Omalizumab in children with uncontrolled allergic asthma: Review of clinical trial and real-world experience

Current perspectives

Omalizumab in children with uncontrolled allergic asthma: Review of clinical trial and real-world experience Bradley E. Chipps, MD,a Bob Lanier, MD,b Henry Milgrom, MD,c Antoine Deschildre, MD,d Gunilla Hedlin, MD,e,f,g Stanley J. Szefler, MD,h Meyer Kattan, MD,i Farid Kianifard, PhD,j Benjamin Ortiz, MD,j Tmirah Haselkorn, PhD,k n, MD,k Benjamin Trzaskoma, MS,k and William W. Busse, MDl Ahmar Iqbal, MD,k Karin Rose Sacramento and South San Francisco, Calif, Fort Worth, Tex, Denver and Aurora, Colo, Lille, France, Stockholm, Sweden, New York, NY, East Hanover, NJ, and Madison, Wis Asthma is one of the most common chronic diseases of childhood. Allergen sensitization and high frequencies of comorbid allergic diseases are characteristic of severe asthma in children. Omalizumab, an anti-IgE mAb, is the first targeted From aCapital Allergy and Respiratory Disease Center, Sacramento; bthe Department of Pediatrics, University of North Texas, Fort Worth; cNational Jewish Health, Denver; d Pneumologie Pediatrique, Centre Hospitalier Regional Universitaire de Lille, Lille; e the Centre for Allergy Research, Karolinska Institutet, Stockholm; fAstrid Lindgren Children’s Hospital, Karolinska University Hospital, Stockholm; gthe Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm; hthe Department of Pediatrics, Breathing Institute, Children’s Hospital Colorado and University of Colorado School of Medicine, Aurora; ithe Pediatric Pulmonary Division, Columbia University Medical Center, New York; jNovartis Pharmaceuticals Corporation, East Hanover; kGenentech, South San Francisco; lthe Department of Medicine, Division of Allergy, Pulmonary and Critical Care, University of Wisconsin School of Medicine and Public Health, Madison. Development of this manuscript and editorial assistance were provided by Jessica Donaldson, Fishawack Communications Ltd, Oxford, United Kingdom, and were supported by Novartis Pharmaceuticals, East Hanover, NJ, and Genentech, South San Francisco, Calif. Disclosure of potential conflict of interest: B. E. Chipps serves as a consultant for AstraZeneca, Boehringer Ingelheim, Genentech, Meda, Merck, and Novartis. B, Lanier serves as a consultant for Novartis and Genentech. H. Milgrom receives grant support from Genentech, Merck, Novartis, GlaxoSmithKline, Sepracor, and SanofiAventis; serves on the advisory board for Genentech, Merck, and Novartis; and receives payments for lectures from Genentech, Merck, and Novartis. A. Deschildre reports personal fees from Novartis, ALK-Abello, TEVA, GlaxoSmithKline, Stallergenes, MSD, MEDA, and Chiesi. S. J. Szefler serves as a consultant for Roche, AstraZeneca, Aerocrine, Daiichi Sankyo, Boehringer Ingelheim, Merck, Genentech, Novartis, and GlaxoSmithKline and receives grant support from GlaxoSmithKline. M. Kattan serves on the Advisory Board for Novartis. F. Kianifard is an employee of Novartis. B. Ortiz is an employee for Novartis and holds stock in Novartis. T. Haselkorn serves as a consultant for Genentech and Novartis. A. Iqbal is an employee of Genentech and holds stock in GlaxoSmithKline and Pfizer. K. Rosen is an employee of Genentech and holds stock in Genentech. B. Trzaskoma is an employee of Genentech. W. W. Busse serves as a consultant for Novartis, Genentech, GlaxoSmithKline, Genentech, Roche, Pfizer, Merck, Boehringer Ingelheim, Sanofi, AstraZeneca, Takeda, Aerocrine, 3M, PrEP Biopharm, and Teva and serves as a member for the DSMB for Boston Scientific and Circassia. The rest of the authors declare that they have no relevant conflicts of interest. Received for publication December 9, 2016; revised February 27, 2017; accepted for publication March 8, 2017. Corresponding author: Bradley E. Chipps, MD, Capital Allergy and Respiratory Disease Center, 5609 J St, Suite C, Sacramento, CA 95819. E-mail: bchipps@capitalallergy. com. The CrossMark symbol notifies online readers when updates have been made to the article such as errata or minor corrections 0091-6749 Ó 2017 The Authors. Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology. This is an open access article under the CC BY-NCND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). http://dx.doi.org/10.1016/j.jaci.2017.03.002

biologic therapeutic approved for the treatment of moderate-tosevere persistent allergic asthma (AA) that remains uncontrolled despite high-dose inhaled corticosteroids plus other controller medications. Since its initial licensing for use in adults and adolescents 12 years of age and older, the clinical efficacy, safety, and tolerability of omalizumab have been demonstrated in several published clinical trials in children aged 6 to less than 12 years with moderate-to-severe AA. These studies supported the approval of the pediatric indication (use in children aged _6 years) by the European Medicines Agency in 2009 and the US > Food and Drug Administration in 2016. After this most recent change in licensing, we review the outcomes from clinical trials in children with persistent AA receiving omalizumab therapy and observational studies from the past 7 years of clinical experience in Europe. Data sources were identified by using PubMed in 2016. Guidelines and management recommendations and materials from the recent US Food and Drug Administration’s Pediatric Advisory Committee meeting are also reviewed. (J Allergy Clin Immunol 2017;139:1431-44.) Key words: Allergy, asthma, IgE, omalizumab, pediatric

In the United States asthma affects approximately 6 million children and poses a high burden measured by disability and premature death.1-3 The disease is estimated to result in more than 10 million school days lost per year,2 and the health care costs are substantial, with pediatric emergency department visits alone totaling approximately US$272 million in 2010.4 Quality of life (QoL) can also be adversely affected; in a national health survey 5.5% of children aged 5 to 17 years with symptomatic asthma experienced limitation of activity caused by asthma.2 Control of symptoms can be achieved in many asthmatic children through avoidance of asthma triggers and/or with conventional medications, assuming adherence.5,6 In a retrospective chart review of 142 children aged 5 to 17 years with uncontrolled asthma who were referred to a hospital-based pediatric asthma clinic over a 5-year period, by addressing remedial causes in the basics of asthma management (including poor adherence, ongoing exposure to environmental triggers, comorbidities, incorrect inhaler technique, and incorrect diagnosis), asthma control was achieved in 138 (97.2%) of 142 cases.7 However, some children fulfill the criteria for true therapy-resistant asthma: 4 (2.8%) of 142 in the retrospective chart review7 and 3 (4.5%) of 67 in a separate childhood asthma study in Oslo, Norway,5 did 1431

