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Long-term effectiveness and safety of omalizumab in pediatric and adult patients with moderate-to-severe inadequately controlled allergic asthma

Open AccessPublished:September 25, 2022DOI:https://doi.org/10.1016/j.waojou.2022.100695

      Abstract

      Omalizumab is recommended as an add-on therapy in patients aged ≥6 years with inadequately controlled, moderate-to-severe persistent allergic asthma. The efficacy and safety of omalizumab treatment in allergic asthma clinical trials and its effectiveness in the real world have been reported in numerous studies. In this review, we examine clinical evidence in pediatric and adult patients with allergic asthma who received omalizumab treatment for at least 2 years, to assess its effectiveness, durability, and trajectory of response over time as well as safety. We performed a literature search from inception until March 2022 in PubMed using the keywords “omalizumab” and “allergic asthma” to retrieve articles examining the effects of omalizumab in patients with allergic asthma, aged ≥6 years. Only articles that evaluated the effectiveness of omalizumab for at least 2 years were included. Data from case reports were excluded. Our review confirmed the long-term effectiveness and safety of omalizumab, demonstrating reduced rate of exacerbations, improved lung function, asthma control, and quality of life, decreased health care resource utilization, and use of corticosteroids (oral/inhaled) with a favorable safety and tolerability profile for up to 9 years in adult patients with moderate-to-severe allergic asthma. Similar results were also observed in the pediatric population with up to 7.5 years of omalizumab treatment. This review highlights and confirms the sustained clinical benefits of omalizumab over long periods of treatment in pediatric and adult populations with allergic asthma.

      Keywords

      Introduction

      Patients with moderate or severe asthma require treatment with medium-to high-dose inhaled corticosteroids (ICS) ± long-acting β2-agonists (LABAs) or other add-on controllers. However, some patients with severe asthma remain uncontrolled despite treatment with high-dose ICS/LABA ± other add-on agents such as leukotriene receptor antagonists and/or long-acting muscarinic antagonists.
      While assessing severe asthma, attention to possible comorbidities, differential diagnoses, and accurate phenotyping are needed prior to consideration of complex therapies, such as biologics. Failure to do so may result in non-response to all biologics.
      • Boulet L.P.
      • Reddel H.K.
      • Bateman E.
      • Pedersen S.
      • FitzGerald J.M.
      • O’Byrne P.M.
      The global initiative for asthma (GINA): 25 years later.
      Omalizumab, an anti-IgE monoclonal antibody, was the first biologic approved for patients aged ≥6 years with moderate-to-severe persistent asthma (USA) or severe persistent allergic asthma (Europe), uncontrolled despite appropriate high-dose ICS treatment., Randomized clinical studies and real-world evidence have demonstrated the efficacy and effectiveness of omalizumab in reducing asthma exacerbations and hospitalization rates, improving quality of life (QoL) and asthma daily symptoms. In addition, omalizumab has a very satisfactory short- and long-term safety profile in children aged 6–12 years, teenagers, and adults.
      • Normansell R.
      • Walker S.
      • Milan S.J.
      • Walters E.H.
      • Nair P.
      Omalizumab for asthma in adults and children.
      • Rodrigo G.J.
      • Neffen H.
      Systematic review on the use of omalizumab for the treatment of asthmatic children and adolescents.
      • Milgrom H.
      • Berger W.
      • Nayak A.
      • et al.
      Treatment of childhood asthma with anti-immunoglobulin E antibody (omalizumab).
      • Just J.
      • Deschildre A.
      • Lejeune S.
      • Amat F.
      New perspectives of childhood asthma treatment with biologics.
      • Braunstahl G.J.
      • Chen C.W.
      • Maykut R.
      • et al.
      The eXpeRience registry: the ‘real-world’ effectiveness of omalizumab in allergic asthma.
      • Caminati M.
      • Senna G.
      • Chieco Bianchi F.
      • et al.
      Omalizumab management beyond clinical trials: the added value of a network model.
      • Dal Negro R.W.
      • Tognella S.
      • Pradelli L.
      A 36-month study on the cost/utility of add-on omalizumab in persistent difficult-to-treat atopic asthma in Italy.
      • Humbert M.
      • Beasley R.
      • Ayres J.
      • et al.
      Benefits of omalizumab as add-on therapy in patients with severe persistent asthma who are inadequately controlled despite best available therapy (GINA 2002 step 4 treatment): innovate.
      • Ledford D.
      • Busse W.
      • Trzaskoma B.
      • et al.
      A randomized multicenter study evaluating Xolair persistence of response after long-term therapy.
      • Menzella F.
      • Galeone C.
      • Formisano D.
      • et al.
      Real-life efficacy of omalizumab after 9 Years of follow-up.
      • Zazzali J.L.
      • Raimundo K.P.
      • Trzaskoma B.
      • Rosén K.E.
      • Schatz M.
      Changes in asthma control, work productivity, and impairment with omalizumab: 5-year EXCELS study results.
      Omalizumab is now widely used for various indications and has recently reached >1.75 million patient-years of exposure.
      In this review, we comprehensively examine the existing clinical evidence from real-world studies, including pediatric and adult patients with allergic asthma who have received omalizumab treatment for ≥2 years, to evaluate its effectiveness and safety and help clinicians assess the durability and trajectory of its response over time.

      Methodology

      We performed a literature search in PubMed published from inception until March 2022, using the keywords “omalizumab” and “allergic asthma” to retrieve articles evaluating the effects of omalizumab in allergic asthma in patients aged ≥6 years. Studies that evaluated the effectiveness of omalizumab for ≥2 years, with real-life experiences, registry-based or observational designs, and published in the English language, were deemed eligible for inclusion. Case reports were excluded. The included articles were further categorized into 2 sections based on treatment duration: omalizumab use for 2–5 years and >5 years (Table 1).
      Table 1Publications that evaluated omalizumab use in asthma patients receiving the drug for >2 years.
      PublicationStudy nameTreatment duration or follow-up periodNumber of patients enrolled (Male: Female)Mean Age (mean ± SD), years
      Omalizumab treatment for 2–5 years
      Studies with adult patients (>18 years)
      Schreiber J et al., 2020
      • Schreiber J.
      • Schwab Sauerbeck I.
      • Mailänder C.
      The long-term effectiveness and safety of omalizumab on patient- and physician-reported asthma control: a three-year, real-life observational study.
      NA3 years153 (M: 60; F: 93)49 ± 12.16
      Cavaliere et al., 2020
      • Cavaliere C.
      • Begvarfaj E.
      • Incorvaia C.
      • et al.
      Long-term omalizumab efficacy in allergic rhinitis.
      NA36 Months10 (M: 06; F: 04)47 (26–70)
      Age represented as mean (range)
      Kirchnerová OR et al., 2019
      • Kirchnerová O.R.
      • Valena T.
      • Novosad J.
      • Teřl M.
      • et al.
      Czech eXpeRience Study Group
      Real-world effectiveness and safety of omalizumab in patients with uncontrolled severe allergic asthma from the Czech Republic.
      eXpeRience registry (Czech Republic subgroup)2 years112 (M: 44; F: 68)44.0 ± 13.0
      Pelaia C et al., 2018
      • Pelaia C.
      • Calabrese C.
      • Barbuto S.
      • et al.
      Omalizumab lowers asthma exacerbations, oral corticosteroid intake and blood eosinophils: results of a 5-YEAR single-centre observational study.
      NA5 years15 (M: 05; F: 10)46.60 ± 13.21
      Ke et al., 2018
      • Ke X.
      • Wertz D.
      • Huang Q.
      • et al.
      Real-world clinical characteristics, treatment patterns, and exacerbations in US patients with asthma newly treated with omalizumab.
      NA12 and 24 Months1564 (M: 598; F: 966)44.9 ± 15.67
      Al-Ahmad M et al., 2018
      • Al-Ahmad M.
      • Arifhodzic N.
      • Nurkic J.
      • et al.
      Real-life" efficacy and safety aspects of 4-year omalizumab treatment for asthma.
      NA4 years65 (M: 22; F: 43)46.69 ± 11.55
      Iribarren C et al., 2017
      • Iribarren C.
      • Rothman K.J.
      • Bradley M.S.
      • Carrigan G.
      • Eisner M.D.
      • Chen H.
      Cardiovascular and cerebrovascular events among patients receiving omalizumab: pooled analysis of patient-level data from 25 randomized, double-blind, placebo-controlled clinical trials.
      EXCELS study (data on cardiovascular and cerebrovascular events)5 years5007 (omalizumab cohort)2829 (non-omalizumab cohort) (M: 7857; F:5079)Omalizumab: 44 ± 17

      Non-omalizumab: 46 ± 17
      Sposato B et al., 2017
      • Sposato B.
      • Scalese M.
      • Latorre M.
      • et al.
      Xolair Italian Study Group
      Can the response to Omalizumab be influenced by treatment duration? A real-life study.
      NAPatients divided into different subgroups based on treatment duration: <12, 12–24, 24–60, and >60 months340 (M: 121; F: 219)≤12 M: 51 (42–64)
      Age represented as mean (range)


      12–24 M: 51 (40–61)
      Age represented as mean (range)


      24–60 M: 54 (46–62)
      Age represented as mean (range)


      >60 M: 53 (44–63)
      Age represented as mean (range)
      Sposato B et al., 2016
      • Sposato B.
      • Scalese M.
      • Latorre M.
      • et al.
      Effects of omalizumab in severe asthmatics across ages: a real life Italian experience.
      NA35.1 ± 21.7 months
      Treatment duration represented as mean ± SD.
      105 (M: 33; F: 72)29 ± 6 (18–39), 54 ± 7 (40–64), 69 ± 4 (≥65)
      Tat TS et al., 2016
      • Tat T.S.
      • Cilli A.
      Evaluation of long-term safety and efficacy of omalizumab in elderly patients with uncontrolled allergic asthma.
      NA35.6 ± 17.8 months
      Treatment duration represented as mean ± SD.
      19 (M: 05; F: 14)69.3 ± 5.8
      Zazzali JL et al., 2015
      • Zazzali J.L.
      • Raimundo K.P.
      • Trzaskoma B.
      • Rosén K.E.
      • Schatz M.
      Changes in asthma control, work productivity, and impairment with omalizumab: 5-year EXCELS study results.
      EXCELS study5 years4930 (omalizumab cohort)

      2779 (non-omalizumab cohort) (M: 2714; F: 4993)
      Omalizumab: 44.4 ± 16.6

      Non-omalizumab: 46.2 ± 17.1
      Novelli F et al., 2015
      • Novelli F.
      • Latorre M.
      • Vergura L.
      • et al.
      Asthma control in severe asthmatics under treatment with omalizumab: a cross-sectional observational study in Italy.
      NA32 (4–120) months
      Treatment duration represented as median (range).
      306 (M: 36.9%; F: 63.1%)52.0 ± 13.7
      Lopez Tiro JJ et al., 2015
      • Lopez Tiro J.J.
      • Contreras E.A.
      • del Pozo M.E.
      • Gómez Vera J.
      • Larenas Linnemann D.
      Real life study of three years omalizumab in patients with difficult-to-control asthma.
      NA3 years52 (M: 10; F: 42)43.5 (15–67)
      Age represented as mean (range)
      Pereira Barbosa M et al., 2015
      • Pereira Barbosa M.
      • Bugalho de Almeida A.
      • Pereira C.
      • Chen C.W.
      • Georgiou P.
      • Peachey G.
      eXpeRience study group.
      Real-life efficacy and safety of omalizumab in Portuguese patients with persistent uncontrolled asthma.
      eXpeRience study (Portuguese subgroup)2 years62 (M: 19; F: 43)49.2 ± 15.0
      Caminati M et al., 2014
      • Caminati M.
      • Senna G.
      • Chieco Bianchi F.
      • et al.
      Omalizumab management beyond clinical trials: the added value of a network model.
      NA22.97 ± 16.55 months
      Treatment duration represented as mean ± SD.
      59 (M: 29; F: 30)45.59 ± 11.51
      Vieira T et al., 2014
      • Vieira T.
      • de Oliveira J.F.
      • da Graca Castel-Branco M.
      Short and long-term quality of life and asthma control with omalizumab therapy in a real life setting in Portugal.
      NA2 years15 (M: 02; F: 13)46.5 ± 10.8
      Braunstahl GJ et al., 2014
      • Braunstahl G.J.
      • Canvin J.
      • Peachey G.
      • Chen C.W.
      • Georgiou P.
      Healthcare resource utilization in patients receiving omalizumab for allergic asthma in a real-world setting.
      eXpeRience study (data on HCRU)2 years925 (M: 325; F: 600)45 ± 15.0
      Long A et al., 2014
      • Long A.
      • Rahmaoui A.
      • Rothman K.J.
      • et al.
      Incidence of malignancy in patients with moderate-to-severe asthma treated with or without omalizumab.
      EXCELS study (safety data)5 years7857 (M: 2778; F: 5079)Omalizumab: 44 ± 17

      Non-omalizumab: 46 ± 17
      Braunstahl GJ et al., 2013
      • Braunstahl G.J.
      • Chen C.W.
      • Maykut R.
      • et al.
      The eXpeRience registry: the ‘real-world’ effectiveness of omalizumab in allergic asthma.
      eXpeRience study2 years925 (M: 325; F: 600)45 ± 15.0
      Braunstahl GJ et al., 2013
      • Braunstahl G.J.
      • Chlumský J.
      • Peachey G.
      • Chen C.W.
      Reduction in oral corticosteroid use in patients receiving omalizumab for allergic asthma in the real-world setting.
      eXpeRience study (data on corticosteroid use)2 years263 (M: 94; F: 169)46 ± 13.13
      Lafeuille MH et al., 2013
      • Lafeuille M.H.
      • Gravel J.
      • Zhang J.
      • Gorsh B.
      • Figliomeni M.
      • Lefebvre P.
      Association between consistent omalizumab treatment and asthma control.
      NA2 years3044 (M: 1146; F: 1898)48.5 ± 15.7
      Chen H et al., 2013
      • Chen H.
      • Eisner M.D.
      • Haselkorn T.
      • Trzaskoma B.
      Concomitant asthma medications in moderate-to-severe allergic asthma treated with omalizumab.
      EXCELS study (interim analysis)2 years∼5000 (omalizumab-treated)

