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Pulmonary - Allergy Drugs Advisory Committee Meeting. January 17, 2002 FLOVENT® DISKUS® NDA 20-833 ADVAIR DISKUS® NDA 21-077. FLOVENT® DISKUS® and ADVAIR DISKUS®. David Wheadon, MD Senior Vice President, Regulatory Affairs GlaxoSmithKline. sNDAs for FLOVENT DISKUS and ADVAIR DISKUS.
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Pulmonary - Allergy Drugs Advisory Committee Meeting January 17, 2002 FLOVENT® DISKUS® NDA 20-833 ADVAIR DISKUS® NDA 21-077
FLOVENT® DISKUS® and ADVAIR DISKUS® David Wheadon, MD Senior Vice President, Regulatory Affairs GlaxoSmithKline
sNDAs forFLOVENT DISKUS and ADVAIR DISKUS INDICATION Long term, twice-daily maintenance treatment of Chronic Obstructive Pulmonary Disease (including emphysema and chronic bronchitis)
SEREVENT®(salmeterol xinafoate) • Serevent Inhalation Aerosol approved for COPD, 1998 • Approval sought for Serevent Diskus for the maintenance treatment of bronchospasm associated with COPD
FLOVENT(fluticasone propionate) • Currently Approved in US for maintenance treatment of asthma • Approved for COPD in 67 countries outside US • Worldwide exposure estimate - 14.4 million patient years • Approval sought for Flovent Diskus for maintenance treatment of COPD at doses of 250mcg and 500mcg BID
ADVAIR DISKUS(fluticasone propionate andsalmeterol inhalation powder) • Currently approved for maintenance treatment of asthma • Worldwide exposure estimate - 1.4 million patient years • Approval sought for maintenance treatment of COPD at doses of 250/50mcg and 500/50mcg BID
Impact of COPD in the US • Affects an estimated 21.7 million Americans1 • 6.5 Million Diagnosed • 4.3 Million Treated With Prescription Medications • The fourth leading cause of death2 • 114,000 deaths in 19982 • Third leading cause of death by 20203 • Annual cost >$30 billion2 • $14.7 billion in direct healthcare costs • $15.7 billion in indirect healthcare costs 1Data on file (analysis of NHANES III data), GlaxoSmithKline. 2National Center for Health Statistics, National Health Interview Survey, 1998. Information cited in: American Lung Association, trends in Chronic bronchitis and Emphysema: Morbidity and Mortality, December, 2000. 3Murray CJL and Lopez AD, eds. The Global Burden of Disease. Vol. 1. 1996:362.
GlobalInitiative for ChronicObstructiveLungDisease Global Initiative for Chronic Obstructive Lung Disease. Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease: NHLBI/WHO Workshop Report. Bethesda, Md: National Heart, Lung, and Blood Institute, National Institutes of Health; March 2001. NIH publication 2701A.
