FDA Review of Clinical Safety Data Omalizumab for treatment of Allergic Asthma Genentech, Inc. FDA/Center for Biologics Evaluation and Research

OmalizumabOverview of Studies Overview of subjects/studies SAE AE Laboratory findings Antibody formation Summary

OmalizumabOverview of Studies Safety database: Exploratory studies  Several dosages/regimens/iterations Major studies:  3507 subjects treated overall  3224 in controlled studies  283 in uncontrolled studies

OmalizumabOverview of Studies Analytical Groupings of Studies: All completed studies All controlled studies (ACS) AA controlled studies (AACS) of adolescents/adults

OmalizumabOverview of Studies “All controlled studies (ACS)” n = AA studies:  ≤ 12 months, market-applicable dosages  n = SAR & 1 PAR studies:  ≤ 6 months, various dosages  n = AD study  n = 16

OmalizumabOverview of Studies “AA controlled studies (AACS)” n = 2076 Subjects ≥ 12 years age in: 4 Double blind studies (008, 009, 011, 012)  n = Open label studies (ALTO, IA04)  n = 1338

OmalizumabOverview of Studies Baseline characteristics: 85% Caucasian 55% Female Ages 18 – 64 years accounts for:  76% “ACS” (n = 2441) Ages ≥ 65 accounts for:  4% “ACS” (n = 142)

OmalizumabOverview of Studies Disposition: Discontinuation for AE OmalizumabControl ACS1.9%0.9% AACS2.6%1.1% Excess related to a variety of AE

OmalizumabSAE Deaths Among Omalizumab group:  MVA  Ischemic heart disease  Meningococcal sepsis Among Placebo group:  Cardiac arrest  MVA

OmalizumabSAE Nonfatal Serious Adverse Events OmalizumabControl ACS4.2%3.8% AACS5.6%4.6% Excess related to a variety of SAE Malignancy & anaphylaxis

OmalizumabMalignancy Malignancy Background: Atopy and malignancy data  Inconclusive  Not adjusted for smoking  Other limitations Biological plausibility

OmalizumabMalignancy Malignancies Omalizumab n = 4127 Control n = 2236 Any event20 (0.5%)5 (0.2%) Skin, non-M53 Breast50 Prostate20 Melanoma20 Parotid20 Other52

OmalizumabMalignancy Malignancy rates (events/1000 patient years) OmalizumabControlO – C (95% CI) Any kind: 6.3 (20/3160) 3.3 (5/1513) 3.0 (-1.0, 7.0) Excluding non-M skin Ca: 5.1 (16/3160) 1.3 (2/1513) 3.7 (0.7, 6.8)

OmalizumabMalignancy Malignancy rate ratio Malignancy Rate ratio, O/C (95% CI) Any kind: 1.9 (0.7, 6.5) Excluding non-M skin Ca: 3.8 (0.9, 34.3)

OmalizumabMalignancy Exploratory comparisons to Surveillance, Epidemiology and End Results (SEER) database Cancer statistics from 14% population Demographics thought to mirror US population (not AA population) Standardized Incidence Ratio: (SIR) = observed n / expected n

OmalizumabMalignancy Observed & expected malignancies, excluding non-M skin CA (SEER comparisons) ObsExpSIR (95% CI) Omalizumab (1.0 – 2.9) Control (0.1 – 1.6)

OmalizumabMalignancy Characteristics of Omalizumab- exposed subjects with malignancies (excluding non-M skin CA) Male, n (%) 9 (56) Female, n (%) 7 (44) Age, median (range) 50 (40 – 74) Recurrence, n (%) 4 (25) Wks exp prior to dx, median (range) 24 (4 – 61)

OmalizumabMalignancy Malignancy by exposure interval, ( excluding non-M skin CA) Wks of study Events/1000 patient years OmalizumabControl 1 - ≤ ≤ ≤ ≤ >

OmalizumabMalignancy Malignancy Studies suggest higher Omalizumab rate:  0.5% vs 0.2%  6.3 vs 3.3 events/1000 pt yrs  Throughout study exposure periods  SEER comparisons: -higher rate for Omalizumab -lower rate for control Not definitive

OmalizumabAnaphylaxis Anaphylaxis Omalizumab, n = 4, temporal associations:  Levofloxacin, n = 1  Omalizumab, n = 3 Placebo, n = 3, temporal associations:  Peanut exposure, n = 1  Ceftriaxone, n = 1  Unknown allergen, n = 1

OmalizumabAnaphylaxis Anaphylaxis Manifestations post Omalizumab:  Onset 1.5 – 2 hrs  Hives, itching, dyspnea, injection site, throat & tongue edema  Outpatient treatment with steroids, antihistamines, epinephrine  Omalizumab discontinued

OmalizumabAE Adverse events Overall Of special interest  Rash  Digestive  Female GU  Bleeding-related Geriatric population

OmalizumabAE Adverse events, Overall All controlled studies (ACS):  Omalizumab 75%, Control 76% Allergic asthma controlled studies (AACS):  Omalizumab 81%, Control 78%

OmalizumabAE Adverse events of special interest Rash, 6.5% vs 4.9%  All severity grades  Rate correlated with blood Omalizumab concentration

OmalizumabAE Adverse events of special interest Digestive, 19% vs 18%  Appendicitis (0.2% vs 0.1%)  Other mild to moderate grade events

OmalizumabAE Adverse events of special interest Female GU, 11% vs 10%  Severe dysmenorrhea  Severe UTI  Mild grade events

OmalizumabAE Adverse events of special interest Bleeding-related, 2.5% vs 1.6%  Epistaxis  Menorrhagia  Hematoma

OmalizumabAE AE in Geriatric Population Omalizumab n = 142, Control = 71 Higher rates (%) for system clusters:  Body as a whole, 20 vs 9  Digestive, 14 vs 10  Cardiovascular, 10 vs 4  Musculoskeletal, 8 vs 4  Nervous, 16 vs 9  GU/repro, 6 vs 3

OmalizumabAE Adverse events Higher rate of all grades of rash severity Slightly higher rate of certain AE potentially related to altered mucosal immunity:  Digestive system  Female GU  Bleeding-related AE Higher rates of several AE system clusters in geriatric population

OmalizumabLaboratory Laboratory Findings More Omalizumab subjects had mild decreases in:  Hemoglobin 73% vs 68% in ACS  Platelet counts 70% vs 63% in ACS

OmalizumabLaboratory Laboratory Findings Thrombocytopenia with high Omalizumab dosages in animals: No thrombocytopenia in subjects with normal/high baseline counts No decrease in platelet counts for most subjects with low baseline counts

OmalizumabAntibody Antibody Formation No antibody formation reported Verification of reports awaiting review of additional information

OmalizumabLaboratory & Antibody Laboratory & Antibody Formation Mild decreases in hemoglobin & platelets more common among Omalizumab than Control subjects No thrombocytopenia development Antibody formation data pending review

OmalizumabSummary Safety Findings Summary/SAE Higher rate of malignancy in studies  0.5% vs 0.2%  6.3 vs 3.3 events/1000 patient years  Throughout study exposure periods  Not definitive Anaphylaxis among some Omalizumab subjects

OmalizumabSummary Safety Findings Summary/AE All grades of rash more common among Omalizumab subjects Slightly higher rates of AE potentially related to altered mucosal immunity: Digestive system, Female GU, Bleeding-related Higher rates of various AE clusters within the geriatric population

OmalizumabSummary Safety Findings Summary Mild decreases in hemoglobin or platelets more common among Omalizumab subjects Antibody formation data under review