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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. Outline. Background PK/PD characteristics Overview of P3 clinical program

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Pulmonary-Allergy Drugs Advisory Committee


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    1. 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

    2. Outline • Background • PK/PD characteristics • Overview of P3 clinical program • Safety findings • Efficacy findings • Bronchodilator efficacy • Dyspnea efficacy • Other efficacy findings • Summary

    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”

    4. Background: COPD Indication • Currently approved drugs: • “treatment of bronchospasm associated with COPD” • Distinction: treatment of bronchospasm vs. treatment of the disease • FEV1 • direct measure of bronchospasm • “surrogate” measure of the disease itself (a constellation of physical signs and symptoms, physiologic processes, and histopathologic features)

    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

    6. Background: COPD Efficacy Variables • Primary: Measure of bronchodilation • Usually FEV1 • After chronic use (for maintenance drugs) • Peak FEV1, FEV1-Time Curve AUC • Secondary (supportive) • Other spirometry variables • “Rescue” albuterol use • Peak flow • Six-minute walk test • Exacerbations, Patient-Reported Outcomes, etc.

    7. Background: Tiotropium P3 Primary Efficacy Variables • All studies: • Change from baseline in “trough” (pre-dose) FEV1 • Two studies: • Change from baseline in “trough” (pre-dose) FEV1 and • Transitional Dyspnea Index (TDI)

    8. Outline • Background • PK/PD characteristics • Overview of P3 clinical program • Safety findings • Efficacy findings • Bronchodilator efficacy • Dyspnea efficacy • Other efficacy findings • Summary

    9. PK/PD Characteristics • Bioavailability of tiotropium • Oral ingestion 2-3% • Oral inhalation 19.5% • Single dose PK (oral inhalation): • Cmax= 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. 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)

    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

    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

    13. PD Effect Increases with Multiple Dosing Phase 3, one-year, placebo-controlled studies:

    14. PD Effect Increases with Multiple DosingOnset of Steady State “Sub-study” • Daily AM PEFR reached maximum effect at Day 6

    15. Outline • Background • PK/PD characteristics • Overview of P3 clinical program • Safety findings • Efficacy findings • Bronchodilator efficacy • Dyspnea efficacy • Other efficacy findings • Summary

    16. Phase 3 Clinical Program

    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)

    18. Phase 3: Demographic and Baseline Features

    19. Outline • Background • PK/PD characteristics • Overview of P3 clinical program • Safety findings • Efficacy findings • Bronchodilator efficacy • Dyspnea efficacy • Other efficacy findings • Summary

    20. Safety Database • 1308 patients exposed in P3 • Phase 3 Safety Evaluations: • adverse events • vital signs • physical examination • clinical labs • ECGs (timing not specified)

    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)

    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).

    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%)

    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%)

    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%)

    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%)

    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

    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

    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

    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

    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).

    32. Adverse Events with Tiotropium(One-year, ipratropium-controlled studies) Event Tiotropium 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. Outline • Background • PK/PD characteristics • Overview of P3 clinical program • Safety findings • Efficacy findings • Bronchodilator efficacy • Dyspnea efficacy • Other efficacy findings • Summary

    34. Outline • Background • PK/PD characteristics • Overview of P3 clinical program • Safety findings • Efficacy findings • Bronchodilator efficacy • Dyspnea efficacy • Other efficacy findings • Summary

    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.

    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:

    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)

    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)

    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.

    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)

    41. Outline • Background • PK/PD characteristics • Overview of P3 clinical program • Safety findings • Efficacy findings • Bronchodilator efficacy • Dyspnea efficacy • Other efficacy findings • Summary

    42. Dyspnea Efficacy:Studies 130 and 137 TDI “responders” at 6 months (Co-primary Endpoint) Study Tiotropium Placebo Salmeterol 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. Exclusions from TDI Data Set

    44. Dyspnea Efficacy:Studies 130 and 137 Number Needed to Treat (NNT) Analyses* Study NNT 130 6.45 137 8.6 Combined 7.5 *To achieve one “responder,” defined as TDI  1

    45. Dyspnea Efficacy:Studies 130 and 137 TDI “responders” at 8 and 16 weeks (Secondary Endpoints) 8 Weeks Study Tiotropium Placebo Salmeterol 130 40%* 24% 34% 137 44%* 31% 47%** 16 Weeks Study Tiotropium Placebo Salmeterol 130 43%* 27% 34% 137 42%* 30% 47%** * p<0.05 (placebo comparison) **p<0.01 (placebo comparison)

    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

    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”)

    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

    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)

    50. Outline • Background • PK/PD characteristics • Overview of P3 clinical program • Safety findings • Efficacy findings • Bronchodilator efficacy • Dyspnea efficacy • Other efficacy findings • Summary