Clinical Effects of ICS in COPD Reference N Duration Treatment/Day Outcome Nishimura et al., 1999 30 4 w BDP 3000mcg FEV1, Sx O’Brien et al., 2001 24 6 w BDP 1500mcg FEV1 preserved Thompson et al., 1992 30 6 w BDP 1000mcg FEV1, bronchitis Weiner et al., 1995 30 6 w BUD 800mcg FEV1, prn med Weiner et al., 1999 168 6 w BUD 1600mcg FEV1, prn med Auffarth et al., 1991 21 8 w BUD 1600mcg dyspnea Kerstjens et al., 1993 39 12 w BDP 800mcg FEV1 Dompeling et al., 1992 28 52 w BDP 800mcg PEF, Sx Paggiaro et al., 1998 281 24 w FP 1000mcg FEV1, exac ISOLDE, 2000 751 3 Y FP 1000mcg FEV1, QoL, exac Euroscope, 1999 1277 3 Y BUD 800mcg FEV1, exac Lung Health II, 2000 1116 3 Y TAA 1200mcg Sx , exac Sin & Tu, 2001 22620 Varied morbidity, mortality
Current Use of ICS for COPD:Prescription Data from July 2001 • 40% of all COPD patients were prescribed ICS therapy • 46% of all patients prescribed 2 or more COPD maintenance medications (any medication other than albuterol) • 72% prescribed an ICS • 57% prescribed an ICS + a maintenance bronchodilator • 17% prescribed Advair Source: NDC Health, July 2001
SUMMARY • COPD is a serious public health issue • Considerable unmet medical needs • New treatment options are needed
Order of GSK Presentation • Scientific and Clinical Rationale • Dr. Malcolm Johnson (15 minutes) • Clinician’s Perspective • Dr. James Donohue (15 minutes) • Clinical Efficacy and Safety • Dr. Tushar Shah (45 minutes) • Conclusion and Q & A • Dr. David Wheadon
Scientific and Clinical Rationale Malcolm Johnson, PhD Global Director of Respiratory Science GlaxoSmithKline
Pathology of COPD Inflammation AirwayObstruction Structural Changes
Pathophysiological Features of COPD Airway Obstruction StructuralChanges Inflammation Increased Neutrophils,macrophages, CD8+ lymphocytes. Elevated IL-8, TNFa Protease/anti-proteaseimbalance Alveolar destruction Collagen deposition Glandular hypertrophy Airway fibrosis Smooth muscle contraction Increased cholinergic tone Loss of elastic recoil Symptoms FEV1 Exacerbations
Do inhaled corticosteroids reduce inflammation in COPD? Are inhaled corticosteroids effective treatment for COPD? Inhaled Corticosteroids
Anti-Inflammatory Effects of ICS in COPD Reference N Duration Treatment/Day Outcome Balbi 8 6 w BDP 1500mcg BAL neutrophils, IL-8 et al., 2000 and MPO Confalonieri 24 8 w BDP 1500mcg Sputum neutrophils et al., 1998 Llewellyn-Jones 17 8 w FP 1500mcg Sputum neutrophil et al., 1996 chemotactic activity Thompson 30 6 w BDP 1000mcg Improvement in bronchial et al., 1992 cell counts and epithelial lining fluid proteins Yildiz 18 8 w FP 1500mcg Sputum neutrophilset al., 2000 Hattotuwa 37 12 w FP 1000mcg Biopsy CD8+/CD4+ et al., 1999, 2000 Tcell ratio and mast cells Verhoeven 20 24 w FP 1000mcg Biopsy CD8+ Tcells and et al., 1999 eosinophils Keatings 13 2 w BUD 1600mcg No change in total and et al.,1996 differential cell counts or TNF, ECP, EPO and MPO Culpitt 13 4 w FP 1000mcg No change in sputum et al., 1999 neutrophils, IL-8 or SLPI O’Brien 5 6 w BDP 400mcg No change in sputum et al., 2001 neutrophils
Fluticasone Propionate Reduces Total Cell Counts and Neutrophils in the Sputum of COPD Patients Neutrophils Total Cell Counts * x106 cells/g * percent Placebo FP 1500 mcg/day * P<0.05 Yildiz et al. Respiration. 2000; 67:71-76.