1432 CHIPPS ET AL

Abbreviations used AA: Allergic asthma AE: Adverse event EMA: European Medicines Agency EXCELS: Epidemiologic Study of Xolair (omalizumab): Evaluating Clinical Effectiveness and Long-term Safety in Patients with Moderate-to-Severe Asthma FDA: US Food and Drug Administration FENO: Fraction of exhaled nitric oxide ICAC: Inner-City Asthma Consortium ICATA: Inner-City Anti-IgE Therapy for Asthma ICS: Inhaled corticosteroid LABA: Long-acting b2-agonist PROSE: Preventative Omalizumab or Step-up Therapy for Fall Exacerbations OCS: Oral corticosteroid QoL: Quality of life RDBPCT: Randomized double-blind, placebo-controlled trial SAE: Serious adverse event

not respond to standard therapy. These children are described as having uncontrolled severe persistent asthma, which was defined as any combination of chronic symptoms, severe exacerbations, and persistent airflow limitation despite receiving high-dose inhaled corticosteroid (ICS) plus a second controller medication.6,8,9 Furthermore, conventional bronchodilatory and antiinflammatory therapeutics do not modify the underlying disease mechanism, and debate continues regarding the safety of prolonged high-dose ICS use in children.10,11 The safe and appropriate use of long-acting b2-agonists (LABAs) has also been widely debated, although a recent randomized, double-blind trial showed that LABA given in combination with ICS did not result in a higher risk of severe asthma events among children versus those receiving ICS alone.12 Consequently, a need remains for safe and efficacious targeted therapeutic options in children with uncontrolled severe asthma. Approved by the US Food and Drug Administration (FDA) in 2003, omalizumab (Xolair; Genentech, San Francisco, Calif), a subcutaneously administered humanized anti-IgE mAb, is the first targeted biologic treatment licensed for use in adults and adolescents 12 years of age and older with moderate-to-severe persistent asthma who have a positive skin test response or in vitro reactivity to a perennial aeroallergen and whose symptoms are inadequately controlled by ICSs.13 Omalizumab was subsequently approved in 2005 by the European Medicines Agency (EMA) as an add-on therapy for patients aged 12 years and older with uncontrolled severe persistent allergic asthma (AA) despite daily high-dose ICS plus inhaled LABA treatment.14 The pediatric indication for omalizumab in asthmatic patients (use in chil_6 years) was approved by the EMA and FDA in dren aged > 2009 and 2016, respectively.14-16 AA is believed to result from polarization of naive airway T cells to a TH2 phenotype. Allergens entering the airway are presented to T cells by antigen-presenting cells, leading to selective recruitment of mast cells, basophils, and eosinophils, along with induction of B-cell immunoglobulin class-switching to IgE, which in turn provides mechanisms for initiating and maintaining allergic inflammation in the airway.17-19 By attaching with high affinity to free (unbound) IgE, omalizumab blocks IgE-receptor binding on the surfaces of

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antigen-presenting cells, mast cells, and basophils.20-22 This prevents subsequent inflammatory cell activation and causes IgE receptor downregulation by reducing levels of free IgE.20,21 Additional evidence supports the role of omalizumab in preventing inflammatory responses to or long-term consequences of allergen exposure, including tissue remodeling, inflammatory cell recruitment, and TH2-type inflammation (Fig 1).8,17-26 IgE sensitization and high frequencies of comorbid allergic diseases characterize severe asthma in children. In the Severe Asthma Research Program pediatric cohort, a cluster analysis revealed 4 defined phenotypic clusters, each featuring atopic characteristics with differing degrees of allergic sensitization,27 and children with severe asthma had significantly higher serum IgE levels, increased aeroallergen sensitization, and higher concentrations of fraction of exhaled nitric oxide (FENO; a marker of airway inflammation) than children with mild-to-moderate asthma.28 High IgE levels, allergen sensitization, high frequencies of allergic comorbidities, and high rates of health care and medication use were also characterizing features of severe or difficult-to-treat asthma in children and adolescents enrolled in the 3-year observational The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens study.29-31 An observational study of the Unbiased Biomarkers in Prediction of Respiratory Disease Outcome Project pediatric cohort documented that children with severe preschool wheeze or severe asthma were typically atopic and had impaired QoL that was associated with inadequate control and airflow limitation.32 These observations differ from adult severe asthma, which is characterized by a broad spectrum of phenotypes; adult mild asthma has a more striking association with allergy than severe disease.33 With the pivotal role of IgE in patients with AA, including severe disease, there is a pathophysiologic rationale for the use of anti-IgE therapy in the management of children with uncontrolled AA. International asthma guidelines and position papers also recommend omalizumab as an add-on therapy for the treatment of severe, IgE-mediated AA in children whose asthma symptoms are uncontrolled despite optimal pharmacologic management and appropriate allergen avoidance.8,34-37 Here we review the experience of children with persistent AA receiving omalizumab therapy by summarizing findings from clinical trials and real-world observational studies.

OVERVIEW OF OMALIZUMAB STUDIES Efficacy outcomes In 2001, Milgrom et al38 evaluated omalizumab use in children aged 6 to 12 years with moderate-to-severe AA that was well controlled with ICSs who received placebo or omalizumab in a randomized double-blind, placebo-controlled trial (RDBPCT). The primary efficacy outcome was corticosteroid reduction. After 28 weeks of therapy, ICS dose reduction was significantly greater in the omalizumab versus placebo groups, and ICS use was withdrawn completely in a greater percentage of omalizumab-treated patients versus placebo-treated patients without compromising asthma control (Table I).25,38-48 Additionally, a reduction in the incidence and frequency of asthma exacerbations was observed in the omalizumab versus placebo groups, and both investigatorand patient-rated Global Evaluation of Treatment Effectiveness results favored improvements in the omalizumab versus placebo groups (Table I). A follow-up study also demonstrated positive effects of omalizumab on asthma-related QoL (Table I).39,40

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Th1

Th2 Atopy/Allergen NO

Pathogen/Physical/Cellular/Metabolic

Smoking

Oxidative/nitrative stress MUC

TSLP, IL-33

Dendritic cells Histamine Leukotrienes Cytokines

CXCL8

iNOS, DUOX, EPO MUC5AC

OX40/L

IL-4/-13

Neutrophils

CXCL11

PGD2 Th2cells

Mast cells

IFN IL-4/-13

CCL24/26

TGFβ

Gland

IL-5 Fibroblasts/matrix

IgE Histamine Leukotrienes Cytokines

Th1-/ Tc1-cells

B-cells

Obesity/metabolic factors

Eosinophils Growth factors

Vessels

= Direct effect of omalizumab = Indirect effect of omalizumab

Airway smooth muscle

FIG 1. Potential immune-inflammatory and cellular interactions contributing to the pathogenesis of asthma phenotypes and the role of omalizumab.8,17-26 Asthma is a chronic inflammatory disorder of considerable heterogeneity in which many cells, cellular mediators, and genetic and environmental factors play a role. Initial exposure to allergen leads to polarization of a TH2-type immune response involving activation of allergen-specific TH2 cells and IgE synthesis (sensitization). Subsequent allergen exposures cause inflammatory cell recruitment, activation, and mediator release.17,18 Nonallergic stimuli and intracellular pathogens/microbial infections tend to be responsible for the generation of TH1-type immune inflammatory responses, the predominance of neutrophils (ie, neutrophilia rather than eosinophilia), and suppression of TH2 cell proliferation.17,18 Omalizumab blocks IgE-receptor binding on the surface of immune cells, such as mast cells, preventing subsequent activation and release of mediators leading to tissue remodeling, inflammatory cell recruitment, and TH2-type inflammation.19-25 CCL, CC chemokine ligand; CXCL, CXC chemokine ligand; DUOX, dual oxidase; EPO, eosinophil peroxidase; iNOS, inducible nitric oxide synthase; MUC, mucin; NO, nitric oxide; OX40/L, CD134 ligand; PGD2, prostaglandin D2; Tc1, cytotoxic T-cell type 1; TSLP, thymic stromal lymphopoietin. Reproduced with permission of the American Thoracic Society and the European Respiratory Society.8

