# Presentation: 697694

## FDA Advisory CommitteeMay 15, 2003

- Genentech Marketing Application
- STN  103976 / 0
- Omalizumab
- Recombinant human anti-IgE
- for treatment of asthma
- Efficacy Review

## Omalizumab: Proposed indication

- Proposed indication:
- 	XOLAIR is indicated as maintenance therapy for the prophylaxis of asthma exacerbations and control of symptoms in adults and adolescents (12 years and above) with moderate to severe allergic asthma that is inadequately controlled despite the use of inhaled corticosteroids.

## Omalizumab: Proposed dosing

- Proposed dose
- Approximately 0.016 mg/kg/IU [IgE] /ml subcutaneously every 4 weeks
- Q4w (150 to 300 mg)
- Q2w dosing (450 to 750 mg, divided)
- Dosing recommendation limits
- Body weight or serum IgE
- Combination of body weight/IgE
- Proposed: no need for dosing adjustment based upon IgE changes over time
- Proposed: dosing adjusted for significant changes in weight over time

## Order of topics

- Role of IgE in the allergic process and mechanism of action of omalizumab
- Asthma overview
- Highlights of notable trial results

## Role of IgE

- IgE
- Produced more in certain (atopic) individuals
- Attaches to certain cells (e.g., mast cells and basophils)
- Reaction with allergens while cell-bound results in release of “mediators” of allergic reaction
- Mediators thought to trigger acute symptoms
- Omalizumab designed to block attachment of IgE to cells and thereby intended to block allergic reaction

## Asthma clinical overview

- Chronic inflammatory condition of airways (NHLBI Guidelines, 1997)
- Symptoms include wheezing, breathlessness, nocturnal awakenings
- Exacerbations may be mild-to-severe, result in hospitalization
- Specific IgE to allergens not identifiable in all sufferers
- Millions with asthma in the U.S., but standard definition of “allergic asthma” does not exist

## Asthma clinical overview

- Treatments
- Short-acting beta agonists
- LABA, leukotriene inhibitors, 5-lipoxygenase inhibitors, cromolyn sodium, theophylline, inhaled corticosteroids
- Oral corticosteroids
- Other agents: troleandomycin, MTX, cyclosporine, other immunomodulators

## NHLBI grades of severity

- 4 grades of severity
- Severe persistent category:
- Continual symptoms, limited physical activity, frequent exacerbations
- Frequent nighttime symptoms
- FEV1 or PEF  60% predicted
- PEF variability >30%
- Moderate persistent
- Mild persistent
- Mild intermittent

## Clinical data overview

- Clinical Trials for efficacy

| Trial | N | Ages | Design |
| --- | --- | --- | --- |
| Q0694g | 317 | 11-50 | Placebo-controlled, double-blind |
| 008 | 525 | 12-74 | Placebo-controlled, double-blind |
| 009 | 546 | 12-76 | Identical to 008 |
| 010 | 334 | 5-12 | Placebo-controlled, double-blind |
| 011 | 341 | 12-75 | Placebo-controlled, double-blind |
| ALTO | 1899 | 6-76 | Open-label, vs. std. treatment  |
| IA04 | 312 | 12-73 | Open-label comparison to std. |

## Critical efficacy trials 008 and 009

- Randomized, double-blind, placebo-controlled
- Inclusion criteria
- Skin test reactivity to environmental allergen
- Body mass and IgE within proposed dosing
- Daily symptom score 3/9
- Daily treatment with moderate dose inhaled corticosteroid
- Exclusion criteria
- Use of many common asthma medications

## Trials 008 and 009: Design

- Several phases
- 4 to 6-week run in to establish steroid dose
- 16-week stable steroid phase
- 12- week steroid reduction phase
- 24-week extension phase
- 12-week follow-up phase

## Trials 008 and 009: Asthma management

- Guidelines for recognition of asthma exacerbations
- Guidelines (NHLBI) for graded treatment of asthma exacerbations depending on severity and response to prior treatment
- Short-term beta agonists only
- Inhaled corticosteroids
- Oral corticosteroids

## Trials 008 and 009: Analytical plan

- Primary outcome measurement: asthma exacerbation, defined as
- worsening of asthma requiring treatment with oral or intravenous corticosteroids or a doubling of the inhaled beclomethasone dose from baseline
- Primary endpoint
- # of exacerbations during stable steroid phase
- # of exacerbations during steroid reduction phase
- Missing data imputation of 1 exacerbation/2 weeks
- Analytical population: receipt of 1 dose
- Equivalent to intent to treat in these trials

