Evolving Xolair Health Outcomes Data: What Does (or Should) it Mean to Patients, Clinicians and PayorsAllan T. Luskin, MDAssociate Clinical Professor of Medicine, University of WisconsinDirector, Respiratory Institute, Dean Medical CenterMadison, Wisconsin Past Chair, Patient and Public Education Committee, NAEPPPast Co-Chair, Managed Care Liaison, NAEPPCommittee on Asthma Measures, AMAAsthma Expert Panel, JCAHORespiratory Measurement Advisory Panel, HEDIS/NCQA

AgendaOutcomes and variability of disease and response to Rx and lack of correlation between outcomesHRQOL with particular attention to newest Xolair analysisPharmacoeconomics: basics, specifics and what current data does and doesnt tell us

Initial Guideline Approach to AsthmaOnly a cursory phenotyping by severityMost adverse outcomes due to poor diagnosis, poor prescribing, poor adherenceMajority of asthmatics respond to CS and b-agonistsOne Size Fits All

Initial Guideline Approach to AsthmaOnly a cursory phenotyping by severityMost adverse outcomes due to poor diagnosis, poor prescribing, poor adherenceMajority of asthmatics respond to CS and b-agonistsOne Size Fits All

Asthma is a syndrome, not a diseaseThe 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 therapyOutcomes do not necessarily correlate with each otherThere are Outcome phenotypes

Healthcare Utilization: Difficult AsthmaBy Guideline Severity* P-value for chi-square test of difference among severity groups 0.05Dolan et al 2004; Annals of Allergy, Asthma & Immunol; 92:32-39.

Current Symptoms and MD Severity Rating80%31% Concordance

Asthma Severity: Patient PerceptionNAEPP GuidelinesPatient Self-ClassificationAsthma in America, 2001Whos Wrong

Confusion, Misunderstanding, Perception and Mixed MessagesClinicians: Avoid triggers to prevent asthmaClinicians: Dont compromise QOL to avoid triggersPatients: My asthma is well-controlledPatients: My asthma diminishes my QOLPatients: I am concerned about addiction and side-effects

Control vs. SymptomsMost people well controlledSymptoms in many despite control21%34%% Total Sample35%49%11%2%

Control vs. Bronchodilator Use24%32%% Total Sample

Control vs. Exacerbations% Total SampleIn Previous 3 months42%9%13%

What Patients Think

What Patients Think

Underlying Severity and Future HCUWho are these Patients?Which Mild patients get sick?Which Severe patients stay well?

Asthma Variability:Moderate-Severe Asthma on b-Agonist Only12 week: mean FEV1: 64%, b-agonist: 4-5/day**Intermittent, Mild, Mod-Severe*Intermittent-Mild, Moderate, SevereAlbuterol: 59%Symptoms: 45%Weeks in Category

Asthma is Well Controlled if in a week.5 days with DSS 1 (0-6 scale)5days with no rescue b-agonistPEFRam 80% every day

1 nocturnal awakeningNo exacerbationsNo ED visitsNo therapy related adverse eventsand2 of 3allAFD = DSS 1, no b-agonist, PEFR 80%, no noc awakening, no exacerbation, no ED

Goal Study: ControlBateman ED Am J Respir Crit Care Med 2004:170:836-844Lowest Dose: Well-45-60% Total-40-53%Max Dose: 57-87%19-36%NOTcontrolledAdherence: 89%

GOAL Study: Persistence of Control(of those who achieved Control)Bateman ED Am J Respir Crit Care Med 2004:170:836-84420-32% not persistent Lose ControlN.B.: 19-36% never achieve control (89% adherence)

Exacerbations and Effect of TherapyDifferent Exacerbations or Different People(not all exacerbations and not all asthmatics are the same)

Asthmas are variable.in controlin severityin response to therapyin natural historyin risk for adverse outcomesin the relationship among features of diseasein the relationship between outcomes

Dimensions of ControlHow the Disease Affects the OrganismPhysiologySymptoms (nocturnal, exercise)Quality of life and Activities of Daily LivingMedications (adverse events, adherence)Health Care Utilization (function of exacerbations)Comorbidities

