Allan T' Luskin, MD

1
Evolving Xolair Health Outcomes Data What Does
(or Should) it Mean to Patients, Clinicians and
Payors

• Allan T. Luskin, MD
• Associate Clinical Professor of Medicine,
  University of Wisconsin
• Director, Respiratory Institute, Dean Medical
  Center
• Madison, Wisconsin
• Past Chair, Patient and Public Education
  Committee, NAEPP
• Past Co-Chair, Managed Care Liaison, NAEPP
• Committee on Asthma Measures, AMA
• Asthma Expert Panel, JCAHO
• Respiratory Measurement Advisory Panel, HEDIS/NCQA

2
Agenda

• Outcomes and variability of disease and response
  to Rx and lack of correlation between outcomes
• HRQOL with particular attention to newest Xolair
  analysis
• Pharmacoeconomics basics, specifics and what
  current data does and doesnt tell us

3
Initial Guideline Approach to Asthma
One Size Fits All

• Only a cursory phenotyping by severity
• Most adverse outcomes due to poor diagnosis, poor
  prescribing, poor adherence
• Majority of asthmatics respond to CS and
  b-agonists

4
Initial Guideline Approach to Asthma
One Size Fits All

• Only a cursory phenotyping by severity
• Most adverse outcomes due to poor diagnosis, poor
  prescribing, poor adherence
• Majority of asthmatics respond to CS and
  b-agonists

5
Asthma is a syndrome, not a disease

• The Asthma phenotype is highly variable
  (clinically, pathologically and physiologically)
• Response to ALL therapy is highly variable
• BHR and Reversible airflow obstruction does
  not predict response to therapy
• Outcomes do not necessarily correlate with each
  other
• There are Outcome phenotypes

6
Healthcare Utilization Difficult AsthmaBy
Guideline Severity
P-value for chi-square test of difference among
severity groups ? 0.05
Dolan et al 2004 Annals of Allergy, Asthma
Immunol 9232-39.
7
Current Symptoms and MD Severity Rating
31 Concordance
80
8
Asthma Severity Patient Perception
Whos Wrong
NAEPP Guidelines
Patient Self-Classification
Asthma in America, 2001
9
Confusion, Misunderstanding, Perception and Mixed
Messages

• Clinicians Avoid triggers to prevent asthma
• Clinicians Dont compromise QOL to avoid
  triggers
• Patients My asthma is well-controlled
• Patients My asthma diminishes my QOL
• Patients I am concerned about addiction and
  side-effects

10
Control vs. Symptoms

• Most people well controlled
• Symptoms in many despite control

34
Total Sample
21
11
2
35
49
11
Control vs. Bronchodilator Use
32
Total Sample
24
12
Control vs. Exacerbations
42
Total Sample
13
9
In Previous 3 months
13
What Patients Think
14
What Patients Think
15
Underlying Severity and Future HCU
Who are these Patients? Which Mild patients get
sick? Which Severe patients stay well?
16
Asthma VariabilityModerate-Severe Asthma on
b-Agonist Only12 week mean FEV1 64,
b-agonist 4-5/day
Intermittent, Mild, Mod-Severe Intermittent-Mil
d, Moderate, Severe
Albuterol 59 Symptoms 45
Weeks in Category
17
Asthma is Well Controlled if in a week.

• 5 days with DSS 1 (0-6 scale)
• 5days with no rescue b-agonist
• PEFRam 80 every day
• 1 nocturnal awakening
• No exacerbations
• No ED visits
• No therapy related adverse events

2 of 3
and
all
AFD DSS 1, no b-agonist, PEFR 80, no noc
awakening, no exacerbation, no ED
18
Goal Study Control
19-36 NOT controlled
Adherence 89
Lowest Dose Well-45-60
Total-40-53 Max Dose 57-87
Bateman ED Am J Respir Crit Care Med
2004170836-844
19
GOAL Study Persistence of Control(of those who
achieved Control)
N.B. 19-36 never achieve control (89 adherence)
20-32 not persistent Lose Control
Bateman ED Am J Respir Crit Care Med
2004170836-844
20
Exacerbations and Effect of Therapy
Different Exacerbations or Different People (not
all exacerbations and not all asthmatics are the
same)
21
Asthmas are variable.