## Trials 008 and 009: Analytical plan (cont’d)

- Notable secondary endpoints
- Puffs of albuterol for symptomatic relief
- Corticosteroid reduction
- Lung function
- Symptom scores

## Trials 008 and 009: Conduct

- Screening failures
- 9 & 12% serum IgE too high
- 5% serum IgE too low
- 3 & 1.5% weight/IgE combination outside dosing recommendation
- Demographics and baseline characteristics
- 90% Caucasians
- 86 to 90% aged 18 to 64 years old
- 70% on medium dose, <1 to 11% on  high-dose inhaled corticosteroid
- 3 & 6% with hospitalization in past year

## Trials 008 and 009: Conduct

- Protocol violations--little impact
- Discontinuations greater in placebo
- Stable steroid 9% vs. 5%
- Steroid reduction 5% vs. 2%
- Did not critically affect primary conclusions

## Trials 008 and 009: Primary endpoint

- Asthma exacerbations using protocol-defined method in stable steroid phase

|  | Trial 008 |  | Trial 009 |  |
| --- | --- | --- | --- | --- |
| # exacerbation | Omlzmb
n=268 | Placebo 
n=257 | Omlzmb
n=274 | Placebo 
n=272 |
| 0 | 229
85% | 197
77% | 239
87% | 189
69% |
| 1 | 39
15% | 60
23% | 35
13% | 83
31% |
| Difference
P-value | 8%
0.006 |  | 18%
<0.001 |  |

## Trials 008 and 009: Primary endpoint

- Asthma exacerbations using protocol-defined method in steroid reduction phase

|  | Trial 008 |  | Trial 009 |  |
| --- | --- | --- | --- | --- |
| # exacerbation | Omlzmb
n=268 | Placebo 
n=257 | Omlzmb
n=274 | Placebo 
n=272 |
| 0 | 211
79% | 174
68% | 231
84% | 191
70% |
| 1 | 57
21% | 83
32% | 43
16% | 81
30% |
| Difference
P-value | 11%
0.003 |  | 14%
<0.001 |  |

## Trials 008 and 009: Sensitivity analyses

- Examination of imputation techniques
- Subjects with at least 1 exacerbation, Trial 008
- Other imputations (single, maximal observed) showed treatment effect
- The intensity of corticosteroids for the treatment of exacerbations was not affected

|  | Stable steroid phase |  | Steroid reduction phase |  |
| --- | --- | --- | --- | --- |
|  | Omlzmb
n=268 | Placebo
n=257 | Omlzmb
n=268 | Placebo
n=257 |
| Protocol | 15% | 23% | 21% | 32% |
| Observed | 11% | 18% | 15% | 20% |

## Trials 008 and 009: Subset analyses

- Race, sex, age, measures of disease burden: mostly continued effect
- Little treatment effect if FEV1 80%
- Pooled 008 and 009 exacerbation rates

| Phase | FEV1  | Total n  | Omlzb rate | Placebo rate | Placebo-omlzb rate  |
| --- | --- | --- | --- | --- | --- |
| Stable steroid |  80% |  258 | 10.8 | 14.6 | 3.9 |
|  | <80% | 813 | 12.3 | 29.8 | 17.5 |
| Steroid reduction |  80% |  246 | 15.9 | 8.6 | -7.3 |
|  | <80% | 749 | 14.3 | 28.3 | 14.0 |

## Trials 008 and 009: Conclusions about primary endpoint

- Reduction in number of exacerbations in both trials, in both stable steroid and steroid reduction phases
- Robust to different imputation techniques
- Subset analyses mostly showed consistent effect
- Exception:  patients with FEV1  80% predicted

## Trials 008 and 009: Secondary endpoints

- Number of daily puffs of beta agonist for rescue
- Approximately 1-puff/day intertreatment difference
- Change in dose of inhaled steroid (subjects)

| BDP dose
category | Trial 008 |  | Trial 009 |  |
| --- | --- | --- | --- | --- |
|  | Omlzmb | Placebo | Omlzmb | Placebo |
| Cessation | 106/268
40% | 49/257
19% | 118/274
44% | 53/272
19% |
| Difference | 21% |  | 25% |  |
| No change | 44/268
16% | 66/257
26% | 30/274
11% | 77/272
28% |
| Difference | 10% |  | 17% |  |

