FDA Advisory CommitteeFDA Advisory CommitteeMay 15, 2003May 15, 2003

Genentech Marketing ApplicationSTN 103976 / 0

Omalizumab Recombinant human anti-IgE

for treatment of asthmaEfficacy Review

Omalizumab: Proposed Omalizumab: Proposed indicationindication

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 dosingOmalizumab: 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 limitsBody weight or serum IgECombination 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 topicsOrder of topics

Role of IgE in the allergic process and mechanism of action of omalizumab

Asthma overview Highlights of notable trial results

Role of IgERole of IgE

IgE Produced more in certain (atopic) individualsAttaches to certain cells (e.g., mast cells and

basophils)Reaction with allergens while cell-bound results

in release of “mediators” of allergic reactionMediators thought to trigger acute symptoms

Omalizumab designed to block attachment of IgE to cells and thereby intended to block allergic reaction

Asthma clinical overviewAsthma 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 overviewAsthma clinical overview

TreatmentsShort-acting beta agonistsLABA, leukotriene inhibitors, 5-lipoxygenase

inhibitors, cromolyn sodium, theophylline, inhaled corticosteroids

Oral corticosteroidsOther agents: troleandomycin, MTX,

cyclosporine, other immunomodulators

NHLBI grades of severityNHLBI grades of severity

4 grades of severitySevere persistent category:

Continual symptoms, limited physical activity, frequent exacerbations

Frequent nighttime symptoms FEV1 or PEF 60% predictedPEF variability >30%

Moderate persistentMild persistentMild intermittent

Clinical data overviewClinical data overviewClinical 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 Critical efficacy trials 008 and 009009 Randomized, double-blind, placebo-controlled Inclusion criteria

Skin test reactivity to environmental allergen

Body mass and IgE within proposed dosing Daily symptom score 3/9Daily treatment with moderate dose inhaled

corticosteroid Exclusion criteria

Use of many common asthma medications

Trials 008 and 009: DesignTrials 008 and 009: Design

Several phases 4 to 6-week run in to establish steroid dose16-week stable steroid phase12- week steroid reduction phase24-week extension phase12-week follow-up phase

Trials 008 and 009: Asthma Trials 008 and 009: Asthma managementmanagement 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 onlyInhaled corticosteroidsOral corticosteroids

Trials 008 and 009: Analytical Trials 008 and 009: Analytical planplan 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

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

Notable secondary endpointsPuffs of albuterol for symptomatic reliefCorticosteroid reductionLung function Symptom scores

Trials 008 and 009: ConductTrials 008 and 009: Conduct Screening failures

9 & 12% serum IgE too high5% serum IgE too low3 & 1.5% weight/IgE combination outside

dosing recommendation Demographics and baseline characteristics

90% Caucasians 86 to 90% aged 18 to 64 years old70% on medium dose, <1 to 11% on high-

dose inhaled corticosteroid3 & 6% with hospitalization in past year

Trials 008 and 009: ConductTrials 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 Trials 008 and 009: Primary endpointendpoint Asthma exacerbations using protocol-

defined method in stable steroid phaseTrial 008 Trial 009

# exacerbati

on

Omlzmbn=268

Placebo n=257

Omlzmbn=274

Placebo n=272

0 22985%

19777%

23987%

18969%

1 3915%

6023%

3513%

8331%

DifferenceP-value

8%0.006

18%<0.001

Trials 008 and 009: Primary Trials 008 and 009: Primary endpointendpoint Asthma exacerbations using protocol-

defined method in steroid reduction phase

Trial 008 Trial 009

# exacerbati

on

Omlzmbn=268

Placebo n=257

Omlzmbn=274

Placebo n=272

0 21179%

17468%

23184%

19170%

1 5721%

8332%

4316%

8130%

DifferenceP-value

11%0.003

14%<0.001

Trials 008 and 009: Sensitivity Trials 008 and 009: Sensitivity analysesanalyses 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

Placebon=257

Omlzmb

n=268

Placebon=257

Protocol 15% 23% 21% 32%

Observed 11% 18% 15% 20%

Trials 008 and 009: Subset Trials 008 and 009: Subset analysesanalyses Race, sex, age, measures of disease burden:

mostly continued effectLittle 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 reductio

n

80%

 246 15.9 8.6 -7.3

<80% 749 14.3 28.3 14.0

Trials 008 and 009: Conclusions Trials 008 and 009: Conclusions about primary endpointabout 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

effectException: patients with FEV1 80%

predicted

Trials 008 and 009: Secondary Trials 008 and 009: Secondary endpointsendpoints Number of daily puffs of beta agonist for

rescueApproximately 1-puff/day intertreatment

difference Change in dose of inhaled steroid (subjects)

BDP dosecategory

Trial 008 Trial 009

Omlzmb Placebo Omlzmb Placebo

Cessation 106/26840%

49/25719%

118/27444%

53/27219%

Difference 21% 25%

No change 44/26816%

66/25726%

30/27411%

77/27228%

Difference 10% 17%

Trials 008 and 009: Secondary Trials 008 and 009: Secondary endpointsendpoints 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=2567%

n=2393%

n=2587%

n=238 2%

Difference 3% 5%

Increase, end of steroid reduction ph.

