Pulmonary-Allergy Drugs Advisory Committee Meeting

1
Pulmonary-Allergy Drugs Advisory Committee Meeting

• July 13, 2005
• Safety of Long-acting Beta2-Agonists

2
Long-Acting Beta2-Agonist Salmeterol

• C. Elaine Jones, PhD.
• Vice President
• Respiratory Regulatory Affairs
• GlaxoSmithKline

3
Burden of Asthma in the US

• Affected an estimated 20 million Americans in
  20021
• Significant morbidity and mortality
• 484,000 hospitalizations in 20021
• 4,261 deaths in 20021
• Risk factors for asthma-related mortality
• Over-use of rescue medication
• Under-use of ICS
• Disease severity
• Delay in seeking care
• Ethnic origin

• Gender
• Age
• Substance Abuse
• Pollution

1National Center for Health Statistics website,
http//www.cdc.gov/nchs/products/pubs/pubd/hestats
/asthma/asthma.htm
4
Salmeterol Approval History

• First approved in the United Kingdom, 1990
• Approved in over 100 countries

US Approval History
ADVAIR DISKUS
SEREVENT DISKUS
SEREVENT Inhalation Aerosol
2000
1997
1994
Asthma
2003
2002
1998
COPD
5
Salmeterol Exposure

• Worldwide exposure estimated to be 45.2 million
  patient-years
• 24.3 million patient-years for salmeterol
• 20.9 million patient-years for salmeterol
  administered with fluticasone propionate in a
  single device

6
NHLBI Asthma Treatment Guidelines
Severity Class
Symptoms
Daily Medications
FEV1
Step 4 Severe Persistent

• Preferred treatmentHigh-dose ICS LABA

Continual
?60
Step 3 Moderate Persistent

• Preferred treatmentLow-to-medium dose ICS LABA

Daily
gt60 - lt80
Step 2 Mild Persistent
gt2/week but lt1x/day

• Preferred treatmentLow-dose ICS

??80
Step 1 Mild Intermittent
?2 days/week

• No daily medication needed

?80
LABA Long-Acting Beta-Agonist Guidelines for
the Diagnosis and Management of AsthmaUpdate on
Selected Topics 2002. NIH, NHLBI. June 2002. NIH
publication no. 02-5075.
7
Salmeterol for theTreatment of Asthma

• Established as an important pharmacologic therapy
  
• Extensive clinical experience
• Exhibits a favorable benefit to risk profile

8
Salmeterol Review

• Katharine Knobil, M.D.
• Vice President
• Respiratory Clinical Development
• GlaxoSmithKline

9
Salmeterol ReviewAsthma

• Benefits of salmeterol
• Safety of salmeterol
• Post-marketing safety surveillance studies
• Epidemiology studies
• Ongoing Studies
• Summary

10
Beta2-AgonistsAlbuterol and Salmeterol

Albuterol
Salmeterol
11
Improvement in FEV1
Treatment Day 1
Treatment Week 12 (Day 84)
90
90
80
80
Percent Predicted FEV1
Percent Predicted FEV1
70
70
Salmeterol 42mcg (n184)
Salmeterol 42mcg (n152)
Albuterol 180mcg (n185)
Albuterol 180mcg (n152)
Placebo (n187)
Placebo (n150)
60
60
0
1
2
3
4
5
6
7
8
9
10
11
12
.5
0
1
2
3
4
5
6
7
8
9
10
11
12
.5
Second albuterol dose
Second albuterol dose
Hours
Hours
Pearlman et al. NEJM 19923271420-25 DAlonzo
et al. JAMA 1994271(18)1412-16
12
Maintenance of Bronchodilator Effect
7
Salmeterol Diskus 50mcg BID (n176)
6
Placebo (n176)

5



4
12 Hr FEV1 AUCBL (Liter Hours)
3
2
1
0
Day 1
Week 8
Week 20
Week 48
plt0.001 vs. placebo Kemp et al. J Allergy Clin
Immunol 19991041189-97
13
Reduction in Symptom Scores
ChestTightness
Shortness of Breath
Wheezing
Cough
0
0
-5
-5
-10
-8
-8
-9
-9
-15
-14
-14
-20
Percent Change from Baseline
-25
-30
-29

