Treatment of Childhood Asthma with Anti-Immunoglobulin E Antibody (Omalizumab)

Treatment of Childhood Asthma With Anti-Immunoglobulin E Antibody (Omalizumab)

Henry Milgrom, MD*; William Berger, MD‡; Anjuli Nayak, MD§; Niroo Gupta, MDʈ; Stephen Pollard, MD¶; Margaret McAlaryʈ; Angel Fowler Taylor, RPhʈ; and Patricia Rohane, MD#

ABSTRACT. Background and Objective. There seems randomized, placebo-controlled study evaluated the to be a strong causal relationship between allergy and the safety, steroid-sparing effects, and impact on disease ex- origins of asthma. Susceptibility to both is determined acerbations of omalizumab in the treatment of childhood by a combination of genetics and environment acting asthma. through a complex network of cytokines. Nearly 90% of Methods. Participants were 334 males and premenar- affected children have positive skin tests indicating the chal females aged 6 to 12 years, with moderate to severe presence of specific immunoglobulin E (IgE), with sen- allergic asthma requiring treatment with inhaled cortico- sitivity to house dust mite, Alternaria, cockroach, cat, and steroids. During a run-in phase, all children were dog most closely linked to the disease. Greater exposure switched to equivalent doses of beclomethasone dipro- to house dust mite during infancy leads to earlier onset pionate (BDP), and the dose was adjusted to assure main- of wheezing, and elevated serum IgE levels correlate tenance of asthma control achieved with previous corti- with the appearance of asthma symptoms. Specific IgE costeroid treatment. Children were randomized to -or oma (109 ؍ binds to high-affinity (Fc⑀RI) receptors on mast cells and subcutaneously administered placebo (N at a dose based on body weight and (225 ؍ basophils. The IgE-mediated reactions that follow expo- lizumab (N sure of sensitized mast cells to an allergen are designated initial serum IgE (0.016 mg/kg/IgE [IU/mL] per 4 weeks). early- and late-phase asthmatic responses (EAR and BDP dose (initial range 168–420 ␮g/d) was kept stable for LAR). EAR is characterized by release of histamine and 16 weeks (stable-steroid phase), reduced over 8 weeks to other preformed mediators within 1 hour of allergen the minimum effective dose (steroid-reduction phase), exposure. It is often followed by LAR, an infiltration of and maintained constant for the final 4 weeks. the airways by inflammatory cells associated with an Results. More participants in the omalizumab group episode of more prolonged, and usually more severe decreased their BDP dose, and their reduction was airflow obstruction, 4 to 8 hours after antigen exposure. greater than that of the placebo group (median reduction Chronic airway symptoms result from persistent LAR 100% vs 66.7%). BDP was withdrawn completely in 55% caused by continuous allergen exposure. IgE antibodies of the omalizumab group versus 39% of the placebo are capable of passive transfer of both EAR and LAR group. sensitivity. IgE-mediated mast cell activation contributes The incidence and the frequency of asthma exacerba- to chronic tissue eosinophilia and airway remodeling, tions requiring treatment with doubling of BDP dose or with permanent loss in pulmonary function. systemic corticosteroids were lower in the omalizumab Omalizumab (rhuMAb-E25) is a recombinant, human- group. The treatment differences were statistically sig- ized, monoclonal anti-IgE antibody of mouse origin de- nificant during the steroid-reduction phase, during veloped for the treatment of IgE-mediated diseases. which fewer participants in the omalizumab group had Omalizumab binds to free IgE at the same site as the asthma exacerbation episodes (18.2% vs 38.5%), and the high-affinity receptor. Although it attaches to free IgE, it mean number of episodes per patient was smaller than does not bind to IgA, IgG, or cell-bound IgE. It therefore with placebo (0.42 vs 2.72). Five asthma exacerbations does not induce cross-linking of cell-bound IgE, which requiring hospitalization all occurred in the placebo would lead to the release of allergic mediators. It has group. been reported to decrease serum IgE levels in a dose- Participants’ and investigators’ global evaluations of dependent manner, inhibit EAR and LAR, and cause a treatment effectiveness were more favorable for omali- down-regulation of Fc⑀RI receptors on basophils. Oma- lizumab has been reported to be safe and effective in zumab than placebo. Investigators rated