FDA Review of Clinical Safety Data Omalizumab for treatment of Allergic Asthma Genentech, Inc.
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FDA Review of Clinical Safety Data
Omalizumab for treatment of Allergic Asthma
Genentech, Inc.
FDA/Center for Biologics Evaluation and Research
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OmalizumabOmalizumab Overview of Overview of StudiesStudies
Overview of subjects/studiesSAEAELaboratory findingsAntibody formationSummary
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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
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OmalizumabOmalizumab Overview of Overview of StudiesStudies
Analytical Groupings of Studies: All completed studies All controlled studies (ACS)AA controlled studies (AACS)
of adolescents/adults
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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
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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
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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)
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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
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OmalizumabOmalizumabSAESAE
DeathsAmong Omalizumab group:
MVA Ischemic heart disease Meningococcal sepsis
Among Placebo group:
Cardiac arrest MVA
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OmalizumabOmalizumabSAESAENonfatal Serious Adverse
EventsOmalizumab Control
ACS 4.2% 3.8%AACS 5.6% 4.6%
Excess related to a variety of SAE Malignancy & anaphylaxis
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OmalizumabOmalizumabMalignancyMalignancy
Malignancy Background: Atopy and malignancy data
Inconclusive Not adjusted for smoking Other limitations
Biological plausibility
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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
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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)
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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)
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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
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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)
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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)
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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
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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
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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
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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
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OmalizumabOmalizumabAEAE
Adverse events Overall Of special interest
Rash Digestive Female GU Bleeding-related
Geriatric population
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OmalizumabOmalizumabAEAE
Adverse events, Overall All controlled studies (ACS):
Omalizumab 75%, Control 76% Allergic asthma controlled
studies (AACS): Omalizumab 81%, Control 78%
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OmalizumabOmalizumabAEAE
Adverse events of special interest
Rash, 6.5% vs 4.9% All severity grades Rate correlated with blood
Omalizumab concentration
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OmalizumabOmalizumabAEAE
Adverse events of special interest
Digestive, 19% vs 18% Appendicitis (0.2% vs 0.1%) Other mild to moderate
grade events
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OmalizumabOmalizumabAEAE
Adverse events of special interest
Female GU, 11% vs 10% Severe dysmenorrhea Severe UTI Mild grade events
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OmalizumabOmalizumabAEAE
Adverse events of special interest
Bleeding-related, 2.5% vs 1.6% Epistaxis Menorrhagia Hematoma
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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
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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
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OmalizumabOmalizumabLaboratoryLaboratory
Laboratory Findings More Omalizumab subjects had
mild decreases in: Hemoglobin
73% vs 68% in ACS Platelet counts
70% vs 63% in ACS
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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
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OmalizumabOmalizumabAntibodyAntibody
Antibody FormationNo antibody formation
reported
Verification of reports awaiting review of additional information
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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
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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
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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
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OmalizumabOmalizumabSummarySummary
Safety Findings SummaryMild decreases in hemoglobin
or platelets more common among Omalizumab subjects
Antibody formation data under review