ICS (FP) Reduces Inflammation in COPD Airway Obstruction StructuralChanges Inflammation ICS (FP) Positive Effect ? Increased Neutrophils,macrophages, CD8+ lymphocytes. Elevated IL-8, TNFa Protease/anti-proteaseimbalance Alveolar destruction Collagen deposition Glandular hypertrophy Airway fibrosis Smooth muscle contraction Increased cholinergic tone Loss of elastic recoil Symptoms FEV1 Exacerbations
Do inhaled corticosteroids reduce inflammation in COPD? Are inhaled corticosteroids effective treatment for COPD? Inhaled Corticosteroids
Clinical Effects of ICS in COPD Reference N Duration Treatment/Day Outcome Nishimura et al., 1999 30 4 w BDP 3000mcg FEV1, Sx O’Brien et al., 2001 24 6 w BDP 1500mcg FEV1 preserved Thompson et al., 1992 30 6 w BDP 1000mcg FEV1, bronchitis Weiner et al., 1995 30 6 w BUD 800mcg FEV1, prn med Weiner et al., 1999 168 6 w BUD 1600mcg FEV1, prn med Auffarth et al., 1991 21 8 w BUD 1600mcg dyspnea Kerstjens et al., 1993 39 12 w BDP 800mcg FEV1 Dompeling et al., 1992 28 52 w BDP 800mcg PEF, Sx Paggiaro et al., 1998 281 24 w FP 1000mcg FEV1, exac ISOLDE, 2000 751 3 Y FP 1000mcg FEV1, QoL, exac Euroscope, 1999 1277 3 Y BUD 800mcg FEV1, exac Lung Health II, 2000 1116 3 Y TAA 1200mcg Sx , exac Sin & Tu, 2001 22620 Varied morbidity, mortality Keatings et al., 1999 13 2 w BUD 1600mcg No PFT, Sx, prn med Culpitt et al., 1999 13 4 w FP 1000mcg No PFT, Sx Engel et al., 1989 18 12 w BUD 800mcg No PFT, SxWatson et al., 1992 14 12 w BUD 1200mcg No PFT, Sx Bourbeau et al., 1998 79 28 w BUD 1600mcg No PFT, Sx, QoL Copenhagen City, 1996 290 3 Y BUD 800mcg No PFT, Sx, exac
1.0 0.9 0.8 0.7 0.6 0.5 ICS associated with a 26% lower relative risk for all-cause mortality and repeat hospitalization Inhaled Corticosteroids COPD Hospitalization Free Survival No Inhaled Corticosteroids 0 2 4 6 8 10 12 Months After Discharge Reduced Risk of Mortality and Repeat Hospitalization with Inhaled Corticosteroids Adapted from Sin DD, Tu JV. Am J Respir Crit Care Med 2001;164:580-584
Fluticasone Propionate Significantly Improves Pre-dose FEV1 in COPD P<0.01 P<0.02 FEV1 (L) Week Paggiaro et al. Lancet. 1998; 351:773-780.
Collection of Exacerbation Data in Paggiaro et al., 1998 • Exacerbation history: at least 1/ year (treated by physician or hospital) for previous 3 years • Exacerbation: worsening of COPD symptoms requiring changes to normal treatment • Exacerbation severity: • Mild: patient self-managed at home • Moderate: patient treated by a physician • Severe: patient hospitalized • Multiple exacerbations requiring OCS were allowed Paggiaro et al. Lancet. 1998; 351:773-780.
Fluticasone Propionate Reduces Moderate/Severe Exacerbations in COPD Treatment Group Fluticasone Placebo propionate (n=139) (n=142) Number of exacerbations* Total 111 76 Number of Patients with one or moreexacerbations Total 51 45 Mild 7 (14%) 17 (38%)‡ Moderate/severe 44 (86%) 27 (60%) ‡ * Each patient may have experienced more than one exacerbation. ‡ p<0.001. Paggiaro et al. Lancet. 1998; 351:773-780.
Inhaled Steroids in Obstructive Lung Disease in Europe (ISOLDE) FP MDI 500mcg BID Corticosteroid Withdrawal PlaceboRun-in Placebo BID 2 Months 3 yrs N = 751 Reversibility <10% predicted Mean FEV1 50% at baseline Burge PS et al. Br Med J. 2000;320:1297-1303.
1.5 * * * FP 500µg BID (n=376) * 1.4 * Post-bronchodilator FEV1 1.3 Placebo BID (n=375) 1.2 -3 0 3 6 9 12 15 18 21 24 27 30 33 36 Time (months) *p<0.001 FP Improves Post-bronchodilator FEV1 Response in COPD: ISOLDE Study Adapted from Burge PS et al. Br Med J. 2000;320:1297-1303.
