1. FDA Advisory Committee May 15, 2003 Genentech Marketing Application STN 103976 / 0 Omalizumab Recombinant human anti-IgE for treatment of asthma Efficacy Review

2. Omalizumab: Proposed indication Proposed indication: XOLAIR is indicated as maintenance therapy for the prophylaxis of asthma exacerbations and control of symptoms in adults and adolescents (12 years and above) with moderate to severe allergic asthma that is inadequately controlled despite the use of inhaled corticosteroids.

3. Omalizumab: Proposed dosing Proposed dose  Approximately 0.016 mg/kg/IU [IgE] /ml subcutaneously every 4 weeks  Q4w (150 to 300 mg)  Q2w dosing (450 to 750 mg, divided) Dosing recommendation limits  Body weight or serum IgE  Combination of body weight/IgE Proposed: no need for dosing adjustment based upon IgE changes over time Proposed: dosing adjusted for significant changes in weight over time

4. Order of topics Role of IgE in the allergic process and mechanism of action of omalizumab Asthma overview Highlights of notable trial results

5. Role of IgE IgE  Produced more in certain (atopic) individuals  Attaches to certain cells (e.g., mast cells and basophils)  Reaction with allergens while cell-bound results in release of “mediators” of allergic reaction  Mediators thought to trigger acute symptoms Omalizumab designed to block attachment of IgE to cells and thereby intended to block allergic reaction

6. Asthma clinical overview Chronic inflammatory condition of airways (NHLBI Guidelines, 1997) Symptoms include wheezing, breathlessness, nocturnal awakenings Exacerbations may be mild-to-severe, result in hospitalization Specific IgE to allergens not identifiable in all sufferers Millions with asthma in the U.S., but standard definition of “allergic asthma” does not exist

7. Asthma clinical overview Treatments  Short-acting beta agonists  LABA, leukotriene inhibitors, 5-lipoxygenase inhibitors, cromolyn sodium, theophylline, inhaled corticosteroids  Oral corticosteroids  Other agents: troleandomycin, MTX, cyclosporine, other immunomodulators

8. NHLBI grades of severity 4 grades of severity  Severe persistent category:  Continual symptoms, limited physical activity, frequent exacerbations  Frequent nighttime symptoms  FEV 1 or PEF  60% predicted  PEF variability >30%  Moderate persistent  Mild persistent  Mild intermittent

9. Clinical data overview Clinical Trials for efficacy TrialNAgesDesign Q0694g31711-50Placebo-controlled, double-blind 00852512-74Placebo-controlled, double-blind 00954612-76Identical to 008 0103345-12Placebo-controlled, double-blind 01134112-75Placebo-controlled, double-blind ALTO18996-76Open-label, vs. std. treatment IA0431212-73Open-label comparison to std.

10. Critical efficacy trials 008 and 009 Randomized, double-blind, placebo-controlled Inclusion criteria  Skin test reactivity to environmental allergen  Body mass and IgE within proposed dosing  Daily symptom score  3/9  Daily treatment with moderate dose inhaled corticosteroid Exclusion criteria  Use of many common asthma medications

11. Trials 008 and 009: Design Several phases  4 to 6-week run in to establish steroid dose  16-week stable steroid phase  12- week steroid reduction phase  24-week extension phase  12-week follow-up phase

12. Trials 008 and 009: Asthma management Guidelines for recognition of asthma exacerbations Guidelines (NHLBI) for graded treatment of asthma exacerbations depending on severity and response to prior treatment  Short-term beta agonists only  Inhaled corticosteroids  Oral corticosteroids

13. Trials 008 and 009: Analytical plan Primary outcome measurement: asthma exacerbation, defined as worsening of asthma requiring treatment with oral or intravenous corticosteroids or a doubling of the inhaled beclomethasone dose from baseline Primary endpoint  # of exacerbations during stable steroid phase  # of exacerbations during steroid reduction phase  Missing data imputation of 1 exacerbation/2 weeks Analytical population: receipt of 1 dose  Equivalent to intent to treat in these trials

14. Trials 008 and 009: Analytical plan (cont’d) Notable secondary endpoints  Puffs of albuterol for symptomatic relief  Corticosteroid reduction  Lung function  Symptom scores

15. Trials 008 and 009: Conduct Screening failures  9 & 12% serum IgE too high  5% serum IgE too low  3 & 1.5% weight/IgE combination outside dosing recommendation Demographics and baseline characteristics  90% Caucasians  86 to 90% aged 18 to 64 years old  70% on medium dose, <1 to 11% on high-dose inhaled corticosteroid  3 & 6% with hospitalization in past year

16. Trials 008 and 009: Conduct Protocol violations--little impact Discontinuations greater in placebo  Stable steroid 9% vs. 5%  Steroid reduction 5% vs. 2%  Did not critically affect primary conclusions

