Omalizumab in children with uncontrolled allergic asthma: Review of clinical trial and real-world experience
Authors: Bradley E. Chipps, Bob Lanier, Henry Milgrom, Antoine Deschildre, Gunilla Hedlin, Stanley J. Szefler, Meyer Kattan, Farid Kianifard, Benjamin Ortiz, Tmirah Haselkorn, Ahmar Iqbal, Karin Rosén, Benjamin Trzaskoma, William W. Busse
Journal: Journal of Allergy and Clinical Immunology (2017)

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 biologic therapeutic approved for the treatment of moderate-to-severe 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. 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 biologic therapeutic approved for the treatment of moderate-to-severe 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. In the United States asthma affects approximately 6 million children and poses a high burden measured by disability and premature death.1Centers for Disease Control and Prevention (CDC). Summary health statistics tables for US children: national health interview survey data, 2014, Table C-1b. Available at: http://ftp.cdc.gov/pub/Health_Statistics/NCHS/NHIS/SHS/2014_SHS_Table_C-1.pdf. Accessed June 20, 2016.Google Scholar, 2Akinbami L.J. Moorman J.E. Liu X. Asthma prevalence, health care use, and mortality: United States, 2005-2009.Natl Health Stat Report. 2011; : 1-14PubMed Google Scholar, 3The Global Asthma Network. The Global Asthma Report. Auckland, New Zealand. 2014. Available at: http://www.globalasthmareport.org/resources/Global_Asthma_Report_2014.pdf. Accessed November 1, 2016.Google Scholar The disease is estimated to result in more than 10 million school days lost per year,2Akinbami L.J. Moorman J.E. Liu X. Asthma prevalence, health care use, and mortality: United States, 2005-2009.Natl Health Stat Report. 2011; : 1-14PubMed Google Scholar and the health care costs are substantial, with pediatric emergency department visits alone totaling approximately US$272 million in 2010.4Pearson W.S. Goates S.A. Harrykissoon S.D. Miller S.A. State-based Medicaid costs for pediatric asthma emergency department visits.Prev Chronic Dis. 2014; 11: E108Crossref PubMed Scopus (36) Google Scholar 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.2Akinbami L.J. Moorman J.E. Liu X. Asthma prevalence, health care use, and mortality: United States, 2005-2009.Natl Health Stat Report. 2011; : 1-14PubMed Google Scholar Control of symptoms can be achieved in many asthmatic children through avoidance of asthma triggers and/or with conventional medications, assuming adherence.5Lang A. Carlsen K.H. Haaland G. Devulapalli C.S. Munthe-Kaas M. Mowinckel P. et al.Severe asthma in childhood: assessed in 10 year olds in a birth cohort study.Allergy. 2008; 63: 1054-1060Crossref PubMed Scopus (117) Google Scholar, 6Szefler S.J. Mitchell H. Sorkness C.A. Gergen P.J. O'Connor G.T. 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Getting the basics right resolves most cases of uncontrolled and problematic asthma.Acta Paediatr. 2015; 104: 916-921Crossref PubMed Scopus (29) Google Scholar However, some children fulfill the criteria for true therapy-resistant asthma: 4 (2.8%) of 142 in the retrospective chart review7de Groot E.P. Kreggemeijer W.J. Brand P.L.P. Getting the basics right resolves most cases of uncontrolled and problematic asthma.Acta Paediatr. 2015; 104: 916-921Crossref PubMed Scopus (29) Google Scholar and 3 (4.5%) of 67 in a separate childhood asthma study in Oslo, Norway,5Lang A. Carlsen K.H. Haaland G. Devulapalli C.S. Munthe-Kaas M. Mowinckel P. et al.Severe asthma in childhood: assessed in 10 year olds in a birth cohort study.Allergy. 2008; 63: 1054-1060Crossref PubMed Scopus (117) Google Scholar did 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.6Szefler S.J. Mitchell H. Sorkness C.A. Gergen P.J. O'Connor G.T. Morgan W.J. et al.Management of asthma based on exhaled nitric oxide in addition to guideline-based treatment for inner-city adolescents and young adults: a randomised controlled trial.Lancet. 2008; 372: 1065-1072Abstract Full Text Full Text PDF PubMed Scopus (374) Google Scholar, 8Chung K.F. Wenzel S.E. Brozek J.L. Bush A. Castro M. Sterk P.J. et al.International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma.Eur Respir J. 2014; 43: 343-373Crossref PubMed Scopus (2433) Google Scholar, 9Hedlin G. Bush A. Lødrup Carlsen K. Wennergren G. De Benedictis F.M. 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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.13US Food and Drug Administration (FDA) Xolair (omalizumab) US Prescribing Information. 2015. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/103976s5224lbl.pdf. Accessed November 23, 2016.Google Scholar 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.14European Medicines Agency (EMA) Xolair (omalizumab) Summary of Product Characteristics. 2016. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000606/WC500057298.pdf. Accessed November 23, 2016.Google Scholar The pediatric indication for omalizumab in asthmatic patients (use in children aged ≥6 years) was approved by the EMA and FDA in 2009 and 2016, respectively.14European Medicines Agency (EMA) Xolair (omalizumab) Summary of Product Characteristics. 2016. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000606/WC500057298.pdf. 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Derelle J. et al.Real-life long-term omalizumab therapy in children with severe allergic asthma.Eur Respir J. 2015; 46: 856-859Crossref PubMed Scopus (85) Google Scholar Additionally, a reduction in the incidence and frequency of asthma exacerbations was observed in the omalizumab versus placebo groups, and both investigator- and 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).39Lemanske R.F. Nayak A. McAlary M. Everhard F. Fowler-Taylor A. Gupta N. Omalizumab improves asthma-related quality of life in children with allergic asthma.Pediatrics. 2002; 110: e55Crossref PubMed Scopus (126) Google Scholar, 40Novartis Pharmaceuticals Corporation, East Hanover, New Jersey. Data on file from study 010. Compiled March, 2000.Google ScholarTable IStudy design and efficacy outcomes in omalizumab studies in pediatric patientsStudy and durationKey inclusion criteriaBaseline patient characteristicsStudy designEfficacy outcomesMilgrom et al (Study 010)38Milgrom H. Berger W. Nayak A. Gupta N. Pollard S. McAlary M. et al.Treatment of childhood asthma with anti-immunoglobulin E antibody (omalizumab).Pediatrics. 2001; 108: e36Crossref PubMed Scopus (442) Google ScholarRDBPCT28 wk•6-12 y of age•Moderate-to-severe AA (≥1-y duration)•Total serum IgE level of 30-1300 IU/mL•Well controlled for ≥3 mo with ICS (168-420 μg/d BDP equivalent) + reliever as needed•FEV1(pred) ≥60%•Randomized patients (no.):○Total, 334○OMA, 225○Pbo, 109•Mean age (y), range:○OMA, 9.4 (5–12)○Pbo, 9.5 (6-12)•Mean serum IgE level (IU/mL), range:○OMA, 348 (20-1269)○Pbo, 323 (29-1212)•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•16-wk stable-steroid phase: constant ICS dose•12-wk steroid-reduction phase: 8-wk steroid-reduction phase to minimum effective dose and then maintained for the final 4 wk•Treatment dose frequency: 0.016 mg/kg/IgE (IU/mL) per 4 wk∗Minimum dose.•Median percentage reduction of ICS dose: OMA, 100%; Pbo, 66.7%; P = .001•Proportion of patients in whom ICS use was withdrawn completely: OMA, 55%; Pbo, 39%; P = .004•Exacerbation rate during steroid-reduction phase: OMA, 18.2%; Pbo, 38.5%; P < .001•Physicians' evaluation (GETE) excellent/good: OMA, 31.5/44.7%; Pbo, 16.3/32.7%; P < .001 for comparison across all 5 GETE categories†GETE categories and study scoring as follows: 1, excellent; 2, good; 3, moderate; 4, poor; and 5, worsening. (mean [SD] score: OMA, 1.98 [0.86]; Pbo, 2.6 [1.06])Lemanske et al (Study 010: AQoL)39Lemanske R.F. Nayak A. McAlary M. Everhard F. Fowler-Taylor A. Gupta N. Omalizumab improves asthma-related quality of life in children with allergic asthma.Pediatrics. 2002; 110: e55Crossref PubMed Scopus (126) Google ScholarRDBPCT28 wk•As described above38Milgrom H. Berger W. Nayak A. Gupta N. Pollard S. McAlary M. et al.Treatment of childhood asthma with anti-immunoglobulin E antibody (omalizumab).Pediatrics. 2001; 108: e36Crossref PubMed Scopus (442) Google Scholar•Randomized patients (no.):○Total, 334○OMA, 225○Pbo, 109•Mean age (y), range:○OMA, 9.4 (5-12)○Pbo, 9.5 (6-12)•Mean serum IgE level (IU/mL), range:○OMA, 348 (20-1269)○Pbo, 323 (29-1212)•As described above38Milgrom H. Berger W. Nayak A. Gupta N. Pollard S. McAlary M. et al.Treatment of childhood asthma with anti-immunoglobulin E antibody (omalizumab).Pediatrics. 2001; 108: e36Crossref PubMed Scopus (442) Google Scholar•The pediatric AQLQ was administered at baseline, week 16, and week 28‡Pediatric AQLQ domains: activity limitation, emotional function, symptoms, and overall.•Treatment dose frequency: 0.016 mg/kg/IgE (IU/mL) per 4 wk∗Minimum dose.•Mean (SD) change in pediatric AQLQ domain scores from baseline to week 28:○Activity limitations40Novartis Pharmaceuticals Corporation, East Hanover, New Jersey. Data on file from study 010. Compiled March, 2000.Google Scholar OMA, 0.5 (1.4); Pbo, 0.1 (1.3); P < .05○Symptoms domain40Novartis Pharmaceuticals Corporation, East Hanover, New Jersey. Data on file from study 010. Compiled March, 2000.Google Scholar OMA, 0.3 (1.2); Pbo, −0.0 (1.3); P < .05○Emotional function40Novartis Ph