FP Reduces Median Annual Exacerbation Rate: ISOLDE Study 1.32 *p=0.026 O.99* Exacerbations/patient/year Burge PS et al., Br Med J. 2000;320:1297-1303
Regression Analysis 12 10 8 6 4 2 0 P = 0.004 Placebo Fluticasone propionate Change in Total Score Threshold of clinical significance 0 6 12 18 24 30 36 Time (months) FP Slows the Decline in Quality of Life as Measured by SGRQ*: ISOLDE Study An increase in score reflects a decrease in quality of life. *St George’s Respiratory Questionnaire Burge PS et al. Br Med J. 2000;320:1297-1303.
ICS (FP) Reduces Inflammation in COPD Airway Obstruction StructuralChanges Inflammation ICS (FP) Positive Effect ? Increased Neutrophils,macrophages, CD8+ lymphocytes. Elevated IL-8, TNFa Protease/anti-proteaseimbalance Alveolar destruction Collagen deposition Glandular hypertrophy Airway fibrosis Smooth muscle contraction Increased cholinergic tone Loss of elastic recoil Symptoms FEV1 Exacerbations
0.4 0.3 0.2 0.1 0 Salmeterol Day 1Salmeterol Day 84Placebo * * * * * FEV1(L) * * * * 0 1 2 3 4 5 6 7 8 9 10 11 12 13 Time (hours) Salmeterol is a Long-Acting Bronchodilator in COPD *P < .001 salmeterol vs placebo. Adapted from Mahler DA et al. Chest. 1999;115:957-965.
Salmeterol Reduces Airway Obstruction in COPD Airway Obstruction StructuralChanges Inflammation Salmeterol Positive Effect Increased Neutrophils,macrophages, CD8+ lymphocytes. Elevated IL-8, TNFa Protease/anti-proteaseimbalance Alveolar destruction Collagen deposition Glandular hypertrophy Airway fibrosis Smooth muscle contraction Increased cholinergic tone Loss of elastic recoil Symptoms FEV1 Exacerbations
Combined Effects of Salmeterol and FP in COPD Salmeterol+FP ? Airway Obstruction StructuralChanges Inflammation Increased Neutrophils,macrophages, CD8+ lymphocytes. Elevated IL-8, TNFa Protease/anti-proteaseimbalance Smooth muscle contraction Increased cholinergic tone Loss of elastic recoil Alveolar destruction Collagen deposition Glandular hypertrophy Airway fibrosis Symptoms FEV1 Exacerbations
Corticosteroids Increase RespiratoryMucosal Beta2-receptors * 0.45 0.40 0.35 0.30 beta2-receptor/actin ratio 0.25 0.20 0.15 0.10 p<0.04 * 0.05 0 Baseline BDP 100mcg for 3 days Baraniuk et al AJRCCM 155: 704-710(1997)
Salmeterol Potentiates the Effect of FP on TNF-induced IL8 Release fromAirway Smooth Muscle Cells IL8 (pg/ml) *P <0.01 (0.1 µM) (0.1 µM) (1 µM) Adapted from Pang L, and Knox AJ. Am J Respir Cell Mol Biol. 2000; 23: 79-85.
Rationale for CombiningFP with Salmeterol • Fluticasone propionate is an effective inhaled anti-inflammatory corticosteroid with clinical benefit in COPD. • Salmeterol is a long-acting b2-adrenoceptor agonist with demonstrated efficacy in COPD. • Each molecule influences a different aspect of COPD pathophysiology, so together they provide a broad therapeutic cover. • There is some evidence of interaction between these molecules which may be important in improving the overall efficacy of the combination.