n=243 5%

n=2221%

n=2493%

n=2230

Difference 4% 3%

Trials 008 and 009: Conclusions Trials 008 and 009: Conclusions about secondary endpoints 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 Trials 008 and 009: Conclusions about extension phaseabout 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 Trials 008 and 009: Overall conclusionsconclusions Population did not include

Refractory asthmaSubstantial numbers of non-Caucasians Substantial numbers of subjects 65 years old or

older Trials demonstrated

Robust effect on asthma exacerbationsException: 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 010Pediatric trial 010

Safety trial Same general design as trials 008 & 009 Subjects

6 to 12 yrs oldMinimal asthma symptoms and medication

use Primary efficacy endpoint: reduction in

corticosteroid after steroid reduction phase Exploratory endpoints: asthma exacerbations

Trial 010: ConductTrial 010: Conduct

Screening failures: about 15% excluded for IgE or IgE/body weight

Demographics and baseline characteristicsCaucasians 76%21% with severe persistent asthma, 44%

with moderate persistent asthma by adapted criteria

Trial 010: Primary endpointTrial 010: Primary endpoint

Change in dose of BDP (subjects)

BDP dose category

Omalizumab n=225

Placebo n=109

Cessation 12455%

4239%

Difference 16%

No change 2612%

1817%

Difference 5%

Trial 010: Exploratory endpointsTrial 010: Exploratory endpoints Asthma exacerbations

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

Stable steroid ph. Steroid reduction ph.

Omlzmbn=225

Placebo n=109

Omlzmbn=225

Placebo n=109

1 exacerbati

on

3516%

2523%

4118%

4239%

Difference 7% 21%

P-value 0.093 <0.001

Trial 010: ConclusionTrial 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: DesignTrial 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 Trial 011: Screen failures and baseline characteristicsbaseline 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 year7 & 13% in inhaled23% in oral corticosteroids

Trial 011: ConductTrial 011: Conduct

DiscontinuationsMore early discontinuers in omalizumab

Protocol violations no notable effect on primary endpoint analysis

Trial 011: Primary endpointTrial 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

Placebon=120 P-

value

Median 60% 50%0.003Range -75 to 100% -100 to

100%

Trial 011: Secondary endpointTrial 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

Placebon=45 P-

value

Median 69% 75%0.675Range -357 to

100%-20 to 100%

Trial 011: Secondary endpoint Trial 011: Secondary endpoint Subjects with at least 1 exacerbation (inhaled corticosteroid

group)

Imputationmethod

Stable steroid ph. Steroid reduction ph.

Omlzmb Placebo

Omlzmb Placebo

Protocol 20/12616%

18/120

15%

28/12622%

32/12027%

Diff.p-value

1%0.85

5%0.5

Observed 13/12610%

15/120

13%

17/11715%

25/11522%

Diff.p-value

3%0.57

7%0.15

Trial 011: Secondary endpoint Trial 011: Secondary endpoint Subjects with at least 1 exacerbation (oral corticosteroid

group)

Imputationmethod

Stable steroid ph. Steroid reduction ph.

Omlzmb Placebo

Omlzmb Placebo

Protocol 16/5032%

10/4522%

21/5042%

19/4542%

Diff.p-value

-10%0.26

00.85

Observed 14/5028%

9/4520%

17/4736%

17/4439%

Diff.p-value

-8%0.40

3%0.63

Trial 011: Other endpointsTrial 011: Other endpoints

Puffs of albuterolInhaled corticosteroid users: ½ to 1 puffOral corticosteroid users: baseline

imbalance; greater effect Symptom scores

Small changes of unclear significance for either corticosteroid group

Lung functionNo notable intertreatment group differences

in peak flow, FEV1, or FVC in either corticosteroid treatment group

Trial 011: ConclusionsTrial 011: Conclusions Corticosteroid use: Some benefit in inhaled, no

benefit in oral corticosteroid users Asthma exacerbations

Inhaled corticosteroid users: limited reductionsOral 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 ALTO

DesignOpen-labelLiberalized concomitant medicationsPrimary 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 ALTO: Results

Asthma Exacerbations

Omalizumab N=1207

ControlN=607

Subjects with at least one exacerbation

22% 28%

Exacerbation rate/24 weeks

0.35 0.44

ALTO: ConclusionsALTO: Conclusions

Widespread use of concomitant medications Consistent with critical efficacy trials, but

conclusions compromised by open-label design

Conclusions regarding clinical Conclusions regarding clinical trialstrials Critical efficacy trials showed

reductions in asthma exacerbations across most subgroups of disease severityBenefit sustained over duration of

observationEffect on corticosteroid reductions

Other effect measures did not show clinically notable treatment benefits

Trials 010 and ALTO were supportive

Conclusions regarding clinical Conclusions regarding clinical trialstrials 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