• in control
• in severity
• in response to therapy
• in natural history
• in risk for adverse outcomes
• in the relationship among features of disease
• in the relationship between outcomes

22
Dimensions of ControlHow the Disease Affects the
Organism

• Physiology
• Symptoms (nocturnal, exercise)
• Quality of life and Activities of Daily Living
• Medications (adverse events, adherence)
• Health Care Utilization (function of
  exacerbations)
• Comorbidities

23
Evaluation of Control
Medical Outcomes
Humanistic Outcomes
Quality of Life Life satisfaction Social
role functioning Sense of community Spiritual
fulfillement Self-esteem Enjoyment
Pleasure Appreciation Patient satisfaction
With asthma control With Quality of Life
Economic Outcomes
Modified from BLAISS MS, JAMA 1997
24
Outcomes

• Functional
• Symptoms/Medication Use
• Exacerbation
• Global QOL, ADL
• Physiologic
• Lung function/BHR
• Progression
• Pathologic (Inflammation)
• Sputum eos/ eNO
• Economic
• Direct and indirect

25
Asthma and HRQOL The Burden
147 million unhealthy functioning days/year
26
Asthma-Specific HRQL and CostsAsthma Costs over
a 12 month Follow-up
27
Clinical Predictors of HRQL
28
Mental Distress and HRQOLPrevalence Rates in
Adult Asthmatics
19 in Asthmatics 9 in Non-Asthmatics
Associated with Obesity, Smoking, Inactivity
29
The ATAQ Questionnaire Scoring

• 1 barrier each if
• NO or UNSURE to did you feel your asthma was
  well-controlled
• YES or UNSURE to missed work/school/activities
  in past 4 weeks or 12 months
• YES or UNSURE to waking at night in past 4
  weeks or 12 months
• Used 9 or more puffs of quick relief inhaler
• Total 0 to 4 barriers

30
Rates (Unadjusted) of Acute Asthma Events by
Baseline Level of Asthma Control
31
Goals of Therapy

• Improve Lung Function
• Prevent exacerbations
• Reduce symptoms
• Improve QOL
• Reduce burden of disease and therapy
• Prevent progression

32
...the Asthma Is Controlled!

• I can ...
• Go out for a drink
• Do work aroundthe house
• Fool around withmy wife
• Forget my medicine

• I can ...
• Play ball
• Stay at my friendswho has a dog
• Forget my medicine

• No inflammation
• Good lung function
• No urgent visits
• Low costs

33
Asthma Quality of Life (AQLQ) Questionnaire

• 32 items 4 domains
• ? activity limitations ? asthma symptoms
  ? emotional function ? environmental
  exposure
• Clinical relevance
• 1.5 large
• 1.0 moderate
• 0.5 small

7
6
Higher scores less impairment in AQoL
5
4
3
2
D Score
1
0
Juniper E et al., Am Rev Respir Dis 1993
34
Patients with ?0.5 Unit Change in AQLQ From
Baseline to End of Steroid-Reduction (Busse)
18



patients
Plt0.05
Kishiyama JL, et al. Allergy Clin Immunol
International. 2000Suppl 2115. Abstract.
35
of Patients With ?1.5 Unit Change in AQLQ From
Baseline to End of Steroid Reduction (Busse)





patients
Plt0.05
Kishiyama JL, et al. Allergy Clin Immunol
International. 2000Suppl 2115. Abstract.
36
Improved Asthma-Related Quality of Life Pivotal
Studies 008, 009
Patients with 0.5 and 1.5 units change in
AQLQ overall score at end of steroid-reduction
phase,
P lt .001
P lt .001
P lt .001
P .002
Fishers Exact test.
37
Anti-IgE QOL in SAR
38
AQLQ Symptom Domain
Luskin AT Annals of Allergy Asthma Immunol. 2004
abs
39
AQLQ Activities Domain
Luskin AT Annals of Allergy Asthma Immunol. 2004
abs
40
AQLQ Emotions/Environment Domain
Luskin AT Annals of Allergy Asthma Immunol. 2004
abs
41
Wake up in the morning with Symptoms
Luskin AT Annals of Allergy Asthma Immunol. 2004
abs
42
Overall Range of Activities
Luskin AT Annals of Allergy Asthma Immunol. 2004
abs
43
Afraid of not having medication available
Luskin AT Annals of Allergy Asthma Immunol. 2004
abs
44
Experience symptoms from dust
Luskin AT Annals of Allergy Asthma Immunol. 2004
abs
45
Hardly Any or No Asthma-Related Limits