      >2800 (non-omalizumab treated) (M: 2753; F: 5082)
      New starts: 44.3 ± 16.0

      Established user: 44.5 ± 16.6

      Non-omalizumab: 46.2 ± 17.1
      Ozgur ES et al., 2013
      • Ozgur E.S.
      • Özge C.
      • Ïlvan A.
      • Naycı S.A.
      Assessment of long-term omalizumab treatment in patients with severe allergic asthma long-term omalizumab treatment in severe asthma.
      NA40.81 ± 8.2 months
      Treatment duration represented as mean ± SD.
      26 (M: 05; F: 21)47.6 ± 13.9
      Vennera Mdel C et al., 2012
      • Vennera Mdel C.
      • Pérez De Llano L.
      • Bardagí S.
      • et al.
      Omalizumab therapy in severe asthma: experience from the Spanish registry--some new approaches.
      NA2 years266 (M: 83; F: 183)51.0 ± 13.7
      Dal Negro RW et al., 2012
      • Dal Negro R.W.
      • Tognella S.
      • Pradelli L.
      A 36-month study on the cost/utility of add-on omalizumab in persistent difficult-to-treat atopic asthma in Italy.
      NA3 years16 (M: 08; F: 08)45.4 (31–64)
      Age represented as mean (range)
      Menzella F et al., 2012
      • Menzella F.
      • Facciolongo N.
      • Piro R.
      • et al.
      Clinical and pharmacoeconomic aspects of omalizumab: a 4-year follow-up.
      NA4 years11 (M: 07; F: 04)47.5 ± 9.64
      Tzortzaki EG et al., 2012
      • Tzortzaki E.G.
      • Georgiou A.
      • Kampas D.
      • et al.
      Long-term omalizumab treatment in severe allergic asthma: the South-Eastern Mediterranean “real-life” experience.
      NA4 years60 (M: 24; F: 36)54 ± 14
      Studies with pediatric patients (≥ 6 years to <18 years)
      Sztafińska A et al., 2017
      • Sztafinska A.
      • Jerzyńska J.
      • Stelmach W.
      • Woicka-Kolejwa K.
      • Stelmach I.
      Quality of life in asthmatic children and their caregivers after two-year treatment with omalizumab, a real-life study.
      NA∼2 years19 (M: 15; F: 4)11.36 (6–15)
      Odajima H et al., 2017
      • Odajima H.
      • Ebisawa M.
      • Nagakura T.
      • et al.
      Long-term safety, efficacy, pharmacokinetics and pharmacodynamics of omalizumab in children with severe uncontrolled asthma.
      NA116.6 (46.9–151.1) weeks
      Treatment duration represented as median (range).
      38 (M: 23; F: 15)11.5 ± 2.52
      Deschildre A et al., 2015
      • Deschildre A.
      • Marguet C.
      • Langlois C.
      • et al.
      Real-life long-term omalizumab therapy in children with severe allergic asthma.
      NA2 years104 (M: 60; F: 44)11.9 (11.3–12.5)
      Age represented as mean (range)
      Omalizumab treatment for >5 years
      Studies with adult patients (>18 years)
      Papaioannou AI et al., 2021
      • Papaioannou A.I.
      • Mplizou M.
      • Porpodis K.
      • et al.
      Long-term efficacy and safety of omalizumab in patients with allergic asthma: a real-life study.
      NA10.6 ± 1.2 years45 (M: 15; F: 30)55.3 ± 12.2
      Mansur AH et al., 2017
      • Mansur A.H.
      • Srivastava S.
      • Mitchell V.
      • Sullivan J.
      • Kasujee I.
      Longterm clinical outcomes of omalizumab therapy in severe allergic asthma: study of efficacy and safety.
      NA60.7 ± 30.9 months
      Treatment duration represented as mean ± SD.
      45 (M: 08; F: 37)44.9 (19–69)
      Age represented as mean (range)
      Menzella F et al., 2017
      • Menzella F.
      • Galeone C.
      • Formisano D.
      • et al.
      Real-life efficacy of omalizumab after 9 Years of follow-up.
      NA9 years8 (M: 05; F: 03)43 ± 9
      Di Bona et al., 2017
      • Di Bona D.
      • Fiorino I.
      • Taurino M.
      • et al.
      Long-term “real-life” safety of omalizumab in patients with severe uncontrolled asthma: a nine-year study.
      NA3.8 ± 2.6 years
      Treatment duration represented as mean ± SD.
      (range 0.2–9 years)
      91 (M: 24; F: 67)49.9 ± 14.9
      Ledford D et al., 2017
      • Ledford D.
      • Busse W.
      • Trzaskoma B.
      • et al.
      A randomized multicenter study evaluating Xolair persistence of response after long-term therapy.
      XPORT6 years (5 years during EXCELS study and 1-year follow-up)176 (M: 53; F: 123)51.5 ± 12.5
      Gemİcİoğlu B et al., 2016
      • Gemİcİoğlu B.
      • Öztürk B.Ç.
      • Duman B.
      Comparison of allergic asthma patients treated with omalizumab and non-allergic patients treated with continuous oral corticosteroids: results of five year follow-up therapies.
      NA5.5–7 years17 (M: 04; F: 13)48.3 ± 16.4
      Storms W et al., 2012
      • Storms W.
      • Bowdish M.S.
      • Farrar J.R.
      Omalizumab and asthma control in patients with moderate-to-severe allergic asthma: a 6-year pragmatic data review.
      NA6 years167 (M: 54; F: 113)52.0 (14–82)
      Age represented as mean (range)
      Pace E et al., 2011
      • Pace E.
      • Ferraro M.
      • Bruno A.
      • Chiappara G.
      • Bousquet J.
      • Gjomarkaj M.
      Clinical benefits of 7 years of treatment with omalizumab in severe uncontrolled asthmatics.
      NA7 years7 (M: 04; F: 03)50 ± 8
      Studies with pediatric patients (≥ 6 years to <18 years)
      Deschildre et al., 2019
      • Deschildre A.
      • Roussel J.
      • Drumez E.
      • et al.
      Omalizumab discontinuation in children with severe allergic asthma: an observational real-life study.
      NA46.2 (31.5–90.3) months60 (M: 30; F: 30)11.25 (6–16.2)
      Age represented as mean (range)
      Folqué MM et al., 2019
      • Folque M.M.
      • Lozano J.
      • Riggioni C.
      • et al.
      “Real-life” experience in asthmatic children treated with omalizumab up to six-years follow-up.
      NAUp to 6 years48 (M: 27; F: 21)11.5 (5–17)
      Age represented as mean (range)
      Namazova-Baranova L et al., 2015
      • Namazova-Baranova L.
      • Vishneva E.
      • Smirnov V.
      • et al.
      The patient registry of children with severe persistent uncontrolled asthma as a tool for long-term dynamic monitoring.
      NA1–72 months10113.4 (6–17)
      Age represented as mean (range)
      Nieto García A et al., 2021
      • Nieto García A.
      • Garriga-Baraut T.
      • Plaza Martín A.M.
      • et al.
      Omalizumab outcomes for up to 6 years in pediatric patients with severe persistent allergic asthma.
      ANCHORSUp to 6 years48411.1 (1.9–17.9)
      Age represented as mean (range)
      HCRU, healthcare resource utilization, NA, not applicable.
      a Treatment duration represented as median (range).
      b Treatment duration represented as mean ± SD.
      c Age represented as mean (range)
      Data on exacerbation rate, lung function, asthma control, QoL, systemic corticosteroid (SCS) or ICS use, and healthcare resource utilization (HCRU) were reported as measures of effectiveness of omalizumab. Although the criterion set for defining exacerbations differed for each study, making between-study comparisons difficult, certain criteria such as exacerbations requiring oral corticosteroids (EROCS), worsening of asthma, increased need for ICS or SCS, hospitalizations, and emergency room (ER) visits are common in many of the studies for definitions of exacerbations (Supplementary Table 1).
      Other parameters assessed were lung function in terms of forced expiratory volume in 1 second (FEV1), asthma control measured by Asthma Control Test (ACT) or Asthma Control Questionnaire (ACQ), QoL assessed using different questionnaires including Asthma Quality of Life Questionnaire (AQLQ), and Asthma Life Questionnaire (ALQ).
      • Braunstahl G.J.
      • Chen C.W.
      • Maykut R.
      • et al.
      The eXpeRience registry: the ‘real-world’ effectiveness of omalizumab in allergic asthma.
      ,
      • Dal Negro R.W.
      • Tognella S.
      • Pradelli L.
      A 36-month study on the cost/utility of add-on omalizumab in persistent difficult-to-treat atopic asthma in Italy.
      ,
      • Vieira T.
      • de Oliveira J.F.
      • da Graca Castel-Branco M.
      Short and long-term quality of life and asthma control with omalizumab therapy in a real life setting in Portugal.
      ,
      • Pereira Barbosa M.
      • Bugalho de Almeida A.
      • Pereira C.
      • Chen C.W.
      • Georgiou P.
      • Peachey G.
      eXpeRience study group.
      Real-life efficacy and safety of omalizumab in Portuguese patients with persistent uncontrolled asthma.
      , In some studies, early clinical response to omalizumab treatment was evaluated using the validated “global evaluation of treatment effectiveness (GETE)” tool.
      • Braunstahl G.J.
      • Chen C.W.
      • Maykut R.
      • et al.
      The eXpeRience registry: the ‘real-world’ effectiveness of omalizumab in allergic asthma.
      HCRU in terms of steroidal use and number of hospitalizations, medical visits and ER visits was also assessed.
      • Braunstahl G.J.
      • Canvin J.
      • Peachey G.
      • Chen C.W.
      • Georgiou P.
      Healthcare resource utilization in patients receiving omalizumab for allergic asthma in a real-world setting.

      Results

      We identified 42 publications meeting the inclusion criteria, 30 of which included a treatment duration/follow-up of 2–5 years and 12 were of >5 years. The eligible literature data with demographic details of the patients are shown in Table 1.

      Long-term effectiveness

      Asthma exacerbations

      Omalizumab treatment showed ≥72% reduction in exacerbation rates in patients with moderate-to-severe allergic asthma.
      • Vieira T.
      • de Oliveira J.F.
      • da Graca Castel-Branco M.
      Short and long-term quality of life and asthma control with omalizumab therapy in a real life setting in Portugal.
      ,
      • Vennera Mdel C.
      • Pérez De Llano L.
      • Bardagí S.
      • et al.
      Omalizumab therapy in severe asthma: experience from the Spanish registry--some new approaches.
      ,
      • Deschildre A.
      • Marguet C.
      • Langlois C.
      • et al.
      Real-life long-term omalizumab therapy in children with severe allergic asthma.
      The proportion of patients experiencing exacerbations decreased over time, and notably, fewer or no episodes of exacerbations requiring ER visits or hospitalizations were observed.
      • Pelaia C.
      • Calabrese C.
      • Barbuto S.
      • et al.
      Omalizumab lowers asthma exacerbations, oral corticosteroid intake and blood eosinophils: results of a 5-YEAR single-centre observational study.
      • Ke X.
      • Wertz D.
      • Huang Q.
      • et al.
      Real-world clinical characteristics, treatment patterns, and exacerbations in US patients with asthma newly treated with omalizumab.
      • Al-Ahmad M.
      • Arifhodzic N.
      • Nurkic J.
      • et al.
      Real-life" efficacy and safety aspects of 4-year omalizumab treatment for asthma.
      ,
      • Novelli F.
      • Latorre M.
      • Vergura L.
      • et al.
      Asthma control in severe asthmatics under treatment with omalizumab: a cross-sectional observational study in Italy.
      Furthermore, these improvements were observed and maintained over a long time period (>5 years).
      • Papaioannou A.I.
      • Mplizou M.
      • Porpodis K.
      • et al.
      Long-term efficacy and safety of omalizumab in patients with allergic asthma: a real-life study.

      Omalizumab use for 2–5 years in adults with asthma

      All the studies included in this review showed that omalizumab treatment resulted in decreased asthma exacerbation rates (Fig. 1).
      • Braunstahl G.J.
      • Chen C.W.
      • Maykut R.
      • et al.
      The eXpeRience registry: the ‘real-world’ effectiveness of omalizumab in allergic asthma.
      • Caminati M.
      • Senna G.
      • Chieco Bianchi F.
      • et al.
      Omalizumab management beyond clinical trials: the added value of a network model.
      • Dal Negro R.W.
      • Tognella S.
      • Pradelli L.
      A 36-month study on the cost/utility of add-on omalizumab in persistent difficult-to-treat atopic asthma in Italy.
      ,
      • Vieira T.
      • de Oliveira J.F.
      • da Graca Castel-Branco M.
      Short and long-term quality of life and asthma control with omalizumab therapy in a real life setting in Portugal.
      ,
      • Pelaia C.
      • Calabrese C.
      • Barbuto S.
      • et al.
      Omalizumab lowers asthma exacerbations, oral corticosteroid intake and blood eosinophils: results of a 5-YEAR single-centre observational study.
      ,
      • Sposato B.
      • Scalese M.
      • Latorre M.
      • et al.
      Effects of omalizumab in severe asthmatics across ages: a real life Italian experience.
      ,
      • Tat T.S.
      • Cilli A.
      Evaluation of long-term safety and efficacy of omalizumab in elderly patients with uncontrolled allergic asthma.
      ,
      • Ozgur E.S.
      • Özge C.
      • Ïlvan A.
      • Naycı S.A.
      Assessment of long-term omalizumab treatment in patients with severe allergic asthma long-term omalizumab treatment in severe asthma.
      • Vennera Mdel C.
      • Pérez De Llano L.
      • Bardagí S.
      • et al.
      Omalizumab therapy in severe asthma: experience from the Spanish registry--some new approaches.
      • Menzella F.
      • Facciolongo N.
      • Piro R.
      • et al.
      Clinical and pharmacoeconomic aspects of omalizumab: a 4-year follow-up.
      • Tzortzaki E.G.
      • Georgiou A.
      • Kampas D.
      • et al.
      Long-term omalizumab treatment in severe allergic asthma: the South-Eastern Mediterranean “real-life” experience.
      ,
      • Deschildre A.
      • Marguet C.
      • Langlois C.
      • et al.
      Real-life long-term omalizumab therapy in children with severe allergic asthma.
      ,
      • Sposato B.
      • Scalese M.
      • Latorre M.
      • et al.
      Xolair Italian Study Group
      Can the response to Omalizumab be influenced by treatment duration? A real-life study.
      Patients treated with omalizumab for 2 years showed a marked decrease in mean annualized exacerbation rate ranging from 71.1% to 95.1% across studies.
      • Braunstahl G.J.
      • Chen C.W.
      • Maykut R.
      • et al.
      The eXpeRience registry: the ‘real-world’ effectiveness of omalizumab in allergic asthma.
      ,
      • Vieira T.
      • de Oliveira J.F.
      • da Graca Castel-Branco M.
      Short and long-term quality of life and asthma control with omalizumab therapy in a real life setting in Portugal.
      ,
      • Ke X.
      • Wertz D.
      • Huang Q.
      • et al.
      Real-world clinical characteristics, treatment patterns, and exacerbations in US patients with asthma newly treated with omalizumab.
      ,
      • Vennera Mdel C.
      • Pérez De Llano L.
      • Bardagí S.
      • et al.
      Omalizumab therapy in severe asthma: experience from the Spanish registry--some new approaches.
      ,
      • Deschildre A.
      • Marguet C.
      • Langlois C.
      • et al.
      Real-life long-term omalizumab therapy in children with severe allergic asthma.
      ,
      • Papaioannou A.I.
      • Mplizou M.
      • Porpodis K.
      • et al.
      Long-term efficacy and safety of omalizumab in patients with allergic asthma: a real-life study.
      In addition, a higher proportion of patients who were free from exacerbations requiring emergency visits or hospital admissions were observed with ∼2 years of omalizumab treatment compared with the pretreatment period (88.6% vs 41.9%).
      • Caminati M.
      • Senna G.
      • Chieco Bianchi F.
      • et al.
      Omalizumab management beyond clinical trials: the added value of a network model.
      Similar results were observed for exacerbations requiring oral steroids with 79% patients reported to be exacerbation free after ∼2 years of omalizumab treatment compared with 16.3% patients during the pretreatment period.
      • Caminati M.
      • Senna G.
      • Chieco Bianchi F.
      • et al.
      Omalizumab management beyond clinical trials: the added value of a network model.
      The effect of omalizumab on exacerbations was observed, irrespective of patients’ baseline lung function, steroid use, or smoking history.
      • Caminati M.
      • Senna G.
      • Chieco Bianchi F.
      • et al.
      Omalizumab management beyond clinical trials: the added value of a network model.
      Evaluation of data from studies with a longer treatment duration of ∼3–4 years also demonstrated reductions in the rate of exacerbations by 54.4%–95% in omalizumab-treated patients, indicating sustained effectiveness.
      • Dal Negro R.W.
      • Tognella S.
      • Pradelli L.
      A 36-month study on the cost/utility of add-on omalizumab in persistent difficult-to-treat atopic asthma in Italy.
      ,
      • Tat T.S.
      • Cilli A.
      Evaluation of long-term safety and efficacy of omalizumab in elderly patients with uncontrolled allergic asthma.
      ,
      • Ozgur E.S.
      • Özge C.
      • Ïlvan A.
      • Naycı S.A.
      Assessment of long-term omalizumab treatment in patients with severe allergic asthma long-term omalizumab treatment in severe asthma.
      ,
      • Menzella F.
      • Facciolongo N.
      • Piro R.
      • et al.
      Clinical and pharmacoeconomic aspects of omalizumab: a 4-year follow-up.
      ,
      • Tzortzaki E.G.
      • Georgiou A.
      • Kampas D.
      • et al.
      Long-term omalizumab treatment in severe allergic asthma: the South-Eastern Mediterranean “real-life” experience.
      Fig. 1
      Fig. 1Effect of omalizumab on exacerbation rate in allergic asthma

      Omalizumab use for >5 years in adults with asthma

      From pretreatment to the end of the 5-year omalizumab treatment period (follow-up: 5.5–7.0 years) the mean annualized exacerbation rate significantly decreased by 77.1% in 17 allergic patients.
      • Gemİcİoğlu B.
      • Öztürk B.Ç.
      • Duman B.
      Comparison of allergic asthma patients treated with omalizumab and non-allergic patients treated with continuous oral corticosteroids: results of five year follow-up therapies.
      Sustained reduction in rate of exacerbations was observed with omalizumab treatment in a 7-year study in 7 patients (∼78% decrease),
      • Pace E.
      • Ferraro M.
      • Bruno A.
      • Chiappara G.
      • Bousquet J.
      • Gjomarkaj M.
      Clinical benefits of 7 years of treatment with omalizumab in severe uncontrolled asthmatics.
      9-year study in 8 patients (∼87% decrease), and ∼10-year study in 45 patients (75% decrease; Fig. 1).
      • Menzella F.
      • Galeone C.
      • Formisano D.
      • et al.
      Real-life efficacy of omalizumab after 9 Years of follow-up.
      ,
      • Papaioannou A.I.
      • Mplizou M.
      • Porpodis K.
      • et al.
      Long-term efficacy and safety of omalizumab in patients with allergic asthma: a real-life study.
      In the XPORT study (Xolair Persistency Of Response After Long-Term Therapy), patients who continued omalizumab beyond 5 years were significantly less likely to experience a protocol-defined exacerbation compared with those who withdrew from treatment (odds ratio: 0.45 [95% CI: 0.24–0.83]). In addition, treatment continuation (1 year) prolonged the time-to-first exacerbation (hazard ratio [HR], 0.49 [95% CI: 0.28–0.86]).
      • Ledford D.
      • Busse W.
      • Trzaskoma B.
      • et al.
      A randomized multicenter study evaluating Xolair persistence of response after long-term therapy.