Longer-term efficacy of omalizumab in this study population was evaluated in a 24-week open-label extension.41 Patients who received placebo during the core study were switched to omalizumab for the extension; those who received omalizumab during the core study continued treatment without interruption. The significant corticosteroid-sparing effect of omalizumab observed in the core study was maintained in the extension

(Table I), with the majority of patients (81.4%) not requiring any concomitant asthma medication. Furthermore, 90.8% of patients who had withdrawn ICS use completely in the core study remained ICS free in the extension. Exacerbation rate remained low, with 55% of omalizumab-treated patients not experiencing an exacerbation over the entire study period (core plus extension).41

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TABLE I. Study design and efficacy outcomes in omalizumab studies in pediatric patients Study and duration Milgrom et al (Study 010)38 RDBPCT 28 wk

Key inclusion criteria

Baseline patient characteristics

Study design

Efficacy outcomes

d

Randomized patients (no.): B Total, 334 B OMA, 225 B Pbo, 109 d Mean age (y), range: B OMA, 9.4 (5–12) B Pbo, 9.5 (6-12) d Mean serum IgE level (IU/mL), range: B OMA, 348 (20-1269) B Pbo, 323 (29-1212)

d

4- to 6-wk run-in phase: all children switched to equivalent BDP dose, adjusted to maintain asthma control achieved with previous ICS, before randomization to OMA or Pbo d 16-wk stable-steroid phase: constant ICS dose d 12-wk steroid-reduction phase: 8-wk steroid-reduction phase to minimum effective dose and then maintained for the final 4 wk d Treatment dose frequency: 0.016 mg/kg/IgE (IU/mL) per 4 wk*

d

d

6-12 y of age Moderate-to-severe AA _1-y duration) (> Total serum IgE level of 30-1300 IU/mL _3 mo with Well controlled for > ICS (168-420 mg/d BDP equivalent) 1 reliever as needed _60% FEV1(pred) >

Lemanske et al (Study 010: AQoL)39 RDBPCT 28 wk

d

As described above38

d

Randomized patients (no.): B Total, 334 B OMA, 225 B Pbo, 109 d Mean age (y), range: B OMA, 9.4 (5-12) B Pbo, 9.5 (6-12) d Mean serum IgE level (IU/mL), range: B OMA, 348 (20-1269) B Pbo, 323 (29-1212)

d

As described above38 The pediatric AQLQ was administered at baseline, week 16, and week 28à d Treatment dose frequency: 0.016 mg/kg/IgE (IU/mL) per 4 wk*

d

Berger et al (Study 010)41 OLE 24-wk extension

d

Randomized patients (no.): B OMA, 225 d Mean age (y), range: B 9.4 (5-12) d Mean serum IgE level (IU/mL), range: B 348 (20-1269)

d

d d d d

Silkoff et al (Study 010)42 addendum (2 centers) 52 wk

Lanier et al (Study IA05)43 RDBPCT 52 wk

6-12 y of age Moderate-to-severe AA _1-y duration) (> d Total serum IgE level 30-1300 IU/mL _3 mo with ICS d Well controlled for > (168-420 mg/d BDP or equivalent) 1 reliever as needed _60% d FEV1(pred) >

d

6-12 y of age Moderate-to-severe AA _1-y duration) (> d Total serum IgE level 30-1300 IU/mL _3 mo with d Well controlled for > ICS (168-420 mg/d BDP or equivalent) 1 reliever as needed _60% d FEV1(pred) >

d

d

d d

6-<12 y of age Moderate-to-severe AA d Total serum IgE level 30-1300 IU/mL d Uncontrolled with ICS _200 mg/d FP or equivalent) (> and history of severe exacerbation within prior 2 y 1 reliever as needed d d

d

Mean (SD) change in pediatric AQLQ domain scores from baseline to week 28: 40 B Activity limitations OMA, 0.5 (1.4); Pbo, 0.1 (1.3); P < .05 40 B Symptoms domain OMA, 0.3 (1.2); Pbo, 20.0 (1.3); P < .05 40 B Emotional function OMA, 0.5 (1.1); Pbo, 0.3 (1.1); P 5 ns 40 B Overall domains OMA, 0.4 (1.1); Pbo, 0.1 (1.1); P < .05 d Proportion of patients achieving a clinically relevant improvement in AQoL domain scores at week 28§: B Activity limitation OMA, 50.6%; Pbo, 39.5%; P < .05 B Symptoms OMA, 41.1%; Pbo, 32.6%; P 5 ns B Emotional function OMA, 45.1%; Pbo, 41.9%; P 5 ns B Overall domains OMA, 46.9%; Pbo, 33.7%; P < .05

28-wk core study: OMA received during the double-blind core study (as described above)38 24-wk extension phase: open-label OMA therapy continued without interruption and minimum effective ICS dose was maintained Treatment dose frequency: 0.016 mg/kg/IgE (IU/mL) per 4 wk* 28-wk core study: patients randomized to receive OMA or Pbo (study design, as described above)38 24-wk extension phase: open-label OMA therapy continued without interruption. Those randomized to Pbo were switched to OMA. Minimum effective ICS dose was maintained Treatment dose frequency: 0.016 mg/kg/IgE (IU/mL) per 4 wk*

d

8-wk run-in phase: asthma control optimized. ICS/controller medication dose adjustment during first 4 wk only. Patients who remained symptomatic during the last 4 wk were randomized to OMA or Pbo d 24-wk stable-steroid phase: constant ICS dose d 28-wk steroid-adjustable phase: ICS dose reduced only if patients met strict predefined criteria43 d Treatment dose frequency: 75-375 mg according to dosing table every 2-4 wk

d

d

d

Randomized patients (no.): B Total, 29 B OMA, 18 B Pbo, 11k d Mean age (y), SD: B OMA, 8.8 (1.8) B Pbo, 10.8 (0.8) d Mean serum IgE level (IU/mL), SD: B OMA, 315.6 (279.7) B Pbo, 301.7 (213.0)

d

Randomized patients (no.): B Total, 627 B OMA, 421 B Pbo, 206 d Mean age (y), SD: B OMA, 8.7 (1.7) B Pbo, 8.4 (1.7) d Mean serum IgE level (IU/mL), SD: B OMA, 476.0 (339.3) B Pbo, 456.9 (335.8)

d

d

Median percentage reduction of ICS dose: OMA, 100%; Pbo, 66.7%; P 5 .001 d Proportion of patients in whom ICS use was withdrawn completely: OMA, 55%; Pbo, 39%; P 5 .004 d Exacerbation rate during steroid-reduction phase: OMA, 18.2%; Pbo, 38.5%; P < .001 d Physicians’ evaluation (GETE) excellent/good: OMA, 31.5/44.7%; Pbo, 16.3/32.7%; P < .001 for comparison across all 5 GETE categories  (mean [SD] score: OMA, 1.98 [0.86]; Pbo, 2.6 [1.06])

d

d

Mean percentage reduction of ICS maintained: core, 74.3%; extension, 72.5% d Exacerbation rate weeks 28-52: 27.6% d Proportion of patients free from exacerbation (core 1 extension): 55%

Mean (SD) percentage reduction of ICS dose at week 52 (vs baseline): OMA, 67.4 (65.7); Pbo, 94.2 (15.4) d Mean (SEM) reduction in AUC for adjusted FENO: B OMA: baseline, 41.9 (29.0) ppm; week 52, 18.0 (21.8) ppb; P 5 .032 B Pbo (switched to OMA): week 28, 82.1 (55.6) ppm; B Week 52, 33.3 (21.6) ppb; P 5 .076 d