-35
-33

-40
Salmeterol 42mcg BID (n184)
-45
Albuterol 180mcg QID (n185)
-46
-46
Placebo (n187)
-50


plt0.05 Salmeterol vs Placebo plt0.05
Salmeterol vs Albuterol QID Pearlman et al. NEJM
19923271420-25 DAlonzo et al. JAMA
1994271(18)1412-16
14
Improvement in Lung Function vs. Increased-Dose
Inhaled Corticosteroids
Salmeterol, 50mcg BID BDP, 200mcg BID(n220)
BDP, 500mcg BID Placebo(n206)
35




30

25
plt 0.001 plt 0.01 plt 0.05
20

Change in PEF (Liters/min)
15
10
5
0
0
1
5
9
13
17
21
Weeks
Greening et al. Lancet 1994344219-24
15
Reduction in Exacerbations
1.00 0.95 0.90 0.85 0.80 0.75
p lt 0.05 vs. FP 220
Probability of No Exacerbation
Salmeterol FP 88mcg BID (n467) FP 220mcg BID
(n458)
14
4
2
6
16
18
20
22
24
0
10
8
12
0
Time to First Exacerbation (weeks)
Matz et al. J Allergy Clin Immunol
2001107783-789
16
Improvement in Quality of Life
Salmeterol 42mcg BID (n240)
2
Placebo (n234)

1.5




Mean Change in AQLQ
1
0.5
0
Activity
Asthma
Emotional
Environment
Global score
Limitation
Function
Exposure
Symptoms
AQLQ Asthma Quality of Life Questionnaire p?0.0
05, salmeterol vs. placebo for all
assessments Lockey et al. Chest 1999115666-673
17
Post-MarketingSurveillance Studies
18
Serevent Nationwide Surveillance Study (SNS)
Salmeterol MDI 42mcg BID Usual Care (n16,787)

• Requirement for regular bronchodilator
• No run-in
• 69 concurrent ICS

21
Albuterol MDI 180mcg QID Usual Care (n8,393)
Day 0 Visit 1
Week 4
Week 8
Week 16
Castle et al. Br Med J 19933061034-1037
19
SNS Results
Salmeterol
Albuterol
Relative Risk
Outcome
(n16,787)
(n8393)
(P value)

All Serious Events Withdrawals
4272 (25.5)
2209 (26.3)
0.97 (P0.200)

Asthma-related Deaths
12 (0.07)
2 (0.02)
3.0 (P0.105)

Asthma-related Hospitalizations
193 (1.15)
102 (1.22)
0.95 (P0.651)

Asthma-related Withdrawals
488 (2.91)
318 (3.79)
0.77 (P0.0002)

Castle et al. Br Med J 19933061034-1037
20
SMARTSalmeterol Multicenter Asthma Research Trial
Salmeterol MDI 42mcg BID Usual Care (n13,176)

• No inhaled long-acting beta2-agonist
• gt 12 years of age

28 week treatment period Phone contact every 4
weeks
R
Placebo MDI BID Usual Care (n13,179)
Clinic Visit
28 week supply of study medication provided
Nelson et al. Chest 2005 (In Press)
21
SMART Study Endpoints

• Primary Endpoint
• Combined respiratory-related deaths or
  life-threatening experiences (intubation and
  ventilation)
• Target sample size increased from 30,000 to
  60,000 patients
• Key Secondary Endpoints
• Respiratory-related deaths
• Combined asthma-related deaths or
  life-threatening experiences
• Asthma-related deaths

22
Adjudication of Serious Adverse Events from SMART
Case Reports of Serious Adverse Events
Phone contacts, spontaneous reports
MMRC

• MMRC reviewed all events
• Determined if respiratory- and/or asthma-related
• Unrelated
• Unlikely related
• Possibly related
• Almost certainly related