      Omalizumab use in pediatric patients with asthma

      In a cohort of 78 severe allergic asthmatic children aged 6–18 years, Deschildre et al observed a continuous decrease in severe exacerbation rates after 2 years of omalizumab treatment, with a trend to zero exacerbations at the end of 2 years, since the rate reached a mean (95% CI) of 0.22 (0.03–0.41) per year in the second year. A significant decrease of –72% and –83% in rate of exacerbation requiring emergency visits or hospitalization was observed during the first and second year (P = 0.0001) with no hospitalization for exacerbation during the second year.
      • Deschildre A.
      • Marguet C.
      • Langlois C.
      • et al.
      Real-life long-term omalizumab therapy in children with severe allergic asthma.
      Folqué et al in a 6-year follow-up study showed a significant decrease in the rate of hospital admissions and visits to the ER for asthma exacerbations during the third and fourth years of follow-up, respectively.
      • Folque M.M.
      • Lozano J.
      • Riggioni C.
      • et al.
      “Real-life” experience in asthmatic children treated with omalizumab up to six-years follow-up.
      In another 6-year follow-up study of 426 patients (ANCHORS), the mean number of moderate-to-severe exacerbations decreased significantly from 7.9 at baseline to 1.1 during the first year [−80.2%, P < 0.001]), and these improvements were sustained during the 6 year follow-up period with exacerbation numbers trending to zero after 2 years of omalizumab treatment.
      • Nieto García A.
      • Garriga-Baraut T.
      • Plaza Martín A.M.
      • et al.
      Omalizumab outcomes for up to 6 years in pediatric patients with severe persistent allergic asthma.
      It is important to highlight the improvements observed in terms of rate of exacerbations requiring systemic corticosteroids, reaching nearly zero in pediatric patients after 2 years of omalizumab treatment,
      • Deschildre A.
      • Marguet C.
      • Langlois C.
      • et al.
      Real-life long-term omalizumab therapy in children with severe allergic asthma.
      ,
      • Nieto García A.
      • Garriga-Baraut T.
      • Plaza Martín A.M.
      • et al.
      Omalizumab outcomes for up to 6 years in pediatric patients with severe persistent allergic asthma.
      which indeed is an important treatment goal in asthma management.

      Asthma control and GETE score

      Overall, omalizumab improved ACT scores in patients across all age groups, with greater improvements in the younger patients compared with the older patients. Patients who continued omalizumab treatment were more likely to have controlled asthma compared with those who discontinued and never reinitiated. The proportion of patients with good or excellent omalizumab response on global evaluation of treatment effectiveness (GETE) scale increased over years of treatment.

      Omalizumab use for 2–5 years in adult with asthma

      In a retrospective study, 44% of patients who received consistent omalizumab treatment for 24 months had uncontrolled asthma during the follow-up period (13–24 months) compared with 55% of patients who discontinued omalizumab at 12 months (and never reinitiated).
      • Lafeuille M.H.
      • Gravel J.
      • Zhang J.
      • Gorsh B.
      • Figliomeni M.
      • Lefebvre P.
      Association between consistent omalizumab treatment and asthma control.
      Omalizumab treatment for ∼2 years improved mean ACT scores by 6.0–7.0 points.
      • Braunstahl G.J.
      • Chen C.W.
      • Maykut R.
      • et al.
      The eXpeRience registry: the ‘real-world’ effectiveness of omalizumab in allergic asthma.
      ,
      • Vieira T.
      • de Oliveira J.F.
      • da Graca Castel-Branco M.
      Short and long-term quality of life and asthma control with omalizumab therapy in a real life setting in Portugal.
      ,
      • Pereira Barbosa M.
      • Bugalho de Almeida A.
      • Pereira C.
      • Chen C.W.
      • Georgiou P.
      • Peachey G.
      eXpeRience study group.
      Real-life efficacy and safety of omalizumab in Portuguese patients with persistent uncontrolled asthma.
      ,
      • Al-Ahmad M.
      • Arifhodzic N.
      • Nurkic J.
      • et al.
      Real-life" efficacy and safety aspects of 4-year omalizumab treatment for asthma.
      ,
      • Vennera Mdel C.
      • Pérez De Llano L.
      • Bardagí S.
      • et al.
      Omalizumab therapy in severe asthma: experience from the Spanish registry--some new approaches.
      A longer duration of treatment (3–4 years) demonstrated a further increase in mean ACT scores (from 4.2 to 11.6 points; Fig. 2).
      • Dal Negro R.W.
      • Tognella S.
      • Pradelli L.
      A 36-month study on the cost/utility of add-on omalizumab in persistent difficult-to-treat atopic asthma in Italy.
      ,
      • Pelaia C.
      • Calabrese C.
      • Barbuto S.
      • et al.
      Omalizumab lowers asthma exacerbations, oral corticosteroid intake and blood eosinophils: results of a 5-YEAR single-centre observational study.
      ,
      • Al-Ahmad M.
      • Arifhodzic N.
      • Nurkic J.
      • et al.
      Real-life" efficacy and safety aspects of 4-year omalizumab treatment for asthma.
      ,
      • Lopez Tiro J.J.
      • Contreras E.A.
      • del Pozo M.E.
      • Gómez Vera J.
      • Larenas Linnemann D.
      Real life study of three years omalizumab in patients with difficult-to-control asthma.
      ,
      • Ozgur E.S.
      • Özge C.
      • Ïlvan A.
      • Naycı S.A.
      Assessment of long-term omalizumab treatment in patients with severe allergic asthma long-term omalizumab treatment in severe asthma.
      ,
      • Tzortzaki E.G.
      • Georgiou A.
      • Kampas D.
      • et al.
      Long-term omalizumab treatment in severe allergic asthma: the South-Eastern Mediterranean “real-life” experience.
      Sposato et al showed that although ACT scores increased in all age groups of patients treated with omalizumab for ∼3 years, the level of improvement was greater in patients aged 18–39 years (by ∼9 points) compared with 40–64 years (by ∼7 points) and ≥65 years (by ∼5 points).
      • Sposato B.
      • Scalese M.
      • Latorre M.
      • et al.
      Effects of omalizumab in severe asthmatics across ages: a real life Italian experience.
      In contrast, Tat et al reported significant improvements in ACT scores by 11.4 points from baseline in elderly patients for the same treatment duration.
      • Tat T.S.
      • Cilli A.
      Evaluation of long-term safety and efficacy of omalizumab in elderly patients with uncontrolled allergic asthma.
      Fig. 2
      Fig. 2Effect of omalizumab on asthma control, as demonstrated by Asthma Control Test (ACT) score, in allergic asthma. Bars indicate the ACT score changes in individual studies. ACT, Asthma Control Test
      Omalizumab treatment for 2 years increased the proportion of patients with controlled or partly controlled asthma by ∼63% from baseline.
      • Braunstahl G.J.
      • Chen C.W.
      • Maykut R.
      • et al.
      The eXpeRience registry: the ‘real-world’ effectiveness of omalizumab in allergic asthma.
      In another real-world study, as compared to 24.1% of patients at baseline, 92.1% and 87.1% patients reported controlled/partially controlled asthma with omalizumab after 12 and 24 months of treatment, respectively.
      • Kirchnerová O.R.
      • Valena T.
      • Novosad J.
      • Teřl M.
      • et al.
      Czech eXpeRience Study Group
      Real-world effectiveness and safety of omalizumab in patients with uncontrolled severe allergic asthma from the Czech Republic.
      Omalizumab treatment for a median duration of 32 months resulted in good asthma control in 25.2%, partial control in 47.1%, and poor control in 24.5% of patients, according to GINA.
      • Novelli F.
      • Latorre M.
      • Vergura L.
      • et al.
      Asthma control in severe asthmatics under treatment with omalizumab: a cross-sectional observational study in Italy.
      Additionally, in the EXCELS study (Epidemiologic Study of Xolair [Omalizumab]: Evaluating Clinical Effectiveness and Long-term Safety in Patients With Moderate to Severe Asthma), more patients were well-controlled (ACT score of >20) after 5 years of omalizumab treatment compared with prior to treatment (66.7% vs 48.6% for omalizumab-naïve cohort, 60.3% vs 25% for new starters, and 61.3% vs 47.8% for established users).
      • Zazzali J.L.
      • Raimundo K.P.
      • Trzaskoma B.
      • Rosén K.E.
      • Schatz M.
      Changes in asthma control, work productivity, and impairment with omalizumab: 5-year EXCELS study results.
      Studies that evaluated response to omalizumab treatment on the GETE scale showed that the proportion of patients with good or excellent response increased from 74.6% at 4 months to 81.6% after 2 years of treatment
      • Vennera Mdel C.
      • Pérez De Llano L.
      • Bardagí S.
      • et al.
      Omalizumab therapy in severe asthma: experience from the Spanish registry--some new approaches.
      and from 72.7% at 8 months to 81.8% after 4 years of treatment.
      • Menzella F.
      • Facciolongo N.
      • Piro R.
      • et al.
      Clinical and pharmacoeconomic aspects of omalizumab: a 4-year follow-up.
      In a real-life, observational surveillance study, Al-Ahmad et al evaluated treatment response of omalizumab using modified physician GETE (mGETE) scale, which demonstrated an excellent response in 53.8% of patients at 16 weeks that increased to 73.8% after 4 years of treatment.
      • Al-Ahmad M.
      • Arifhodzic N.
      • Nurkic J.
      • et al.
      Real-life" efficacy and safety aspects of 4-year omalizumab treatment for asthma.

      Omalizumab use for >5 years in adults with asthma

      Significant improvements in asthma control from baseline have been reported in most studies that assessed omalizumab treatment for >5 years. This was demonstrated by a 5.1-point increase in mean ACT score
      • Gemİcİoğlu B.
      • Öztürk B.Ç.
      • Duman B.
      Comparison of allergic asthma patients treated with omalizumab and non-allergic patients treated with continuous oral corticosteroids: results of five year follow-up therapies.
      and a 1.7-point decrease in mean ACQ7 score over 5 years,
      • Mansur A.H.
      • Srivastava S.
      • Mitchell V.
      • Sullivan J.
      • Kasujee I.
      Longterm clinical outcomes of omalizumab therapy in severe allergic asthma: study of efficacy and safety.
      a 96.4% increase in ACT scores during a 6-year treatment,
      • Storms W.
      • Bowdish M.S.
      • Farrar J.R.
      Omalizumab and asthma control in patients with moderate-to-severe allergic asthma: a 6-year pragmatic data review.
      and a 2.2-point decrease in the mean symptom score after 7 years of omalizumab treatment (Fig. 2).
      • Pace E.
      • Ferraro M.
      • Bruno A.
      • Chiappara G.
      • Bousquet J.
      • Gjomarkaj M.
      Clinical benefits of 7 years of treatment with omalizumab in severe uncontrolled asthmatics.
      A recent study with ∼10 years of omalizumab treatment demonstrated nearly 6-point increase in ACT score at 3 years which remained high up to 8 years of treatment.
      • Papaioannou A.I.
      • Mplizou M.
      • Porpodis K.
      • et al.
      Long-term efficacy and safety of omalizumab in patients with allergic asthma: a real-life study.
      The XPORT study showed benefits of continuation of omalizumab treatment after long-term treatment results, supported by improved symptom control and reduced exacerbation risk.
      • Ledford D.
      • Busse W.
      • Trzaskoma B.
      • et al.
      A randomized multicenter study evaluating Xolair persistence of response after long-term therapy.

      Omalizumab use in pediatric patients with asthma

      Omalizumab treatment for ∼2 years improved Japanese pediatric asthma control program (JPAC) mean score by 3 points.
      • Odajima H.
      • Ebisawa M.
      • Nagakura T.
      • et al.
      Long-term safety, efficacy, pharmacokinetics and pharmacodynamics of omalizumab in children with severe uncontrolled asthma.
      In a French cohort of uncontrolled severe allergic asthmatic children, 80% of 73 children were well-controlled (Global Initiative for Asthma – GINA criteria) after 2 years of omalizumab treatment.
      • Deschildre A.
      • Marguet C.
      • Langlois C.
      • et al.
      Real-life long-term omalizumab therapy in children with severe allergic asthma.
      In severe allergic asthmatic children who had received omalizumab for 24 months, 76.7% of 30 children were controlled who were still on omalizumab maintenance therapy after a mean treatment duration of 46.2 months.
      • Deschildre A.
      • Roussel J.
      • Drumez E.
      • et al.
      Omalizumab discontinuation in children with severe allergic asthma: an observational real-life study.
      In the ANCHORS study (Asthma iN CHildren: Omalizumab in Real-life in Spain), 8.4% of 334 patients were controlled at baseline which improved significantly to 45.0% (148/329; [P < 0.001]) during the first year of omalizumab treatment and increased to 89.3% (75/84) at year 6.
      • Nieto García A.
      • Garriga-Baraut T.
      • Plaza Martín A.M.
      • et al.
      Omalizumab outcomes for up to 6 years in pediatric patients with severe persistent allergic asthma.

      Quality of life

      Omalizumab use for 2–5 years in adults with asthma

      Omalizumab treatment for ∼2 years increased mean AQLQ score by 0.94 points
      • Kirchnerová O.R.
      • Valena T.
      • Novosad J.
      • Teřl M.
      • et al.
      Czech eXpeRience Study Group
      Real-world effectiveness and safety of omalizumab in patients with uncontrolled severe allergic asthma from the Czech Republic.
      and mean QoL score by 9 points.
      • Odajima H.
      • Ebisawa M.
      • Nagakura T.
      • et al.
      Long-term safety, efficacy, pharmacokinetics and pharmacodynamics of omalizumab in children with severe uncontrolled asthma.
      Sustained improvement in QoL was observed with omalizumab for 3–4 years, as reflected by an increase in median AQLQ scores by 3.4 points after 3 years
      • Ozgur E.S.
      • Özge C.
      • Ïlvan A.
      • Naycı S.A.
      Assessment of long-term omalizumab treatment in patients with severe allergic asthma long-term omalizumab treatment in severe asthma.
      and by 2.8 points after 4 years
      • Menzella F.
      • Facciolongo N.
      • Piro R.
      • et al.
      Clinical and pharmacoeconomic aspects of omalizumab: a 4-year follow-up.
      of treatment; a decrease in mean St. George's Respiratory Questionnaire score of 21.4 points was observed after 3 years of treatment.
      • Dal Negro R.W.
      • Tognella S.
      • Pradelli L.
      A 36-month study on the cost/utility of add-on omalizumab in persistent difficult-to-treat atopic asthma in Italy.

      Omalizumab use for >5 years in adults with asthma

      In the only study that evaluated the effect of omalizumab on QoL beyond 5 years, a significant increase in median AQLQ score by 3.4 points was observed over 9 years from baseline.
      • Menzella F.
      • Galeone C.
      • Formisano D.
      • et al.
      Real-life efficacy of omalizumab after 9 Years of follow-up.

      Omalizumab use in pediatric patients with asthma

      The Pediatric Asthma Quality of Life Questionnaire (PAQLQ) scores improved after 16, 24, and 104 weeks of omalizumab treatment compared with baseline, although the difference between time points was not significant. Significant improvements in total PAQLQ scores >1.5 points were achieved by 41.5% and 39.6% of children after 52 and 104 weeks of treatment, respectively. Of the total population, only 5% of children did not respond (improvement of PAQLQ <0.5 points) to omalizumab therapy.
      • Sztafinska A.
      • Jerzyńska J.
      • Stelmach W.
      • Woicka-Kolejwa K.
      • Stelmach I.
      Quality of life in asthmatic children and their caregivers after two-year treatment with omalizumab, a real-life study.