effectiveness improving asthma control and reducing the requirement excellent for 31.5% of the omalizumab group versus for oral and inhaled corticosteroids. This double-blind, 16.3% of the placebo group and good for 44.7% of the omalizumab group versus 32.7% of the placebo group. There was little change in asthma symptom scores or From the *National Jewish Medical and Research Center, Denver, Colorado; spirometry measurements during either the stable-ste- ‡Southern California Research Center, Mission Viejo, California; §Univer- roid or steroid dose-reduction phase, with minimal dif- sity of Illinois, Peoria, Illinois; ʈNovartis Pharmaceuticals, East Hanover, ferences between the treatment groups. New Jersey; ¶Allergy & Asthma Research Institute, Louisville, Kentucky; The requirement for rescue medication in the omali- and #Schering-Plough Corporation, Kenilworth, New Jersey. (Work was zumab group during both the stable-steroid and steroid done during tenure at Novartis Pharmaceuticals, East Hanover, New Jer- dose-reduction phases was consistently lower than at sey.) baseline. At week 28, the median number of puffs of Received for publication Jan 3, 2001; accepted Apr 23, 2001. rescue medication taken daily was 0 in the omalizumab Address correspondence to Henry Milgrom, MD, National Jewish Medical and Research Center, 1400 Jackson St, Denver CO 80206. E-mail: group and 0.46 in the placebo group. The change from [email protected] baseline was significant in favor of omalizumab. PEDIATRICS (ISSN 0031 4005). Copyright © 2001 by the American Acad- Over the entire treatment period, patients in the oma- emy of Pediatrics. lizumab group missed a mean of 0.65 school days, com- http://www.pediatrics.org/cgi/content/full/108/2/Downloaded from www.aappublications.org/newse36 by guestPEDIATRICS on September Vol. 26, 1082021 No. 2 August 2001 1of10 pared with a mean of 1.21 days in the placebo group. The on mast cells and basophils.13 The IgE-mediated re- mean number of unscheduled medical contacts attribut- actions that follow the exposure of the sensitized able to asthma-related medical problems was signifi- mast cells of an individual with asthma to an aller- cantly smaller in the omalizumab group than in the pla- gen have been designated as early- and late-phase cebo group throughout the treatment period (0.15 vs 5.35). asthmatic responses (EAR and LAR).14 EAR is char- Median reduction in serum free IgE was 95% to 99% acterized by a release of histamine and other pre- among omalizumab patients. Median free IgE ranged from 133 to 790 IU/mL at baseline and was in the range of formed mediators from the mast cells and a short- 6 to 9 IU/mL during the treatment period. The dosing lived fall in forced expiratory volume in 1 second 15–17 scheme used in the trial therefore effectively reduced (FEV-1) within 1 hour of allergen exposure. It is serum IgE in patients with initial concentrations as high often followed by LAR, an infiltration of the airways as 1300 IU/mL. There was no reduction in free IgE in the by inflammatory cells associated with an episode of placebo group. more prolonged, and usually more severe airflow Omalizumab treatment was well tolerated. There were obstruction, 4 to 8 hours after antigen exposure. no serious treatment-related adverse events. The fre- Chronic airway symptoms result from persistent quency and types of all adverse events were similar in LAR caused by continuous allergen exposure.18 IgE the omalizumab and placebo groups. The majority of antibodies are capable of passive transfer of both adverse events were mild to moderate in severity. No EAR and LAR sensitivity.18 IgE-mediated mast cell adverse events suggestive of serum sickness or immune complex formation were observed. Study-drug–related activation contributes to chronic tissue eosinophilia adverse events occurred more frequently in the omali- and airway remodeling, an irreversible change in zumab group than in the placebo group (6.2% vs 0.9%). airway architecture with permanent loss in pulmo- Urticaria was reported in 9 omalizumab patients (4%) nary function.19 compared with 1 (0.9%) placebo patient and was mild or Omalizumab (rhuMAb-E25) is a recombinant, hu- moderate in nearly all cases. manized, monoclonal anti-IgE antibody of mouse Conclusion. Treatment with omalizumab is safe in origin developed for the treatment of IgE-mediated children with asthma. It reduces the requirement for diseases. Omalizumab