Risk vs Benefit Considerations for the LongActing BetaAgonists

1
Risk vs Benefit Considerations for the
Long-Acting Beta-Agonists

• Christine A. Sorkness, Pharm.D.
• Professor of Pharmacy and Medicine
• University of Wisconsin-Madison

2
Presentation Objectives

• Provide an overview of the clinical pharmacology
  of the long-acting beta-agonists (LABAs)
• Discuss the selection of therapeutic outcomes for
  assessment of risks vs. benefits of the LABAs
• Review selected clinical trials which provide
  insight into the risk/benefit of LABAs
• Outline the controversies and remaining questions
  related to the role of LABAs

3
Overview of Clinical Pharmacology of
theLong-Acting Beta-Agonists
4
Chemical Structures of Albuterol, Salmeterol, and
Formoterol
Prescribing Information, GlaxoSmithKline. Prescrib
ing Information, Novartis.
5
Comparison of bAdrenergic Agents
Kelly HW and Sorkness CA. Asthma. In
PharmacotherapyA Pathophysiologic Approach,
Sixth Edition, McGraw Hill 2005.
6
Comparison of Formoterol and Salmeterol
7
Interaction Between LABA and GCS
8
What Therapeutic Outcomes Should be Used to
Assess the Risks vs. Benefits of the Long-Acting
Beta-Agonists?
9
Lung Function Measures

• Longitudinal studies of lung health
• Gold-standard measure for trial entry
• FEV1 60-80 predicted with 15 reversibility
• Primary endpoint to measure efficacy of
  controller therapies
• Standardization of procedures for on-site and
  home measurements

10
Long-Acting b2-Agonist Monotherapy vs. Continued
ICS Therapy
Lazarus S et al. JAMA 2001 2852583-2593 ACRN
Group
11
SOCS Primary Outcome AM Peak FlowIntent-to-treat
Analysis
Lazarus et al. JAMA 2001 2852583-2593 (ACRN
Group)
12
SOCS Secondary OutcomesSalmeterol versus
Triamcinolone
Pulmonary Function PM peak flow FEV1 Methacholi
ne PC20 Symptom Control Asthma symptom
scores Rescue medication use Quality of
life Markers of Inflammation Sputum
eosinophils Sputum ECP Sputum tryptase Exhaled
nitric oxide
P-value 0.951 0.048 0.042 0.321 0.452 0.331 0.0
003 0.005 0.0001 0.059
significant p
13
Kaplan-Meier Survival Curves for Treatment
Failure and Asthma Exacerbations
Lazarus S et.al. JAMA 20012852583-2593 ACRN
Group
14
SOCS Summary

• Patients with persistent asthma well controlled
  by low doses of ICS cannot be switched to
  salmeterol monotherapy without risk of clinically
  significant loss of asthma control.
• Clear disparity between lung function measures
  and other outcome measures
• Multiple measurements and dimensions of control
  are needed to adequately assess therapies

15
Composite Measures of Asthma Control

• Days of asthma control
• Treatment failure
• Asthma exacerbations
• Improvement in NAEPP-defined asthma severity
  classification
• Total Control
• GINA 2002
• Gaining Optimal Asthma Control (GOAL)
• Patient surveys of asthma control and quality of
  life
• Asthma Control Questionnaire (ACQ)
• Asthma Therapy Assessment Questionnaire (ATAQ)
• Asthma Control Test (ACT)
• Asthma Quality-of-Life Questionnaire (AQLQ)

16
How Much Benefit Can be Achieved by the
Combination of ICS and LABA?
17
Low Dose Inhaled Budesonide and Formoterol in
Mild Persistent AsthmaThe OPTIMA Randomized
Trial
OByrne PM et al. Am J Respir Crit Care Med
20011641392-9
18
Design Group A
Am. J. Respir. Crit. Care Med., 164(8)1392-1397,
2001
19
Low Dose Inhaled Budesonide and Formoterol in
Mild Persistent Asthma The OPTIMA Randomized
Trial
Figure 1.   (A) Kaplan-Meier survival curve for
the time to the first severe asthma exacerbation.
(B) Proportion () of poorly controlled asthma
days in Group A (corticosteroid-free patients).
BUD 200  budesonide 100 µg twice daily F
 formoterol 4.5 µg twice daily.
Am. J. Respir. Crit. Care Med., 164(8)1392-1397,
2001
20
Low Dose Inhaled Budesonide and Formoterol in
Mild Persistent Asthma The OPTIMA Randomized
Trial
Figure 2.   Adjusted mean change from baseline in
morning peak expiratory flow in Group A. BUD
200  budesonide 100 µg twice daily F
 formoterol 4.5 µg twice daily.
Am. J. Respir. Crit. Care Med., 164(8)1392-1397,
2001
21
Addition of Salmeterol to Low-dose Fluticasone vs
Higher-dose Fluticasone An Analysis of Asthma
Exacerbations
Matz J, Emmett A, Rickard K, Kalberg C. JACI
107783, 2001
22
FP/Salm Combination vs FPTime to First
Exacerbation
Matz J et al. JACI107783, 2001
23
FP/Salm vs FP aloneEffect of Disease Severity
on Exacerbation Rates
Matz J et al. JACI107783, 2001
24
FACET Study Formoterol and Budesonide in
Moderate Asthma
Pauwels, et al. N Engl J Med 1997 337 1405-1411
25
Pharmacological Management to Reduce
Exacerbations in Adults with AsthmaA Systematic
Review and Meta-Analysis
Sinn DD et al. JAMA 2004 292367-376.
26
Effects of LABAs on Exacerbations
27
Effects of ICS LABA vs Higher-Dose ICS
28
Can Guideline-defined Asthma Control Be Achieved?
The Gaining Optimal Asthma Control Study
Bateman ED, Boushey HA, Bousquet J, Busse WW,
Clark TJH, Pauwels RA, and Pederson SE for the
GOAL Investigators Group. Am J Respir Crit Care
Med 2004 170836-844.
29
Gaining Optimal Asthma Control (GOAL)
Research Question Is GINA / NIH guideline-based
control achievable, and in what proportion of
patients, with SFC compared with FP alone?
Bateman ED et al. Am J Respir Crit Care Med
2004 170836-844.
30
GOAL Study Design