Medical OutcomesHumanistic Outcomes

Quality of Life* Life satisfaction* Social & role functioning* Sense of community* Spiritual fulfillement* Self-esteem* Enjoyment* Pleasure* AppreciationPatient satisfaction* With asthma control* With Quality of Life

Economic OutcomesEvaluation of ControlModified from BLAISS MS, JAMA 1997

OutcomesFunctionalSymptoms/Medication UseExacerbationGlobal: QOL, ADLPhysiologicLung function/BHRProgressionPathologic (Inflammation)Sputum eos/ eNOEconomicDirect and indirect

Asthma and HRQOL: The Burden147 million unhealthy functioning days/year

Asthma-Specific HRQL and Costs:Asthma Costs over a 12 month Follow-up

Clinical Predictors of HRQL

Mental Distress and HRQOLPrevalence Rates in Adult Asthmatics19% in Asthmatics9% in Non-AsthmaticsAssociated with Obesity, Smoking, Inactivity

The ATAQ Questionnaire: Scoring1 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

Rates (Unadjusted) of Acute Asthma Events by Baseline Level of Asthma Control

Goals of TherapyImprove Lung FunctionPrevent exacerbationsReduce symptomsImprove QOLReduce burden of disease and therapyPrevent progression

...the Asthma Is Controlled!No inflammationGood lung functionNo urgent visitsLow costsI can ...Play ball Stay at my friends who has a dogForget my medicineI can ...Go out for a drinkDo work around the houseFool around with my wifeForget my medicine

Asthma Quality of Life (AQLQ) Questionnaire32 items; 4 domainsactivity limitationsasthma symptoms emotional function environmental exposureClinical relevance + 1.5 large + 1.0 moderate + 0.5smallD Score 01234567Higher scores=less impairmentin AQoLJuniper E et al., Am Rev Respir Dis 1993

% Patients with 0.5 Unit Change in AQLQ From Baseline to End of Steroid-Reduction (Busse)*18% patients***P

% of Patients With 1.5 Unit Change in AQLQ From Baseline to End of Steroid Reduction (Busse)% patients******P

Improved Asthma-Related Quality of Life Pivotal Studies 008, 009 Fishers Exact test.Patients with 0.5 and 1.5 units change in AQLQ overall score at end of steroid-reduction phase, %P < .001P < .001P < .001P = .002

Anti-IgE: QOL in SAR

Adelroth. JACI 2000;106:253-259

AQLQ: Symptom DomainLuskin AT Annals of Allergy Asthma Immunol. 2004 abs

AQLQ: Activities DomainLuskin AT Annals of Allergy Asthma Immunol. 2004 abs

AQLQ: Emotions/Environment DomainLuskin AT Annals of Allergy Asthma Immunol. 2004 abs

Wake up in the morning with SymptomsLuskin AT Annals of Allergy Asthma Immunol. 2004 abs

Overall Range of ActivitiesLuskin AT Annals of Allergy Asthma Immunol. 2004 abs

Afraid of not having medication availableLuskin AT Annals of Allergy Asthma Immunol. 2004 abs

Experience symptoms from dustLuskin AT Annals of Allergy Asthma Immunol. 2004 abs

% Hardly Any or No Asthma-Related Limits*********Luskin AT Annals of Allergy Asthma Immunol. 2004 abs

Summary and Conclusions Consistent and positive impact of omalizumab on AQLQ overall and domain scores (p

Summary and Conclusions (cont) Symptoms Domain:Waking with symptoms in the morningp

Summary and Conclusions (cont) ARQL assessment provides non-overlapping information on clinical benefit distinct from other outcomesExamination 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

Health-Care Utilization:Omalizumab vs. PlaceboOba Y J Allergy Clin Immunol 2004;114:265-9

Cost of Therapy~0.5 exacerbations/pt/year (~1 in pts on po CS) compared to plOba Y J Allergy Clin Immunol 2004;114:265-9