Luskin AT Annals of Allergy Asthma Immunol. 2004
abs
46
Summary and Conclusions

• Consistent and positive impact of omalizumab on
  AQLQ overall and domain scores (plt0.05)
• Specific drivers of improvement in each of the
  domains were noted
• Correlations between AQLQ and other clinical
  outcomes were low-moderate
• r0.14 to r0.60

47
Summary and Conclusions (cont)

• Symptoms Domain
• Waking with symptoms in the morning
• plt0.001
• Activities Domain
• all activities done
• plt0.001
• Emotions Domain
• fear of not having medication available
• plt0.01
• Environment Domain
• symptoms from being exposed to dust
• plt0.001

48
Summary and Conclusions (cont)

• ARQL assessment provides non-overlapping
  information on clinical benefit distinct from
  other outcomes
• Examination of variability in mean scores reveals
  item-level responses strongly influence symptom
  and activity improvement
• Symptoms likely to be important to patients are
  significantly improved by omalizumab compared to
  placebo in patients with mod-severe asthma

49
Health-Care UtilizationOmalizumab vs. Placebo
Oba Y J Allergy Clin Immunol 2004114265-9
50
Cost of Therapy0.5 exacerbations/pt/year (1 in
pts on po CS) compared to pl
Oba Y J Allergy Clin Immunol 2004114265-9
51
Cost of Symptom Free Day
Oba Y J Allergy Clin Immunol 2004114265-9
52
Xolair Cost-EffectivenessIssues with Current
Data

• RCT data not representative of real-world
• Overestimates placebo arm
• Underestimates active drug arm
• Placebo and Protocol effect
• 67 of placebo patients improved at 1 year
• ED visits and likely hospitalizations lower
  because of use of study investigator and with
  more frequent OV than usual

53
Xolair Cost-EffectivenessIssues with Current
Data

• RCT data not representative of real-world
• Overestimates placebo arm
• Underestimates active drug arm
• Placebo and Protocol effect
• 67 of placebo patients improved at 1 year
• ED visits and likely hospitalizations lower
  because of use of study investigator and with
  more frequent OV than usual

Asche CV. JACI.2005
54
Xolair Cost-EffectivenessIssues with Current
Data

• Hospitalization rate 16 in the literature
• Placebo-3
• Xolair-lt1
• Dropout rates for Rx failure not quantified
• 141 placeboxolair
• QALY not used
• comparisons with other drugs not valid
• No data on economic benefit of AQLQ (QOL)

Asche CV. JACI.2005
55

• Conclusions reflect studies that were designed to
  assess efficacy, rather than effectiveness
• Conclusions dependent on key assumptions about
  dosing and efficacy in a controlled clinical
  setting--not actual clinical practice
• Retrospective C-E analyses have limited
  generalizability to actual clinical practice
• If the RCT underestimate benefits patients
  achieve in actual clinical practice, then C-E
  ratios for omalizumab are overestimated

56

• Without assessing cost and efficacy in the same
  patient population, direct comparisons of
  cost-effectiveness are misleading
• Incremental C-E ratios for other asthma therapies
  should only provide context ICS, LTRAs, and
  ICS-LABA combination are indicated for different
  patient populations
• Omalizumab is indicated for patients with
  moderate-to-severe persistent IgE-mediated asthma
  who have failed other therapy

57

• Identifying eligible patients based on
  break-even criteria for cost-effectiveness
  would exclude most patients the clinical benefit
  that a therapy like omalizumab can deliver
• Omalizumab is intended to address the disease
  process to prevent exacerbations and related
  cascade of healthcare utilization
• Patients with persistent IgE-mediated asthma who
  may benefit significantly from omalizumab therapy
  are likely to be excluded from receiving therapy