      Use of oral corticosteroids

      Omalizumab use for 2–5 years in adults with asthma

      Treatment with omalizumab for 2 years resulted in decrease in the rate of OCS use as well as proportion of patients receiving OCS compared with baseline.
      • Humbert M.
      • Beasley R.
      • Ayres J.
      • et al.
      Benefits of omalizumab as add-on therapy in patients with severe persistent asthma who are inadequately controlled despite best available therapy (GINA 2002 step 4 treatment): innovate.
      ,
      • Schreiber J.
      • Schwab Sauerbeck I.
      • Mailänder C.
      The long-term effectiveness and safety of omalizumab on patient- and physician-reported asthma control: a three-year, real-life observational study.
      ,
      • Al-Ahmad M.
      • Arifhodzic N.
      • Nurkic J.
      • et al.
      Real-life" efficacy and safety aspects of 4-year omalizumab treatment for asthma.
      ,
      • Iribarren C.
      • Rothman K.J.
      • Bradley M.S.
      • Carrigan G.
      • Eisner M.D.
      • Chen H.
      Cardiovascular and cerebrovascular events among patients receiving omalizumab: pooled analysis of patient-level data from 25 randomized, double-blind, placebo-controlled clinical trials.
      ,
      • Tat T.S.
      • Cilli A.
      Evaluation of long-term safety and efficacy of omalizumab in elderly patients with uncontrolled allergic asthma.
      In addition, mean daily dose of prednisolone-equivalent OCS decreased from baseline to 2 years.
      • Humbert M.
      • Beasley R.
      • Ayres J.
      • et al.
      Benefits of omalizumab as add-on therapy in patients with severe persistent asthma who are inadequately controlled despite best available therapy (GINA 2002 step 4 treatment): innovate.
      ,
      • Al-Ahmad M.
      • Arifhodzic N.
      • Nurkic J.
      • et al.
      Real-life" efficacy and safety aspects of 4-year omalizumab treatment for asthma.
      Additionally, patients consistent (patient with ≥1 dispensing of omalizumab, ≥6 months of continuous eligibility before their first omalizumab dispensing [washout period], and had ≥1 diagnosis for asthma during the baseline period) with omalizumab treatment at 2 years showed a greater decrease in OCS use compared with those who were not consistent.
      • Sztafinska A.
      • Jerzyńska J.
      • Stelmach W.
      • Woicka-Kolejwa K.
      • Stelmach I.
      Quality of life in asthmatic children and their caregivers after two-year treatment with omalizumab, a real-life study.
      A similar profile was observed when omalizumab was continued for 3–4 years.
      • Schreiber J.
      • Schwab Sauerbeck I.
      • Mailänder C.
      The long-term effectiveness and safety of omalizumab on patient- and physician-reported asthma control: a three-year, real-life observational study.
      ,
      • Braunstahl G.J.
      • Chlumský J.
      • Peachey G.
      • Chen C.W.
      Reduction in oral corticosteroid use in patients receiving omalizumab for allergic asthma in the real-world setting.
      ,
      • Vennera Mdel C.
      • Pérez De Llano L.
      • Bardagí S.
      • et al.
      Omalizumab therapy in severe asthma: experience from the Spanish registry--some new approaches.
      ,
      • Deschildre A.
      • Marguet C.
      • Langlois C.
      • et al.
      Real-life long-term omalizumab therapy in children with severe allergic asthma.
      • Papaioannou A.I.
      • Mplizou M.
      • Porpodis K.
      • et al.
      Long-term efficacy and safety of omalizumab in patients with allergic asthma: a real-life study.
      • Mansur A.H.
      • Srivastava S.
      • Mitchell V.
      • Sullivan J.
      • Kasujee I.
      Longterm clinical outcomes of omalizumab therapy in severe allergic asthma: study of efficacy and safety.
      • Di Bona D.
      • Fiorino I.
      • Taurino M.
      • et al.
      Long-term “real-life” safety of omalizumab in patients with severe uncontrolled asthma: a nine-year study.
      ,
      • Berger W.
      • Gupta N.
      • McAlary M.
      • et al.
      Evaluation of long-term safety of the anti-IgE antibody, omalizumab, in children with allergic asthma.

      Omalizumab use for >5 years in adults with asthma

      During a mean follow-up of >5 years in patients receiving omalizumab, mean daily maintenance OCS dose significantly decreased by >75%, along with a decrease in mean annualized number of steroid courses per patient.
      • Gemİcİoğlu B.
      • Öztürk B.Ç.
      • Duman B.
      Comparison of allergic asthma patients treated with omalizumab and non-allergic patients treated with continuous oral corticosteroids: results of five year follow-up therapies.
      Approximately half of the patients receiving maintenance OCS at baseline discontinued OCS therapy during omalizumab treatment.
      • Gemİcİoğlu B.
      • Öztürk B.Ç.
      • Duman B.
      Comparison of allergic asthma patients treated with omalizumab and non-allergic patients treated with continuous oral corticosteroids: results of five year follow-up therapies.
      ,
      • Deschildre A.
      • Roussel J.
      • Drumez E.
      • et al.
      Omalizumab discontinuation in children with severe allergic asthma: an observational real-life study.
      Omalizumab decreased the number of OCS cycles after 4 and 7 years of treatment. The improvements observed at 4 years were more evident after 7 years of treatment.
      • Ortiz B.
      • Chipps B.E.
      • Zeiger R.S.
      • et al.
      Long-term outcomes from a pediatric subgroup of tenor I: 10 Years follow up.
      During a 9-year follow-up study, 7 of 8 patients were using OCS at baseline, whereas after omalizumab treatment, only 1 patient used OCS. The mean daily OCS dose was decreased to 1.6 mg/day after 8 years of omalizumab treatment as compared to 7.8 mg of prednisolone or the equivalent per day.
      • Gemİcİoğlu B.
      • Öztürk B.Ç.
      • Duman B.
      Comparison of allergic asthma patients treated with omalizumab and non-allergic patients treated with continuous oral corticosteroids: results of five year follow-up therapies.
      In pediatric patients with asthma, at the end of first year of omalizumab treatment, in a cohort of 92 severe allergic asthmatic children aged 6–18 years, no patient remained under daily OCS treatment (6 at baseline).
      • Deschildre A.
      • Marguet C.
      • Langlois C.
      • et al.
      Real-life long-term omalizumab therapy in children with severe allergic asthma.

      Use of inhaled corticosteroids

      Omalizumab use for 2–5 years in adults with asthma

      Omalizumab treatment resulted in a decrease in the mean daily dose of beclomethasone-equivalent ICS and budesonide-equivalent ICS from baseline to 2 years.
      • Tzortzaki E.G.
      • Georgiou A.
      • Kampas D.
      • et al.
      Long-term omalizumab treatment in severe allergic asthma: the South-Eastern Mediterranean “real-life” experience.
      ,
      • Papaioannou A.I.
      • Mplizou M.
      • Porpodis K.
      • et al.
      Long-term efficacy and safety of omalizumab in patients with allergic asthma: a real-life study.
      In the EXCELS study, following 2 years of omalizumab therapy, the mean total ICS daily dose was reduced by 57.7%, 44.7%, and 42.4% in new starters, established users, and omalizumab-naïve patients, respectively. Similarly, ICS monotherapy dose was also reduced by 60%–68% in all groups.
      • Odajima H.
      • Ebisawa M.
      • Nagakura T.
      • et al.
      Long-term safety, efficacy, pharmacokinetics and pharmacodynamics of omalizumab in children with severe uncontrolled asthma.
      A decrease in ICS dose with omalizumab treatment was observed across all age groups.
      • Lopez Tiro J.J.
      • Contreras E.A.
      • del Pozo M.E.
      • Gómez Vera J.
      • Larenas Linnemann D.
      Real life study of three years omalizumab in patients with difficult-to-control asthma.
      ,
      • Iribarren C.
      • Rahmaoui A.
      • Long A.A.
      • et al.
      Cardiovascular and cerebrovascular events among patients receiving omalizumab: results from EXCELS, a prospective cohort study of moderate-to-severe asthma.

      Omalizumab use for >5 years in adult patients with asthma

      Omalizumab treatment for 7 years decreased the need for nebulized corticosteroid/bronchodilator and reduced the dose of ICS/LABA in 4 of 7 patients, with 2 patients discontinuing ICS/LABA.
      • Ortiz B.
      • Chipps B.E.
      • Zeiger R.S.
      • et al.
      Long-term outcomes from a pediatric subgroup of tenor I: 10 Years follow up.
      In addition, of all patients receiving high-dose ICS at baseline, only 1 patient remained on high dose after 9 years of treatment. Other patients reported a 65% decrease in ICS dose.
      • Menzella F.
      • Galeone C.
      • Formisano D.
      • et al.
      Real-life efficacy of omalizumab after 9 Years of follow-up.
      ,
      • Gemİcİoğlu B.
      • Öztürk B.Ç.
      • Duman B.
      Comparison of allergic asthma patients treated with omalizumab and non-allergic patients treated with continuous oral corticosteroids: results of five year follow-up therapies.

      Omalizumab use in pediatric patients with asthma

      In a pediatric study, a decrease of 30% of mean ICS dose (703 μg at initiation and 488 μg fluticasone equivalent per day after 1 year) was noted during the first year. No further significant decrease was observed at 2 years (mean = 429 μg/day); however, 63% of patients benefited from ≥50% decrease in initial dose of ICS.
      • Deschildre A.
      • Marguet C.
      • Langlois C.
      • et al.
      Real-life long-term omalizumab therapy in children with severe allergic asthma.
      In a long-term study by Deschildre et al the median daily ICS dose (range, μg/d) decreased significantly from 1000 (250–1250) to 375 (0–1000) in a subgroup of 30 children still treated after a mean of 46.2 months (31.5–90.3).
      • Deschildre A.
      • Roussel J.
      • Drumez E.
      • et al.
      Omalizumab discontinuation in children with severe allergic asthma: an observational real-life study.
      Sztafińska et al showed that 63.33% of pediatric patients achieved a reduction in ICS dose (median reduction of 300 μg/day after 52-weeks of omalizumab treatment). No further reduction in ICS use was observed between 52 and 104 weeks of treatment.
      • Sztafinska A.
      • Jerzyńska J.
      • Stelmach W.
      • Woicka-Kolejwa K.
      • Stelmach I.
      Quality of life in asthmatic children and their caregivers after two-year treatment with omalizumab, a real-life study.
      A 6-year follow-up study in 48 children with allergic asthma reported a significant decrease in the use of maintenance therapy (fluticasone) in patients after six months (329.89 μg/day) of omalizumab therapy compared to baseline (452 μg/day). The difference was maintained throughout the follow-up period.
      • Folque M.M.
      • Lozano J.
      • Riggioni C.
      • et al.
      “Real-life” experience in asthmatic children treated with omalizumab up to six-years follow-up.
      In the ANCHORS study, the mean daily ICS dose decreased significantly after 1 year (867.3 vs 663.4 μg budesonide equivalent) of omalizumab treatment that continued over 6 years (350.2 μg budesonide equivalent compared with baseline).
      • Nieto García A.
      • Garriga-Baraut T.
      • Plaza Martín A.M.
      • et al.
      Omalizumab outcomes for up to 6 years in pediatric patients with severe persistent allergic asthma.

      Lung function

      Patients with severe asthma experience an accelerated decline in lung function over time, which may further increase the risk of exacerbations.
      • Pereira Barbosa M.
      • Bugalho de Almeida A.
      • Pereira C.
      • Chen C.W.
      • Georgiou P.
      • Peachey G.
      eXpeRience study group.
      Real-life efficacy and safety of omalizumab in Portuguese patients with persistent uncontrolled asthma.
      Of the 19 studies evaluating the effect of omalizumab on lung function in patients with allergic asthma for ∼2–5 years, omalizumab improved lung function in 16 studies.
      • Braunstahl G.J.
      • Chen C.W.
      • Maykut R.
      • et al.
      The eXpeRience registry: the ‘real-world’ effectiveness of omalizumab in allergic asthma.
      • Caminati M.
      • Senna G.
      • Chieco Bianchi F.
      • et al.
      Omalizumab management beyond clinical trials: the added value of a network model.
      • Dal Negro R.W.
      • Tognella S.
      • Pradelli L.
      A 36-month study on the cost/utility of add-on omalizumab in persistent difficult-to-treat atopic asthma in Italy.
      ,
      • Pereira Barbosa M.
      • Bugalho de Almeida A.
      • Pereira C.
      • Chen C.W.
      • Georgiou P.
      • Peachey G.
      eXpeRience study group.
      Real-life efficacy and safety of omalizumab in Portuguese patients with persistent uncontrolled asthma.
      ,
      • Cavaliere C.
      • Begvarfaj E.
      • Incorvaia C.
      • et al.
      Long-term omalizumab efficacy in allergic rhinitis.
      • Kirchnerová O.R.
      • Valena T.
      • Novosad J.
      • Teřl M.
      • et al.
      Czech eXpeRience Study Group
      Real-world effectiveness and safety of omalizumab in patients with uncontrolled severe allergic asthma from the Czech Republic.
      • Pelaia C.
      • Calabrese C.
      • Barbuto S.
      • et al.
      Omalizumab lowers asthma exacerbations, oral corticosteroid intake and blood eosinophils: results of a 5-YEAR single-centre observational study.
      ,
      • Al-Ahmad M.
      • Arifhodzic N.
      • Nurkic J.
      • et al.
      Real-life" efficacy and safety aspects of 4-year omalizumab treatment for asthma.
      ,
      • Sposato B.
      • Scalese M.
      • Latorre M.
      • et al.
      Effects of omalizumab in severe asthmatics across ages: a real life Italian experience.
      • Tat T.S.
      • Cilli A.
      Evaluation of long-term safety and efficacy of omalizumab in elderly patients with uncontrolled allergic asthma.
      • Novelli F.
      • Latorre M.
      • Vergura L.
      • et al.
      Asthma control in severe asthmatics under treatment with omalizumab: a cross-sectional observational study in Italy.
      • Lopez Tiro J.J.
      • Contreras E.A.
      • del Pozo M.E.
      • Gómez Vera J.
      • Larenas Linnemann D.
      Real life study of three years omalizumab in patients with difficult-to-control asthma.
      ,
      • Ozgur E.S.
      • Özge C.
      • Ïlvan A.
      • Naycı S.A.
      Assessment of long-term omalizumab treatment in patients with severe allergic asthma long-term omalizumab treatment in severe asthma.
      • Vennera Mdel C.
      • Pérez De Llano L.
      • Bardagí S.
      • et al.
      Omalizumab therapy in severe asthma: experience from the Spanish registry--some new approaches.
      • Menzella F.
      • Facciolongo N.
      • Piro R.
      • et al.
      Clinical and pharmacoeconomic aspects of omalizumab: a 4-year follow-up.
      • Tzortzaki E.G.
      • Georgiou A.
      • Kampas D.
      • et al.
      Long-term omalizumab treatment in severe allergic asthma: the South-Eastern Mediterranean “real-life” experience.
      ,
      • Sposato B.
      • Scalese M.
      • Latorre M.
      • et al.
      Xolair Italian Study Group
      Can the response to Omalizumab be influenced by treatment duration? A real-life study.
      In pediatric patients, Deschildre et al showed improvement in lung function (FEV1) during the first year of omalizumab treatment with no significant additional improvement in the second year.
      • Deschildre A.
      • Marguet C.
      • Langlois C.
      • et al.
      Real-life long-term omalizumab therapy in children with severe allergic asthma.

      Omalizumab use for 2–5 years in adults with asthma

      Omalizumab treatment for 2 years significantly increased mean FEV1 (% predicted) by 7.5%–16.75% and mean peak expiratory flow (PEF) by 21.8–45.4 L/min.
      • Braunstahl G.J.
      • Chen C.W.
      • Maykut R.
      • et al.
      The eXpeRience registry: the ‘real-world’ effectiveness of omalizumab in allergic asthma.
      ,
      • Vieira T.
      • de Oliveira J.F.
      • da Graca Castel-Branco M.
      Short and long-term quality of life and asthma control with omalizumab therapy in a real life setting in Portugal.
      ,
      • Pereira Barbosa M.
      • Bugalho de Almeida A.
      • Pereira C.
      • Chen C.W.
      • Georgiou P.
      • Peachey G.
      eXpeRience study group.
      Real-life efficacy and safety of omalizumab in Portuguese patients with persistent uncontrolled asthma.
      ,
      • Cavaliere C.
      • Begvarfaj E.
      • Incorvaia C.
      • et al.
      Long-term omalizumab efficacy in allergic rhinitis.
      ,
      • Kirchnerová O.R.
      • Valena T.
      • Novosad J.
      • Teřl M.
      • et al.
      Czech eXpeRience Study Group
      Real-world effectiveness and safety of omalizumab in patients with uncontrolled severe allergic asthma from the Czech Republic.
      ,
      • Vennera Mdel C.
      • Pérez De Llano L.
      • Bardagí S.
      • et al.
      Omalizumab therapy in severe asthma: experience from the Spanish registry--some new approaches.
      Further improvement in lung function was observed with longer periods of omalizumab treatment (∼3–4 years), with an increase in mean FEV1 (% predicted) ranging from 16.8% to 24.5%.
      • Dal Negro R.W.
      • Tognella S.
      • Pradelli L.
      A 36-month study on the cost/utility of add-on omalizumab in persistent difficult-to-treat atopic asthma in Italy.
      ,
      • Cavaliere C.
      • Begvarfaj E.
      • Incorvaia C.
      • et al.
      Long-term omalizumab efficacy in allergic rhinitis.
      ,
      • Al-Ahmad M.
      • Arifhodzic N.
      • Nurkic J.
      • et al.
      Real-life" efficacy and safety aspects of 4-year omalizumab treatment for asthma.
      ,
      • Lopez Tiro J.J.
      • Contreras E.A.
      • del Pozo M.E.
      • Gómez Vera J.
      • Larenas Linnemann D.
      Real life study of three years omalizumab in patients with difficult-to-control asthma.
      ,
      • Ozgur E.S.
      • Özge C.
      • Ïlvan A.
      • Naycı S.A.
      Assessment of long-term omalizumab treatment in patients with severe allergic asthma long-term omalizumab treatment in severe asthma.
      ,
      • Menzella F.
      • Facciolongo N.
      • Piro R.
      • et al.
      Clinical and pharmacoeconomic aspects of omalizumab: a 4-year follow-up.
      ,
      • Tzortzaki E.G.
      • Georgiou A.
      • Kampas D.
      • et al.
      Long-term omalizumab treatment in severe allergic asthma: the South-Eastern Mediterranean “real-life” experience.
      A study by Vennera et al showed that omalizumab treatment for 2 years significantly increased FEV1 (% predicted) in patients aged <50 years (14.2%) compared with those aged ≥50 years (3.2%).
      • Vennera Mdel C.
      • Pérez De Llano L.
      • Bardagí S.
      • et al.
      Omalizumab therapy in severe asthma: experience from the Spanish registry--some new approaches.
      A non-significant increase in FEV1 (% predicted) of 12.2% was observed in elderly patients aged ≥65 years who received omalizumab for a mean duration of ∼3 years.
      • Tat T.S.
      • Cilli A.
      Evaluation of long-term safety and efficacy of omalizumab in elderly patients with uncontrolled allergic asthma.
      In contrast, omalizumab treatment for a mean of 35 months resulted in comparable improvements in lung function (overall increase in FEV1 [% predicted] of 12%–14%) in 3 subgroups of patients categorized by age (18–39, 40–64, and ≥65 years).
      • Sposato B.
      • Scalese M.
      • Latorre M.
      • et al.
      Xolair Italian Study Group
      Can the response to Omalizumab be influenced by treatment duration? A real-life study.

