospitalizations St. George’s Hospital Respiratory Questionnaire Medical Outcomes Study SF-36 Studies 114 and 115 –Tiotropium was statistically superior to placebo: Physician’s Global Evaluation (effect size of 0.25 to 0.59 on a scale of 1-8) As-needed albuterol (5-6 fewer doses per week) –No consistent meaningful difference shown: COPD exacerbations or hospitalizations St. George’s Hospital Respiratory Questionnaire Medical Outcomes Study SF-36

52. Pulmonary-Allergy Drugs Advisory Committee September 6, 2002 52 Other Efficacy Findings Studies 122A and 122B (ipratropium- controlled) –No consistent effect: as-needed albuterol use COPD exacerbations or hospitalizations Studies 122A and 122B (ipratropium- controlled) –No consistent effect: as-needed albuterol use COPD exacerbations or hospitalizations

53. Pulmonary-Allergy Drugs Advisory Committee September 6, 2002 53 Other Efficacy Findings Studies 130 and 137 –Tiotropium was statistically superior to placebo: Physician’s Global Evaluation (all test days except one; effect size of 0.11 to 0.59 on a scale of 1-8) –No consistent, meaningful difference shown: As-needed albuterol COPD exacerbations or hospitalizations St. George’s Hospital Respiratory Questionnaire Patient Satisfaction Questionnaire Studies 130 and 137 –Tiotropium was statistically superior to placebo: Physician’s Global Evaluation (all test days except one; effect size of 0.11 to 0.59 on a scale of 1-8) –No consistent, meaningful difference shown: As-needed albuterol COPD exacerbations or hospitalizations St. George’s Hospital Respiratory Questionnaire Patient Satisfaction Questionnaire

54. Pulmonary-Allergy Drugs Advisory Committee September 6, 2002 54 OutlineOutline Background PK/PD characteristics Overview of P3 clinical program Safety findings Efficacy findings –Bronchodilator efficacy –Dyspnea efficacy –Other efficacy findings Summary Background PK/PD characteristics Overview of P3 clinical program Safety findings Efficacy findings –Bronchodilator efficacy –Dyspnea efficacy –Other efficacy findings Summary

55. Pulmonary-Allergy Drugs Advisory Committee September 6, 2002 55 SummarySummary PK features of tiotropium are somewhat unique among inhaled bronchodilators –Very large volume of distribution –Very long terminal elimination half-life –Apparent tight tissue binding with slow release back into the circulation PK features of tiotropium are somewhat unique among inhaled bronchodilators –Very large volume of distribution –Very long terminal elimination half-life –Apparent tight tissue binding with slow release back into the circulation

56. Pulmonary-Allergy Drugs Advisory Committee September 6, 2002 56 SummarySummary Safety: –Dry mouth is common, shows an age and gender interaction, and is more frequent than with ipratropium –Several AEs occurred more frequently with tiotropium than placebo. Based on the mechanism of action and the observed age interaction, constipation and urinary tract infection may be important. –Possible effect on heart rate/rhythm may merit further evaluation Safety: –Dry mouth is common, shows an age and gender interaction, and is more frequent than with ipratropium –Several AEs occurred more frequently with tiotropium than placebo. Based on the mechanism of action and the observed age interaction, constipation and urinary tract infection may be important. –Possible effect on heart rate/rhythm may merit further evaluation

57. Pulmonary-Allergy Drugs Advisory Committee September 6, 2002 57 SummarySummary Efficacy: –Appears to provide clinically meaningful bronchodilation –Duration of action supports once-daily dosing –Maximum bronchodilator effect reached after multiple daily doses –Demonstrable effect on TDI. However, the clinical significance of this effect is not known. Issues with the instrument and its implementation in the studies Effect size (NNT) Efficacy: –Appears to provide clinically meaningful bronchodilation –Duration of action supports once-daily dosing –Maximum bronchodilator effect reached after multiple daily doses –Demonstrable effect on TDI. However, the clinical significance of this effect is not known. Issues with the instrument and its implementation in the studies Effect size (NNT)

58. Pulmonary-Allergy Drugs Advisory Committee September 6, 2002 58 SummarySummary Other: –Safety/efficacy of concurrent “as-needed” ipratropium not addressed Other: –Safety/efficacy of concurrent “as-needed” ipratropium not addressed

59. Pulmonary-Allergy Drugs Advisory Committee September 6, 2002 59

60. Pulmonary-Allergy Drugs Advisory Committee September 6, 2002 60

61. Pulmonary-Allergy Drugs Advisory Committee September 6, 2002 61 Questions for the Committee 1. Is the safety database for tiotropium bromide inhalation powder for the treatment of COPD patients adequate? A) If not, what further safety data should be obtained? B) Which of the safety data should be obtained prior to approval? 2. Are there specific safety concerns regarding the use of tiotropium bromide inhalation powder in the COPD patient population that merit specific attention in the product label? 1. Is the safety database for tiotropium bromide inhalation powder for the treatment of COPD patients adequate? A) If not, what further safety data should be obtained? B) Which of the safety data should be obtained prior to approval? 2. Are there specific safety concerns regarding the use of tiotropium bromide inhalation powder in the COPD patient population that merit specific attention in the product label?

62. Pulmonary-Allergy Drugs Advisory Committee September 6, 2002 62 Questions for the Committee 3. Do the data provide substantial and convincing evidence that tiotropium bromide inhalation powder provides a clinically meaningful bronchodilator effect when used in the chronic treatment of patients with COPD?

63. Pulmonary-Allergy Drugs Advisory Committee September 6, 2002 63 Questions for the Committee 4. Do the data provide substantial and convincing evidence that tiotropium bromide inhalation powder provides a clinically meaningful effect for the symptom of dyspnea in patients with COPD? 5. In general, what quality and quantity of data would constitute substantial and convincing evidence of a clinically meaningful benefit for the symptom of dyspnea in patients with COPD? 4. Do the data provide substantial and convincing evidence that tiotropium bromide inhalation powder provides a clinically meaningful effect for the symptom of dyspnea in patients with COPD? 5. In general, what quality and quantity of data would constitute substantial and convincing evidence of a clinically meaningful benefit for the symptom of dyspnea in patients with COPD?

64. Pulmonary-Allergy Drugs Advisory Committee September 6, 2002 64