58
Public Health Impact of Omalizumab in High-Risk
Patients

• Risk difference omalizumab prevented
  exacerbations in about 17 additional patients for
  every 100 treated
• Prevented fraction 50 of potential
  exacerbations were prevented by treatment with
  omalizumab
• Number needed to treat 5.7 patients needed to be
  treated with omalizumab to maintain 1 patient
  free of an exacerbation

Holgate S, et al.Curr Med Res Opin.
200117(4)233-240.
59
Societal Burden of Asthma

• Calculating societal burden of asthma requires
  assessment of both direct and indirect costs
• Direct costs include
• Costs attributed to medical care (office visits,
  hospitalizations, emergency visits, medications,
  etc.)
• Indirect costs
• Dollars expended by the patient, family,
  employer, and/or society because of illness
  (including loss of productivity and quality of
  life)
• Can be determined using either a cost of illness
  or cost of wellness approach

Stempel DA, et al. J Allergy Clin Immunol.
20031111203-4.
60
Cost of Illness Approach

• Traditional view of government and other third
  party payers
• Determines costs by multiplying average medical
  costs for one person with asthma by the total
  number of expected patients in the population
• Focused on direct cost of care
• Minimal emphasis on prevention or long-term
  control

Stempel DA, et al. J Allergy Clin Immunol.
20031111203-4.
61
Wall Street Journal, July 18, 2001
62
Cost of Wellness Approach

• Goal of wellness is to minimize expenses caused
  by treatment failures and enhance productivity
• Direct costs targeted for preventative health
  care and use of effective controller medications
• Indirect costs are used for environmental
  control, lifestyle changes, and other
  interventions that promote better health
• On balance, an investment in wellness promotes
• Enhanced disease control
• Greater productivity at work or school
• Improved quality of life

Stempel DA, et al. J Allergy Clin Immunol.
20031111203-4.
63
Direct and Indirect Costs of Asthma
N 401 adults with asthma 18-50 yrs old
transportation to ED and outpatient procedures,
purchase of asthma-control products,
asthma-related home repairs, etc. Lost
productivity at work and inability to perform
daily activities
Cisternas, MG et al. J Allergy Clin Immunol.
20031111212-8.
64
Summary Burden of Asthma

• Costs increase with disease severity
• Relative costs of medications decrease as asthma
  worsens
• Interventions such as effective controller
  medications that minimize severity can reduce
  costs
• Savings accrued from a 5 shift in the proportion
  of patients from severe to moderate asthma is
  estimated to be 1.4 billion dollars annually
• Feeling well has an intrinsic value that is
  difficult to quantify in monetary terms

Stempel DA, et al. J Allergy Clin Immunol.
20031111203-4.
65
Asthma Costs Rise with Severity
Cisternas MA, Blanc PD, Yen IH, et al. A
comprehensive study of the direct and indirect
costs of adult asthma. J Allergy Clin Immunol
20031111212-8.
66
Lack of Consistency in Utilization

• Pitfall of the 20-80 Rule

This Year
Next Year
2/3
20 of patients
80 of costs
High-cost member
Low-cost member
67
Economic Burden of Asthma in the U.S.
Direct Costs 7.4B (US)
Indirect Costs 5.3B (US)
Cost to Patient ARQoL

• Hospital Care
• Inpatient 2B
• ER 500M
• Hosp outpatient 700M
• Physician Services
• Inpatient care 110M
• Office Visits 740M
• Prescriptions 3.2B
• Pharmacist Services

• Work Loss
• Employed 1.5B
• At Home 800M
• Mortality 1.8B
• School Days Lost 1.1B

• Activity avoidance
• Mortality
• 16 Asthma deaths per day
• Missing school
• Missing work
• Unscheduled office visits and visits to ER
• Lifestyle disruptions have become embedded in
  patient expectations for disease

Sullivan SD, and Weiss KB, Health economics of
asthma and rhinitis, I and II. Assessing the
value of interventions, Current Reviews of
Allergy and Clinical Immunology, January 2001,
Volume 107, No. 12, p. 3-8 and 203-210.
68
Direct and Indirect Asthma Costs

• Estimated direct and indirect costs in 1998
  11.3 Billion.
• Asthma is the fifth most common cause of
  workplace limitation.
• 1997-1998 annual asthma-specific treatment
  charges in a managed care setting were 927 per
  asthmatic.
• 1992 cost of treating asthmatic children was 615
  and had larger non-asthma- related direct medical
  expenses in the asthmatic population than among
  controls.