DSMB
Study oversight Interim analysis Recommendations
to GSK
MMRC Mortality and Morbidity Review
Committee DSMB Data Safety Monitoring Board
23
SMART Interim Analysis

• SMART did not reach predetermined stopping
  criteria at the interim analysis
• DSMB recommended
• Timely completion (within two years)
• If this was not possible
• Discontinuation of study and rapid dissemination
  of the interim results
• SMART was discontinued due to difficulties in
  enrollment and findings in African American
  patients

24
Baseline Characteristics
Salmeterol
Placebo


(n13,176)
(n13,179)


Age, mean

39.2

39.1




Sex, n ()




Female
8334 (64)
8337 (64)



Male
4703 (36)
4686 (36)






Ethnic Origin, n ()



Caucasian
9281 (71)
9361 (72)



African American
2366 (18)
2319 (18)



Hispanic
996 (8)
999 (8)



Asian
173 (1)
149 (1)
Other
230 (2)
224 (2)
Peak Expiratory Flow ( Predicted) 84.0 83.8
25
Asthma Medications at Baseline
Salmeterol PlaceboConcurrent Medications, n
() n13,176 n13,179 Subjects using asthma
medicationsat Baseline 12,715 (97) 12,660
(96) Subjects with no asthma medicationsat
Baseline 461 (3) 519 (4) Inhaled or oral
beta2-agonists(excluding inhaled LABAs) 12,059
(92) 12,043 (91) Inhaled corticosteroids 6127
(47) 6138 (47) Methylxanthines 1766 (13) 1767
(13) Leukotriene modifiers 1437 (11) 1402 (11)
26
Baseline Asthma Characteristics in Caucasians and
African Americans
85
78
Peak expiratory flow ( predicted)
Nocturnal symptoms present
64
57
?
1 ER visit last 12 months
22
41
?
1 ER visit lifetime
59
72
?
6
15
1 hospitalization last 12 months
?
1 hospitalization lifetime
30
44
4
8
Baseline ICS Use
49
38
27
SMART ResultsAll Patients and Ethnic Subgroups
RR (95 CI) SAL n PLA n
1 Endpoint
Respiratory Death or Life Threatening Experience
2 Endpoints
Respiratory Death
Asthma Death or Life Threatening Experience
Asthma Death
Total N13176 N13179 Caucasian N9281 N9361 Af
rican American N2366 N2319
.031
.062
.125
.25
.5
4
2
1
16
8
64
32
128
28
SMART ResultsAll Patients and by ICS Use at
Baseline
RR (95 CI) SAL n PLA n
1 Endpoint
Respiratory Death or Life Threatening Experience
2 Endpoints
Respiratory Death
Asthma Death or Life Threatening Experience
Asthma Death
Total N13176 N13179 ICS N6127 N6138 Non-I
CS N7049 N7041
.031
.062
.25
.5
4
2
1
16
8
64
32
128
.125
29
SMART ResultsEthnic Subgroups by ICS Use at
Baseline
RR (95 CI) SAL n PLA n
1 Endpoint
0.88 (0.42, 1.84) 13 15
Respiratory Death or Life Threatening Experience
1.25 (0.60, 2.60) 16 13
3.02 (0.82, 11.11) 9 3
5.61 (1.25, 25.26) 11 2
2 Endpoints
Respiratory Death
Asthma Death or Life Threatening Experience
Asthma Death
.031
.062
.125
.25
.5
4
2
1
16
8
64
32
128
30
SMART Summary

• More events occurred in patients receiving
  salmeterol
• Suggestion of higher risk in African Americans
• Suggestion of higher risk in patients not
  reporting ICS use at baseline
• Low number of events prevents definitive
  conclusions
• No clear explanation from these data

31
Dissemination of SMART Results

• Two Dear Health Care Professional Letters
• On the day SMART was stopped
• When the labels were updated
• Labeling Revisions
• Boxed warning added Clinical Trials and Warnings
  sections updated for Serevent and Advair
• Updated with final results

32
Important Safety Information

• WARNING Data from a large placebo-controlled US
  study that compared the safety of salmeterol
  (SEREVENT Inhalation Aerosol) or placebo added
  to usual asthma therapy showed a small but
  significant increase in asthma-related deaths in
  patients receiving salmeterol (13 deaths out of
  13,176 patients treated for 28 weeks) versus
  those on placebo (3 of 13,179) (see WARNINGS in
  complete Prescribing Information).