Exacerbation rate reduction (OMA vs Pbo): B Baseline to week 24: 31% (RR, 0.69 [95% CI, 0.53-0.90]; P 5 .007) B Baseline to week 52: 43% (RR, 0.57 [95% CI, 0.45-0.73]; P < .001) d Severe exacerbation rate reduction (OMA vs Pbo): B Baseline to week 24: 44% (RR, 0.55 [95% CI, 0.320.95]; P 5 .031)

(Continued)

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TABLE I. (Continued) Study and duration

Key inclusion criteria

Baseline patient characteristics

Study design

Efficacy outcomes B

Baseline to week 52: 50% (RR, 0.49 [95% CI, 0.300.80]; P 5 .004) d GETE, excellent or good: B Physicians’ evaluation OMA, 79%; Pbo, 56%; P < .001 for comparison across all 5 GETE categories  B Patients’ evaluation OMA, 80%; Pbo, 72%; P < .001 for comparison across all 5 GETE categories  Kulus et al (Study IA05 subgroup analysis)44 RDBPCT 52 wk

Busse et al (ICATA study)45 RDBPCT 60 wk

6-<12 y of age Severe AA d Total serum IgE level 30-1300 IU/mL d Inadequately controlled with _500 mg/d FP or high-dose ICS (> equivalent) 1 LABA 6 additional controller d d

6-20 y of age Persistent AA (>1-y duration) d Total serum IgE level 30-1300 IU/mL. Uncontrolled asthma indicated by persistent symptoms or hospitalization/unscheduled urgent care in prior 612 mo d d

Randomized patients (no.): B Total, 235 B OMA, 159 B Pbo, 76 d Mean age (y), SD: B OMA, 9.1 (1.71) B Pbo, 8.6 (1.74) d Mean serum IgE level (IU/mL), SD: B OMA, 452.4 (328.3) B Pbo, 414.0 (305.6)

d

Randomized patients (no.): B Total, 419 B OMA, 208 B Pbo, 211 d Mean age (y), SD: B OMA, 10.9 (3.6) B Pbo, 10.8 (3.4) d Mean serum IgE level (IU/mL): B NA

d

d

d

d

As described above43 Treatment dose frequency: 75-375 mg according to dosing table every 2-4 wk

d

d

4-wk run-in phase: asthma control optimized before randomization to OMA or Pbo d 60-wk treatment period: ongoing treatment adjustments were made to achieve good asthma control d Treatment dose frequency: 0.016 mg/kg/IgE (IU/mL) per 4 wk*

d

d

d

d

Teach et al (PROSE study)25 RDBPCT 8- to 13-mo intervention

6-17 y of age Persistent AA (>1-y duration) d Total serum IgE level 30-1300 IU/mL d Uncontrolled with ICS _200 mg/d FP or equivalent) and (> > _1 exacerbations requiring OCS or hospitalization in prior 19 mo d d

Randomized patients (no.): B Total, 478{ B OMA, 259# B Pbo, 89# B ICS boost, 130** d Mean age (y), SD: B Total, 10.2 (2.93) d Mean serum IgE level (IU/mL): B NA d

4- to 9-mo prefall run-in phase: B Patients receiving 500 mg/bid FP or equivalent (treatment step 5) randomized (3:1) to OMA or Pbo B Patients receiving <500 mg/ bid FP or equivalent (steps 2-4) were randomized (3:3:1) to OMA (1 inhaled placebo), ICS boost (1 injected Pbo), or guidelines-based care with injected and inhaled Pbo d 90-d intervention period: commenced 4-6 wk before start of school. Treatment step levels remained fixed. d Treatment dose frequency: 75-375 mg according to dosing table every 2-4 wk d

Exacerbation rate reduction (OMA vs Pbo): B Baseline to week 24: 34% (RR, 0.662 [95% CI, 0.441-0.995]; P 5 .047) B Baseline to week 52: 50% (RR, 0.504 [95% CI, 0.3500.725]; P < .001) Physicians’ evaluation (GETE) excellent or good: OMA, 74.2%; Pbo, 55.3%; P < .001 for comparison across all 5 GETE categories  Number of days with asthma symptoms (OMA vs Pbo): 24.5% reduction. Mean (SEM) number of days: 1.48 (0.10) vs 1.96 (0.10); P < .001 _1 Percentage of patients with > exacerbation: OMA, 30.3%; Pbo, 48.8%; P < .001 Reduction in controller medication: B Mean (SEM) ICS (mg/d): OMA, 663 (23.3); Pbo, 771 (23.5); difference, 2109 (95% CI, 2172 to 245); P < .001 B Mean (SEM) LABA (% prescribed): OMA, 55.4 (2.44); Pbo, 65.5 (2.47); difference, 210.1 (95% CI, 216.8 to 23.4); P 5 .003 Reduction in seasonal exacerbations after OMA treatment (post hoc analysis) B Placebo: fall 9.0%, spring 8.1%, vs summer 4.6% B OMA: fall 4.3%, spring 4.2%, vs summer 3.3% B P < .001 for interaction vs placebo

Significant reduction in fall exacerbation rate (steps 2-5): OMA, 11.3%; Pbo, 21.0% OR, 0.48 (95% CI, 0.25-0.92); P 5 .03 d Reduction in fall exacerbation rate _1 in patient subgroup with > exacerbation during the run-in phase B OMA vs Pbo (steps 2-5): 6.4% vs 36.3% B OMA vs Pbo (step 5): 18.9% vs 53.0% B OMA vs ICS boost (steps 2-4): 2.0% vs 27.8% d Reduction in fall exacerbation rate during the run-in phase in patients _1 exacerbation vs no with > exacerbations d

(Continued)

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TABLE I. (Continued) Study and duration

Key inclusion criteria

Baseline patient characteristics

Study design

Efficacy outcomes

Brodlie et al (Observational therapeutic trial, UK)46 16 wk

d

5-16 y of age d Severe asthma maintained on oral _3 mo before prednisolone for > commencing trial

d

Randomized patients (no.): B OMA total, 34 B Aged <12 y, 15 _12 y, 19 B Aged > d Mean age (y), range: B NA (5-16) d Mean serum IgE level (IU/mL): B NA

d

Diagnosis of severe asthma confirmed in a tertiary pediatric respiratory clinic d Therapeutic trial of omalizumab was performed as part of routine clinical management d Other asthma therapies were not altered during the trial d Treatment dose frequency: 75-375 mg according to dosing table every 2-4 wk

d

Baseline to week 16 (subgroup analysis of children aged <12 y): B Median OCS dose reduced from 20 to 5 mg/d (P < .0001) B Median mini-AQLQ score significantly increased from 2.3 to 5.2 (P 5 .0078) B Median ACT score significantly increased from 11 to 18 (P 5 .0021) B Median FEV1 significantly increased from 1.8 to 2.1 L (P 5 .0058)