17. Trials 008 and 009: Primary endpoint Asthma exacerbations using protocol-defined method in stable steroid phase Trial 008Trial 009 # exacerbation Omlzmb n=268 Placebo n=257 Omlzmb n=274 Placebo n=272 0 229 85% 197 77% 239 87% 189 69% 11 39 15% 60 23% 35 13% 83 31% Difference P-value 8% 0.006 18% <0.001

18. Trials 008 and 009: Primary endpoint Asthma exacerbations using protocol-defined method in steroid reduction phase Trial 008Trial 009 # exacerbation Omlzmb n=268 Placebo n=257 Omlzmb n=274 Placebo n=272 0 211 79% 174 68% 231 84% 191 70% 11 57 21% 83 32% 43 16% 81 30% Difference P-value 11% 0.003 14% <0.001

19. Trials 008 and 009: Sensitivity analyses Examination of imputation techniques Subjects with at least 1 exacerbation, Trial 008 Other imputations (single, maximal observed) showed treatment effect The intensity of corticosteroids for the treatment of exacerbations was not affected Stable steroid phase Steroid reduction phase Omlzmb n=268 Placebo n=257 Omlzmb n=268 Placebo n=257 Protocol15%23%21%32% Observed11%18%15%20%

20. Trials 008 and 009: Subset analyses Race, sex, age, measures of disease burden: mostly continued effect  Little treatment effect if FEV 1  80% Pooled 008 and 009 exacerbation rates PhaseFEV 1 Total n Omlzb rate Placebo rate Placebo-omlzb rate Stable steroid  80% 258 10.814.63.9 <80% 813 12.329.817.5 Steroid reduction  80% 246 15.98.6-7.3 <80% 749 14.328.314.0

21. Trials 008 and 009: Conclusions about primary endpoint Reduction in number of exacerbations in both trials, in both stable steroid and steroid reduction phases Robust to different imputation techniques Subset analyses mostly showed consistent effect  Exception: patients with FEV 1  80% predicted

22. Trials 008 and 009: Secondary endpoints Number of daily puffs of beta agonist for rescue  Approximately 1-puff/day intertreatment difference Change in dose of inhaled steroid (subjects) BDP dose category Trial 008Trial 009 OmlzmbPlaceboOmlzmbPlacebo Cessation 106/268 40% 49/257 19% 118/274 44% 53/272 19% Difference21%25% No change 44/268 16% 66/257 26% 30/274 11% 77/272 28% Difference10%17%

23. Trials 008 and 009: Secondary endpoints Lung function Trial 008 lung function (mean) Symptom score, AQLQ data of uncertain meaning PEFR (morning)FEV 1 OmlzmbPlaceboOmlzmbPlacebo Baseline n n=268n=257n=268n=257 Increase, end of stable steroid ph. n=256 7% n=239 3% n=258 7% n=238 2% Difference3%5% Increase, end of steroid reduction ph. n=243 5% n=222 1% n=249 3% n=223 0 Difference4%3%

24. Trials 008 and 009: Conclusions about secondary endpoints Small effect on rescue medication use Effect on use of inhaled corticosteroids No remarkable effect on lung function Intertreatment group differences in symptom scores of uncertain clinical meaning

25. Trials 008 and 009: Conclusions about extension phase No apparent diminution of treatment effect on asthma exacerbations over the duration of observation Continued intertreatment difference in corticosteroids dosing at end of steroid reduction phase Continued finding of no effect on lung function

26. Trials 008 and 009: Overall conclusions Population did not include  Refractory asthma  Substantial numbers of non-Caucasians  Substantial numbers of subjects 65 years old or older Trials demonstrated  Robust effect on asthma exacerbations  Exception: baseline FEV 1  80%  Effect on corticosteroid reduction, after period of omalizumab treatment  Inconsequential intertreatment differences in lung function  Changes of unclear significance in symptom measures and asthma quality of life questionnaire

27. Pediatric trial 010 Safety trial Same general design as trials 008 & 009 Subjects  6 to 12 yrs old  Minimal asthma symptoms and medication use Primary efficacy endpoint: reduction in corticosteroid after steroid reduction phase Exploratory endpoints: asthma exacerbations

28. Trial 010: Conduct Screening failures: about 15% excluded for IgE or IgE/body weight Demographics and baseline characteristics  Caucasians 76%  21% with severe persistent asthma, 44% with moderate persistent asthma by adapted criteria

29. Trial 010: Primary endpoint Change in dose of BDP (subjects) BDP dose categoryOmalizumab n=225 Placebo n=109 Cessation124 55% 42 39% Difference16% No change26 12% 18 17% Difference5%

30. Trial 010: Exploratory endpoints Asthma exacerbations Lung function, symptom scores, rescue medication use: no important intertreatment differences Stable steroid ph.Steroid reduction ph. Omlzmb n=225 Placebo n=109 Omlzmb n=225 Placebo n=109  1 exacerbation 35 16% 25 23% 41 18% 42 39% Difference7%21% P-value0.093<0.001

31. Trial 010: Conclusion Support for asthma exacerbation and corticosteroid reduction endpoint Other endpoint data similar to trials 008 and 009; no clinically important differences.