Cost of Symptom Free DayOba Y J Allergy Clin Immunol 2004;114:265-9

Xolair Cost-Effectiveness:Issues with Current DataRCT data not representative of real-worldOverestimates placebo armUnderestimates active drug armPlacebo and Protocol effect67% of placebo patients improved at 1 yearED visits and likely hospitalizations lower because of use of study investigator and with more frequent OV than usual

Xolair Cost-Effectiveness:Issues with Current DataRCT data not representative of real-worldOverestimates placebo armUnderestimates active drug armPlacebo and Protocol effect67% of placebo patients improved at 1 yearED visits and likely hospitalizations lower because of use of study investigator and with more frequent OV than usual Asche CV. JACI.2005

Xolair Cost-Effectiveness:Issues with Current DataHospitalization rate ~16% in the literaturePlacebo-3%Xolair-

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 practiceRetrospective 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

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

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 utilizationPatients with persistent IgE-mediated asthma who may benefit significantly from omalizumab therapy are likely to be excluded from receiving therapy

Public Health Impact of Omalizumab in High-Risk PatientsRisk 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. 2001;17(4):233-240.

Societal Burden of AsthmaCalculating societal burden of asthma requires assessment of both direct and indirect costs Direct costs includeCosts attributed to medical care (office visits, hospitalizations, emergency visits, medications, etc.)Indirect costsDollars 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 approachStempel DA, et al. J Allergy Clin Immunol. 2003;111:1203-4.

Cost of Illness ApproachTraditional view of government and other third party payersDetermines 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 careMinimal emphasis on prevention or long-term controlStempel DA, et al. J Allergy Clin Immunol. 2003;111:1203-4.

Wall Street Journal, July 18, 2001

Cost of Wellness ApproachGoal of wellness is to minimize expenses caused by treatment failures and enhance productivityDirect costs targeted for preventative health care and use of effective controller medicationsIndirect costs are used for environmental control, lifestyle changes, and other interventions that promote better healthOn balance, an investment in wellness promotesEnhanced disease controlGreater productivity at work or schoolImproved quality of lifeStempel DA, et al. J Allergy Clin Immunol. 2003;111:1203-4.

Direct and Indirect Costs of AsthmaN = 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 activitiesCisternas, MG et al. J Allergy Clin Immunol. 2003;111:1212-8.

Summary: Burden of AsthmaCosts increase with disease severityRelative costs of medications decrease as asthma worsensInterventions such as effective controller medications that minimize severity can reduce costsSavings accrued from a 5% shift in the proportion of patients from severe to moderate asthma is estimated to be $1.4 billion dollars annuallyFeeling well has an intrinsic value that is difficult to quantify in monetary terms Stempel DA, et al. J Allergy Clin Immunol. 2003;111:1203-4.

Asthma Costs Rise with SeverityCisternas MA, Blanc PD, Yen IH, et al. A comprehensive study of the direct and indirect costs of adult asthma. J Allergy Clin Immunol 2003;111:1212-8.

Lack of Consistency in UtilizationPitfall of the 20-80 RuleLow-costmemberThis YearNext YearHigh-cost member2/320%of patients80%of costs

Economic Burden of Asthma in the U.S.Hospital CareInpatient $2BER $500MHosp outpatient $700M

Physician ServicesInpatient care $110MOffice Visits $740MPrescriptions $3.2B

Pharmacist ServicesDirect Costs $7.4B (US)Work LossEmployed $1.5BAt Home $800M

Mortality $1.8B

School Days Lost $1.1B

Indirect Costs $5.3B (US)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. 1&2, p. 3-8 and 203-210.Activity avoidanceMortality16 Asthma deaths per dayMissing schoolMissing workUnscheduled office visits and visits to ERLifestyle disruptions have become embedded in patient expectations for diseaseCost to Patient ARQoL

Direct and Indirect Asthma CostsEstimated 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 1996;3:688-96

NHLBI Data Fact Sheet. Asthma Statistics Bethesda, Md: USDHH; 1999.Stemple D. et al Arch Fam Med 1996;5:36-40.Lozano P. at al Pediatrics 1997;99:757-64.Yazdani C. et al Value in Health 2000;3:146.