Deschildre et al (Real-life observational study, France)47,48 104 wk

d

6-18 y of age Severe AA d Partially/poorly controlled asthma (18%/82%); mean ICS dose 703 mg/d FP or equivalent

d

Randomized patients (no.): B OMA, 104 d Mean age (y), range: B 11.9 (6-18) d Mean serum IgE level (IU/mL), range: B 1125 (934-1315)

d

Multicenter survey conducted in pediatric pulmonology and allergy tertiary care centers d Treatment dose frequency: 75-375 mg according to dosing table every 2-4 wk

d

Week 52 vs baseline (initiation)47: B Control improvement: good control, 67% vs 0% B Rate of exacerbation: 72% reduction (mean, 1.25 [95% CI, 0.55-1.95] vs 4.4 [95% CI, 3.7-5.2]; P < .0001) B Proportion of patients requiring hospitalization: 6.7% vs 44% (in 1 y before initiation), P < .001 B Mean improvement in FEV1(pred): 4.9% (95% CI, 0.69-9.19); P 5 .023 B Mean ICS dose (mg/d): 30% reduction; 481 (95% CI, 412-551) vs 703 (95% CI, 642-764), P < .0001 n 46.7% of patients _50% achieved > reduction

d

At week 104 vs week 5248: B Control improvement: good control, 80% vs 67%, respectively B Rate of exacerbation: 83% reduction (mean, 0.22 [95% CI, 0.03-0.41]; P 5 .0001) B No additional gain in FEV1(pred) B Mean ICS dose unchanged

d

ACT, Asthma Control Test; AQLQ, Asthma Quality of Life Questionnaire; AQoL, asthma-related quality of life; AUC, area under the curve; BDP, beclomethasone dipropionate; bid, twice daily; FEV1(pred), percent predicted FEV1 for a person of the same sex, age, and height; FP, fluticasone propionate; GETE, Global Evaluation of Treatment Effectiveness; NA, not available; ns, no statistically significant difference; OLE, open-label extension; OMA, omalizumab; OR, odds ratio; Pbo, placebo; RR, rate ratio. *Minimum dose.  GETE categories and study scoring as follows: 1, excellent; 2, good; 3, moderate; 4, poor; and 5, worsening. àPediatric AQLQ domains: activity limitation, emotional function, symptoms, and overall. §Clinically relevant was defined as an increase in pediatric AQLQ score of 0.5 points or greater from baseline. kPatients received placebo in the 28-week core study and were switched to omalizumab in the 28-week OLE. {Total represents the overall modified intent-to-treat population. #Randomized participants receiving asthma medication at treatment steps 2 to 5. **Randomized participants receiving a doubling in ICS dose versus those patients at steps 2 to 4 at randomization.

A reduction in serum free IgE levels after omalizumab treatment suggests that a therapeutic effect of omalizumab might result from the binding of free IgE to prevent an IgEreceptor interaction on immune cells and subsequent initiation of an allergic response.38,41 An addendum to the study by Milgrom et al38 also supports the proposed antiinflammatory effect of omalizumab therapy.42 By the end of the extension, despite a high degree of ICS dose reduction versus baseline values, FENO levels were significantly reduced in children receiving continuous omalizumab therapy and in

those who switched from placebo to omalizumab at the end of the core study (Table I).42 The studies above focused on a well-controlled population with asthma and ultimately demonstrated the corticosteroidsparing effect of omalizumab treatment over 1 year in children.38,41 In 2009, Lanier et al43 published the results of a pivotal study in children aged 6 to less than 12 years with moderate-to-severe AA uncontrolled with medium/highdose ICS 6 other controller medication. The primary objective of this 1-year RDBPCT was to assess the effect of

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Exacerbations (%)

10

Placebo

5 Omalizumab

Fe

Ja

nu

ar y br ua r M y ar ch Ap ril M ay Ju ne Ju Au ly Se g u pt st em b O er ct o N ov ber em b D ec er em be r

0

FIG 2. Seasonal variation in frequency of exacerbations, as observed in the ICATA study.45 Band width represents the 95% CI. ICATA, Inner-City AntiIgE Therapy for Asthma. Copyright Ó 2016 Massachusetts Medical Society.

add-on omalizumab on the rate of asthma exacerbations. Compared with placebo, omalizumab therapy significantly reduced the rate of exacerbations during a 24-week fixed corticosteroid phase. This efficacy was maintained over the entire 52-week treatment period.43 Similar effects of omalizumab were also observed in a subgroup analysis of children with inadequately controlled severe AA (Table I)44; this study was prospectively planned to provide data aligned with the pre-existing European Union license indication in adults and adolescents aged greater than 12 years, which specified use of omalizumab in patients with severe persistent AA who remained symptomatic despite receiving high-dose ICSs and LABAs.49 The National Institute of Allergy and Infectious Diseases’ Inner-City Asthma Consortium (ICAC), a multistudy multicenter initiative to address the public health burden of asthma in inner-city children, further highlighted omalizumab’s potential to improve asthma control in children.50 The ICAC InnerCity Anti-IgE Therapy for Asthma (ICATA) study was a 60week RDBPCT to assess the efficacy of omalizumab versus placebo when added to guidelines-based therapy in children, adolescents, and young adults with persistent AA (60% aged 6-11 years).45 The primary outcome was the number of days with asthma symptoms. The study demonstrated that, in addition to improving asthma control, add-on omalizumab therapy significantly reduced the proportion of children who had 1 or more exacerbations and reduced the ICS dose required to maintain asthma control versus placebo (Table I). Furthermore, a post hoc analysis found that seasonal peaks in exacerbations, including those outside of the pollen season, were significantly reduced in the omalizumab versus placebo groups (Fig 2 and Table I).45 Outside of the pollen season, viruses are the major cause of seasonal exacerbations, and thus these observations indicate an important interaction between IgE levels and viral respiratory tract infections. Based on the positive seasonal effects of add-on omalizumab therapy, the ICAC Preventative Omalizumab or Stepup Therapy for Fall Exacerbations (PROSE) study investigated whether omalizumab is beneficial when used preventatively in children aged 6 to 17 years before a period of high exacerbation risk during the fall after school resumes.25

The primary objective in this 3-arm RDBPCT was to compare the effect of the 3 treatment strategies of omalizumab, a boost in ICS dose, or continued guidelines-directed care (inhaled and/or injected placebo) in preventing asthma exacerbations during the fall season. After enrollment (November-March), participants completed a 4- to 9-month run-in phase during which guidelines-directed care was delivered to achieve asthma control. Omalizumab, ICS boost, or placebo was then added to the established treatment regimen 4 to 6 weeks before school resumed, ending 90 days after the school start date. The fall seasonal exacerbation rate was significantly lower in the group receiving omalizumab versus placebo (Fig 3, A, and Table I).25 However, omalizumab was most efficacious in children requiring 500 mg of fluticasone equivalence twice daily during the run-in phase (step 5 therapy; Fig 3, B); there was no difference between omalizumab and ICS boost in patients receiving less than 500 mg of fluticasone equivalence twice daily (steps 2-4; Fig 3, C).25 Furthermore, omalizumab was more efficacious (vs placebo) in preventing exacerbations among children experiencing 1 or more exacerbations during the run-in phase versus those who had not experienced an exacerbation, even among those receiving step 5 therapy (Fig 4, A and B, and Table I); a similar effect was seen for the omalizumab versus ICS boost groups (Fig 4, C).25 High peripheral blood eosinophil counts and FENO levels were a characterizing feature of those who experienced an exacerbation during the run-in phase versus those who did not.25 This might reflect higher levels of inflammation despite guidelines-directed treatment,25 further supporting an anti-inflammatory effect of omalizumab, including in patients with high blood eosinophil counts or FENO levels, as shown by Silkoff et al.42 An ex vivo investigation within the PROSE study demonstrated that omalizumab improved the antiviral IFN-a response to rhinovirus infection and that in the omalizumab arm those patients demonstrating a greater IFN-a response experienced fewer exacerbations (Fig 5).25 The authors postulated that downregulation of the IgE receptor on plasmacytoid dendritic cells (a key source of type 1 interferons) and thus the restoration of virus-induced IFN-a release might be a mechanism for the clinically proven preventative effects of omalizumab on exacerbation risk.25 Add-on omalizumab therapy to improve asthma control in children aged 6 to less than 12 years with severe persistent AA has been approved by the EMA for more than 7 years, allowing for accumulation of real-world experience in Europe. Observational studies (Table I)46-48 provide complementary data to the clinical trials that have demonstrated the efficacy of omalizumab in pediatric patients.25,38,43,45,51 In a United Kingdom therapeutic trial of omalizumab, 15 children aged 5 to less than 12 years with severe asthma requiring maintenance on oral corticosteroids (OCSs) were observed for 16 weeks.46 As seen previously,38 a significant corticosteroidsparing effect of omalizumab treatment was reported. Furthermore, measures of asthma control and QoL scores were improved (Table I).46 Positive effects of omalizumab treatment have since been reported in a larger observational study conducted in tertiary care centers in France: children and adolescents aged 6 to