33
Dissemination of SMART Results

• Two Dear Health Care Professional Letters
• On the day SMART was stopped
• When the labels were updated
• Labeling Revisions
• Boxed warning added Clinical Trials and Warnings
  sections updated for Serevent and Advair
• Updated with final results
• Publications
• Abstract at American College of Chest Physicians
• Manuscript accepted for publication by Chest

34
Epidemiology Studies
35
Epidemiology Studies

• Strengths
• Utilization of comprehensive medical and pharmacy
  databases
• Identification of a greater number of events
• Limitations
• Assignment of treatment is not random
• Potential confounding by differences in baseline
  characteristics

36
Studies of Severe Asthma Outcomes and Salmeterol
10
1
Relative Risk
0.1
0.01
Theo
Usual Care
1Meier. Thorax 199752612-7 (n16,919) 2Lanes et
al. Am J Respir Crit Care Med 1998158857-61
(n6533) 3Williams et al. Thorax 1998537-13 (n
233) 4Anderson et al. BMJ 2005330117-24 (n1064)
37
Ongoing Studies to Help AddressSMART Findings

• Studies in African Americans
• Exacerbations in African American Subjects
• 1 year duration, 460 subjects
• FP/salmeterol vs. FP
• Epidemiology study of African Americans and
  Caucasians
• Medicaid data from 7 states, 1995 to 1999
• Association of asthma-related prescription
  medication use and asthma morbidity and mortality

38
Ongoing Studies to Help AddressSMART Findings

• Studies Including Genetic Evaluations
• Response by beta2-receptor genotype
• 38-week duration, 540 subjects
• FP/salmeterol vs. salmeterol
• Beta2-receptor and glucocorticoid pathway
  polymorphisms and clinical response
• 1000 subjects from completed clinical trials
• FP/salmeterol vs. salmeterol vs. FP

39
Ongoing Studies in Patientswith COPD

• Mortality in patients with COPD
• 3-year duration, 6200 subjects
• FP/salmeterol, salmeterol, FP vs. placebo
• COPD Exacerbations
• Two 1-year studies, 740 subjects each
• FP/salmeterol vs. salmeterol

40
Benefit to Risk Summary

• Asthma is a serious disease with significant
  morbidity and mortality
• Salmeterol provides substantial therapeutic
  benefits
• Improves lung function and asthma-related quality
  of life
• Reduces symptoms, use of rescue medication, and
  exacerbations
• Endorsed by evidenced-based treatment guidelines
• Salmeterol and serious asthma-related events
• Association observed in SNS and SMART
• No association observed in epidemiology studies

41
Benefit to Risk Summary

• Prescribing information provides guidance on use
  of salmeterol
• Should not be used to treat acute symptoms
• Is not a substitute for inhaled or oral
  corticosteroids
• Consideration should be given to adding
  anti-inflammatory agents (e.g. corticosteroids)
• Should not be initiated in patients with
  significantly worsening or acutely deteriorating
  asthma
• Incorporation of SNS and SMART results

42
Benefit to Risk Summary

• Salmeterol is an important therapeutic option
• Remains a valuable medication
• Improves the level of care
• Favorable benefit to risk profile

43
External Experts

• Professor Richard Beasley, MBChB, DM, FRCP
  
• Director of the Medical Research Institute of New
  Zealand
• Eugene Bleecker, M.D.
  
• Professor of Medicine and Section Head Pulmonary,
  Critical Care, Allergy and Immunologic Diseases
  at Wake Forest University Health Sciences
• Co-Director, Center for Human Genomics
• George OConnor, M.D., M.S.
• Professor of MedicineDivision of Pulmonary and
  Critical Care MedicineBoston University School
  of Medicine
• Director, Adult Asthma Program, Boston Medical
  Center