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

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

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

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).

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

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

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

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’

Efficacy results

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)

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)

% 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 14.2-2.10 Severe exacerbations at 52 weeks 0.24 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

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

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 0.565 (0.399 , 0.799) (143 oma+67 plac) Percent predicted FEV1 >80%: RR 0.567 (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)

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 *** IA05 Study 10 INNOVATE1 SOLAR2 Busse3 Solèr4 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 2004 3. Busse W, et al. JACI 2001; 4. Solèr M, et al. ERJ 2001 5. Holgate ST, et al. Clin Exp Allergy 2004

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

Safety

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

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