1438 CHIPPS ET AL

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B

Treatment steps 2 to 5 0.48 (0.25, 0.92)

30 20

21.0

10

11.3

0

n=89 Placebo

Treatment steps 2 to 4

0.37 (0.17, 0.81)

40 Proportion with at least one exacerbation (%)

Proportion with at least one exacerbation (%)

40

C

Treatment step 5

32.6

30 20

15.1

10 0

n=259 Omalizumab

n=46 Placebo

40 Proportion with at least one exacerbation (%)

A

0.73 (0.33, 1.64)

30 20 10

12.7

11.1

8.4 0

n=138 Omalizumab

0.86 (0.32, 2.30) 0.63 (0.22, 1.78)

n=43 Placebo

n=121 n=130 Omalizumab ICS Boost

FIG 3. Proportion of participants with 1 or more exacerbations during the fall-season outcome period in the PROSE study.25 Proportion of participants by treatment arm with 1 or more exacerbations in the placebo and omalizumab arms randomized at steps 2 to 5 (A), placebo and omalizumab arms randomized at step 5 (B), and placebo, omalizumab, and ICS boost arms randomized at steps 2 to 4 (C). Values at the top of each panel are odds ratios (95% CIs). All values are adjusted for site, dosing group, and treatment step. Error bars are SEs. Reprinted Teach et al.25 Copyright 2016, with permission from Elsevier.

A

B

n=35 Placebo

20 13.6 n=54 Placebo

12.2 n=153 Omalizumab

20

18.9

n=24 Placebo

14.3 n=22 Placebo

12.7 n=58 Omalizumab

20

0.05 (0.003, 0.98)

27.8 22.4 2.0 n=11 Placebo

60

0.87 (0.21, 3.64)

20

0.07 (0.003, 1.68)

40

0

n=80 Omalizumab

40

0

Proportion with at least one exacerbation (%)

40

60

0.88 (0.35, 2.18)

40

53.0

0

n=106 Omalizumab

60

Proportion with at least one exacerbation (%)

6.4

Proportion with at least one exacerbation (%)

20

Proportion with at least one exacerbation (%)

Proportion with at least one exacerbation (%)

36.3

0

1.34 (0.24, 7.53)

60

40

60

Treatment steps 2 to 4

0.21 (0.07, 0.58)

60

Proportion with at least one exacerbation (%)

No exacerbation during run-in

Exacerbation during run-in

0.12 (0.02, 0.64)

0

C

Treatment step 5

Treatment steps 2 to 5

n=26 n=27 Omalizumab ICS Boost 0.66 (0.21, 2.07)

0.88 (0.29, 2.72)

1.34 (0.56, 3.25)

40

20 12.9 0

n=32 Placebo

11.6

8.9

n=95 n=103 Omalizumab ICS Boost

FIG 4. Proportion of participants with 1 or more exacerbations during the fall-season outcome period in the PROSE study stratified by exacerbation status during the run-in phase.25 A, Placebo and omalizumab arms randomized at steps 2 to 5. B, Placebo and omalizumab arms randomized at step 5. C, Placebo, omalizumab, and ICS boost arms randomized at steps 2 to 4. Stratification according to participants experiencing exacerbation or no exacerbation during the run-in period are shown in the upper and lower panels, respectively. Values at the top of each panel are odds ratios (95% CIs). All values are adjusted for site, dosing group, and treatment step. Error bars are SEs. Bars represent placebo- and omalizumab-treated patients at all assigned treatment steps in the study. Reprinted from Teach et al.25 Copyright 2016, with permission from Elsevier.

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A

B

Increased ex vivo RV-induced IFN-α in the presence of IgE cross-linking Pre-randomization

Exacerbations in relation to ex vivo IFN-α responses

Post-randomization

0.95 (0.38, 2.33) 1.19 (0.49, 2.88)

Omalizumab post-randomization 0.14 (0.01, 0.88)

1.36 (0.50, 3.69) 3.22 (1.23, 8.45)

2000 25

20

500

Exacerbations (%)

IFN-α (Geometric means)

1000

200 100

10

5

50 0

15

n= 23

64

No

23

56

23

64

Yes No IgE cross-linking Placebo

23

56

Yes

0

28

28

median IFN-α increase

Omalizumab

FIG 5. Enhanced ex vivo IFN-a responses to rhinovirus in the omalizumab group and relationship to exacerbation rates in the PROSE study.25 A, Pre- and post-randomization, patients’ PBMCs were incubated ex vivo with rhinovirus in the presence or absence of an IgE cross-linking antibody, and IFN-a levels were measured in culture supernatants. A 3.22-fold increase in IFN-a levels were observed in the omalizumab group versus placebo in the postrandomization phase (P 5 .03). B, Among omalizumab-treated patients, those with the greatest increase in ex vivo IFN-a levels in the presence of IgE cross-linking were less likely to have an asthma exacerbation during the study outcome period. Values at the top of each panel are odds ratios (95% CIs). Error bars are SEs. RV, Rhinovirus. Reprinted from Teach et al.25 Copyright 2016, with permission from Elsevier.

18 years (45% aged <12 years) with severe AA received omalizumab as an add-on to high-level maintenance therapy (ie, high-dose ICS); approximately 90% of patients also received more than 2 long-term controller medications, and 5.5% received daily OCSs.47 Patients were highly atopic and characterized by high IgE levels, polysensitization, and a high frequency of allergic rhinitis, and/or atopic dermatitis, and/or food allergy. The primary objective was evaluation of omalizumab in controlling asthma over 1 year. Compared with baseline, omalizumab treatment resulted in a large improvement in asthma control (per Global Initiative for Asthma guidelines34), reduced rate of exacerbations, reduced health care use, reduced airflow limitation, decrease in mean ICS dose, and complete withdrawal of OCS maintenance therapy (Table I). After 1 year, 92 patients continued taking omalizumab47; of those children, 73 (79.3%) continued to receive omalizumab 2 years after initiation and sustained the treatment-associated positive effects reported at year 1.48 At year 2 versus year 1, there was a nonsignificant improvement in the level of asthma control and a continued and significant decrease in the mean rate of exacerbations. The mean daily ICS dose remained relatively unchanged versus year 1 (Table I).48

