FDA Review of Clinical Safety Data

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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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Omalizumab Overview of Studies

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

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Omalizumab Overview of Studies

• 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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Omalizumab Overview of Studies

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

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Omalizumab Overview of Studies

• All controlled studies (ACS)
• n 3224
• 7 AA studies
• 12 months, market-applicable dosages
• n 2386
• 3 SAR 1 PAR studies
• 6 months, various dosages
• n 822
• 1 AD study
• n 16

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Omalizumab Overview of Studies

• 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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Omalizumab Overview 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)

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Omalizumab Overview of Studies

• Disposition
• Discontinuation for AE

Omalizumab Control
ACS 1.9 0.9
AACS 2.6 1.1

• Excess related to a variety of AE

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Omalizumab SAE

• Deaths
• Among Omalizumab group
• MVA
• Ischemic heart disease
• Meningococcal sepsis

• Among Placebo group
• Cardiac arrest
• MVA

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Omalizumab SAE

• Nonfatal Serious Adverse Events

Omalizumab Control
ACS 4.2 3.8
AACS 5.6 4.6

• Excess related to a variety of SAE
• Malignancy anaphylaxis

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Omalizumab Malignancy

• Malignancy Background
• Atopy and malignancy data
• Inconclusive
• Not adjusted for smoking
• Other limitations
• Biological plausibility

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Omalizumab Malignancy

• Malignancies

Omalizumab n 4127 Control n 2236
Any 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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Omalizumab Malignancy

• 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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Omalizumab Malignancy

• 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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Omalizumab Malignancy

• 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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Omalizumab Malignancy

• Observed expected malignancies, excluding non-M
  skin CA
• (SEER comparisons)

Obs Exp SIR (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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Omalizumab Malignancy

• 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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Omalizumab Malignancy

• Malignancy by exposure interval, (excluding non-M
  skin CA)

Wks of study Events/1000 patient years Events/1000 patient years
Omalizumab Control
1 - 13 4.9 0
13 26 4.6 2.1
26 39 3.8 4.6
39 52 7.6 0
gt 52 5.8 0
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Omalizumab Malignancy

• 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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Omalizumab Anaphylaxis

• 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

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Omalizumab Anaphylaxis

• 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

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Omalizumab AE

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

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Omalizumab AE

• Adverse events, Overall
• All controlled studies (ACS)
• Omalizumab 75, Control 76
• Allergic asthma controlled studies (AACS)
• Omalizumab 81, Control 78

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Omalizumab AE

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

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Omalizumab AE

• 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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Omalizumab AE

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

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Omalizumab AE

• Adverse events of special interest
• Bleeding-related, 2.5 vs 1.6
• Epistaxis
• Menorrhagia
• Hematoma

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Omalizumab AE

• 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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Omalizumab AE

• 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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Omalizumab Laboratory

• 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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Omalizumab Laboratory

• 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

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Omalizumab Antibody

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

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Omalizumab Laboratory Antibody

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

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Omalizumab Summary

• 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

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Omalizumab Summary

• 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

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Omalizumab Summary

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