Blanc P. et. Al Chest 19963688-96
Stemple D. et al Arch Fam Med 1996536-40. Lozano
P. at al Pediatrics 199799757-64. Yazdani C.
et al Value in Health 20003146.
NHLBI Data Fact Sheet.
Asthma Statistics Bethesda, Md USDHH 1999.
69
Annual Direct Cost of Treating Asthma Patients
Impact of Severe Asthma
High cost patients make up 20 of all asthmatics
and account for 80 of the direct costs of
treating the disease
3000
2584.04
2500
2000
per year
1500
1000
500
140.17
0
High Cost
Low Cost
Smith DH, et al. Am J Respir Crit Care Med
1997156787-793.
70
Annual Cost of Asthma Care/ Member
Exacerbations are expensive

• 4 of asthma patients comprise 50 of overall
  costs
• Controlled asthma carries less morbidity and is lt
  40 as costly
• NIH 1995

71
Total Health Care ExpendituresModerate-Severe
Asthma vs Non-Asthmatics
4,692
10,890
72
Cost of Asthma to Employers
Wage replacement 40 (Sporadic
absenteeism/disability) Medical care 43
73
Cost of Asthma to Employers
Control
Asthma
74
Work Loss in Parents of AsthmaticsChildren 6-16
y/o with persistent asthma (GINA 2)
30 lost work days 13 lost gt 5 work days
Severity
Control
75
Cost of Illness
76
Effect of Presenteeism
77
Effect of Presenteeism
78
Cost-Sharing

• In an attempt to reduce costs, payors will shift
  costs to patients
• consumer-driven health plans
• Utilization control and influence choice
• This will demand a FULLY educated consumer
• We will need to help patient evaluate the full
  cost-benefit (not just HCU but QOL)

79
Rx Noncompliance due to Costs
NHIS Surveys
80
(No Transcript)
81
Omalizumab Patients Likely to Benefit

• Patients using oral corticosteroids on a regular
  basis
• Inadequate control despite ICS and LABA or LM
• Controlled with high-dose ICS
• Patients not tolerant of other medications
• Patients who are not adherent to prescribed
  therapy
• Occupational exposure
• Patients with comorbid allergic conditions
• (allergic rhinitis, eczema, food allergy, latex
  allergies)
• Controlled due to lifestyle adaptation
• In combination with immunotherapy
• Rush IT
• Additive to IT

Personal Opinion Luskin AT, Bukstein DA. Not
FDA Approved
82
Discussion Questions

• Are the current outcomes that we consider in the
  treatment algorithm for asthma adequate?
• If not, what else should we be considering?
• What are the benefits and challenges of looking
  at these other outcomes?
• What endpoints would help clarify and communicate
  the value proposition for Xolair? 
• What indirect costs are most strongly associated
  with poor control of asthma symptoms?
• With increasing focus on the concept of control,
  should we rethink the conventional
  cost-effectiveness approach for asthma
  interventions?
• Is an outcome measure other than the symptom
  free-day warranted?
• Should analyses take into account the significant
  burden associated with indirect costs that may be
  mitigated by therapies that reduce activity
  limitations?

83
Discussion Questions

• Are the current outcomes that we consider in the
  treatment algorithm for asthma adequate?
• If not, what else should we be considering?
• What are the benefits and challenges of looking
  at these other outcomes?
• What endpoints would help clarify and communicate
  the value proposition for Xolair? 

84
Discussion Questions

• What indirect costs are most strongly associated
  with poor control of asthma symptoms?
• With increasing focus on the concept of control,
  should we rethink the conventional
  cost-effectiveness approach for asthma
  interventions?
• Is an outcome measure other than the symptom
  free-day warranted?
• Should analyses take into account the significant
  burden associated with indirect costs that may be
  mitigated by therapies that reduce activity
  limitations?