# Presentation: 383707

## FDA Review of Clinical Safety Data

Omalizumab for treatment 
of Allergic Asthma
Genentech, Inc.

FDA/Center for Biologics Evaluation and Research

**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**

## 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**

## Omalizumab				Overview of Studies

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

## 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**

## 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**

## 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)***

## 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**

## Omalizumab						SAE

**Deaths**
**Among Omalizumab group:**
** ****MVA**
** ****Ischemic heart disease**
** ****Meningococcal sepsis**

** ****Among Placebo group:**
** ****Cardiac arrest**
** ****MVA**

## 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 **

## Omalizumab					Malignancy

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

## 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 |

## 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) |

## 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) |

## 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**

## 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) |

## 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) |

## Omalizumab					Malignancy

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

| Wks of study | 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 |
| > 52 | 5.8 | 0 |

## 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**

## 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**

## 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**

## Omalizumab						AE

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

## Omalizumab						AE

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

## Omalizumab						AE

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

## Omalizumab						AE

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

## Omalizumab						AE

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

## Omalizumab						AE

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

## 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**

## 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**

## Omalizumab					Laboratory

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

## 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**

## Omalizumab					Antibody

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

## 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**

## 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**

## 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**

## Omalizumab					Summary

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