FDA Review of Clinical Safety Data

Omalizumab for treatment of Allergic Asthma

Genentech, Inc.

FDA/Center for Biologics Evaluation and Research

OmalizumabOmalizumab Overview of Overview of StudiesStudies

Overview of subjects/studiesSAEAELaboratory findingsAntibody formationSummary

OmalizumabOmalizumab Overview of Overview of StudiesStudies

Safety database:Exploratory studies

Several dosages/regimens/iterations

Major studies: 3507 subjects treated overall 3224 in controlled studies 283 in uncontrolled studies

OmalizumabOmalizumab Overview of Overview of StudiesStudies

Analytical Groupings of Studies: All completed studies All controlled studies (ACS)AA controlled studies (AACS)

of adolescents/adults

OmalizumabOmalizumab Overview of Overview of StudiesStudies“All controlled studies (ACS)”

n = 32247 AA studies:

≤ 12 months, market-applicable dosages

n = 23863 SAR & 1 PAR studies:

≤ 6 months, various dosages n = 822

1 AD study n = 16

OmalizumabOmalizumab Overview of Overview of StudiesStudies

“AA controlled studies (AACS)”n = 2076

Subjects ≥ 12 years age in:4 Double blind studies (008, 009,

011, 012) n = 738

2 Open label studies (ALTO, IA04) n = 1338

OmalizumabOmalizumab Overview of Overview of StudiesStudiesBaseline characteristics: 85% Caucasian 55% Female Ages 18 – 64 years accounts

for: 76% “ACS” (n = 2441)

Ages ≥ 65 accounts for: 4% “ACS” (n = 142)

OmalizumabOmalizumab Overview of Overview of StudiesStudies

Disposition:Discontinuation for AE

Omalizumab ControlACS 1.9% 0.9%AACS 2.6% 1.1%

Excess related to a variety of AE

OmalizumabOmalizumabSAESAE

DeathsAmong Omalizumab group:

MVA Ischemic heart disease Meningococcal sepsis

Among Placebo group:

Cardiac arrest MVA

OmalizumabOmalizumabSAESAENonfatal Serious Adverse

EventsOmalizumab Control

ACS 4.2% 3.8%AACS 5.6% 4.6%

Excess related to a variety of SAE Malignancy & anaphylaxis

OmalizumabOmalizumabMalignancyMalignancy

Malignancy Background: Atopy and malignancy data

Inconclusive Not adjusted for smoking Other limitations

Biological plausibility

OmalizumabOmalizumabMalignancyMalignancy Malignancies

Omalizumab

n = 4127

Controln =

2236Any event 20 (0.5%) 5

(0.2%) Skin, non-M

5 3

Breast 5 0 Prostate 2 0 Melanoma

2 0

Parotid 2 0 Other 5 2

OmalizumabOmalizumabMalignancyMalignancy

Malignancy rates (events/1000 patient years)

Omalizumab

Control O – 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)

OmalizumabOmalizumabMalignancyMalignancy

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)

OmalizumabOmalizumabMalignancyMalignancy 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

OmalizumabOmalizumab MalignancyMalignancy

Observed & expected malignancies, excluding non-

M skin CA (SEER comparisons)

Obs ExpSIR (95%

CI)Omalizumab 16 9 1.8 (1.0 –

2.9)

Control 2 4.7 0.4 (0.1 – 1.6)

OmalizumabOmalizumabMalignancyMalignancy

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)

OmalizumabOmalizumabMalignancyMalignancyMalignancy by exposure

interval, (excluding non-M skin CA)Wks of study

Events/1000 patient years

Omalizumab

Control

1 - ≤ 13 4.9 013 ≤ 26 4.6 2.126 ≤ 39 3.8 4.639 ≤ 52 7.6 0

> 52 5.8 0

OmalizumabOmalizumabMalignancyMalignancy 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

OmalizumabOmalizumabAnaphylaxisAnaphylaxis

AnaphylaxisOmalizumab, 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

OmalizumabOmalizumabAnaphylaxisAnaphylaxis

AnaphylaxisManifestations post Omalizumab:

Onset 1.5 – 2 hrs Hives, itching, dyspnea, injection

site, throat & tongue edema Outpatient treatment with

steroids, antihistamines, epinephrine

Omalizumab discontinued

OmalizumabOmalizumabAEAE

Adverse events Overall Of special interest

Rash Digestive Female GU Bleeding-related

Geriatric population

OmalizumabOmalizumabAEAE

Adverse events, Overall All controlled studies (ACS):

Omalizumab 75%, Control 76% Allergic asthma controlled

studies (AACS): Omalizumab 81%, Control 78%

OmalizumabOmalizumabAEAE

Adverse events of special interest

Rash, 6.5% vs 4.9% All severity grades Rate correlated with blood

Omalizumab concentration

OmalizumabOmalizumabAEAE

Adverse events of special interest

Digestive, 19% vs 18% Appendicitis (0.2% vs 0.1%) Other mild to moderate

grade events

OmalizumabOmalizumabAEAE

Adverse events of special interest

Female GU, 11% vs 10% Severe dysmenorrhea Severe UTI Mild grade events

OmalizumabOmalizumabAEAE

Adverse events of special interest

Bleeding-related, 2.5% vs 1.6% Epistaxis Menorrhagia Hematoma

OmalizumabOmalizumabAEAE 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

OmalizumabOmalizumabAEAE 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

OmalizumabOmalizumabLaboratoryLaboratory

Laboratory Findings More Omalizumab subjects had

mild decreases in: Hemoglobin

73% vs 68% in ACS Platelet counts

70% vs 63% in ACS

OmalizumabOmalizumabLaboratoryLaboratory

Laboratory FindingsThrombocytopenia with high

Omalizumab dosages in animals: No thrombocytopenia in subjects

with normal/high baseline countsNo decrease in platelet counts for

most subjects with low baseline counts

OmalizumabOmalizumabAntibodyAntibody

Antibody FormationNo antibody formation

reported

Verification of reports awaiting review of additional information

OmalizumabOmalizumab Laboratory & Laboratory & AntibodyAntibody

Laboratory & Antibody FormationMild decreases in hemoglobin &

platelets more common among Omalizumab than Control subjects

No thrombocytopenia development

Antibody formation data pending review

OmalizumabOmalizumabSummarySummarySafety 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

OmalizumabOmalizumabSummarySummarySafety 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

OmalizumabOmalizumabSummarySummary

Safety Findings SummaryMild decreases in hemoglobin

or platelets more common among Omalizumab subjects

Antibody formation data under review