Annual Direct Cost of Treating Asthma Patients: Impact of Severe AsthmaSmith DH, et al. Am J Respir Crit Care Med 1997;156:787-793.050010001500200025003000High Cost Low Cost$ per year$2584.04$140.17High cost patients make up 20% of all asthmatics and account for 80% of the direct costs of treating the disease

Annual Cost of Asthma Care/ Member4% of asthma patients comprise 50% of overall costs*Controlled asthma carries less morbidity and is < 40% as costly NIH 1995Exacerbations are expensive

Total Health Care ExpendituresModerate-Severe Asthma vs Non-Asthmatics4,69210,890

Cost of Asthma to EmployersWage replacement: 40%(Sporadic absenteeism/disability)Medical care: 43%

Cost of Asthma to EmployersAsthmaControl

Work Loss in Parents of AsthmaticsChildren 6-16 y/o with persistent asthma (GINA 2)SeverityControl30% lost work days13% lost > 5 work days

Cost of Illness

Kemp P Harvard Business Review. October 2004. Presented in part at AAAAI, 2001. Based on data from Bank One, Chicago, 2000

Effect of Presenteeism

Effect of Presenteeism

Cost-SharingIn an attempt to reduce costs, payors will shift costs to patients: consumer-driven health plansUtilization control and influence choiceThis will demand a FULLY educated consumerWe will need to help patient evaluate the full cost-benefit (not just HCU but QOL)

Rx Noncompliance due to CostsNHIS Surveys

Omalizumab: Patients Likely to BenefitPatients using oral corticosteroids on a regular basis Inadequate control despite ICS and LABA or LMControlled with high-dose ICSPatients not tolerant of other medicationsPatients who are not adherent to prescribed therapyOccupational exposurePatients with comorbid allergic conditions (allergic rhinitis, eczema, food allergy, latex allergies)Controlled due to lifestyle adaptationIn combination with immunotherapyRush ITAdditive to ITPersonal Opinion: Luskin AT, Bukstein DA. Not FDA Approved

Discussion QuestionsAre 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?

Discussion QuestionsAre 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?

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?

Key Points of Emphasis:Patients health-related quality of life was evaluated during asthma therapy with ICS alone or in combination with omalizumab in order to obtain a holistic view of the patients health status.AQLQ is comprised of 32 questions which construct four domains: Activities, emotions, symptoms, exposure (to environment) All questions receive equal weightAQLQ overall score and each domain score range from 1 to 7, with higher scores indicating improvement in quality of lifeOverall score calculated as the mean score of all questionsAQLQ has been validated and tested for both reliability and responsiveness

Key Points of Emphasis:This slide presents the percentage of patients achieving a small clinically significant improvement in QOL scores during treatment with omalizumab or placebo from baseline to the end of the steroid-reduction phase (28-week treatment period).11Omalizumab produced a significant and small clinically meaningful improvement in asthma-related QOL (all domains) compared with placebo and particularly in the most relevant domains for an asthmatic patient: activity and symptoms.Improvements in QOL were maintained in addition to the reduction in the requirement for ICS in patients receiving omalizumab.Improved patient compliance with ICS may partly explain the improvements in QOL experienced in placebo-treated patients.

Key Points of Emphasis:This slide presents the percentage of patients achieving a large clinically significant improvement in QOL scores during treatment with omalizumab or placebo from baseline to the end of the steroid-reduction phase (28-week treatment period). 11Omalizumab produced a significant and large clinically meaningful improvement in asthma-related QOL (all domains) compared with placebo and particularly in the most relevant domains for an asthmatic patient: activity and symptoms.Improvements in QOL were maintained in addition to the reduction in the requirement for ICS in patients receiving omalizumab.Improved patient compliance with ICS may partly explain the improvements in QOL experienced in placebo-treated patients.

Clinically relevant improvement is 0.51.5 is a big changeTotally consistent with the change in all other efficacy parameters measuredKey Educational Message: Findings from this analysis show that for every 100 patients treated during the stable-steroid phase, omalizumab prevented the development of exacerbations in about 17 additional patients.