Safety outcomes Current guidelines state that omalizumab is a well-tolerated, efficacious add-on treatment in patients with persistent AA.34 The prescribing information warns of adverse events (AEs), including

anaphylaxis, malignancy, symptoms similar to serum sickness, eosinophilic conditions, parasitic (helminth) infection, and low blood platelet count.14,15 A summary of evidence resulting in or in support of inclusion of the possible risk of anaphylaxis or malignancy in the omalizumab prescribing information is seen in Table II.52-59 The 5-year Epidemiologic Study of Xolair (omalizumab): Evaluating Clinical Effectiveness and Long-term Safety in Patients with Moderate-to-Severe Asthma (EXCELS) evaluated the incidence of serious adverse events (SAEs), including malignancy, in omalizumab-treated patients aged 12 years and older in real-world clinical practice as part of a phase IV FDA postmarketing commitment (Table II).57 Similar incidence rates of primary malignancies were reported in the omalizumab and control arms in EXCELS. Although the study did not include children aged less than 12 years, the FDA believed that the results contributed to the overall risk/ benefit evaluation of omalizumab, leading to reconsideration of the omalizumab indication in patients aged 6 to 11 years.15,60 Clinical studies and real-world experience provide data on the safety and tolerability profile of omalizumab therapy in children aged 6 to less than 12 years with AA (Table III).25,45,47,48,51,61 A pooled analysis of 2 pivotal studies of omalizumab in children aged 6 to 11 years did not identify new or unexpected safety findings, and observations remained consistent with those of prior publications.38,43,51 Omalizumab was associated with an overall frequency of AEs similar to placebo (Table III); 90% of AEs were mild or moderate, and SAEs were uncommon and less

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TABLE II. Summary of evidence that resulted in inclusion of the warning of anaphylaxis and malignancy in the omalizumab product labeling Anaphylaxis*

Pooled analysis of completed phase I to III studies (up to 1 year) involving more than 7500 patients (including children, adolescents, and adults) with asthma, rhinitis, or related conditions52: d Incidence in controlled studies was higher in the omalizumab vs control arms (0.14% vs 0.07%) Postmarketing survey (exposure of ;57,300 patients, June 2003 to December 2006)53: d Incidence of 0.2% d 39% of cases occurred with the first dose, but cases also occurred on subsequent administration and after a longer period after administration than observed in clinical trials Case-control study comparing patients with a history of omalizumab-associated anaphylaxis (cases; n 5 30) with current/former omalizumab-treated patients without anaphylaxis (controls; n 5 88; X-PAND study; March 27, 2009, to April 3, 2014)54: d Anaphylaxis occurred most frequently within the first 3 doses (39.3% of cases ) and within 1 h of dosing (70% of cases) d Anaphylactic events were considered life-threatening in 40% of cases and required hospitalization in 20% of cases d No anaphylactic events resulted in disability or death d Potential risk factors identified for omalizumab-associated anaphylaxis: total number of doses, food allergies, female sex, presence of urticaria/hives, and race d Assuming an overall 0.2% risk (based on postmarketing reports), the estimated absolute increase in risk was 0.62% and 0.08% for patients with and without a history of anaphylaxis, respectively

Malignancy

Pooled analysis of phase I to III clinical trials (up to 4 years’ duration)55: d Marginally higher rates of malignancies in omalizumab vs control arms (0.5% vs 0.2%, respectively) d Ratio of observed to expected number of events in the omalizumab group was similar to that expected in the general population (standardized incidence ratio, 0.98 [95% CI, 0.55-1.62]) Pooled analysis of completed phase I to III studies (up to 1 year) involving more than 7500 patients (including children, adolescents, and adults) with asthma, rhinitis, or related conditions52: d Overall frequency consistent with the incidence in the general population Pooled analysis of 67 phase I to IV clinical trials56: d No difference in rates of malignancy between the omalizumab and control arms (0.33% vs 0.35%, respectively) _12 y57: 5-y EXCELS study in real-world clinical practice of patients aged > d No difference in rates of primary malignancy (per 1000 patient-years) between omalizumab and control arms (rate ratio, 0.84 [95% CI, 0.62-1.13]) d Overall frequency consistent with incidence in the general population d The most common malignancy AEs reported in each treatment arm were skin cancer (nonmelanoma), breast cancer, prostate cancer, colorectal cancer, melanoma, and lung cancer FDA safety announcement (2014)58: 59 d Because of limitations in the EXCELS study (discussed by Li et al ), the potential risk of omalizumab-associated malignancy could not be ruled out

*Described as presentation of any of the following: bronchospasm, hypotension, syncope, urticaria, and/or angioedema of the throat or tongue.  Eleven of 28 patients in whom the number of previous doses had been recorded.

frequent with omalizumab versus placebo.51 One anaphylactic event was reported in each patient group, and neither was considered study drug related. No malignancies were observed in omalizumab-treated patients.51 In the ICATA study the overall incidence of AEs was similar in both the omalizumab and placebo groups, with the incidence of SAEs significantly lower in omalizumab-treated patients (Table III).45 Seven cases of anaphylaxis were reported: 6 in the placebo group and 1 in the omalizumab group. No cases of malignancy were reported.45 In a recent meta-analysis of 1381 pediatric and adolescent patients enrolled in the 2 pivotal studies and ICATA, there was no statistically significant difference in the overall risk of anaphylaxis in omalizumab-treated (0.58%) versus placebo-treated (1.04%) patients, and there was no evidence of increased malignancy risk.61 Additionally, the PROSE study did not reveal any new safety signals, with the incidence of AEs comparable among the placebo, omalizumab, and ICS boost groups (Table III).25 A French observational study of add-on omalizumab therapy in a pediatric cohort concluded that omalizumab was well tolerated (Table III).47,48 Treatment was discontinued in 6 patients because of SAEs attributed to omalizumab but was successfully reinitiated in 2 patients.47 In year 2, treatment was discontinued in 15 patients, 8 because of AEs attributed to omalizumab. Although treatment was reintroduced with

success in 2 patients, the authors suggest that delayed onset of side effects warrants long-term follow-up of omalizumabtreated children.48 One anaphylactic event was reported over 2 years and was determined to be unrelated to omalizumab.47,48 It should be noted that for patients in whom omalizumab is indicated, history of anaphylaxis, asthma severity, and atopy are risk factors for anaphylaxis after omalizumab administration, and yet omalizumab-associated anaphylactic events are relatively rare.52 Despite the low risk of anaphylaxis or malignancy in omalizumab-treated pediatric patients (Table II), the studies conducted thus far are of relatively short duration. To adequately assess the risk of malignancy in children, longer-term studies may need to be designed as druginduced cancers typically occur after long exposure. In August 2016, the FDA conducted a safety review of omalizumab after the pediatric study of omalizumab in patients with chronic idiopathic urticaria.60 Drug use data from hospitals, clinics, and pharmacies showed that approximately 55,000 US patients had a prescription or medical claim for omalizumab from March 2014 to February 2016. Of these, approximately 7% were pediatric patients (<17 years of age).60 Review of the FDA Adverse Event Reporting System database from August 1, 2011, to January 31, 2016, identified 123 pediatric cases (40 [32.5%] and 79 [64.2%] cases in patients aged 6-11 and

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TABLE III. Safety outcomes in major omalizumab studies in pediatric patients Study and duration

Safety population (no.)