## Trials 008 and 009: Secondary endpoints

- Lung function
- Trial 008 lung function (mean)
- Symptom score, AQLQ data of uncertain meaning

|  | PEFR (morning) |  | FEV1  |  |
| --- | --- | --- | --- | --- |
|  | Omlzmb | Placebo  | Omlzmb | Placebo  |
| Baseline n | n=268 | n=257 | n=268 | n=257 |
| Increase, end of stable steroid ph. | n=256
7% | n=239
3% | n=258
7% | n=238 2% |
| Difference | 3% |  | 5% |  |
| Increase, end of steroid reduction ph. | n=243 
5% | n=222
1% | n=249
3% | n=223
0 |
| Difference | 4% |  | 3% |  |

## Trials 008 and 009: Conclusions about secondary endpoints 

- Small effect on rescue medication use
- Effect on use of inhaled corticosteroids
- No remarkable effect on lung function
- Intertreatment group differences in symptom scores  of uncertain clinical meaning

## Trials 008 and 009: Conclusions about extension phase

- No apparent diminution of treatment effect on asthma exacerbations over the duration of observation
- Continued intertreatment difference in corticosteroids dosing at end of steroid reduction phase
- Continued finding of no effect on lung function

## Trials 008 and 009: Overall conclusions

- Population did _not_ include
- Refractory asthma
- Substantial numbers of non-Caucasians
- Substantial  numbers of subjects 65 years old or older
- Trials demonstrated
- Robust effect on asthma exacerbations
- Exception: baseline FEV1 80%
- Effect on corticosteroid reduction, after period of omalizumab treatment
- Inconsequential intertreatment differences in lung function
- Changes of unclear significance in symptom measures and asthma quality of life questionnaire

## Pediatric trial 010

- Safety trial
- Same general design as trials 008 & 009
- Subjects
- 6 to 12 yrs old
- Minimal asthma symptoms and medication use
- Primary efficacy endpoint: reduction in corticosteroid after steroid reduction phase
- Exploratory endpoints: asthma exacerbations

## Trial 010: Conduct

- Screening failures: about 15% excluded for IgE or IgE/body weight
- Demographics and baseline characteristics
- Caucasians 76%
- 21% with severe persistent asthma,  44% with moderate persistent asthma by adapted criteria

## Trial 010: Primary endpoint

- Change in dose of BDP (subjects)

| BDP dose category | Omalizumab 
n=225 | Placebo 
n=109 |
| --- | --- | --- |
| Cessation | 124
55% | 42
39% |
| Difference | 16% |  |
| No change | 26
12% | 18
17% |
| Difference | 5% |  |

## Trial 010: Exploratory endpoints

- Asthma exacerbations
- Lung function, symptom scores, rescue medication use: no important intertreatment differences

|  | Stable steroid ph. |  | Steroid reduction ph. |  |
| --- | --- | --- | --- | --- |
|  | Omlzmb
n=225 | Placebo 
n=109 | Omlzmb
n=225 | Placebo 
n=109 |
|  1 
exacerbation | 35
16% | 25
23% | 41
18% | 42
39% |
| Difference | 7% |  | 21% |  |
| P-value | 0.093 |  | <0.001 |  |

## Trial 010: Conclusion

- Support for asthma exacerbation and corticosteroid reduction endpoint
- Other endpoint data similar to trials 008 and 009; no clinically important differences.

## Trial 011: Design

- Randomized, double-blind, placebo-controlled
- 350 subjects with asthma controlled by
- high-dose inhaled corticosteroid (n=250)
- oral corticosteroids (n=100)
- Many  concomitant medications prohibited
- Same dosing as in trials 008 & 009
- Stable steroid and steroid reduction phases
- Primary endpoint: reduction in inhaled corticosteroid
- Secondary endpoints included asthma exacerbations

## Trial 011: Screen failures and baseline characteristics

- Screening failures for IgE somewhat more frequent
- Demographics similar to critical efficacy trials
- Baseline dose of corticosteroid
- 99% in high dose category for inhaled corticosteroid
- Of the 95 subjects on oral corticosteroids: mean dose of about 10 to 11 mg/d
- Overnight hospital admission in prior year
- 7 & 13% in inhaled
- 23% in oral corticosteroids

## Trial 011: Conduct

- Discontinuations
- More early discontinuers in omalizumab
- Protocol violations no notable effect on primary endpoint analysis