      Omalizumab use for >5 years in patients with asthma

      Patients who received omalizumab for ≥5 years reported an 11% increase in FEV1 relative to baseline
      • Gemİcİoğlu B.
      • Öztürk B.Ç.
      • Duman B.
      Comparison of allergic asthma patients treated with omalizumab and non-allergic patients treated with continuous oral corticosteroids: results of five year follow-up therapies.
      and by 17% of predicted.
      • Mansur A.H.
      • Srivastava S.
      • Mitchell V.
      • Sullivan J.
      • Kasujee I.
      Longterm clinical outcomes of omalizumab therapy in severe allergic asthma: study of efficacy and safety.
      A further increase in FEV1% predicted by 18% was observed after 7 years,
      • Pace E.
      • Ferraro M.
      • Bruno A.
      • Chiappara G.
      • Bousquet J.
      • Gjomarkaj M.
      Clinical benefits of 7 years of treatment with omalizumab in severe uncontrolled asthmatics.
      27% after 9 years,
      • Menzella F.
      • Galeone C.
      • Formisano D.
      • et al.
      Real-life efficacy of omalizumab after 9 Years of follow-up.
      and ∼12% after 12 years of omalizumab treatment.
      • Papaioannou A.I.
      • Mplizou M.
      • Porpodis K.
      • et al.
      Long-term efficacy and safety of omalizumab in patients with allergic asthma: a real-life study.
      A 13% improvement in mean FEV1/FVC % predicted was observed from baseline to 7 years.
      • Pace E.
      • Ferraro M.
      • Bruno A.
      • Chiappara G.
      • Bousquet J.
      • Gjomarkaj M.
      Clinical benefits of 7 years of treatment with omalizumab in severe uncontrolled asthmatics.

      Omalizumab use in pediatric patients with asthma

      Sztafińska et al reported no significant improvement in FEV1 in children and adolescents with severe persistent allergic asthma after 2 years of omalizumab treatment.
      • Sztafinska A.
      • Jerzyńska J.
      • Stelmach W.
      • Woicka-Kolejwa K.
      • Stelmach I.
      Quality of life in asthmatic children and their caregivers after two-year treatment with omalizumab, a real-life study.
      In children aged 6–18 years, compared with baseline (FEV1, 88% [% predicted value] [95% CI: 83.8; 92.2]), mean FEV1% predicted increased by 4.9% during 1 year of follow-up with no significant modification during the second year. Indeed, FEV1 was maintained at a high level, 89.9% predicted (95% CI: 86.7%–93.0%) at the end of 2-year treatment.
      • Deschildre A.
      • Marguet C.
      • Langlois C.
      • et al.
      Real-life long-term omalizumab therapy in children with severe allergic asthma.
      The increase, although small, did provide a positive outcome, close to the expected value in controlled children,
      • Deschildre A.
      • Marguet C.
      • Langlois C.
      • et al.
      Real-life long-term omalizumab therapy in children with severe allergic asthma.
      as a decline in lung function has been described in severe asthmatic children followed up for many years.
      • Ortiz B.
      • Chipps B.E.
      • Zeiger R.S.
      • et al.
      Long-term outcomes from a pediatric subgroup of tenor I: 10 Years follow up.
      These results were confirmed by Deschildre et al showing an pre-β2 agonist FEV1 (% predictive value) of 97 (50–119) after 31.5–90.3 months of omalizumab treatment.
      • Deschildre A.
      • Roussel J.
      • Drumez E.
      • et al.
      Omalizumab discontinuation in children with severe allergic asthma: an observational real-life study.
      In the ANCHORS study, FEV1% predicted increased significantly from 84.6% at baseline to 92.3% after one year of treatment (P < 0.001), and these improvements remained consistent during 6 years of follow-up (92.8%).
      • Nieto García A.
      • Garriga-Baraut T.
      • Plaza Martín A.M.
      • et al.
      Omalizumab outcomes for up to 6 years in pediatric patients with severe persistent allergic asthma.

      Healthcare resource utilization

      Omalizumab use for 2–5 years in adults with asthma

      Omalizumab treatment for 2 years reduced the mean number of annualized healthcare visits per patient (6.4 vs 0.5) and increased the proportion of patients with no annualized healthcare visit (12.3% vs 75.4%).
      • Braunstahl G.J.
      • Chen C.W.
      • Maykut R.
      • et al.
      The eXpeRience registry: the ‘real-world’ effectiveness of omalizumab in allergic asthma.
      ,
      • Braunstahl G.J.
      • Canvin J.
      • Peachey G.
      • Chen C.W.
      • Georgiou P.
      Healthcare resource utilization in patients receiving omalizumab for allergic asthma in a real-world setting.
      ,
      • Kirchnerová O.R.
      • Valena T.
      • Novosad J.
      • Teřl M.
      • et al.
      Czech eXpeRience Study Group
      Real-world effectiveness and safety of omalizumab in patients with uncontrolled severe allergic asthma from the Czech Republic.
      Patients who received consistent omalizumab treatment for 24 months showed a 70% reduction in asthma-related ER visits and 39% reduction in hospitalizations compared with patients who discontinued omalizumab at 12 months and did not reinitiate. Furthermore, consistent omalizumab treatment for 2 years demonstrated ∼94% reduction in HCRU and significantly prolonged time-to-first asthma-related ER visit/hospitalization (HR: 0.70; 95% CI: 0.58–0.84; P < 0.01).
      • Kirchnerová O.R.
      • Valena T.
      • Novosad J.
      • Teřl M.
      • et al.
      Czech eXpeRience Study Group
      Real-world effectiveness and safety of omalizumab in patients with uncontrolled severe allergic asthma from the Czech Republic.
      ,
      • Lafeuille M.H.
      • Gravel J.
      • Zhang J.
      • Gorsh B.
      • Figliomeni M.
      • Lefebvre P.
      Association between consistent omalizumab treatment and asthma control.
      Other studies also reported improvement in HCRU in terms of decreased hospitalizations and ER/intensive care unit visits with omalizumab for 2–4 years.
      • Dal Negro R.W.
      • Tognella S.
      • Pradelli L.
      A 36-month study on the cost/utility of add-on omalizumab in persistent difficult-to-treat atopic asthma in Italy.
      ,
      • Vieira T.
      • de Oliveira J.F.
      • da Graca Castel-Branco M.
      Short and long-term quality of life and asthma control with omalizumab therapy in a real life setting in Portugal.
      ,
      • Pereira Barbosa M.
      • Bugalho de Almeida A.
      • Pereira C.
      • Chen C.W.
      • Georgiou P.
      • Peachey G.
      eXpeRience study group.
      Real-life efficacy and safety of omalizumab in Portuguese patients with persistent uncontrolled asthma.
      ,
      • Lopez Tiro J.J.
      • Contreras E.A.
      • del Pozo M.E.
      • Gómez Vera J.
      • Larenas Linnemann D.
      Real life study of three years omalizumab in patients with difficult-to-control asthma.
      ,
      • Ozgur E.S.
      • Özge C.
      • Ïlvan A.
      • Naycı S.A.
      Assessment of long-term omalizumab treatment in patients with severe allergic asthma long-term omalizumab treatment in severe asthma.
      • Vennera Mdel C.
      • Pérez De Llano L.
      • Bardagí S.
      • et al.
      Omalizumab therapy in severe asthma: experience from the Spanish registry--some new approaches.
      • Menzella F.
      • Facciolongo N.
      • Piro R.
      • et al.
      Clinical and pharmacoeconomic aspects of omalizumab: a 4-year follow-up.
      Of note, in one study, omalizumab treatment for 4 years resulted in no hospitalizations during the treatment period compared with almost two-thirds of patients who reported ≥1 annualized hospitalization prior to treatment.
      • Menzella F.
      • Facciolongo N.
      • Piro R.
      • et al.
      Clinical and pharmacoeconomic aspects of omalizumab: a 4-year follow-up.
      In elderly asthmatics, the rate of hospitalization during omalizumab treatment decreased in ∼90% of patients.
      • Tat T.S.
      • Cilli A.
      Evaluation of long-term safety and efficacy of omalizumab in elderly patients with uncontrolled allergic asthma.

      Omalizumab use for >5 years in adults with asthma

      Omalizumab treatment from the pre-treatment period to ≥5 years resulted in reduction in number of hospitalizations and ER visits by 80.7% and 48.5%, respectively. A reduction in mean annual per-patient hospitalization and ER visit was also observed.
      • Mansur A.H.
      • Srivastava S.
      • Mitchell V.
      • Sullivan J.
      • Kasujee I.
      Longterm clinical outcomes of omalizumab therapy in severe allergic asthma: study of efficacy and safety.

      Omalizumab use in pediatric patients with asthma

      Improvement in HCRU with omalizumab has also been reported in pediatric patients. In children, the rate of hospitalizations and ER visits/patient-year significantly decreased from baseline during omalizumab treatment.
      • Odajima H.
      • Ebisawa M.
      • Nagakura T.
      • et al.
      Long-term safety, efficacy, pharmacokinetics and pharmacodynamics of omalizumab in children with severe uncontrolled asthma.
      In the French cohort, there was a huge improvement with 88.5% decrease in hospitalizations during the first year and no patients hospitalized for exacerbations in the second year of treatment, compared to 44% in the year preceding the initiation.
      • Deschildre A.
      • Marguet C.
      • Langlois C.
      • et al.
      Real-life long-term omalizumab therapy in children with severe allergic asthma.
      In the 6-year ANCHORS study, the number of healthcare visits decreased significantly after 1 year of omalizumab treatment (P < 0.001), with no ICU admissions from the second year onward.
      • Nieto García A.
      • Garriga-Baraut T.
      • Plaza Martín A.M.
      • et al.
      Omalizumab outcomes for up to 6 years in pediatric patients with severe persistent allergic asthma.
      Table 2 summarizes the efficacy findings from the studies included in this review.
      Table 2An overview of clinical experience with omalizumab from studies included in this review.
      Author;

      Treatment duration
      ExacerbationsLung functionAsthma control/QoLHealthcare utilizationCorticosteroid use
      Schreiber J et al., 2020
      • Schreiber J.
      • Schwab Sauerbeck I.
      • Mailänder C.
      The long-term effectiveness and safety of omalizumab on patient- and physician-reported asthma control: a three-year, real-life observational study.


      Treatment duration: 3 years
      Proportion of patients experiencing ≥ 2 severe exacerbations remained low and stable:

      First year: 12.42%, Second year: 7.87% Third year: 11.97%
      Reduction in mean ± SD ACQ-6 total score vs baseline: 1.7 ± 1.23 vs 2.0 ± 1.22 at 3 years change from baseline: −0.18 ± 1.07 (P = 0.340)

      Improvement in Mini-AQLQ total score vs baseline (4.5 ± 1.26):

      Month 6: 5.0 ± 1.35; P = 0.002

      1 year: 4.9 ± 1.36; P = 0.001

      1.5 years: 4.8 ± 1.40; P = 0.009

      2 years: 4.9 ± 1.48; P = 0.011

      3 years: 4.7 ± 1.48; P = 0.186

      Increase in Mini AQLQ score at 3 years vs baseline:

      0.26 ± 1.35, P = 0.186
      Cavaliere et al., 2020
      • Cavaliere C.
      • Begvarfaj E.
      • Incorvaia C.
      • et al.
      Long-term omalizumab efficacy in allergic rhinitis.


      Treatment duration: 36 Months
      Improvement in %FEV1 predicted vs baseline (81.25 ± 11.57):

      Month 6: 88.37 ± 6.25; P = 0.10

      Month 12: 94.25 ± 6.11

      Month 24: 98 ± 11.33

      Month 36: 99.37 ± 6.11 (P < 0.001)
      Improvement in mean ± SD asthma control (ACT) vs baseline (18.25 ± 1.58):

      Month 6: 21.62 ± 0.91

      Month 12: 22 ± 0.92 Month 24: 21.62 ± 1.5

      Month 36: 23 ± 1.69 (P < 0.001)
      Kirchnerová OR et al., 2019
      • Kirchnerová O.R.
      • Valena T.
      • Novosad J.
      • Teřl M.
      • et al.
      Czech eXpeRience Study Group
      Real-world effectiveness and safety of omalizumab in patients with uncontrolled severe allergic asthma from the Czech Republic.


      Treatment duration: 2 years
      Reduction in clinically significant exacerbations vs baseline:

      0.7 vs 5.7 at months 24

      Proportion of patients with no clinically significant exacerbations:

      Month 12: 56.2%

      Month 24: 63.0%

      Reduction in severe exacerbations vs baseline: 2.2 vs 0.1 at months 24

      Proportion of patients with no severe exacerbations:

      Month 12: 89.9%

      Month 24: 95.1%
      Improvement in mean FEV1 (mL):

      Change from baseline:

      Week 16:205

      Month 8: 215

      Month 12: 273

      Month 18: 200

      Month 24: 137

      Improvement in PEF (L/min);

      Mean change from baseline:

      Week 16: 11.01

      Month 8: 18.38

      Month 12: 32.82

      Month 18: 25.18

      Month 24: 21.85
      Improvement in ACT scores vs baseline:

      17.3 vs 12.4 at months 24

      Proportion of patients with controlled/partly controlled asthma vs baseline:

      Month 12: 92.1%

      Month 24: 87.7%

      Mean change in mini-AQLQ vs baseline:

      Month 12: 0.8 points

      Month 24: 0.94 points
      Reduction in mean number of asthma-related hospitalizations vs pre-treatment period:

      0.0 ± 0.2 vs 0.5 ± 1.2 at month 24

      Reduction in mean

       ± SD number of days stayed in hospital vs pre-treatment period:

      0.2 ± 2.2 vs 3.3 ± 9.8 at month 12

      Patients free from asthma-related hospitalizations at months 12 and 24: 100% and 98.8%
      Reduction in OCS use vs baseline:

      Month 12: 50% vs 33.9%

      Month 24: 52.6% vs 33.9%

      Reduction in mean total daily dose (in prednisolone

      equivalent mg) of OCS vs baseline: 6.4 vs 11.6 at months 24
      Pelaia C et al., 2018
      • Pelaia C.
      • Calabrese C.
      • Barbuto S.
      • et al.
      Omalizumab lowers asthma exacerbations, oral corticosteroid intake and blood eosinophils: results of a 5-YEAR single-centre observational study.


      Treatment duration: 5 years
      Reduction in mean annualized exacerbation rates vs baseline: 0.63 ± 0.99 vs 3.66 ± 2.01 after 5 years; P < 0.0001Increase in mean FEV1 vs baseline: 1929 ± 564.8 mL vs 1636 ± 628.4 mL after 5 years; P < 0.05Increase in ACT scores vs baseline: 21.67 ± 2.38 vs 14.60 ± 2.97 at 5 years; P < 0.0001Mean reduction in corticosteroids use (mg/day) vs baseline: 1.66 ± 3.61 vs 22.50 ± 5.17 at 5 years; P < 0.0001
      Ke et al., 2018
      • Ke X.
      • Wertz D.
      • Huang Q.
      • et al.
      Real-world clinical characteristics, treatment patterns, and exacerbations in US patients with asthma newly treated with omalizumab.