Milgrom et al Total, 926 (Studies 010 1 IA05)51 OMA, 624 Pooled safety analysis Pbo, 302 28 and 52 wk (mean OMA exposure, 42 wk)

Mean age (y), range or SD

OMA, 8.8 (1.70)* Pbo, 8.6 (1.68)*

Safety outcomes d

d

d d

d

d d

d

Busse et al (ICATA study)45 RDBPCT 60 wk

Total, 419 OMA, 208 Pbo, 211

OMA, 10.9 (3.6) Pbo, 10.8 (3.4)

d

d

d

Rodrigo and Neffen (Studies 010 1 IA05 1 ICATA)61 Meta-analysis

Total, 1381 OMA, 854 Pbo, 527

Study 010, 9.4 (6-12) Study IA05, 8.6 (6-12) ICATA, 10.8 (6-20)

d

d

d

d

d

Teach et al (PROSE study)25 RDBPCT 8- to 13-mo intervention

Total, 492 OMA, 268à Pbo, 93à ICS boost, 131§

Total, 10.2 (2.93)

d

d

d

d d

Deschildre et al (real-life observational study, France)47,48 104 wk

OMA, 101

11.9 (6-18)

d

d

_1 AE: Proportion of participants experiencing > B OMA, 89.7%; Pbo, 91.7% Proportion of patients reporting treatment-related AEs: B OMA, 6.6%; Pbo, 5.0% B Most common: headache, erythema, and urticaria 90% AEs mild or moderate in severity _1 SAE: Proportion of patients reporting > B OMA, 3.4%; Pbo, 6.6% B Most common: appendicitis, pneumonia, and bronchitis Number (percentage) of treatment discontinuations because of AEs: B OMA, 3 (0.5%); urticaria,  serious bronchitis, and nonserious headache  B Pbo, 1 (0.3%); medulloblastoma No deaths Number of anaphylactic episodes: B OMA, 1; moderate in severity, subsequent to pain medication exposure B Pbo, 1; moderate in severity, attributed to peanut ingestion Number of cases of malignancy: B Pbo, 1; medulloblastoma _1 AE: Proportion of participants experiencing > B OMA, 39.4%; Pbo, 47.4%; P 5 .06 _1 SAE: Proportion of patients reporting > B OMA, 6.3%; Pbo, 13.7%; P 5 .02 B Most common: asthma-related hospitalizations Number of anaphylactic episodes: B OMA, 1; mild cough and itchy throat subsequent to final OMA dose B Pbo, 6 _1 AE: Proportion of participants experiencing > B OMA, 76.3%; Pbo, 74.2% B RR, 1.02 (95% CI, 0.96-1.09); P 5 .50 _1 SAE: Proportion of patients reporting > B OMA, 5.2%; Pbo, 5.6% B RR, 0.91 (95% CI, 0.58-1.42); P 5 .57 Proportion of patients experiencing an anaphylactic reaction: B OMA, 0.58%; Pbo, 1.04% B RR, 0.51 (95% CI, 0.09-2.82); P 5 .44 Number of cases of malignancy: B Pbo, 1; medulloblastoma No deaths _1 AE: Proportion of participants experiencing > B Steps 2-5: OMA, 54.5%; Pbo, 54.8%; P > .99 B Steps 2-4: ICS boost, 43.5%; Pbo, 53.3%; P 5 .30 Number of SAEs: B Pbo, 1: seventh nerve palsy B ICS boost, 1: anaphylaxis Number of anaphylactic episodes: B OMA, 3; Pbo, 2; ICS boost, 3 One neoplasm reported in the OMA group No deaths Baseline (initiation) to week 52: _1 AE. Most common: pain at injection site B 47 participants experienced > B 6 participants experienced SAEs, leading to treatment discontinuation. Included: extended urticaria, anaphylaxis, and systemic reactions B 1 anaphylactic event reported subsequent to kiwi ingestion Week 52 to week 104: B 8 participants experienced AEs leading to treatment discontinuation. Most common: fatigue

OMA, Omalizumab; Pbo, placebo; RR, relative risk. *Children aged 12 years enrolled in the IA05 study were excluded from the pooled analyses.  Suspected to be related to omalizumab treatment. àParticipants receiving asthma medication at treatment steps 2-5. §Participants receiving a doubling in ICS dose versus those patients at treatment steps 2 to 4.

1442 CHIPPS ET AL

12-16 years, respectively) of serious unlabeled events (including 7 deaths); of these, there were 24 cases in which the role of omalizumab could not be excluded. There was no apparent increased severity or frequency of any labeled AEs, and no deaths were directly attributable to omalizumab. Given the small number of reports and the number of pediatric patients who received prescriptions for these products, the reports do not suggest new pediatric safety signals at this time.60 Overall, the FDA review60 concluded that the safety profile of omalizumab in children described in these reports was consistent with the current label and known safety profile. Furthermore, although the cost of omalizumab is often considered a limitation, there is accumulating evidence that supports the cost-effectiveness of omalizumab in both children and adults with severe persistent AA.62,63 Additionally, the PROSE study demonstrated that an efficacious preventative strategy for fall exacerbations can be achieved with targeted seasonal treatment in children with persistent AA.25 This targeted approach to dosing with shorter courses of omalizumab versus a full year of treatment is a novel approach to improve costeffectiveness.

DISCUSSION Uncontrolled persistent AA can greatly affect the healthrelated QoL of an affected child, with the potential for reducing school attendance and the capacity to perform activities.2 However, evidence from clinical trials and realworld experience from more than 7 years of approved use in Europe in pediatric patients suggest that omalizumab can help address the important unmet need in children with a high disease burden. Omalizumab treatment has been shown to generate a sustained reduction in free IgE levels, improve asthma control, reduce the incidence and frequency of exacerbations, reduce health care use for severe exacerbations, have corticosteroid-sparing effects, and ultimately improve QoL in pediatric patients, thus providing protection beyond that conferred with guidelines-directed care.38,43,45-48,61 The corticosteroid-sparing effects of omalizumab in children with severe asthma are important outcomes caused by AEs related to regular and high-dose ICS use. Local and systemic corticosteroid-related AEs appear to be dose dependent and most common in patients receiving high-dose ICSs and concomitant OCSs.11,64 Therefore omalizumab can reduce the burden of corticosteroids in children with severe disease and might be an efficacious alternative to OCSs in particular, although an OCS-sparing trial in a large pediatric cohort should be conducted to confirm this.46 Low proportions of patients studied reported issues with the tolerability of omalizumab and/or discontinued treatment.25,45,47,48,51 These outcomes support current international guidelines that recommend omalizumab as an add-on treatment in children aged 6 years and older with uncontrolled persistent AA,8,34,35 as well as the recent FDA approval of omalizumab use in children aged 6 years and older.65 Reduction in serum free IgE levels in omalizumab-treated children provides evidence that the therapeutic effect of omalizumab results from the binding of free IgE.38,41 Reduced IgE levels after omalizumab treatment might also be linked to a reduction in seasonal exacerbations as a result of an improved antiviral interferon response to rhinovirus infection in children with AA.25 Additionally, an anti-inflammatory effect of omalizumab therapy

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is supported by the observed reduction in FENO levels in omalizumab-treated children despite a high degree of ICS dose reduction42 and the association of reduced IgE levels and decreased levels of circulating basophils with improved clinical outcomes.66 Therefore omalizumab might play a central role in the control of TH2-type disease. One uncontrolled study tentatively suggests that omalizumab can change the natural course of disease: of 7 children with moderate-to-severe uncontrolled AA who had been treated for 1 year with omalizumab, only 2 experienced relapse (mild exacerbations requiring rescue medication only) after a 3-year symptom-free period after withdrawal of omalizumab.67 Further longitudinal follow-up studies and continued monitoring of children receiving omalizumab will supplement the growing evidence supporting the safety and efficacy profile of long-term omalizumab exposure48 and the effects of omalizumab withdrawal in pediatric patients, thus enabling evaluation of treatment effects throughout the disease course.

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