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FDA Review of Clinical Safety Data Omalizumab for treatment of Allergic Asthma Genentech, Inc.

FDA Review of Clinical Safety Data Omalizumab for treatment of Allergic Asthma Genentech, Inc. FDA/Center for Biologics Evaluation and Research. Omalizumab Overview of Studies. Overview of subjects/studies SAE AE Laboratory findings Antibody formation Summary.

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FDA Review of Clinical Safety Data Omalizumab for treatment of Allergic Asthma Genentech, Inc.

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

  2. Omalizumab Overview of Studies • Overview of subjects/studies • SAE • AE • Laboratory findings • Antibody formation • Summary

  3. 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

  4. Omalizumab Overview of Studies Analytical Groupings of Studies: • All completed studies • All controlled studies (ACS) • AA controlled studies (AACS) of adolescents/adults

  5. 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

  6. 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

  7. 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)

  8. Omalizumab Overview of Studies Disposition: Discontinuation for AE • Excess related to a variety of AE

  9. Omalizumab SAE Deaths • Among Omalizumab group: • MVA • Ischemic heart disease • Meningococcal sepsis • Among Placebo group: • Cardiac arrest • MVA

  10. Omalizumab SAE Nonfatal Serious Adverse Events • Excess related to a variety of SAE • Malignancy & anaphylaxis

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

  12. Omalizumab Malignancy Malignancies

  13. Omalizumab Malignancy Malignancy rates (events/1000 patient years)

  14. Omalizumab Malignancy Malignancy rate ratio

  15. 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

  16. Omalizumab Malignancy Observed & expected malignancies, excluding non-M skin CA (SEER comparisons)

  17. Omalizumab Malignancy Characteristics of Omalizumab-exposed subjects with malignancies (excluding non-M skin CA)

  18. Omalizumab Malignancy Malignancy by exposure interval, (excluding non-M skin CA)

  19. 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

  20. 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

  21. 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

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

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

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

  25. Omalizumab AE Adverse events of special interest • Digestive, 19% vs 18% • Appendicitis (0.2% vs 0.1%) • Other mild to moderate grade events

  26. Omalizumab AE Adverse events of special interest • Female GU, 11% vs 10% • Severe dysmenorrhea • Severe UTI • Mild gradeevents

  27. Omalizumab AE Adverse events of special interest • Bleeding-related, 2.5% vs 1.6% • Epistaxis • Menorrhagia • Hematoma

  28. 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

  29. 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

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

  31. 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

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

  33. 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

  34. 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

  35. 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

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

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