FLOVENT

1
FLOVENT DISKUS NDA 20-833, S004GlaxoSmithKline

• Pulmonary-Allergy Drugs Advisory Committee
• January 17, 2002
• Charles E. Lee, M.D.
• Medical Reviewer
• Division of Pulmonary and Allergy Drug Products
• CDER/FDA

2
Proposed Indication

• FLOVENT DISKUS is indicated for the long-term,
  twice-daily maintenance treatment of COPD
  (including emphysema and chronic bronchitis).

3
Proposed Dose

• The starting dosage for adults is 1 inhalation
  (250 mcg) twice daily. For patients who do not
  respond adequately to the starting dose,
  increasing the dose to 500 mcg twice daily may
  provide additional control.

4
Introduction

• Efficacy
• Pivotal studies
• Safety
• Pivotal studies
• Supportive studies

5
Overview

• Efficacy
• Small changes in primary and secondary efficacy
  endpoints
• Majority of patients had reversibility with
  bronchodilator
• Safety concerns
• Respiratory infections
• Systemic effects
• Adrenal
• Bone

6
Questions for Consideration

• Efficacy
• Clinical interpretation of the primary efficacy
  endpoint results
• Higher percentage of reversibility in COPD
  population than generally found
• All patients had chronic bronchitis, could have
  self-reported emphysema
• Safety
• Adequacy of long-term safety database
• Risk versus benefit

7
Pivotal Studies
8
Efficacy Assessment

• Primary efficacy variable
• Pre-dose FEV1
• Secondary efficacy variables
• CBSQ, BDI/TDI
• PEFR, albuterol use
• COPD exacerbations
• Patient Reported Outcomes
• CRDQ

9
Safety Assessment

• AEs, SAEs, Withdrawals
• Vital signs, physical examination, oropharyngeal
  exam
• ECG
• Hematology and chemistry studies
• Serum cortisol (FLTA3025)
• Cosyntropin stimulation (SFCA3006, SFCA3007)

10
DemographicsPivotal Studies
11
Demographics

• FLTA3025 SFCA3006 SFCA3007
• Gender, M 69 66 63
• Mean age, yr 64 63 64
• Race, C 94 94 93
• Race, B 4 5 4
• Race, O 1 2 3
• ICS use, 31 25 25
• Current smokers, 45 48 47

12
ReversibilityPercent of Population

• Reversible
• FLTA3025 59
• SFCA3006 54
• SFCA3007 55

Reversible Increase in FEV1 ?12 and ?0.2 L
13
Mean Response to Bronchodilator Change in FEV1

• Reversible Non Overall
• Reversible
• FLTA3025 32 9 23
• SFCA3006 30 9 20
• SFCA3007 30 9 20

Reversible Increase in FEV1 ?12 and ?0.2 L
14
EfficacyPivotal Studies
15
Mean Change From Baseline in Pre-dose FEV1,
LitersDifference from Placebo
p lt0.05
16
Secondary Endpoints and Patient Reported Outcomes

• Small differences from placebo group
• CBSQ
• BDI/TDI
• COPD Exacerbations
• AM PEFR
• Albuterol use
• CRDQ

17
COPD Exacerbations of Patients with ?1
Exacerbation
18
Daily Albuterol UseMean Change From Baseline
Difference from Placebo
Baseline 4.5 to 5.7 puffs/day
19
CRDQChange from Baseline in Overall Score
Difference from Placebo
MCIC 10.0 Baseline 83.6 to 88.8
20
Subgroup AnalysisNon-reversible Group
Non-reversible Increase in FEV1 lt12 or lt0.2 L
21
Subgroup Analysis, Non-reversible Group Mean
Change From Baseline in Pre-dose FEV1 Difference
from Placebo
22
Efficacy, Pivotal Studies

• Primary efficacy endpoint
• Statistically significant and replicated for FP
  500
• Not replicated for FP 250
• Smaller effect in the non-reversible group
• Secondary endpoints and patient reported outcomes
• Small differences from the placebo group

23
Safety Pivotal Studies
24
Notable AEs, Pivotal Studies
25
Notable AEs, Pivotal Studies
26
Adrenal Effects

• Serum cortisol
• FLTA3025
• Cosyntropin stimulation testing
• SFCA3006, SFCA3007

27
FLTA3025 Serum Cortisol Percent Difference from
Placebo
28
Cosyntropin Stimulation Testing

• SFCA3006, SFCA3007
• No evidence of adrenal insufficiency
• Insensitive test for less than complete adrenal
  insufficiency

29
Safety Other Studies
30
FLTA1003

• Phase 1 PK and PD study
• Single center, open label, randomized, single
  dose, 4-way crossover design
• 1000 mcg of FP administered with Diskus
• Washout of 5 days between periods

31
FLTA1003Mean 24 Hour Urinary Cortisol Excretion
32
FLIT78

• Multicenter, double blind, randomized, placebo
  controlled, parallel group study
• Flovent MDI, 500 mcg BID for 3 years
• COPD
• ISOLDE
• Burge PS, et. al. BMJ 20003201297-1303

33
Notable AEs, FLIT78
34
Notable AEs, FLIT78
35
FLIT98

• Multicenter, randomized, double blind, placebo
  controlled, parallel group study
• 1000 mcg BID of FP MDI for 4 weeks
• Patients with acute COPD exacerbation
• N 249 (126 FP, 123 pbo)
• One FP-treated patient had SAE for decreased
  cortisol

36
Bone Mineral Density

• 2-year studies
• FLTA3001
• FLTA3017
• Asthma patients
• Ages 18-50 years
• Females were premenopausal
• Study population at lower risk for osteoporosis
  than the population proposed in this NDA

37
Bone Mineral Density

• FLTA3001
• FP MDI 88 mcg BID, 440 mcg BID
• N 160
• Small decrease at lumbar spine for FP 440 mcg,
  but increase for FP 88 mcg and placebo
• No changes for proximal femur or total body
• FLTA3017
• FP Rotadisk 500 mcg BID
• N 64
• Decrease at femoral neck
• No changes for lumbar spine or total body

38
Conclusions

• Primary efficacy endpoint
• Replication for FP 500 only, not for FP 250
• Small differences from placebo from secondary
  endpoints
• Majority of patients were reversible
• Safety concerns
• Respiratory infections
• Adrenal effects
• Bone density
• Risk versus benefit

39
(No Transcript)