fda advisory committee may 15, 2003 genentech marketing application stn 103976 / 0 omalizumab...
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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