      Treatment duration: 1–2 years
      Proportion of patients with any asthma exacerbation:

      Pre-index and Post-index periods: 66.6% and 44.2%; relative difference, 33.6%; P < 0.001)
      Overall reduction in OCS use: 20.3% (83.3% pre-index to 66.4% post-index, P < 0.001)
      Al-Ahmad M et al., 2018
      • Al-Ahmad M.
      • Arifhodzic N.
      • Nurkic J.
      • et al.
      Real-life" efficacy and safety aspects of 4-year omalizumab treatment for asthma.


      Treatment duration: 4 years
      Reduction in severe asthma exacerbations vs pre-treatment:

      1.5% vs 47.7% patients after 4 years; P < 0.001
      Improvement in %FEV1 predicted vs baseline:

      76.6% vs 55.6% at 4 years; P = 0.003
      Increase in ACT score vs baseline: 23 ± 3 vs 15 ± 3 at 4 years; P < 0.001Decrease in HCRU:

      No. of ER visits decreased by 90.8% after 4 years (P < 0.001)

      Patients with ≥1 hospitalizations due to severe asthma exacerbation decreased from 47.7% at baseline to by 1.5% after 4 years (P < 0.001)
      Reduction in OCS use:

      Proportion of patients who did not use OCS Week 16: 55.4%

      1 year: 78.0%

      4 years: 83.1

      Proportion of patients with reduction in ICS/LABA use at different time points:

      Week 16: 35.4%

      1 year: 44.6%; P < 0.014

      4 years: 56.9%; P < 0.001
      Odajima H et al., 2017
      • Odajima H.
      • Ebisawa M.
      • Nagakura T.
      • et al.
      Long-term safety, efficacy, pharmacokinetics and pharmacodynamics of omalizumab in children with severe uncontrolled asthma.


      Median exposure: 116.6 weeks
      Baseline of the core study vs end of treatment period of the extension study:

      Mean FEV1% predicted: 90.3% vs 89.2%

      Mean FEF25%-75% predicted:

      76.3% vs 75.1%
      Mean change in JPAC score from start of the extension study to end of the treatment period: 3.0 (P < 0.001)

      % of patients with well controlled asthma at start of extension study vs end of treatment period:

      23.7% vs 76.3%

      Median QoL scores at baseline of the core study vs end of treatment period: 39 vs 48 (P < 0.001)
      Rate per patient-year at baseline of the core study vs overall treatment period of the extension study:

      Hospitalizations:

      1.33 vs 0.16 (P < 0.001)

      ER visits:

      0.68 vs 0.15 (P = 0.002)
      ICS dose decreased by 13.2% from baseline of the core study to end of treatment period
      Sposato B et al., 2016
      • Sposato B.
      • Scalese M.
      • Latorre M.
      • et al.
      Effects of omalizumab in severe asthmatics across ages: a real life Italian experience.


      Mean treatment duration: 35.1 ± 21.7 months
      After omalizumab treatment, 76.9%, 49.2% and 29% of younger, middle-aged, and elderly subjects were exacerbation-free (P = 0.049)Median FEV1% predicted vs baseline:

      Younger:

      82.1% vs 70%

      Middle-aged:

      82% vs 68%

      Elderly:

      80% vs 67%

      P < 0.001 in all groups
      Median ACT scores before vs after treatment:

      Younger: 24 vs 15

      Middle-aged:

      21 vs 14

      Elderly: 20 vs 15

      P < 0.001 in all groups
      Tat TS et al., 2016
      • Tat T.S.
      • Cilli A.
      Evaluation of long-term safety and efficacy of omalizumab in elderly patients with uncontrolled allergic asthma.


      Mean treatment duration: 35.6 ± 17.8 months
      Mean number of exacerbations vs baseline: 0.53 vs 4.12 (P < 0.001)Mean FEV1% predicted vs baseline: 67.01 vs 54.84 (P = 0.11)Well controlled symptoms in 47.4% of patients and partly-controlled in 42.1% of patients

      Mean ACT score vs baseline: 21.8 vs 10.44 (P < 0.001)
      Mean number of hospitalizations vs baseline: 0.23 vs 1.12 (P = 0.004)
      Zazzali JL et al., 2015 (EXCELS study)
      • Zazzali J.L.
      • Raimundo K.P.
      • Trzaskoma B.
      • Rosén K.E.
      • Schatz M.
      Changes in asthma control, work productivity, and impairment with omalizumab: 5-year EXCELS study results.


      Treatment duration: 5 years
      % of patients with asthma control vs baseline:

      Omalizumab-naïve cohort:

      Well-controlled asthma: 66.7% vs 48.6%

      Poorly controlled asthma: 14.8% vs 26.6%

      Omalizumab cohort:

      Well-controlled asthma: 61.2% vs 45.2%

      Poorly controlled asthma: 19.0% vs 31.6%
      Deschildre A et al., 2015
      • Deschildre A.
      • Marguet C.
      • Langlois C.
      • et al.
      Real-life long-term omalizumab therapy in children with severe allergic asthma.


      Treatment duration: 2 years
      Mean rate of severe exacerbations per patient vs baseline:

      0.22 vs 4.4 (P = 0.0001)
      Mean FEV1% predicted vs baseline:

      88% vs 89.9%
      Mean ICS daily dose (fluticasone equivalent) vs baseline:

      429 μg vs 703 μg
      Novelli F et al., 2015
      • Novelli F.
      • Latorre M.
      • Vergura L.
      • et al.
      Asthma control in severe asthmatics under treatment with omalizumab: a cross-sectional observational study in Italy.


      Median treatment duration:

      32 months (range: 4–120 months)
      Significant reduction in exacerbation rate during treatment (P < 0.001)% of patients with good, partial, and poor asthma control after treatment:

      25.2%, 47.1% and 24.5%
      Percentage of patients with HCRU vs baseline:

      ER visits: 7.5% vs 57.2%

      Hospitalizations: 6.5% vs 45.7%

      Intensive care treatment: 0.3% vs 3.6%
      Lopez Tiro JJ et al., 2015
      • Lopez Tiro J.J.
      • Contreras E.A.
      • del Pozo M.E.
      • Gómez Vera J.
      • Larenas Linnemann D.
      Real life study of three years omalizumab in patients with difficult-to-control asthma.


      Treatment period: 3 years
      Mean FEV1% predicted vs baseline:

      88.4% vs 66.3%
      Mean ACT score vs baseline:

      20.5 vs 12.4
      % of patients with HCRU vs baseline with:

      ≥1 hospitalization:

      2.1% vs 38.2% (P < 0.0001)

      ≥1 ER visits:

      19.1% vs 95.7% (P < 0.0001)

      ≥1 intensive care admission: 0% vs 4.2%
      Mean ICS dose vs baseline: 765 μg/day (n = 42) vs 1750 μg/day (n = 47)

      After 3 years: 5 patients discontinued ICS
      Pereira Barbosa M et al., 2015
      • Pereira Barbosa M.
      • Bugalho de Almeida A.
      • Pereira C.
      • Chen C.W.
      • Georgiou P.
      • Peachey G.
      eXpeRience study group.
      Real-life efficacy and safety of omalizumab in Portuguese patients with persistent uncontrolled asthma.
      (eXpeRience study –Portuguese subgroup)

      Treatment duration: 2 years
      % of patients free from clinically significant exacerbations vs baseline:

      60% vs 6.5%
      Increase from baseline in Mean FEV1% predicted: 9.6%

      Mean PEF: 45.4 L/min
      Increase from baseline in mean ACT score: 7.0

      mean mini-AQLQ score: 2.7

      Increase in ACT score by ≥ 2 points and mini-AQLQ scores by ≥ 0.5 points is considered minimal clinically important difference
      Corticosteroids use vs baseline:

      Patients on OCS: 8.2% vs 17.7%

      Patients on ICS: 88.9% vs 96.8%

      Mean total daily OCS dose (prednisolone equivalent): 13.1 mg vs 16.7 mg

      Mean total daily ICS dose (beclomethasone equivalent): 1351.1 μg vs 1497.5 μg
      Caminati M et al., 2014
      • Caminati M.
      • Senna G.
      • Chieco Bianchi F.
      • et al.
      Omalizumab management beyond clinical trials: the added value of a network model.


      Mean treatment duration: 22.97 ± 16.55 months
      % of patients free from exacerbations vs baseline:

      Major exacerbations:

      88.6% vs 41.9%; P < 0.001

      Minor exacerbations:

      79.6% vs 16.3%; P < 0.001
      Significant improvement in FEV1 and FVC from baseline to the end of treatment period (P < 0.001)
      Vieira T et al., 2014
      • Vieira T.
      • de Oliveira J.F.
      • da Graca Castel-Branco M.
      Short and long-term quality of life and asthma control with omalizumab therapy in a real life setting in Portugal.


      Treatment duration: 2 years
      Exacerbation rate decreased from baseline to 1st year by 70.1% (P = 0.002) and from 1st year to 2nd year by 75.9% (P = 0.05)Mean FEV1% predicted vs baseline:

      65% vs 51.7%

      P = 0.007
      Mean ACT score vs baseline:

      18.9 vs 12.3

      P = 0.008

      Mean ALQ score vs baseline:

      11.8 vs 15.3

      P = 0.024
      Unscheduled health care visits decreased from baseline to 1st year by 86.1% (P = 0.002) and from 1st year to 2nd year by 69% (P = 0.12)Corticosteroid use vs baseline:

      Mean daily ICS dose (budesonide equivalent): 1111.1 μg vs 1653.3 μg

      P = 0.028

      Percentage of patients with daily OCS use:

      10% vs 53%
      Braunstahl et al., 2013/2014
      • Braunstahl G.J.
      • Chen C.W.
      • Maykut R.
      • et al.
      The eXpeRience registry: the ‘real-world’ effectiveness of omalizumab in allergic asthma.
      ,
      • Braunstahl G.J.
      • Canvin J.
      • Peachey G.
      • Chen C.W.
      • Georgiou P.
      Healthcare resource utilization in patients receiving omalizumab for allergic asthma in a real-world setting.
      ,
      • Braunstahl G.J.
      • Chlumský J.
      • Peachey G.
      • Chen C.W.
      Reduction in oral corticosteroid use in patients receiving omalizumab for allergic asthma in the real-world setting.
      (eXpeRience)

      Treatment duration: 2 years
      At 2 years vs baseline, % of patients free from clinically significant exacerbations:

      67.3% vs 6.8% severe clinically significant exacerbations:

      89.9% vs 30.2%

      Mean annualized no. of clinically significant and severe clinically significant exacerbations vs baseline: 0.6 and 0.1 vs 4.9 and 2.2 respectively
      Increase from baseline in mean FEV1% predicted: 8.7%

      mean PEF: 34.0 L/min
      Mean change from baseline in ACT score: +6.2

      ACQ score: −0.80

      AQLQ score: 0.75

      Mini-AQLQ: 1.62

      Increase in ACT score by ≥ 3 points, AQLQ/mini-AQLQ scores by ≥ 0.5 points and decrease in ACQ score by ≥ 0.5 points is considered minimal clinically important difference
      Mean annualized no. of health-care visits/patient vs baseline: 0.5 vs 6.2

      % of patients vs baseline with:

      No annualized asthma-related medical healthcare use:

      75.4% vs 12.3%

      No hospitalization: 93.8% vs 62.3%

      No ER visit: 91.9% vs 49.3%

      No unscheduled doctor visit: 78.4% vs 19.3%
      Corticosteroids use vs baseline:

      Maintenance OCS therapy: 14.2% vs 28.6%

      Mean total daily OCS dose (prednisolone equivalent): 5.8 mg vs 15.5 mg

      Mean total daily ICS dose (beclomethasone equivalent): 1381 μg vs 1675 μg
      Lafeuille MH et al., 2013
      • Lafeuille M.H.
      • Gravel J.
      • Zhang J.
      • Gorsh B.
      • Figliomeni M.
      • Lefebvre P.
      Association between consistent omalizumab treatment and asthma control.


      Treatment duration: 2 years
      % of patients with uncontrolled asthma who were consistent with omalizumab at 24 months vs non-consistent at 12 months and never re-initiated omalizumab: 44% vs 55%Mean number of asthma-related ER visits and hospitalizations in patients consistent with omalizumab at 24 months vs non-consistent at 12 months and never re-initiated omalizumab: 0.038 vs 0.126 and 0.106 vs 0.173, respectivelyMean number of OCS claims in patients consistent with omalizumab at 24 months vs non-consistent at 12 months and never re-initiated omalizumab: 1.648 vs 2.446
      Chen H et al., 2012
      • Chen H.
      • Eisner M.D.
      • Haselkorn T.
      • Trzaskoma B.
      Concomitant asthma medications in moderate-to-severe allergic asthma treated with omalizumab.
      (EXCELS Study)

      Treatment duration: 2 years
      % reduction in dose from baseline in new starters, established users, and omalizumab-naïve patients respectively, by: total ICS dose: 57.7%, 44.7%, and 42.4%

      ICS monotherapy dose: 67.8%, 67.9%, and 60.1%
      Ozgur ES et al., 2013
      • Ozgur E.S.
      • Özge C.
      • Ïlvan A.
      • Naycı S.A.
      Assessment of long-term omalizumab treatment in patients with severe allergic asthma long-term omalizumab treatment in severe asthma.


      Mean treatment duration: 40.81 ± 8.2 months
      Number of exacerbations decreased by 90% from baseline to 12 months and improvement sustained until end of treatment (P < 0.05)Increase in FEV1% predicted from baseline:

      Month 24: 21.5

      Month 36: 23

      End of visit: 20.4 (All P < 0.05)
      Increase in mean ACT score from baseline:

      Month 24: 10.3

      Month 36: 11.6

      End of visit: 11 (P = 0.001, all)

      Mean AQLQ total score vs baseline: 5.34 vs 1.98

      Increase in AQLQ scores by ≥ 0.5 points is considered minimal clinically important difference
      Decrease in HCRU vs baseline:

      No. of exacerbations by 90%

      No. of ER visits by 93.3%

      No. of hospitalizations by 71.3%

      Improvement was maintained until end of treatment (P < 0.05)
      Number of patients with systemic steroid use vs baseline: 0 vs 6
      Vennera Mdel C et al., 2012
      • Vennera Mdel C.
      • Pérez De Llano L.
      • Bardagí S.
      • et al.
      Omalizumab therapy in severe asthma: experience from the Spanish registry--some new approaches.


      Treatment duration: 2 years
      Mean exacerbation rate vs baseline: 1.04 vs 3.6

      P < 0.05
      Mean FEV1% predicted vs baseline:

      71.3% vs 63.8%

      P < 0.05
      Mean ACT score vs baseline: 20.3 vs 14.3

      P < 0.05
      Mean annualized hospitalizations rate vs baseline: 0.2 vs 0.6

      P < 0.05
      Corticosteroid use vs baseline:

      Mean ICS dose (budesonide equivalent):

      1147.4 μg vs 1676.6 μg

      P < 0.05

      No. of patients: 19 vs 89

      P < 0.05
      Dal Negro RW et al., 2012
      • Dal Negro R.W.
      • Tognella S.
      • Pradelli L.
      A 36-month study on the cost/utility of add-on omalizumab in persistent difficult-to-treat atopic asthma in Italy.


      Treatment duration: 3 years
      Mean exacerbation rate vs baseline:

      0.94 vs 2.06; P < 0.01
      Mean FEV1% predicted vs baseline:

      76% vs 57%; P < 0.01
      Mean ACT score vs baseline:

      19.91 vs 11.56; P < 0.01
      Mean annualized hospitalization rate vs baseline:

      0 vs 0.94; P < 0.01

      Mean annualized ER visit rate vs baseline: 0.25 vs 0.69; P < 0.05
      No. of patients vs baseline with OCS use: 5 vs 16

      Parenteral corticosteroids: 0 vs 6
      Menzella F et al., 2012
      • Menzella F.
      • Facciolongo N.
      • Piro R.
      • et al.
      Clinical and pharmacoeconomic aspects of omalizumab: a 4-year follow-up.


      Treatment duration: 4 years
      Rate of severe exacerbations and mild-to-moderate exacerbations decreased by 94.7% and 41.8%, respectively, from baselineMedian FEV1% predicted vs baseline: 75.4% vs 58.6% (P = 0.009)Median AQLQ score vs baseline:

      5.6 vs 2.8

      Increase in AQLQ scores by ≥ 0.5 points is considered minimal clinically important difference
      Tzortzaki EG et al., 2012
      • Tzortzaki E.G.
      • Georgiou A.
      • Kampas D.
      • et al.
      Long-term omalizumab treatment in severe allergic asthma: the South-Eastern Mediterranean “real-life” experience.


