Allan T. Luskin, MD Associate Clinical Professor of Medicine, University of Wisconsin

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 doesn’t tell us

3. 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

4. Asthma Severity: Patient Perception Who’s “Wrong” NAEPP Guidelines Patient Self-Classification Asthma in America, 2001

5. “Control” vs. Symptoms • Most people “well controlled” • Symptoms in many despite “control” 34% % Total Sample 21% 11% 2% 35% 49%

6. “Control” vs. Bronchodilator Use 32% % Total Sample 24%

7. “Control” vs. Exacerbations 42% % Total Sample 13% 9% In Previous 3 months

8. 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, Severe Albuterol: 59% Symptoms: 45% Weeks in Category

9. 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

10. 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 2004:170:836-844

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

12. 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

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

14. Asthma and HRQOL: The Burden 147 million unhealthy functioning days/year

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

16. Clinical Predictors of HRQL

17. 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

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

19. “...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 friend’swho has a dog • Forget my medicine • No inflammation • Good lung function • No urgent visits • Low costs

20. 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

21. 18 % Patients with 0.5 Unit Change in AQLQ From Baseline to End of Steroid-Reduction (Busse) * * * % patients *P<0.05 Kishiyama JL, et al. Allergy Clin Immunol International. 2000;Suppl 2:115. Abstract.

22. % of Patients With 1.5 Unit Change in AQLQ From Baseline to End of Steroid Reduction (Busse) * * * * * % patients *P<0.05 Kishiyama JL, et al. Allergy Clin Immunol International. 2000;Suppl 2:115. Abstract.

23. Anti-IgE: QOL in SAR Adelroth. JACI 2000;106:253-259

24. AQLQ: Symptom Domain Luskin AT Annals of Allergy Asthma Immunol. 2004 abs

25. AQLQ: Activities Domain Luskin AT Annals of Allergy Asthma Immunol. 2004 abs

26. AQLQ: Emotions/Environment Domain Luskin AT Annals of Allergy Asthma Immunol. 2004 abs

27. “Wake up in the morning with Symptoms” Luskin AT Annals of Allergy Asthma Immunol. 2004 abs

28. “Overall Range of Activities” Luskin AT Annals of Allergy Asthma Immunol. 2004 abs

29. “Afraid of not having medication available” Luskin AT Annals of Allergy Asthma Immunol. 2004 abs

30. “Experience symptoms from dust” Luskin AT Annals of Allergy Asthma Immunol. 2004 abs

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

32. Summary and Conclusions • Consistent and positive impact of omalizumab on AQLQ overall and domain scores (p<0.05) • Specific drivers of improvement in each of the domains were noted • Correlations between AQLQ and other clinical outcomes were low-moderate • r=0.14 to r=0.60

33. Summary and Conclusions (cont) • Symptoms Domain: • “Waking with symptoms in the morning” • p<0.001 • Activities Domain • “all activities done” • p<0.001 • Emotions Domain • “fear of not having medication available” • p<0.01 • Environment Domain • “symptoms from being exposed to dust” • p<0.001

34. 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

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

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

37. Cost of Symptom Free Day Oba Y J Allergy Clin Immunol 2004;114:265-9

38. Xolair Cost-Effectiveness:Issues 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

39. Xolair Cost-Effectiveness:Issues 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

40. Xolair Cost-Effectiveness:Issues with Current Data • Hospitalization rate ~16% in the literature • Placebo-3% • Xolair-<1% • Dropout rates for Rx failure not quantified • 14:1 placebo:xolair • QALY not used • comparisons with other drugs not valid • No data on economic benefit of AQLQ (QOL) Asche CV. JACI.2005

41. 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

42. 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

43. 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

44. Public Health Impact of Omalizumab in High-Risk Patients • Risk difference: omalizumab prevented exacerbations in about 17 additional patientsfor 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.

45. 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. 2003;111:1203-4.

46. 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. 2003;111:1203-4.

47. Wall Street Journal, July 18, 2001

48. 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. 2003;111:1203-4.

49. 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. 2003;111:1212-8.

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