# Presentation: 698351

## Pulmonary-Allergy Drugs Advisory Committee Meeting

**Pulmonary-Allergy Drugs Advisory Committee Meeting**

**July 13, 2005**
**Safety of Long-acting Beta****2****-Agonists**

## Long-Acting Beta2-Agonist Salmeterol 

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

## Burden of Asthma in the US

**Affected an estimated 20 million Americans in 2002****1**
**Significant morbidity and mortality**
**484,000 hospitalizations in 2002****1**
**4,261 deaths in 2002****1**
**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

## Salmeterol Approval History

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

**2003**

**2002**

**1998**

**COPD**

**2000**

**1997**

**1994**

**Asthma**

**ADVAIR DISKUS****®**

**SEREVENT****®**** DISKUS****®**

**SEREVENT****®**** **
**Inhalation Aerosol**

**US Approval History**

## 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**

## NHLBI Asthma Treatment Guidelines

**NHLBI Asthma Treatment Guidelines**

**Severity Class**

**Step 4**
**Severe Persistent**

**Step 3**
**Moderate Persistent**

**Step 2**
**Mild Persistent**

**Step 1**
**Mild Intermittent**

**Symptoms**

**Continual**

**Daily**

**>2/week but <1x/day**

******2 days/week**_**   **_

**Daily Medications**

**Preferred treatment:****High-dose ICS + LABA**

**Preferred treatment:****Low-to-medium dose ICS + LABA**

**Preferred treatment:****Low-dose ICS**

**No daily medication needed**

**FEV****1**

******60%**

**>60% - <80%**

******80%**

******80%**

- LABA = Long-Acting Beta-Agonist
- Guidelines for the Diagnosis and Management of Asthma—Update on Selected Topics 2002. NIH, NHLBI. June 2002.  NIH publication no. 02-5075.

## Salmeterol for theTreatment of Asthma

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

## Salmeterol Review

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

## Salmeterol ReviewAsthma

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

## Beta2-Agonists:Albuterol and Salmeterol

**Albuterol**

**Salmeterol**

** **

## Improvement in FEV1

- Treatment Day 1

- Percent Predicted FEV1

- Salmeterol 42mcg (n=184)

- Albuterol 180mcg (n=185)

- Placebo (n=187)

- 60

- 70

- 80

- 90

- 0

- 1

- 2

- 3

- 4

- 5

- 6

- 7

- 8

- 9

- 10

- 11

- 12

- .5

- Hours

- Second albuterol dose

- Percent Predicted FEV1

- Treatment Week 12 (Day 84)

- Hours

- Salmeterol 42mcg (n=152)

- Albuterol 180mcg (n=152)

- Placebo (n=150)

- 60

- 70

- 80

- 90

- 0

- 1

- 2

- 3

- 4

- 5

- 6

- 7

- 8

- 9

- 10

- 11

- 12

- .5

- Second albuterol dose

- Pearlman et al.  NEJM 1992;327:1420-25
- D’Alonzo et al.  JAMA 1994;271(18):1412-16

## Maintenance of Bronchodilator Effect

- Salmeterol *Diskus* 50mcg BID (n=176)

- Placebo (n=176)

- 12 Hr FEV1 AUCBL (Liter Hours)

- 6

- 2

- 1

- 0

- Day 1

- Week 8

- Week 20

- Week 48

- 3

- 4

- 5

- 7

- *p<0.001 vs. placebo
- Kemp et al.  J Allergy Clin Immunol 1999;104:1189-97

- *

- *

- *

- *

## Reduction in Symptom Scores

- † p<0.05 Salmeterol vs Placebo
- ‡ p<0.05 Salmeterol vs Albuterol QID
- Pearlman et al.  NEJM 1992;327:1420-25
- D’Alonzo et al.  JAMA 1994;271(18):1412-16

- -46

- 0

- -8

- -46

- -5

- -8

- -33

- -9

- -9

- -29

- -14

- -14

- -50

- -45

- -40

- -35

- -30

- -25

- -20

- -15

- -10

- -5

- 0

- Salmeterol 42mcg BID (n=184)

- Albuterol 180mcg QID (n=185)

- Placebo (n=187)

- Percent Change from Baseline

- ChestTightness

- Shortness
- of Breath

- Wheezing

- Cough

- † ‡

- † ‡

- † ‡

- ‡

## Improvement in Lung Function vs. Increased-Dose Inhaled Corticosteroids

- Salmeterol, 50mcg BID + BDP, 200mcg BID(n=220)

- BDP, 500mcg BID + Placebo(n=206)