• 1 year, R, DB, PG, stratified study
• Stratum 1 CS-naïve or CS-free x 6 months
• Stratum 2
• Stratum 3 500 - equivalent
• 12 yrs, asthma 6 months, not well-controlled
  2/4 weeks during run-in, history, reversibility of 15
• At randomization either SFC or FP alone via
  DiskusÒ dose based on strata
• Study Phase I doses stepped up every 12 weeks
  until Total Control achieved or maximum dose
  reached
• Study Phase II dose of Total Control or maximum
  study dose (SFC 50/500 or FP 500 mcg bid) x 52
  weeks

Bateman ED et al. Am J Respir Crit Care Med
2004 170836-844.
31
GOAL Study Population
Bateman ED et al. Am J Respir Crit Care Med
2004 170836-844.
32
GOAL Results
33
GOAL Results
34
GOAL Results

• Significantly more patients achieved control with
  SFC vs FP in each stratum
• In each stratum, the time to achieve the first
  individual week of Well-Controlled asthma was
  significantly lower with SFC than with FP alone
  (p
• More patients achieved control at the same or
  lower dose of ICS in each stratum for SFC vs FP
  alone
• The majority of patients who achieved
  Well-Controlled asthma in Phase I, maintained
  this status when reassessed in the last 8 weeks
  of the study additional patients were able to
  gain control with sustained treatment

35
The Pediatric Asthma Controller Trial (PACT)
A One-Year Prospective Comparison of Three
Controller Medications for the Treatment of
Mild-Moderate Persistent Asthma in Children
36
Study Schematic
48-week treatment period
Randomization
2-week run-in






37
Inclusion Criteria

• 6-14 year-old children with mild-moderate
  persistent asthma
• Symptoms or b-agonist rescue use or PEF in the
  yellow zone on average of at least 3 days/wk
  during run-in
• PC20 methacholine FEV1 ? 12.5 mg/ml
• FEV1 ? 80 predicted at screen and ? 70
  predicted at randomization
• Nonsmoker within the past year
• Naïve to controller medications for specified
  periods
• Otherwise healthy

38
Primary Outcome

• Percent of Asthma Control Days (ACD) during the
  12-month treatment period
• Using self-reported daily diary data, an ACD was
  defined as a day without
• Albuterol rescue use (pre-exercise treatment
  permitted)
• Use of non-study asthma medications
• Daytime asthma symptoms
• Unscheduled health care provider visits for
  asthma
• School absenteeism for asthma

39
What Potential Safety Concerns Have Been Raised
by the Use of Beta-Agonists?
40
Studies in the early 1990s suggested that
regular use of the ß-agonist fenoterol might
produce adverse effects
Taylor et al., 1993. Thorax 48134-138
41
BAGS (ß-Agonist) TRIAL DESIGN
REGULAR ALBUTEROL AS NEEDED
M
B
M
B
B
M
B
M
B
M
RUN-IN
RUN-OUT
PLACEBO INHALER AS NEEDED
Drazen JM for the ACRN. NEJM 1996 335841.
42
BAGS AM Peak Flow
Drazen the ACRN, NEJM, 1996
43
?2-Adrenoceptor (?2-AR) Variants
Reishaus et al., 1993. AJRCMB 8334339
44
BAGS Genetic Analysis

• No effect seen at the B27 locus
• No effect seen in B16 heterozygotes (Arg/Gly)
• However, when B16 Arg/Arg patients (1/6 of the
  population) were compared to B16 Gly/Gly
  patients, a difference was found in the primary
  outcome variable - - AM PEF

45
Scheduled vs As Needed Albuterol Response by
GenotypeBAGS Retrospective Analysis
Weeks After Randomization
BAGS, Beta-agonist in mild asthma study.
Israel E, et al. Am J Respir Crit Care Med.
200016275-80.
46
The Influence of Beta2-adrenergic Receptor
Polymorphisms on Asthma Exacerbations