      Treatment duration: 4 years
      Mean number of exacerbations vs baseline:

      0.66 vs 2.27 (P < 0.0001)
      Mean FEV1% predicted vs baseline:

      71.76% vs 60.13% (P < 0.0001)

      Mean FVC% predicted vs baseline:

      82.29% vs 71% (P = 0.0002)
      Mean ACT score vs baseline: 21.50 vs 17.28 (P < 0.0001)

      % of patients with controlled asthma vs baseline: 87% vs 39%
      ICS dose vs baseline: 893.24 μg vs 1021.62 μg (P = 0.014)
      Omalizumab treatment for >5 years
      Papaioannou AI et al., 2021
      • Papaioannou A.I.
      • Mplizou M.
      • Porpodis K.
      • et al.
      Long-term efficacy and safety of omalizumab in patients with allergic asthma: a real-life study.


      Treatment duration: 10.6 ± 1.2 years
      Reduction in exacerbations vs pretreatment:

      1.1 vs 4.1 per year after 1 year of treatment and remained low during all the years up to the 8th year of treatment (P < 0.001)
      Improvement in FEV1% predicted vs baseline:

      73.6% vs 61.5% after 12 years of treatment (P < 0.001)

      Improvement in FEV1 (ml) vs baseline:

      239.8 vs. 160.8 after 12 years of treatment (P < 0.001)
      Improvement in asthma control expressed as ACT vs pre-treatment: 22.1 vs 16.2 after 3 years and remained as high up to the 8th year of treatment (P < 0.001)Discontinuation of OCS use:

      21.1% patients discontinue at 6 months;

      47.4% and 31.6% of patients were on OCS after 4 years and 8 years, respectively

      Proportion of patients with ≥50% OCS reduction:

      Month 6: 36.8%

      2 years: 68.4%
      Mansur AH et al., 2017
      • Mansur A.H.
      • Srivastava S.
      • Mitchell V.
      • Sullivan J.
      • Kasujee I.
      Longterm clinical outcomes of omalizumab therapy in severe allergic asthma: study of efficacy and safety.


      Mean treatment duration: 60.7 ± 30.9 months
      Mean FEV1% predicted vs baseline:

      75.7% vs 59.2% (P = 0.0013)
      Mean ACQ7 score vs baseline:

      2.3 vs 4.0 (P < 0.0001)
      Treatment vs baseline:

      Number of hospitalizations:

      40 vs 207

      Mean annual per patient hospitalizations: 0.89 vs 4.8 (P < 0.00001)

      Number of emergency visits:

      42 vs 80

      Mean annual per patient emergency attendance: 3.0 vs 4.4 (P = 0.17)

      Mean annual per patient ICU admissions: 0.19 vs 0.48 (P = 0.13)
      Treatment vs baseline:

      % of patients with maintenance OCS use:

      44.2% vs 82%

      Mean daily maintenance OCS dose (prednisolone equivalent): 6.0 mg vs 25.8 mg (P < 0.0001)

      Mean annual number of steroid courses per patient: 3.1 vs 6.1 (P < 0.001)
      Menzella F et al., 2017
      • Menzella F.
      • Galeone C.
      • Formisano D.
      • et al.
      Real-life efficacy of omalizumab after 9 Years of follow-up.


      Treatment duration: 9 years
      Mean annualized severe exacerbation rate vs baseline:

      0.63 vs 5
      Median FEV1% predicted vs baseline:

      85.5% vs 58.5%
      Median AQLQ score vs baseline:

      5.9 vs 2.5 (P < 0.001)
      Number of patients with steroids vs baseline:

      High-dose ICS: 1 vs 8

      Medium-dose ICS: 2 vs 0

      Low-dose ICS: 5 vs 0

      OCS: 1 vs 7
      Ledford et al., 2017
      • Ledford D.
      • Busse W.
      • Trzaskoma B.
      • et al.
      A randomized multicenter study evaluating Xolair persistence of response after long-term therapy.
      (XPORT study)

      Treatment duration: 6 years
      Time-to-first exacerbation was longer in the omalizumab-continuation group versus the omalizumab-discontinuation group (HR, 0.49 [95% CI: 0.28, 0.86])Mean change in score from baseline to Week 52 in omalizumab-continuation group vs omalizumab-discontinuation group:

      ACT score: −1.16 vs −2.88; P = 0.0188

      ACQ score: 0.22 vs 0.63; P = 0.0039
      Gemİcİoğlu B et al., 2016
      • Gemİcİoğlu B.
      • Öztürk B.Ç.
      • Duman B.
      Comparison of allergic asthma patients treated with omalizumab and non-allergic patients treated with continuous oral corticosteroids: results of five year follow-up therapies.


      Treatment duration: 5.5–7 years
      Mean exacerbation rates vs baseline:

      0.59 vs 2.57; P < 0.001
      Mean FEV1 vs baseline

      1.50 L vs 1.34 L
      Mean ACT score vs baseline:

      22.8 vs 17.7; P < 0.01
      Baseline vs 5 years:

      Drop in the inhaled steroid dosage by 65%
      Storms W et al., 2012
      • Storms W.
      • Bowdish M.S.
      • Farrar J.R.
      Omalizumab and asthma control in patients with moderate-to-severe allergic asthma: a 6-year pragmatic data review.


      Treatment duration: 6 years
      Mean FEV1% predicted at 3 years vs baseline: 69.8% vs 66.8%Mean ACT score increased by 96.4% at 6 years
      Pace E et al., 2011
      • Pace E.
      • Ferraro M.
      • Bruno A.
      • Chiappara G.
      • Bousquet J.
      • Gjomarkaj M.
      Clinical benefits of 7 years of treatment with omalizumab in severe uncontrolled asthmatics.


      Treatment duration: 7 years
      Mean FEV1% predicted vs baseline:

      71% vs 53% (P < 0.05)

      Mean FEV1/FVC % predicted vs baseline:

      65% vs 52% (P < 0.05)
      Mean symptom score vs baseline:

      0.3 vs 2.5 (P < 0.02)
      Corticosteroid use vs baseline:

      No. of nebulized corticosteroids and bronchodilator cycles: 1 vs 9

      No. of OCS cycles: 0.25 vs 3.5
      Nieto García A et al., 2021
      • Nieto García A.
      • Garriga-Baraut T.
      • Plaza Martín A.M.
      • et al.
      Omalizumab outcomes for up to 6 years in pediatric patients with severe persistent allergic asthma.


      Treatment duration: 6 years
      Mean number of exacerbations vs baseline:

      1.1 vs 7.9 per year, after 1 year of treatment and remained low during all the years up to the 6th year of treatment (P < 0.001)
      Mean FEV1% predicted vs baseline:

      92.8% vs 84.6% (P < 0.001)
      % of patients with controlled asthma vs baseline: 89.3% vs 8.4%Mean annualized hospitalizations rate vs baseline: 0.1 vs 1.0 (P < 0.001)

      Mean annualized pediatric ICU admissions rate:

      0.0 vs 0.1 (P < 0.001)
      ICS dose vs baseline (budesonide equivalent): 350.2 μg vs 867.3 μg (P < 0.001)
      ACQ, asthma control questionnaire; ACT, asthma control test; ALQ, asthma life quality; AQLQ, asthma quality of life questionnaire; ER, emergency room; FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; HCRU, healthcare resource utilization; HR, hazards ratio; ICS, inhaled corticosteroids; JPAC, Japanese pediatric asthma control; LABA, long-acting β2 agonist; OCS, oral corticosteroids; PEF, peak expiratory flow; QoL, quality of life

      Long-term safety

      Data from studies that evaluated the short-term use of omalizumab (<2 years) in asthma patients have reported that omalizumab has a favorable safety and tolerability profile.
      • Humbert M.
      • Beasley R.
      • Ayres J.
      • et al.
      Benefits of omalizumab as add-on therapy in patients with severe persistent asthma who are inadequately controlled despite best available therapy (GINA 2002 step 4 treatment): innovate.
      ,
      • Corren J.
      • Casale T.B.
      • Lanier B.
      • Buhl R.
      • Holgate S.
      • Jimenez P.
      Safety and tolerability of omalizumab.
      Overall, the incidences of adverse events (AEs) and serious adverse events (SAEs) were similar between long- and short-term use, reassuring the safety profile of omalizumab after prolonged use. These results are supported by at ≥1.75 million patient-years of omalizumab exposure in the post-marketing setting.
      Table 3 summarizes the safety findings from the studies included in this review.
      Table 3Clinical experience with omalizumab in asthma and other disease conditions – Summary of safety data.
      Study acronym or AuthorDisease conditionFollow-up periodAdverse eventsSerious adverse events/deaths
      Papaioannou AI et al., 2021
      • Gemİcİoğlu B.
      • Öztürk B.Ç.
      • Duman B.
      Comparison of allergic asthma patients treated with omalizumab and non-allergic patients treated with continuous oral corticosteroids: results of five year follow-up therapies.
      Severe uncontrolled allergic asthma (n = 45)10.6 ± 12 yearsLocal reactions and/or erythema at injection sites: 11 patients; upper respiratory tract infection: 8

      patients; ankle swelling: 1 patient
      No SAEs
      Schreiber J et al., 2020
      • Schreiber J.
      • Schwab Sauerbeck I.
      • Mailänder C.
      The long-term effectiveness and safety of omalizumab on patient- and physician-reported asthma control: a three-year, real-life observational study.
      Seasonal allergic asthma (n = 161)3 years79.5% of patients reported at least one AE;

      Infections and infestations: 28.5%

      Respiratory, thoracic, or mediastinal disorders: 24.8%
      13.0% of patients reported SAEs (related to omalizumab)
      Kirchnerová OR et al., 2019
      • Al-Ahmad M.
      • Arifhodzic N.
      • Nurkic J.
      • et al.
      Real-life" efficacy and safety aspects of 4-year omalizumab treatment for asthma.
      Uncontrolled persistent allergic (n = 114)2 yearsNA11 SAEs reported from 112 patients
      Al-Ahmad M et al., 2018
      • Tat T.S.
      • Cilli A.
      Evaluation of long-term safety and efficacy of omalizumab in elderly patients with uncontrolled allergic asthma.
      Poorly controlled allergic asthma patients (n = 80)4 years12 patients reported mild adverse reactions: headache 5 (6.3%); tiredness/fatigue 2 (2.5%); hair loss 1 (1.3%); local reactions (mild pain and swelling at the site of injection) 4 (6.1%)2 patients developed serious comorbidities: Malignancy and Liver cirrhosis
      Menzella F et al., 2017
      • Menzella F.
      • Galeone C.
      • Formisano D.
      • et al.
      Real-life efficacy of omalizumab after 9 Years of follow-up.
      Severe persistent allergic asthma (n = 8)9 yearsNo eventsNA
      Di Bona et al., 2017
      • Di Bona D.
      • Fiorino I.
      • Taurino M.
      • et al.
      Long-term “real-life” safety of omalizumab in patients with severe uncontrolled asthma: a nine-year study.
      Poorly controlled severe asthma (n = 91)Mean treatment: 3.8 ± 2.6 years (range: 0.2–9 years)Treatment-related AEs: n = 6

      AEs causing discontinuation: Arthralgia/Myalgia (n = 3), urticaria, angioedema (n = 1), bleeding (n = 1), and relapsing herpes labialis (n = 1)
      NA
      Iribarren C et al., 2017
      • Iribarren C.
      • Rahmaoui A.
      • Long A.A.
      • et al.
      Cardiovascular and cerebrovascular events among patients receiving omalizumab: results from EXCELS, a prospective cohort study of moderate-to-severe asthma.
      8 (EXCELS)
      Moderate-to-severe asthma (n = 7836)>5 yearsNARate (per 1000 person-years) of cardiovascular or cerebrovascular SAEs and arterial thromboembolic events in the omalizumab vs omalizumab-naïve group: 13.4 and 6.66 vs 8.1 and 4.64, respectively
      Ledford D et al., 2017
      • Ledford D.
      • Busse W.
      • Trzaskoma B.
      • et al.
      A randomized multicenter study evaluating Xolair persistence of response after long-term therapy.
      Moderate-to-severe persistent asthma (n = 176)6 yearsRate of AEs/100 patient-year in omalizumab-continuation vs omalizumab-discontinuation groups: 413.2 vs 425.9

      Most common AEs: asthma, sinusitis, upper respiratory tract infection, acute sinusitis
      Rate of SAEs/100 patient-year in omalizumab-continuation vs omalizumab-discontinuation groups: 8.3 vs 9.1

      Most common SAE: asthma

      Malignancy SAEs: adenocarcinoma of colon (omalizumab-continuation group) and Müllerian tumor (omalizumab-discontinuation group

      Deaths: 1 (omalizumab-discontinuation group)
      Mansur AH et al., 2017
      • Mansur A.H.
      • Srivastava S.
      • Mitchell V.
      • Sullivan J.
      • Kasujee I.
      Longterm clinical outcomes of omalizumab therapy in severe allergic asthma: study of efficacy and safety.
      Severe allergic asthma (n = 45)Mean treatment: 60.7 ± 30.9 monthsGeneralized arthralgia and myalgia (n = 2), headache (n = 2), symptoms of fatigue and sleepiness (n = 1), isolated episodes of skin rashes (n = 2), mouth ulcers and boils (n = 1); shingles (n = 1), gout associated with severe weight loss (n = 1)Breast cancer (n = 1) and multiple basal cell carcinoma (n = 1)
      Odajima H et al., 2017
      • Odajima H.
      • Ebisawa M.
      • Nagakura T.
      • et al.
      Long-term safety, efficacy, pharmacokinetics and pharmacodynamics of omalizumab in children with severe uncontrolled asthma.
      Uncontrolled severe asthma (n = 38)Median exposure: 116.6 weeks (range: 46.9–151.1 weeks)At least 1 AE: 100% patients (n = 38)

      Most common AEs: nasopharyngitis, influenza, upper respiratory tract infection, asthma exacerbations

      Drug-related: n = 11 (most common: injection-site swelling)
      At least 1 SAE: 26.3% patients (n = 10)

      Most common SAE: asthma exacerbations

      Drug-related SAE: peri-tonsillar abscess (n = 1)
      Tat TS et al., 2016
      • Tat T.S.
      • Cilli A.
      Evaluation of long-term safety and efficacy of omalizumab in elderly patients with uncontrolled allergic asthma.
      Allergic asthma in elderly patients (n = 19)Mean treatment duration: 35.6 ± 17.8 monthsLocal adverse reaction (n = 1), myalgia (n = 1; drug-related)Deaths (n = 1 due to bronchial cancer)
      Barbosa MP et al., 2015
      • Pereira Barbosa M.
      • Bugalho de Almeida A.
      • Pereira C.
      • Chen C.W.
      • Georgiou P.
      • Peachey G.
      eXpeRience study group.
      Real-life efficacy and safety of omalizumab in Portuguese patients with persistent uncontrolled asthma.
      (eXpeRience – Portugal subgroup)
      Uncontrolled persistent allergic asthma (n = 62)2 yearsNA2 SAEs: pulmonary embolism (suspected to be drug-related and led to study discontinuation) and tracheobronchitis
      Lopez Tiro JJ et al., 2015
      • Lopez Tiro J.J.
      • Contreras E.A.
      • del Pozo M.E.
      • Gómez Vera J.
      • Larenas Linnemann D.
      Real life study of three years omalizumab in patients with difficult-to-control asthma.
      Difficult-to-treat asthma (n = 49)3 years4 AEs: osteo-articular pain (n = 1), mild headache (n = 2) and vasovagal syncope (n = 1)NA
      Namazova-Baranova L et al., 2015
      • Namazova-Baranova L.
      • Vishneva E.
      • Smirnov V.
      • et al.
      The patient registry of children with severe persistent uncontrolled asthma as a tool for long-term dynamic monitoring.
      Severe persistent uncontrolled asthma (n = 65)1–72 monthsFrequency of local AEs: 1/100–1/200

      Local allergic reactions such as rashes: n = 2
      NA
      Long A et al., 2014
      • Long A.
      • Rahmaoui A.
      • Rothman K.J.
      • et al.
      Incidence of malignancy in patients with moderate-to-severe asthma treated with or without omalizumab.
      (EXCELS study)
      Moderate-to-severe asthma (n = 7836)>5 years295 malignancy AEs in 220 patients in omalizumab group and 190 malignancy AEs in 126 patients in omalizumab-naïve group.