Clinician’s Perspective James F. Donohue, MD Chief, Pulmonary and Critical Care MedicineUniversity of North Carolina, Chapel Hill
Overview • Diagnosis of COPD • Evaluating treatment effects in COPD • FEV1 • Other measures • GOLD guidelines • Clinician’s Perspective
Diagnosis of COPD • Clinically based on: • Smoking history • Age • Symptoms • Persistent airflow obstruction (spirometry) • FEV1 post bronchodilator < 80% predicted • FEV1 / FVC < 70% • The presence of reversibility does not exclude a diagnosis of COPD
Bronchodilator Response in COPDIntermittent Positive Pressure Breathing Trial (IPPB) • Evaluated the BD response to inhaled isoproteronol in 985 subjects with COPD (asthma excluded) • Pre and post- bronchodilator FEV1 evaluated every 3 months for 3 yrs. • Key demographics: • Age: 60.9 • Male: 79% • Smoking Status: • 54 pack yrs • 40% current smokers • FEV1 (% predicted): 36 % Anthonisen, et al. Am Rev Respir Dis, 1986;133:14-20.
Bronchodilator Response in COPD IPPB Trial • Approximately half of the subjects were reversible at screening (>12% increase in FEV1 over baseline) • In subjects non-reversible at screening (<10% increase in FEV1) • 30% of these subjects had a >15% increase in FEV1 at each subsequent test day • 68% of these subjects had a >15% increase in FEV1 on at least one of the 7 follow-up test days Annals of Internal Medicine, 1983;99:612-620. Anthonisen, et al. Am Rev Respir Dis, 1986;133:814-819.
Demographic and Reversibility Data from Clinical Trials in COPD Salmeterol Combivent Formoterol (n=816) (n=1067) (n=780) Age 63 64 63 % male 68 69 75 Pack yr 63 na 42 FEV1 L (% pred) 1.25 (40) 0.99 (36) 1.3 (45) % Pts Rev 62 68-73 42 Data on file: SLGA 4004, SLGA 4005, Chest 1994; 105:1411-1419. Chest 1999; 115;966-971. Am J Respir Crit Care Med. Vol 165. p. 778-784, 2001.
Efficacy Measures Used to Assess Treatment Response in COPD • Spirometry (FEV1) • Objective, reproducible • Diagnostic and prognostic • Other Measures • Health Status (QOL) • Symptoms • Exacerbations
FEV1 Response withCombivent® on Day 85 Ipratropium + Albuterol (n = 173)Albuterol (n = 165)Ipratropium (n = 176) FEV1 (%) Postdose (hours) Combivent is a registered trademark of Boehringer Ingelheim.Bone R et al. Chest. 1994;105:1411-1419.
Other Efficacy Measures Observed with Combivent Ipratropium + Albuterol Ipratropium Albuterol Measure (n=173) (n=176) (n=165) CRDQ (QOL)nsns ns Physician Global nsnsnsEvaluation Symptom Score nsnsns PEFR ns ns ns ns = not significant compared to baseline and/or components CRDQ = Chronic Respiratory Index Questionnaire Bone R et al. Chest. 1994;105:1411-1419.
Other Efficacy Measures Observed with Serevent MDI Rennard et al.* Mahler et al.**Measure (n=405) (n=411) PEF NT Awakenings Ventolin use TDI (Dyspnea) — — CRDQ — — Diary Symptoms — — Borg Dyspnea — — Six min walk — — COPD exac. (% pts) — — Time to first exac. — = p≤0.05 salmeterol vs. placebo — = p>0.05 salmeterol vs. placebo *Am. J. Respir. Crit. Care Med. 2001;163:1087-1092 **Chest 1999;115:957-965.
GlobalInitiative for ChronicObstructiveLungDisease Global Initiative for Chronic Obstructive Lung Disease. Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease: NHLBI/WHO Workshop Report. Bethesda, Md: National Heart, Lung, and Blood Institute, National Institutes of Health; March 2001. NIH publication 2701A.