Pulmonary-Allergy Drugs Advisory Committee January 17, FLOVENT ® DISKUS ® NDA , S004 GlaxoSmithKline Pulmonary-Allergy Drugs Advisory Committee January 17, 2002 Charles E. Lee, M.D. Medical Reviewer Division of Pulmonary and Allergy Drug Products CDER/FDA Pulmonary-Allergy Drugs Advisory Committee January 17, 2002 Charles E. Lee, M.D. Medical Reviewer Division of Pulmonary and Allergy Drug Products CDER/FDA

Pulmonary-Allergy Drugs Advisory Committee January 17, Proposed Indication “FLOVENT DISKUS is indicated for the long-term, twice-daily maintenance treatment of COPD (including emphysema and chronic bronchitis).”

Pulmonary-Allergy Drugs Advisory Committee January 17, 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.”

Pulmonary-Allergy Drugs Advisory Committee January 17, IntroductionIntroduction Efficacy –Pivotal studies Safety –Pivotal studies –Supportive studies Efficacy –Pivotal studies Safety –Pivotal studies –Supportive studies

Pulmonary-Allergy Drugs Advisory Committee January 17, OverviewOverview Efficacy –Small changes in primary and secondary efficacy endpoints –Majority of patients had reversibility with bronchodilator Safety concerns –Respiratory infections –Systemic effects Adrenal Bone Efficacy –Small changes in primary and secondary efficacy endpoints –Majority of patients had reversibility with bronchodilator Safety concerns –Respiratory infections –Systemic effects Adrenal Bone

Pulmonary-Allergy Drugs Advisory Committee January 17, 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 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

Pulmonary-Allergy Drugs Advisory Committee January 17, Pivotal Studies

Pulmonary-Allergy Drugs Advisory Committee January 17, Efficacy Assessment Primary efficacy variable –Pre-dose FEV1 Secondary efficacy variables –CBSQ, BDI/TDI –PEFR, albuterol use –COPD exacerbations Patient Reported Outcomes –CRDQ Primary efficacy variable –Pre-dose FEV1 Secondary efficacy variables –CBSQ, BDI/TDI –PEFR, albuterol use –COPD exacerbations Patient Reported Outcomes –CRDQ

Pulmonary-Allergy Drugs Advisory Committee January 17, Safety Assessment AEs, SAEs, Withdrawals Vital signs, physical examination, oropharyngeal exam ECG Hematology and chemistry studies Serum cortisol (FLTA3025) Cosyntropin stimulation (SFCA3006, SFCA3007) AEs, SAEs, Withdrawals Vital signs, physical examination, oropharyngeal exam ECG Hematology and chemistry studies Serum cortisol (FLTA3025) Cosyntropin stimulation (SFCA3006, SFCA3007)

Pulmonary-Allergy Drugs Advisory Committee January 17, Demographics Pivotal Studies

Pulmonary-Allergy Drugs Advisory Committee January 17, DemographicsDemographics FLTA3025SFCA3006SFCA3007 Gender, %M Mean age, yr Race, %C Race, %B454 Race, %O123 ICS use, % Current smokers, % FLTA3025SFCA3006SFCA3007 Gender, %M Mean age, yr Race, %C Race, %B454 Race, %O123 ICS use, % Current smokers, %454847

Pulmonary-Allergy Drugs Advisory Committee January 17, Reversibility Percent of Population Reversible % FLTA SFCA SFCA Reversible % FLTA SFCA SFCA Reversible: Increase in FEV1  12% and  0.2 L

Pulmonary-Allergy Drugs Advisory Committee January 17, Mean Response to Bronchodilator % Change in FEV1 ReversibleNonOverall Reversible %% FLTA SFCA SFCA ReversibleNonOverall Reversible %% FLTA SFCA SFCA Reversible: Increase in FEV1  12% and  0.2 L

Pulmonary-Allergy Drugs Advisory Committee January 17, Efficacy Pivotal Studies

Pulmonary-Allergy Drugs Advisory Committee January 17, Mean Change From Baseline in Pre-dose FEV1, Liters Difference from Placebo * p <0.05

