1. The efficacy and safety of omalizumab in pediatric allergic asthma
IA05: the largest controlled study of omalizumab in pediatric allergic asthma

2. IA05: study design Design:
a 1-year, randomized, double blind, placebo-controlled trial in children (6–<12 years) with moderate-to-severe, persistent, inadequately controlled allergic asthma
Inclusion criteria
allergic (skin-prick positive or RAST)
≥12% increase in FEV1 after taking SABA
past medical history of exacerbations
inadequate asthma symptom control (day or night) despite ICS dose equivalent to fluticasone DPI ≥200 µg/day (with or without other controller asthma medications)
One or more of the following criteria of inadequate control:
daytime asthma symptoms on at least 20 out of the last 28 days AND mean symptom score over last 28 days of ≥1.5
night-time awakening due to asthma symptoms requiring rescue medication use on each event during last 4 weeks of run-in (averaging >1 a week)
ICS dose ≥200 µg/day fluticasone DPI (or equivalent) for:
12 weeks prior to screening visit
last 4 weeks of the run-in period and at randomization
If receiving regular long-acting β2-agonist (LABA), therapy must have been for ≥3 months prior to screening
If receiving maintenance oral corticosteroids (OCS), therapy must have been for ≥3 months prior to screening
patients receiving OCS must have had ≥1 qualifying exacerbation while on OCS
RAST = radioallergosorbent test; SABA = short-acting β2-agonist; DPI = dry powder inhaler

3. Uncontrolled population despite very high asthma medication use in study IA05
Overall IA05
(n=576 )
High-dose ICS + LABA
(n=235)
Age (years), mean (SD)
8.6 (1.7)
9.0 (1.7)
Female, %
32.3
34.5
Duration of asthma, mean (SD)
5.7 (2.6)
6.1(2.8)
IgE (IU/mL), mean (SD)
469.7 (338.0)
440.0 (321.0)
FEV1 [% predicted], mean (SD)
86.4 (18.0)
82.1 (18.1)
FEV1 [% reversibility], mean (SD)
25.1 (16.5)
28.0 (18.5)
ICS daily dose, mean (SD)
(fluticasone equivalent)
515.1 (285.4)
744.0 (262.7)
LABA use, %
67.4
100
Daily OCS use, %
1.3
2.6
Anti-leukotriene, %
36.6
57.4
LABA = long-acting β2-agonist; SD = standard deviation

4. Unmet need in IA05 despite high medication use
99.7% of patients were uncontrolled according to GINA guidelines despite level of ICS use
Mean % predicted FEV1 of 82–86% consistent with a relatively severe asthma children population
76% (sub-group 77%) of patients had night-time awakenings requiring rescue medication use on average >1 per week
75% (sub-group 78%) of patients had daytime symptoms causing at least some discomfort and limiting activities in 4 weeks prior to randomization
On average 2.6 clinically significant asthma exacerbations per patient per year
NHLBI pag 51
Predictors that have been reported to be associated with increased risk of exacerbations (See Evidence Table 1, Predictors of Exacerbations.) or death include:
Two or more ED visits or hospitalizations for asthma in the past year; any history of intubation or ICU admission, especially if in the past 5 years (Belessis et al. 2004; Cowie et al. 2001).

5. IA05: study design Screening Double-blind treatment period Run-in
Follow-up
Screening
Steroid stable
Steroid adjustment
–9 –8 24 40 52 68
Evaluate steroid dose sparing every 2 weeks
Reduction every 8 weeks

6. Primary endpoint: clinically significant asthma exacerbation rate (24 weeks)
Definition
Worsening of asthma symptoms as judged clinically by the investigator, requiring
doubling of the baseline ICS dose for at least 3 days
and/or
treatment with rescue systemic (oral or IV) corticosteroids
88% of patients with exacerbations treated with OCS

7. Criteria for clinically significant asthma exacerbation
PEF or FEV1 <60% of personal best
PEF or FEV1 60–80% of personal best following β2-agonist administration
Fall in PEF of >20% on at least 2 of any 3 consecutive days compared to personal best
>50% increase in 24-hour rescue medication use on at least 2 of any 3 consecutive days compared to normal use (≥8 puffs of salbutamol)
At least 2 night-time awakenings due to asthma symptoms requiring rescue medication within the previous 7 days
Any other specified clinically important reason

8. Additional IA05 endpoints
Other endpoints included
severe exacerbation rate
hospital admissions
global patient and physician treatment evaluations (GETE)
Analysis of primary and secondary endpoints for the sub-group ‘inadequately controlled, on high-dose ICS and a LABA’