## Trial 011: Primary endpoint

- Reduction in inhaled corticosteroid dose in subjects using inhaled corticosteroid only at baseline
- Reduction from baseline in inhaled corticosteroid dose
- Subjects able to cease use of inhaled corticosteroids: 21% omalizumab, 15% placebo

|  | Omalizumab 
n=126 | Placebo
n=120  | 
P-value |
| --- | --- | --- | --- |
| Median | 60% | 50% | 
0.003 |
| Range  | -75 to 100% | -100 to 100% |  |

## Trial 011: Secondary endpoint

- Reduction in oral corticosteroid dose in subjects using oral corticosteroid at baseline
- Reduction from baseline in oral corticosteroid dose
- Subjects able to cease use of inhaled corticosteroids: No intertreatment group difference

|  | Omalizumab 
n=50 | Placebo
n=45  | 
P-value |
| --- | --- | --- | --- |
| Median | 69% | 75% | 
0.675 |
| Range  | -357 to 100% | -20 to 100% |  |

## Trial 011: Secondary endpoint 

- Subjects with at least 1 exacerbation (inhaled corticosteroid group)

| Imputation
method | Stable steroid ph. |  | Steroid reduction ph. |  |
| --- | --- | --- | --- | --- |
|  | Omlzmb | Placebo | Omlzmb | Placebo |
| Protocol | 20/126
16% | 18/120
15% | 28/126
22% | 32/120
27% |
| Diff.
p-value | 1%
0.85 |  | 5%
0.5 |  |
| Observed | 13/126
10% | 15/120
13% | 17/117
15% | 25/115
22% |
| Diff.
p-value | 3%
0.57 |  | 7%
0.15 |  |

## Trial 011: Secondary endpoint 

- Subjects with at least 1 exacerbation (oral corticosteroid group)

| Imputation
method | Stable steroid ph. |  | Steroid reduction ph. |  |
| --- | --- | --- | --- | --- |
|  | Omlzmb | Placebo | Omlzmb | Placebo |
| Protocol | 16/50
32% | 10/45
22% | 21/50
42% | 19/45
42% |
| Diff.
p-value | -10%
0.26 |  | 0
0.85 |  |
| Observed | 14/50
28% | 9/45
20% | 17/47
36% | 17/44
39% |
| Diff.
p-value | -8%
0.40 |  | 3%
0.63 |  |

## Trial 011: Other endpoints

- Puffs of albuterol
- Inhaled corticosteroid users: 1⁄2 to 1 puff
- Oral corticosteroid users: baseline imbalance; greater effect
- Symptom scores
- Small changes of unclear significance for either corticosteroid group
- Lung function
- No notable intertreatment group differences in peak flow, FEV1, or FVC in either corticosteroid treatment group

## Trial 011: Conclusions

- Corticosteroid use: Some benefit in inhaled, no benefit in oral corticosteroid users
- Asthma exacerbations
- Inhaled corticosteroid users: limited reductions
- Oral corticosteroid users: No reductions
- Symptom scores and lung function: minimal intertreatment group differences
- Overall: This trial does not replicate in subjects on oral corticosteroids the treatment effects previously seen in subjects with modest use of inhaled corticosteroids, who were studied in trials 008-010.

## ALTO 

- Design
- Open-label
- Liberalized concomitant medications
- Primary endpoint safety, also collected asthma exacerbations
- Screening failures
- IgE too low or too high: 42%
- IgE/body mass combination outside dosing recommendation: 17%
- Enrolled subjects
- Similar age, race to critical efficacy trials

## ALTO: Results 

- Asthma Exacerbations

|  | Omalizumab 
N=1207 | Control
N=607 |
| --- | --- | --- |
| Subjects with at least one exacerbation  | 22%
 | 28% |
| Exacerbation rate/24 weeks | 0.35 | 0.44 |

## ALTO: Conclusions

- Widespread use of concomitant medications
- Consistent with critical efficacy trials, but conclusions compromised by open-label design

## Conclusions regarding clinical trials

- Critical efficacy trials showed
- reductions in asthma exacerbations across most subgroups of disease severity
- Benefit sustained over duration of observation
- Effect on corticosteroid reductions
- Other effect measures did not show clinically notable treatment benefits
- Trials 010  and ALTO were supportive

## Conclusions regarding clinical trials

- Trial 011
- Inhaled corticosteroid cessation supportive, less than in critical efficacy trials
- No reductions in oral corticosteroid
- Exacerbation rates decreased in inhaled corticosteroid users, only in steroid reduction phase
- No exacerbation benefit in oral corticosteroids users
- No data on subjects without skin test reactivity; minimal data in subjects 65 years old