P0.003 vs Gly/Arg. P0.033 vs Gly/Gly.
Exacerbations (per patient per year)
Taylor DR, et al. Thorax. 200055762-767.
47
BARGE

• Prospective randomized, placebo-controlled,
  double-blind trial of regular vs minimal
  albuterol in each genotype
• To minimize beta-agonist use patients were
  provided with ipratropium bromide (IB) for rescue
  use and instructed only to use albuterol if
  symptoms were not relieved by IB

Israel E, et al. Lancet. 20043641505-1512.
48
Regularly Scheduled Albuterol Response by
GenotypeBARGE-Prospective Analysis
16 weeks placebo or active treatment
8 weeks run-outall on placebo
6 weeks run-in all on placebo
16 weeks active treatment or placebo
Screen and genotype
8 weeks run-outall on placebo
PretreatmentBaseline 1weeks 3-6
Baselineweeks 0-2
PretreatmentBaseline 2weeks 27-30
BARGE, Beta-Adrenergic Response by GenotypE.
Israel E, et al. Lancet. 20043641505-1512.
49
BARGE Patient Population

• Patients with mild asthma not using controller
  therapy
• Mean age 31 years
• Mean FEV1 90 of predicted
• Patients were matched in pairs for FEV1 according
  to whether they had Arg/Arg (n 37) or Gly/Gly
  (n 41) genotype

4 of the 41 matches withdrew from the study
before randomization.
BARGE, Beta-Adrenergic Response by GenotypE.
Israel E, et al. Lancet. 20043641505-1512.
50
BARGE Change in AM PEF by Genotype
BARGE, Beta-Adrenergic Response by GenotypE.
Israel E, et al. Lancet. 20043641505-1512.
51
Mean Change in AM PEF by Genotype at Week 16



Albuterol Arg/Arg
Placebo Gly/Gly
Placebo Arg/Arg
Albuterol Gly/Gly
Mean Arg/Arg minus Gly/Gly treatment
difference -24 (-37 to -12), P0.0003.
P0.0209 vs Placebo Arg/Arg. P0.0175 vs
Placebo Gly/Gly.
Israel E, et al. Lancet. 20043641505-1512.
52
FEV1 Difference between Regular vs. Placebo
Treatment-induced Changes over 16 Wk
P0.002
P0.094
Liters
P0.002
Israel E for the ACRN, Lancet 2004 3641505-1512.
53
AM SYMPTOMS Difference between Regular vs.
Placebo Treatment-induced Changes over 16 Wk
P
P0.001
P
Israel E for the ACRN, Lancet 2004 3641505-1512.
54
INHALER USE Difference between Regular vs.
Placebo Treatment-induced Changes over 16 Wk
P0.0002
P
P0.019
P0.043
PUFFS / WK
P0.0003
P
IB
Alb
Israel E for the ACRN, Lancet 2004 3641505-1512.
55
BARGE

• AM PM PEF, FEV1 , symptoms, and rescue inhaler
  use improved significantly in Arg/Arg patients
  with asthma when ß-agonists were withdrawn and
  prn IB was substituted, as c/w regular albuterol
  use
• The pattern was reversed in Gly/Gly patients with
  asthma
• They improved with regular ß-agonist use as c/w
  prn IB use
• Suggested that Arg/Arg patients (1/6 of
  asthmatics) may benefit from minimizing
  short-acting ß-agonist use

Israel E for the ACRN, Lancet 2004 3641505-1512.
56
Do Similar Effects Occur With Long-acting
Beta2-agonists (LABA) and What Is the Impact of
Concurrent Use of Inhaled Corticosteroids?
57
Methods

• Genotype stratified retrospective analysis of 2
  ACRN trials that used long-acting ß-agonists
• SOCS trial Salmeterol Or CorticoSteroid
• Well-controlled patients on ICS were randomized
  to LABA or continued ICS
• SLIC trial SalmeteroL /- Inhaled Corticosteroid
• Less well controlled patients on ICS were
  randomized to add LABA continue ICS or add LABA
  taper ICS

58
Does Regular Use of LABAs Delay Awareness of
Asthma Progression or Effect Recovery From an
Exacerbation?
59
FP/Salm vs FP AloneEffect on Rate of Symptom
Decrease following Exacerbation
Matz J et al. JACI107783, 2001
60
Evidence for Increased Asthma Exacerbations with
LABAs

• Salmeterol
• Serevent National Surveillance Study (SNS)
• BMJ 1993 3061034-7
• Salmeterol Multicenter Asthma Research Trial
  (SMART)
• Formoterol
• Review of 3 clinical studies submitted to the FDA
• Chest 2003 1247074

61
Summary

• Strong evidence of the ability of ICS LABA to
  achieve asthma control and reduce asthma
  exacerbations
• More evidence in adults than children
• Remaining concerns about safety
• ? genotypic predictors
• ? phenotypic predictors
• ? need for larger and longer trials which
  incorporate multiple outcomes
• ? class effect
• ? dose effect