      Most common malignancy AEs: non-melanoma, breast cancer, prostate cancer, colorectal cancer, melanoma, lung cancer
      At least 1 non-malignant SAE in 1263 patients (25.2%) in omalizumab group and 571 patients (20.2%) in the omalizumab-naïve group
      Vieira T et al., 2014
      • Vieira T.
      • de Oliveira J.F.
      • da Graca Castel-Branco M.
      Short and long-term quality of life and asthma control with omalizumab therapy in a real life setting in Portugal.
      Uncontrolled severe persistent allergic asthma (n = 15)2 yearsAEs: Headache (n = 4), nausea (n = 4), myalgia (n = 2), exuberant injection site reaction (n = 2), repeated acute asthma episodes (n = 1), breast neoplasm (n = 1)NA
      Caminati M et al., 2014
      • Caminati M.
      • Senna G.
      • Chieco Bianchi F.
      • et al.
      Omalizumab management beyond clinical trials: the added value of a network model.
      Allergic asthma (n = 59)Mean omalizumab treatment: 22.97 ± 16.55 monthsLarge local reaction at injection site: 13.4% patients (n = 8)NA
      Braunstahl GJ et al., 2013
      • Braunstahl G.J.
      • Chen C.W.
      • Maykut R.
      • et al.
      The eXpeRience registry: the ‘real-world’ effectiveness of omalizumab in allergic asthma.
      (eXpeRience)
      Uncontrolled persistent allergic asthma (n = 943)2 yearsNASAEs: 150 SAEs

      No of patients who reported SAEs: 64 patients (6.9%)

      Most common SAEs: asthma, dyspnea, and pneumonia

      Drug-related SAEs: 25

      Deaths: 9 (not related to omalizumab)

      Discontinued omalizumab due to SAEs: 38
      Ozgur ES et al., 2013
      • Ozgur E.S.
      • Özge C.
      • Ïlvan A.
      • Naycı S.A.
      Assessment of long-term omalizumab treatment in patients with severe allergic asthma long-term omalizumab treatment in severe asthma.
      Severe allergic asthma (n = 26)Mean duration: 40.81 ± 8.2 months1 patient reported moderate local injection-site reaction during 32nd month of treatmentNA
      Menzella F et al., 2012
      • Menzella F.
      • Facciolongo N.
      • Piro R.
      • et al.
      Clinical and pharmacoeconomic aspects of omalizumab: a 4-year follow-up.
      Severe persistent allergic asthma (n = 11)4 yearsNo eventsNA
      Tzortzaki EG et al., 2012
      • Tzortzaki E.G.
      • Georgiou A.
      • Kampas D.
      • et al.
      Long-term omalizumab treatment in severe allergic asthma: the South-Eastern Mediterranean “real-life” experience.
      Severe allergic asthma (n = 60)4 yearsAt least 1 AE: 11.6% patients (n = 7)

      Most frequent: headache (n = 3), local injection-site reaction (n = 2), arthralgia (n = 2)
      NA
      Vennera M del C et al., 2012
      • Vennera Mdel C.
      • Pérez De Llano L.
      • Bardagí S.
      • et al.
      Omalizumab therapy in severe asthma: experience from the Spanish registry--some new approaches.
      Uncontrolled severe asthma (n = 266)2 yearsAEs in 11.4% patients (n = 30)

      Most common AEs: arthralgia, cephalea
      No severe adverse events
      Dal Negro RW et al., 2012
      • Dal Negro R.W.
      • Tognella S.
      • Pradelli L.
      A 36-month study on the cost/utility of add-on omalizumab in persistent difficult-to-treat atopic asthma in Italy.
      Difficult-to-treat allergic asthma (n = 16)3 yearsNo eventsNA
      Domingo C et al., 2011
      • Domingo C.
      • Moreno A.
      • José Amengual M.
      • Montón C.
      • Suárez D.
      • Pomares X.
      Omalizumab in the management of oral corticosteroid-dependent IGE-mediated asthma patients.
      OCS-dependent asthma (n = 31)Mean follow-up 17.2 ± 8.5 monthsFlu-like syndrome: n = 3NA
      Pace E et al., 2011
      • Pace E.
      • Ferraro M.
      • Bruno A.
      • Chiappara G.
      • Bousquet J.
      • Gjomarkaj M.
      Clinical benefits of 7 years of treatment with omalizumab in severe uncontrolled asthmatics.
      Uncontrolled persistent severe asthma (n = 7)7 yearsNANA
      Nieto García A et al., 2021
      • Nieto García A.
      • Garriga-Baraut T.
      • Plaza Martín A.M.
      • et al.
      Omalizumab outcomes for up to 6 years in pediatric patients with severe persistent allergic asthma.
      Severe persistent allergic asthma (n = 484)Up to 6 yearsAt least 1 AE: 4.3% patients (n = 21).

      Most frequent AEs: headache (n = 8); malaise, fatigue, asthenia, low-grade fever, myalgia, and/or flu-like

      syndrome (n = 5), injection-site pain/reaction (n = 4), dizziness/loss of consciousness/vasovagal syncope (n = 4), transient urticaria (n = 2)
      NA
      AE, adverse event; OCS, oral corticosteroids; SAE, serious adverse event.
      NA: information not available

      Adverse events (AEs)

      Omalizumab use in adults with asthma

      Long-term omalizumab treatment for 2–5 years was well-tolerated in most studies. As anticipated with most subcutaneous biological agents, local injection-site reaction with omalizumab was reported in a few studies.
      • Caminati M.
      • Senna G.
      • Chieco Bianchi F.
      • et al.
      Omalizumab management beyond clinical trials: the added value of a network model.
      ,
      • Al-Ahmad M.
      • Arifhodzic N.
      • Nurkic J.
      • et al.
      Real-life" efficacy and safety aspects of 4-year omalizumab treatment for asthma.
      ,
      • Ozgur E.S.
      • Özge C.
      • Ïlvan A.
      • Naycı S.A.
      Assessment of long-term omalizumab treatment in patients with severe allergic asthma long-term omalizumab treatment in severe asthma.
      ,
      • Tzortzaki E.G.
      • Georgiou A.
      • Kampas D.
      • et al.
      Long-term omalizumab treatment in severe allergic asthma: the South-Eastern Mediterranean “real-life” experience.
      ,
      • Papaioannou A.I.
      • Mplizou M.
      • Porpodis K.
      • et al.
      Long-term efficacy and safety of omalizumab in patients with allergic asthma: a real-life study.
      In a 2-year post-marketing observational study, 11.4% of patients experienced ≥1 AE; most commonly reported AEs were arthralgia and cephalgia.
      • Vennera Mdel C.
      • Pérez De Llano L.
      • Bardagí S.
      • et al.
      Omalizumab therapy in severe asthma: experience from the Spanish registry--some new approaches.
      Furthermore, only 7 of 266 enrolled patients discontinued treatment because of AEs.
      • Vennera Mdel C.
      • Pérez De Llano L.
      • Bardagí S.
      • et al.
      Omalizumab therapy in severe asthma: experience from the Spanish registry--some new approaches.
      In another study, headache and nausea (26.7%) and fatigue and paresthesia (13.3%) were the most frequent AEs reported during 2 years of omalizumab treatment; however, most of these events did not lead to treatment discontinuation.
      • Vieira T.
      • de Oliveira J.F.
      • da Graca Castel-Branco M.
      Short and long-term quality of life and asthma control with omalizumab therapy in a real life setting in Portugal.
      Repeat acute asthma episodes, myalgia and paresthesia, and breast neoplasm (causal relationship with omalizumab not established) reported in 1 patient each led to treatment discontinuation.
      • Vieira T.
      • de Oliveira J.F.
      • da Graca Castel-Branco M.
      Short and long-term quality of life and asthma control with omalizumab therapy in a real life setting in Portugal.
      In a 3-year real-life study, osteo-articular pain and vasovagal syncope were reported in 1 patient each, and mild headache was reported in 2 of 49 patients. Two cases, one of severe headache and another of mild anaphylaxis, were reported after initiating omalizumab; hence, treatment was discontinued in these patients.
      • Lopez Tiro J.J.
      • Contreras E.A.
      • del Pozo M.E.
      • Gómez Vera J.
      • Larenas Linnemann D.
      Real life study of three years omalizumab in patients with difficult-to-control asthma.
      In elderly patients who received omalizumab for ∼3 years, 2 of 19 patients reported a local adverse reaction and drug-related myalgia.
      • Tat T.S.
      • Cilli A.
      Evaluation of long-term safety and efficacy of omalizumab in elderly patients with uncontrolled allergic asthma.
      No systemic adverse reactions related to omalizumab use (such as anaphylaxis) were reported in these patients.
      • Tat T.S.
      • Cilli A.
      Evaluation of long-term safety and efficacy of omalizumab in elderly patients with uncontrolled allergic asthma.
      Similar to the AE profile observed with 2–3 years of omalizumab treatment, 11.6% of patients treated with omalizumab for 4 years reported AEs (of mild to moderate severity), with headache, local injection-site reaction, and arthralgia being the most frequent; none of these events led to treatment discontinuation.
      • Tzortzaki E.G.
      • Georgiou A.
      • Kampas D.
      • et al.
      Long-term omalizumab treatment in severe allergic asthma: the South-Eastern Mediterranean “real-life” experience.

      Severe adverse events (SAEs)

      Omalizumab use for 2–5 years in adults with asthma

      In the 2-year eXpeRience study, 150 SAEs were reported in 64 (6.9%) patients; asthma (3.5%), dyspnea (0.8%), and pneumonia (0.8%) were the most common SAEs. Of 25 SAEs suspected of being drug-related, dyspnea, sudden chest tightness, and headache were the most common (3 events each); 14 SAEs led to treatment discontinuation. Nine deaths were reported during the study, none of which was omalizumab-related.
      • Braunstahl G.J.
      • Chen C.W.
      • Maykut R.
      • et al.
      The eXpeRience registry: the ‘real-world’ effectiveness of omalizumab in allergic asthma.
      Although individual cases of bronchial cancer
      • Tat T.S.
      • Cilli A.
      Evaluation of long-term safety and efficacy of omalizumab in elderly patients with uncontrolled allergic asthma.
      and malignant breast neoplasm
      • Vieira T.
      • de Oliveira J.F.
      • da Graca Castel-Branco M.
      Short and long-term quality of life and asthma control with omalizumab therapy in a real life setting in Portugal.
      are reported in different studies after 3 and 3.5 years of omalizumab treatment, respectively, no association between tumor and omalizumab treatment is reported. Further evidence on the correlation of omalizumab treatment with malignancy was evaluated in the dedicated 5-year EXCELS study, which demonstrated that crude malignancy rates for all malignancies, and all malignancies excluding non-melanoma skin cancer were similar in omalizumab and non-omalizumab users, with a rate ratio of 0.84 (95% CI, 0.62–1.13) and 0.98 (95% CI, 0.71–1.36).
      • Long A.
      • Rahmaoui A.
      • Rothman K.J.
      • et al.
      Incidence of malignancy in patients with moderate-to-severe asthma treated with or without omalizumab.
      The rate (per 1000 person-years) of cardiovascular/cerebrovascular SAEs was higher in omalizumab versus non-omalizumab–treated patients
      • Folque M.M.
      • Lozano J.
      • Riggioni C.
      • et al.
      “Real-life” experience in asthmatic children treated with omalizumab up to six-years follow-up.
      (Table 4). After control for measured confounders, the estimated increase in risk was reduced considerably. In addition, rates of ischemic stroke (0.5 [95% CI: 0.2–1.0] vs 0.7 [95% CI: 0.3–1.4]) and cardiovascular death (2.4 [95% CI: 1.6–3.3] vs 2.0 [95% CI: 1.2–3.1]) were similar in both groups.
      • Iribarren C.
      • Rahmaoui A.
      • Long A.A.
      • et al.
      Cardiovascular and cerebrovascular events among patients receiving omalizumab: results from EXCELS, a prospective cohort study of moderate-to-severe asthma.
      Table 4Rate (per 1000 person-years) of SAEs in omalizumab and non-omalizumab users.
      • Iribarren C.
      • Rothman K.J.
      • Bradley M.S.
      • Carrigan G.
      • Eisner M.D.
      • Chen H.
      Cardiovascular and cerebrovascular events among patients receiving omalizumab: pooled analysis of patient-level data from 25 randomized, double-blind, placebo-controlled clinical trials.
      SAEsOmalizumab treatedNon-omalizumab-treated
      Any cardiovascular/cerebrovascular event13.4, 95% CI: 11.6–15.48.1, 95% CI: 6.5–10.1
      Arterial thromboembolic6.66, 95% CI: 5.43–8.104.64, 95% CI: 3.40–6.19
      Transient ischemic attack0.7, 95% CI: 0.4–1.30.1, 95% CI: 0.0–0.6
      Myocardial infarction2.1, 95% CI: 1.4–3.00.8, 95% CI: 0.3–1.6
      Pulmonary hypertension0.5, 95% CI: 0.2–1.00.0, 95% CI: 0.0–0.4
      Pulmonary embolism/venous thrombosis3.2, 95% CI: 2.4–4.31.5, 95% CI: 0.8–2.5
      Unstable angina2.2, 95% CI: 1.5–3.01.4, 95% CI: 0.8–2.4
      SAEs, severe adverse events
      As the primary endpoint in the EXCELS study was to assess malignancy risk, patients were not randomized or balanced based on their cardiovascular risk at baseline, and this constitutes one of the confounders for cardiovascular risk assessment. After considering confounding imbalances between the cohorts, crude associations between omalizumab and cardiovascular/cerebrovascular SAEs were substantially reduced.
      • Iribarren C.
      • Rahmaoui A.
      • Long A.A.
      • et al.
      Cardiovascular and cerebrovascular events among patients receiving omalizumab: results from EXCELS, a prospective cohort study of moderate-to-severe asthma.

      Omalizumab use for >5 years in adults with asthma

      In the XPORT study, the rate (per 100 patient-years) of SAEs was similar in omalizumab-continuation and omalizumab-discontinuation groups (8.3 vs 9.1).
      • Ledford D.
      • Busse W.
      • Trzaskoma B.
      • et al.
      A randomized multicenter study evaluating Xolair persistence of response after long-term therapy.
      Asthma exacerbation was the most common SAE (5.9 vs 6.8 per 100 patient-years) reported in omalizumab continuation versus discontinuation groups. Among 176 patients, 2 patients reported malignant SAEs: (i) adenocarcinoma of the colon (omalizumab-continuation group) and (ii) a mixed Müllerian tumor (omalizumab-discontinuation group); one death due to an SAE of a mixed Müllerian tumor was reported (placebo group) 7 months after withdrawal from the study.
      • Ledford D.
      • Busse W.
      • Trzaskoma B.
      • et al.
      A randomized multicenter study evaluating Xolair persistence of response after long-term therapy.
      No patient from the omalizumab-continuation group reported an AE leading to study withdrawal.
      • Ledford D.
      • Busse W.
      • Trzaskoma B.
      • et al.
      A randomized multicenter study evaluating Xolair persistence of response after long-term therapy.

      Omalizumab use in pediatric patients in asthma

      In a study conducted in 38 children, ≥1 SAE was reported in 10 patients treated with omalizumab for ∼2 years; 7 patients reported asthma exacerbations. Peri-tonsillar abscess reported in one patient was suspected of being drug-related.
      • Odajima H.
      • Ebisawa M.
      • Nagakura T.
      • et al.
      Long-term safety, efficacy, pharmacokinetics and pharmacodynamics of omalizumab in children with severe uncontrolled asthma.
      In the ANCHORS study, 21 of 484 (4.3%) patients experienced ≥1 AE; headache was the most frequently reported AE (1.7%).
      • Nieto García A.
      • Garriga-Baraut T.
      • Plaza Martín A.M.
      • et al.
      Omalizumab outcomes for up to 6 years in pediatric patients with severe persistent allergic asthma.

      Discussion

      Despite treatment with standard-of-care medications, patients with moderate-to-severe allergic asthma may remain uncontrolled.
      • Vennera Mdel C.
      • Pérez De Llano L.
      • Bardagí S.
      • et al.
      Omalizumab therapy in severe asthma: experience from the Spanish registry--some new approaches.
      ,
      • Bourdin A.
      • Molinari N.
      • Vachier I.
      • Pahus L.
      • Suehs C.
      • Chanez P.
      In such patients, once asthma has been confirmed as the cause despite adherence to therapy, omalizumab treatment is recommended to achieve daily symptom control and decrease exacerbation rates.
      • Berger W.
      • Gupta N.
      • McAlary M.
      • et al.
      Evaluation of long-term safety of the anti-IgE antibody, omalizumab, in children with allergic asthma.
      Even though substantial evidence exists regarding the efficacy and effectiveness of omalizumab, understanding its effectiveness and safety in long-term/chronic use is of utmost importance.
      In this review, we examined data from various studies to evaluate the long-term effectiveness of omalizumab in different patient populations. Overall, omalizumab demonstrated up to 9 years of continuous treatment effectiveness in reducing the rate of (severe) exacerbations, improving lung function, asthma control, and QoL, and decreasing HCRU and use of corticosteroids (oral/inhaled) in patients with moderate-to-severe allergic asthma.
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      ,
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      Xolair Italian Study Group
      Can the response to Omalizumab be influenced by treatment duration? A real-life study.