- 0

- 5

- 10

- 15

- 20

- 25

- 30

- 35

- 0

- 1

- 5

- 9

- 13

- 17

- 21

- Weeks

- Change in PEF (Liters/min)

- *** 	p< 0.001**   p< 0.01*    	p< 0.05

- **

- *

- **

- **

- ***

- ***

**Improvement in Lung Function vs. Increased-Dose Inhaled Corticosteroids**

- Greening et al. Lancet 1994;344:219-24

## Reduction in Exacerbations

**p < 0.05 vs. FP 220**

- 1.00
- 0.95
- 0.90
- 0.85
- 0.80
- 0.75

**Time to First Exacerbation (weeks)**

**Probability of No Exacerbation**

**Salmeterol + FP 88mcg BID (n=467)** **FP 220mcg BID**** (n=458)**

- 24

- 0

- 14

- 4

- 2

- 6

- 10

- 16

- 8

- 18

- 20

- 22

- 12

- Matz et al. J Allergy Clin Immunol 2001;107:783-789

- 0

## Improvement in Quality of Life

- Limitation

- Function

- Exposure

- Symptoms

- Mean Change in AQLQ

- 0

- 0.5

- 1

- 1.5

- 2

- Activity

- Asthma

- Emotional

- Environment

- Global score

- Salmeterol 42mcg BID (n=240)

- Placebo (n=234)

- AQLQ = Asthma Quality of Life Questionnaire
- *p0.005, salmeterol vs. placebo for all assessments
- Lockey et al. Chest 1999;115:666-673

- *

- *

- *

- *

- *

## Post-MarketingSurveillance Studies    

## Serevent Nationwide Surveillance Study (SNS)

- (n=16,787)

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

- Albuterol MDI 180mcg QID + Usual Care
- (n=8,393)

- Day 0
- Visit 1

- Week 4

- Week 8

- Week 16

***Serevent***** Nationwide Surveillance Study (SNS)**

- Castle et al. Br Med J 1993:306;1034-1037

**2:1**

## SNS Results

**Salmeterol**

**(n=16,787)**

**Albuterol**

**(n=8393)**

**Relative Risk**

**(*****P***** value)**

- Asthma-related Deaths

- 12 (0.07%)

- 2 (0.02%)

- 3.0 (*P*=0.105)

- Asthma-related Hospitalizations

- 193 (1.15%)

- 102 (1.22%)

- 0.95 (*P*=0.651)

- Asthma-related Withdrawals

- 488 (2.91%)

- 318 (3.79%)

- 0.77 (*P*=0.0002)

- All Serious Events & Withdrawals

- 4272 (25.5%)

- 2209 (26.3%)

- 0.97 (*P*=0.200)

**SNS Results**

- Castle et al. Br Med J 1993:306;1034-1037

## SMARTSalmeterol Multicenter Asthma Research Trial

- (n=13,176)

-  No inhaled long-acting beta2-agonist
-  _>_ 12 years of age

- Placebo MDI BID + Usual Care
- (n=13,179)

- Clinic Visit

- 28 week treatment period
- Phone contact every 4 weeks

**28 week supply of study medication provided**

**R**

**SMART****Salmeterol Multicenter Asthma Research Trial**

- Nelson et al. Chest 2005 (In Press)

## 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**

## Adjudication of Serious Adverse Events from SMART

- Case Reports of Serious Adverse Events

- MMRC

- DSMB

- Study oversight
- Interim analysis
- Recommendations to GSK

**Adjudication of Serious Adverse Events from SMART**

- MMRC= Mortality and Morbidity Review Committee
- DSMB= Data Safety Monitoring Board

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

## 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**

## Baseline Characteristics

** **

**(n=13,176)**

** **

**Placebo**

** **

**(n=13,179)**

** **

**Age, mean**

** **

**39.2**

** **

**39.1**

** **

**Sex, n (%)**

** **

**    **

- Female

-     Male

** **

- 8334 (64)

- 4703 (36)

- 8337 (64)

- 4686 (36)

**Ethnic Origin, n (%)**

** **

-     Caucasian

-     African American

-     Hispanic

-     Asian

-     Other

** **

- 9281 (71)

- 2366 (18)

- 996 (8)

- 173 (1)

- 230 (2)

- 9361 (72)

- 2319 (18)

- 999 (8)

- 149 (1)

- 224 (2)