32. Trial 011: Design Randomized, double-blind, placebo-controlled 350 subjects with asthma controlled by  high-dose inhaled corticosteroid (n=250)  oral corticosteroids (n=100) Many concomitant medications prohibited Same dosing as in trials 008 & 009 Stable steroid and steroid reduction phases Primary endpoint: reduction in inhaled corticosteroid Secondary endpoints included asthma exacerbations

33. Trial 011: Screen failures and baseline characteristics Screening failures for IgE somewhat more frequent Demographics similar to critical efficacy trials Baseline dose of corticosteroid  99% in high dose category for inhaled corticosteroid  Of the 95 subjects on oral corticosteroids: mean dose of about 10 to 11 mg/d Overnight hospital admission in prior year  7 & 13% in inhaled  23% in oral corticosteroids

34. Trial 011: Conduct Discontinuations  More early discontinuers in omalizumab Protocol violations no notable effect on primary endpoint analysis

35. Trial 011: Primary endpoint Reduction in inhaled corticosteroid dose in subjects using inhaled corticosteroid only at baseline Reduction from baseline in inhaled corticosteroid dose Subjects able to cease use of inhaled corticosteroids: 21% omalizumab, 15% placebo Omalizumab n=126 Placebo n=120 P-value Median60%50% 0.003 Range-75 to 100%-100 to 100%

36. Trial 011: Secondary endpoint Reduction in oral corticosteroid dose in subjects using oral corticosteroid at baseline Reduction from baseline in oral corticosteroid dose Subjects able to cease use of inhaled corticosteroids: No intertreatment group difference Omalizumab n=50 Placebo n=45 P-value Median69%75% 0.675 Range-357 to 100%-20 to 100%

37. Trial 011: Secondary endpoint Subjects with at least 1 exacerbation (inhaled corticosteroid group) Imputation method Stable steroid ph.Steroid reduction ph. OmlzmbPlaceboOmlzmbPlacebo Protocol 20/126 16% 18/120 15% 28/126 22% 32/120 27% Diff. p-value 1% 0.85 5% 0.5 Observed 13/126 10% 15/120 13% 17/117 15% 25/115 22% Diff. p-value 3% 0.57 7% 0.15

38. Trial 011: Secondary endpoint Subjects with at least 1 exacerbation (oral corticosteroid group) Imputation method Stable steroid ph.Steroid reduction ph. OmlzmbPlaceboOmlzmbPlacebo Protocol 16/50 32% 10/45 22% 21/50 42% 19/45 42% Diff. p-value -10% 0.26 0 0.85 Observed 14/50 28% 9/45 20% 17/47 36% 17/44 39% Diff. p-value -8% 0.40 3% 0.63

39. Trial 011: Other endpoints Puffs of albuterol  Inhaled corticosteroid users: ½ to 1 puff  Oral corticosteroid users: baseline imbalance; greater effect Symptom scores  Small changes of unclear significance for either corticosteroid group Lung function  No notable intertreatment group differences in peak flow, FEV 1, or FVC in either corticosteroid treatment group

40. Trial 011: Conclusions Corticosteroid use: Some benefit in inhaled, no benefit in oral corticosteroid users Asthma exacerbations  Inhaled corticosteroid users: limited reductions  Oral corticosteroid users: No reductions Symptom scores and lung function: minimal intertreatment group differences Overall: This trial does not replicate in subjects on oral corticosteroids the treatment effects previously seen in subjects with modest use of inhaled corticosteroids, who were studied in trials 008-010.

41. ALTO Design  Open-label  Liberalized concomitant medications  Primary endpoint safety, also collected asthma exacerbations Screening failures  IgE too low or too high: 42%  IgE/body mass combination outside dosing recommendation: 17% Enrolled subjects  Similar age, race to critical efficacy trials

42. ALTO: Results Asthma Exacerbations Omalizumab N=1207 Control N=607 Subjects with at least one exacerbation 22%28% Exacerbation rate/24 weeks 0.350.44

43. ALTO: Conclusions Widespread use of concomitant medications Consistent with critical efficacy trials, but conclusions compromised by open-label design

44. Conclusions regarding clinical trials Critical efficacy trials showed  reductions in asthma exacerbations across most subgroups of disease severity  Benefit sustained over duration of observation  Effect on corticosteroid reductions Other effect measures did not show clinically notable treatment benefits Trials 010 and ALTO were supportive

45. Conclusions regarding clinical trials Trial 011  Inhaled corticosteroid cessation supportive, less than in critical efficacy trials  No reductions in oral corticosteroid  Exacerbation rates decreased in inhaled corticosteroid users, only in steroid reduction phase  No exacerbation benefit in oral corticosteroids users No data on subjects without skin test reactivity; minimal data in subjects  65 years old