Pulmonary-Allergy Drugs Advisory Committee January 17, Secondary Endpoints and Patient Reported Outcomes Small differences from placebo group –CBSQ –BDI/TDI –COPD Exacerbations –AM PEFR –Albuterol use –CRDQ Small differences from placebo group –CBSQ –BDI/TDI –COPD Exacerbations –AM PEFR –Albuterol use –CRDQ

Pulmonary-Allergy Drugs Advisory Committee January 17, COPD Exacerbations % of Patients with  1 Exacerbation

Pulmonary-Allergy Drugs Advisory Committee January 17, Daily Albuterol Use Mean Change From Baseline Difference from Placebo Baseline: 4.5 to 5.7 puffs/day

Pulmonary-Allergy Drugs Advisory Committee January 17, CRDQ Change from Baseline in Overall Score Difference from Placebo MCIC = 10.0 Baseline: 83.6 to 88.8

Pulmonary-Allergy Drugs Advisory Committee January 17, Subgroup Analysis Non-reversible Group Non-reversible: Increase in FEV1 <12% or <0.2 L

Pulmonary-Allergy Drugs Advisory Committee January 17, Subgroup Analysis, Non-reversible Group Mean Change From Baseline in Pre-dose FEV1 Difference from Placebo

Pulmonary-Allergy Drugs Advisory Committee January 17, 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 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

Pulmonary-Allergy Drugs Advisory Committee January 17, Safety Pivotal Studies

Pulmonary-Allergy Drugs Advisory Committee January 17, Notable AEs, Pivotal Studies

Pulmonary-Allergy Drugs Advisory Committee January 17, Notable AEs, Pivotal Studies

Pulmonary-Allergy Drugs Advisory Committee January 17, Adrenal Effects Serum cortisol –FLTA3025 Cosyntropin stimulation testing –SFCA3006, SFCA3007 Serum cortisol –FLTA3025 Cosyntropin stimulation testing –SFCA3006, SFCA3007

Pulmonary-Allergy Drugs Advisory Committee January 17, FLTA3025: Serum Cortisol Percent Difference from Placebo

Pulmonary-Allergy Drugs Advisory Committee January 17, Cosyntropin Stimulation Testing SFCA3006, SFCA3007 –No evidence of adrenal insufficiency –Insensitive test for less than complete adrenal insufficiency SFCA3006, SFCA3007 –No evidence of adrenal insufficiency –Insensitive test for less than complete adrenal insufficiency

Pulmonary-Allergy Drugs Advisory Committee January 17, Safety Other Studies

Pulmonary-Allergy Drugs Advisory Committee January 17, FLTA1003FLTA1003 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 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

Pulmonary-Allergy Drugs Advisory Committee January 17, FLTA1003 Mean 24 Hour Urinary Cortisol Excretion

Pulmonary-Allergy Drugs Advisory Committee January 17, FLIT78FLIT78 Multicenter, double blind, randomized, placebo controlled, parallel group study Flovent MDI, 500 mcg BID for 3 years COPD “ISOLDE” –Burge PS, et. al. BMJ 2000;320: Multicenter, double blind, randomized, placebo controlled, parallel group study Flovent MDI, 500 mcg BID for 3 years COPD “ISOLDE” –Burge PS, et. al. BMJ 2000;320:

Pulmonary-Allergy Drugs Advisory Committee January 17, Notable AEs, FLIT78

Pulmonary-Allergy Drugs Advisory Committee January 17, Notable AEs, FLIT78

Pulmonary-Allergy Drugs Advisory Committee January 17, FLIT98FLIT98 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 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

Pulmonary-Allergy Drugs Advisory Committee January 17, Bone Mineral Density 2-year studies –FLTA3001 –FLTA3017 Asthma patients Ages years Females were premenopausal Study population at lower risk for osteoporosis than the population proposed in this NDA 2-year studies –FLTA3001 –FLTA3017 Asthma patients Ages years Females were premenopausal Study population at lower risk for osteoporosis than the population proposed in this NDA

Pulmonary-Allergy Drugs Advisory Committee January 17, 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 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

Pulmonary-Allergy Drugs Advisory Committee January 17, ConclusionsConclusions 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 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

Pulmonary-Allergy Drugs Advisory Committee January 17,