**Baseline Characteristics**

**Peak Expiratory Flow (% Predicted)****	**84.0	83.8

## Asthma Medications at Baseline

**	****Salmeterol****	****Placebo****Concurrent Medications, n (%)****	**** n=13,176****	**** n=13,179**
**Subjects using asthma medications****at Baseline****	****12,715 (97)****	****12,660 (96)**
**Subjects with no asthma medications****at Baseline****	****461 (3)****	****519 (4)**
**Inhaled or oral beta****2****-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)**

## Baseline Asthma Characteristics in Caucasians and African Americans 

**Peak expiratory flow (% predicted)**

**85%**

**78%**

**Baseline ICS Use**

**49%**

**38%**

**Nocturnal symptoms present**

**57%**

**64%**

**6%**

**15%**

**1 hospitalization last 12 months**

****

**30%**

**44%**

**1 hospitalization lifetime**

****

**4%**

**8%**

**59%**

**72%**

**1 ER visit lifetime**

****

**22%**

**41%**

**1 ER visit last 12 months**

****

## SMART ResultsAll Patients and Ethnic Subgroups

**SMART Results****All Patients and Ethnic Subgroups**

**	****RR (95% CI)****	****SAL n****	****PLA n**

***1******° ******Endpoint***

- Asthma Death

- Asthma
- Death or Life
- Threatening
- Experience

- Respiratory
- Death

- Respiratory
- Death or Life
- Threatening
- Experience

- Total	N=13176	  N=13179
- Caucasian	N=9281	N=9361
- African American	N=2366	N=2319

- .031

- .062

- .125

- .25

- .5

- 4

- 2

- 1

- 16

- 8

- 64

- 32

- 128

***2******° ******Endpoints***

## SMART ResultsAll Patients and by ICS Use at Baseline

- 	Total	 N=13176	 N=13179
- 	ICS	N=6127	N=6138
- 	Non-ICS	N=7049	N=7041

**	****RR (95% CI)****	****SAL n****	****PLA n**

***1° Endpoint***

- Asthma Death

- Asthma
- Death or Life
- Threatening
- Experience

- Respiratory
- Death or Life
- Threatening
- Experience

**SMART Results****All Patients and by ICS Use at Baseline**

- .031

- .062

- .25

- .5

- 4

- 2

- 1

- 16

- 8

- 64

- 32

- 128

- Respiratory
- Death

***2******° ******Endpoints***

- .125

## SMART ResultsEthnic Subgroups by ICS Use at Baseline

**	****RR (95% CI)****	****SAL n****	****PLA n**

- Asthma Death

- Asthma
- Death or Life
- Threatening
- Experience

- Respiratory
- Death or Life
- Threatening
- Experience

**SMART Results****Ethnic Subgroups by ICS Use at Baseline**

- .031

- .062

- .125

- .25

- .5

- 4

- 2

- 1

- 16

- 8

- 64

- 32

- 128

**	****3.02 (0.82, 11.11)****	****9****	****3**

**	****5.61 (1.25, 25.26)****	****11****	****2**

**	****1.25 (0.60, 2.60)****	****16****	****13**

**	****0.88 (0.42, 1.84)****	****13****	****15**

- Respiratory
- Death

***2******° ******Endpoints***

***1° Endpoint***

## 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**

## 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**

## 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).

**Important Safety Information**

## 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**

## Epidemiology Studies

## 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**

## Studies of Severe Asthma Outcomes and Salmeterol

**Studies of Severe Asthma Outcomes and Salmeterol**

- 0.01

- 0.1

- 1

- 10

- 1Meier. Thorax 1997;52:612-7 (n=16,919)
- 2Lanes et al. Am J Respir Crit Care Med 1998;158:857-61 (n=6533)
- 3Williams et al. Thorax 1998;53:7-13 (n= 233)
- 4Anderson et al. BMJ 2005;330:117-24 (n=1064)

- Relative Risk

- Theo

- Usual Care

## Ongoing Studies to Help AddressSMART 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 **

## Ongoing Studies to Help AddressSMART Findings

***Studies Including Genetic Evaluations***
**Response by beta****2****-receptor genotype**
**38-week duration, 540 subjects**
**FP/salmeterol vs. salmeterol**
**Beta****2****-receptor and glucocorticoid pathway polymorphisms and clinical response **
**1000 subjects from completed clinical trials**
**FP/salmeterol vs. salmeterol vs. FP**

## Ongoing Studies in Patientswith 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**

## 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**

## 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**

## Benefit to Risk Summary

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

## 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 O’Connor, M.D., M.S.**
**Professor of Medicine****Division of Pulmonary and Critical Care Medicine****Boston University School of Medicine**
**Director, Adult Asthma Program, Boston Medical Center**