Key Managed Care Educational Message: High-Risk Severe Asthma while low in prevalence is high in utilization. Providing greater asthma control for this patient type eliminates the utilization of costly services and enhances patient quality of life measures, thus increasing the value of therapy as evidenced by the low number needed to treat to maintain 1 patient free of an exacerbation.

Key Points of Emphasis:Ninety-four percent of exacerbations in this high-risk population required treatment with systemic corticosteroids, and in clinical practice, these exacerbations are likely to constitute medical emergencies that may result in ER visits, hospitalization, or death. Therefore, it is of clinical and economic interest to determine the number of patients whose treatment with omalizumab prevented them from experiencing any potentially fatal and costly exacerbations.Omalizumab prevented the development of exacerbations in 17 additional patients for every 100 treated. This corresponds to a prevented fraction of 50% in the incidence of exacerbations in patients randomized to omalizumab.13The risk difference translated to the need to treat 5.7 patients with omalizumab to maintain 1 patient free of exacerbations.13 As a comparison, a meta-analysis of studies comparing the addition of salmeterol to low-moderate doses of inhaled corticosteroids with increasing dose of inhaled corticosteroids found that addition of salmeterol to the treatment of nearly 40 patients was necessary to prevent exacerbations in 1 additional patient. (Shrewsbury 2000. BMJ)These results are of particular economic significance considering that the cost of treating acute asthma attacks is far greater than the cost of providing preventive drug treatment.2There are lots of examples of cost-effectiveness analysis to be found in the literature, and in the press This one appeared in the Wall Street Journal just a few days ago Id suggest that this is probably NOT how we should look at management of disease like asthma Not that different from the way that one of our competitors is spinning their pharmacoeconomic data - theyre essentially arguing that they realize that patients are less adherent to their chronic asthma controller medication, but in the long run this is good because it saves in drug costs, lowering the overall cost of care. Is this the right way to interpret health economic data?? We arent sure, which is why weve asked you to help us in the development of an approach to doing health outcomes analyses.

The upfront investment in wellness has potential returns both in terms of direct and indirect costs. According to Cisternas et al. (2003), pharmaceuticals are the largest contributor to total health care costs in asthma. It is interesting to note that as disease severity increases from mild to severe, the percentages of total costs attributed to medication declines from 47% to 19%. Effective controller medications have been demonstrated to reduce other high-cost components of health care including hospitalizations. The expenses of the treatment failures are magnified in indirect costs.

The Cisternas et al study also demonstrates that as disease severity increases, indirect costs increase from 22% to 46% of the total asthma costs, illustrating that investment in wellness might have its greatest effect in its reduction of indirect expenses measured on the basis of increased productivity and fewer days of school and work lost. In addition, there is an intrinsic value in feeling well that is difficult to quantify in monetary terms.

Cisternas MG, et al. J Allergy Clin Immunol 2003;111:1212-8.Asthmas costs rise significantly with severity.

In one recent study from northern California, the severe cohort had average per-patient costs more than five times greater than the mild cohort, and nearly three times greater than the moderate cohort.

Although the severe cohort (n=64) was less than a third the size of the mild cohort (n=200), its total costs ($820,032) were 55% higher than the total costs ($529,200) of the mild cohort.The impact of severe asthma treatment is even more dramatic.High cost patients make up 20% of asthmatics who account for 80% of the direct costs of treating the disease.

This chart demonstrates that the annual cost of asthma care per member is directly affected by the type of services used by the patient.For example, a controlled patient (the far right column) is $450 per year, with the patient with more than 1 hospital admission at $5,000 per year. 4% of all asthma patients use 50% of asthma dollars.Controlling asthma is a clinical and a financial goal since there is significantly less morbidity and is less than 40% as costly to treat.

KEY POINT: There are many patient types that could potentially benefit from Xolair therapy. But based upon the available clinical data and the current healthcare environment, who are the most appropriate patient types for Xolair therapy today?