9. Efficacy results

10. Exacerbations are reduced and efficacy is maintained over time
1st 24 weeks – primary analysis
2nd 28 weeks
 –31%
p=0.007
 –54.2%
p<0.001
1.0
0.8
0.6
0.4
0.2
1.0
0.8
0.6
0.4
0.2
Clinically significant exacerbation rate
Clinically significant exacerbation rate
Omalizumab (n=384)
Placebo (n=192)
Omalizumab (n=384)
Placebo (n=192)

11. 1st 24 weeks – primary analysis
Exacerbations in study IA05 are reduced and efficacy is maintained over time in sub-group on high-dose ICS + LABA
1st 24 weeks – primary analysis
2nd 28 weeks
 –34%
p=0.047
 –63%
p<0.001
1.0
0.8
0.6
0.4
0.2
1.0
0.8
0.6
0.4
0.2
Clinically significant exacerbation rate
Clinically significant exacerbation rate
Omalizumab (n=159)
Placebo (n=76)
Omalizumab (n=159)
Placebo (n=76)

12. % reduction compared with placebo
Meaningful reductions in other important measures of asthma exacerbation over 52 weeks
Study IA05
% reduction compared with placebo
Severe exacerbations*
50%, p=0.004
Hospitalization rate†
47%, p=0.08
Table Severe exacerbations at 52 weeks vs 0.12 (50 % reduction)
Rates of hospitalisation 0.13 vs 0.07
In an adult population, a pooled analyses showed 56% reduction in severe exacerbation rate (p<0.001) and 52% reduction in hospitalization (p=0.041)1
*FEV1 or PEF <60% personal best and need of oral steroid use †Hospitalization rate
1. Bousquet J, et al. Allergy 2005

13. Consistent reduction in asthma exacerbation rates across pediatric and adult studies
Percent reduction
p value
IA05
31%
0.007
IA05: patients on high ICS + LABA
34%
0.047
Study 10
46%
<0.001 
Adult studies
INNOVATE study
19%
0.156
ETOPA study
60% 
<0.001  
SOLAR study
38%
0.027
Busse study
40%
<0.001
Solèr study
58%
Holgate study
27%
0.165
ALTO study
15%
0.077
Pooled adult studies1
Study 010 % reduction based on the 28 weeks period
1. Bousquet J, et al. Allergy 2005

14. Consistent reduction in asthma exacerbation rates irrespective of lung function
Percent predicted FEV1
FEV1 <80%
predicted n=143
FEV1 ≥80%
predicted n=240
Percent predicted FEV1 <80%: RR (0.399 , 0.799) (143 oma+67 plac)
Percent predicted FEV1 >80%: RR (0.411 , 0.783) (240 oma+ 125 plac)
0.1
0.5 1 2
Decreased risk of exacerbations
Increased risk of exacerbations
Rate ratio (logarithmic scale)

15. Physician’s overall assessment – consistently greater proportion of omalizumab patients achieve marked improvement
Marked improvement or complete control† (% patients)
Omalizumab
Placebo
100 80 60 40 20
60.5
***
42.8
60.2
42.0
53.1
33.3
66.2
34.7
68.5 **
44.2
84.8
59.2
55.7
79.1
***
IA Study INNOVATE SOLAR Busse Solèr Holgate5
**p<0.01; ***p<0.001 †As assessed by physician’s global evaluation of treatment effectiveness (GETE)
1. Humbert M, et al. Allergy 2005; 2. Vignola AM, et al. Allergy Busse W, et al. JACI 2001; 4. Solèr M, et al. ERJ Holgate ST, et al. Clin Exp Allergy 2004

16. Summary of efficacy: omalizumab in children 6–<12 years demonstrates clear benefit
Following treatment with omalizumab:
31% reduction in clinically significant exacerbation rate after 24 weeks (p<0.007)
34% reduction in high-dose ICS and LABA sub-group (p=0.047)
benefit was maintained over time with 54.2% reduction in second study period of 28 weeks (p<0.001)
63% reduction in high-dose ICS and LABA sub-group (p<0.001)
reductions in hospitalization and severe exacerbation rates
Benefit was irrespective of baseline LABA use or baseline FEV1
Results are consistent across previous adult and pediatric omalizumab studies

17. Safety

18. Summary of safety results from IA05
Omalizumab was well tolerated by asthma patients aged 6–<12 years
no differences in AEs compared with placebo
fewer serious AEs in the omalizumab group (3.4 vs 6.6%)
Safety profile of omalizumab in children is consistent with experience in other age groups

19. AEs identified in adults were specifically followed in pediatric clinical program
No malignancy in omalizumab-treated children
In placebo-controlled studies, the risk of anaphylaxis was no different in the omalizumab and placebo groups
No thrombocytopenia
No serum sickness