binds to free IgE at the same inhaled corticosteroids while protecting against disease site as the high-affinity (Fc⑀RI) receptor.20 Although exacerbation. Pediatrics 2001;108(2). URL: http://www. it attaches to free IgE, it does not bind to IgA, IgG, or pediatrics.org/cgi/content/full/108/2/e36; asthma, child, cell-bound IgE. It is termed nonanaphylactogenic be- omalizumab, rhuMAb-E25, anti-IgE, beclomethasone dipro- cause it does not induce cross-linking of cell-bound pionate, steroid-sparing, inhaled corticosteroid, asthma exacerbation. IgE that would lead to the release of allergic mediators.21 It decreases serum IgE levels in a dose-dependent manner, inhibits EAR21–25 and LAR,26 and ABBREVIATIONS. IgE, immunoglobulin E; EAR, early-phase causes a down-regulation of Fc⑀RI receptors on ba- asthmatic response; LAR, late-phase asthmatic response; FEV-1, sophils.27 It has been found safe and effective in forced expiratory volume in 1 second; ICS, inhaled corticosteroid; BDP, beclomethasone dipropionate; AE, adverse event; PEFR, improving asthma control and reducing the require- peak expiratory flow rate; FVC, forced vital capacity; FEF 25%– ment for oral and inhaled corticosteroids.28 75%, forced expiratory volume during middle half of forced vital We report here on a multicenter, randomized, capacity. double-blind, placebo-controlled, parallel-group, 28- week trial designed primarily to evaluate the safety and steroid-sparing effect and secondarily, the im- he prevalence of asthma, the most common pact on asthma exacerbations of omalizumab in chil- chronic illness of children, has increased dra- dren with moderate to severe allergic asthma who Tmatically over the past several decades, culmi- require daily treatment with inhaled corticosteroids nating in a 75% rise between 1980 and 1994 in the (ICSs). United States.1 Despite progress in the understand- ing of its pathophysiology and an increase in the METHODS number of treatment modalities, the age-adjusted Patients mortality rate of asthma has accelerated from 0.93 The study enrolled male and premenarchal female asthmatic per 100 000 between 1979 and 1980 to 1.49 between patients aged 6 to 12 years, whose asthma was well controlled 2 1993 and 1994. There seems to be a strong causal with ICSs equivalent to 168 to 420 ␮g/d of beclomethasone dipro- relationship between allergy and the origins of asth- pionate (BDP) and bronchodilator therapy as needed for Ն3 ma.3 The susceptibility to both is determined by a months before randomization. To be included in the study, pa- combination of genetics and environment acting tients had to have: 1) a diagnosis of allergic asthma of at least 1 year’s duration; 2) a positive skin prick test to at least 1 of the through a complex network of cytokines. Nearly 90% following allergens, to which the children were exposed during of affected children have positive skin tests, indicat- the study: Dermatophagoides farinae, Dermatophagoides pteronyssinus, ing the presence of specific immunoglobulin E (IgE), cockroach (whole body), dog or cat; 3) total serum IgE level Ͻ with sensitivity to the common allergens—house between 30 and 1300 IU/mL; 4) body weight 90 kg; 5) baseline forced expiratory volume at 1 second (FEV-1) Ն60% of the pre- dust mite, Alternaria, cockroach, cat, and dog—most dicted normal value; 6) at least a 12% increase in FEV-1 over 4–7 closely linked to the disease. Significantly, greater baseline within 30 minutes of taking 1 or 2 puffs of albuterol (90 exposure to house dust mite during infancy leads to ␮g/puff); 7) stable asthma, defined as no significant change in the earlier onset of wheezing,8 and elevated serum IgE regular asthma medication and no acute asthma exacerbation requiring corticosteroid rescue for at least 4 weeks before enroll- levels correlate with the appearance of asthma symp- ment. Patients were excluded from the study if they had previ- 9–12 toms. ously been treated with omalizumab; known hypersensitivity to Specific IgE binds to high-affinity (Fc⑀RI) receptors any study drug; a history of acute infectious sinusitis or respira-

2of10 TREATMENTDownloaded OF CHILDHOOD from www.aappublications.org/news ASTHMA WITH ANTI-IgE by guest on ANTIBODY September 26, 2021 tory tract infection or active lung disease other than allergic ductions in the dose of BDP from baseline value and the propor- asthma within 1 month or any other significant systemic disease tion of patients with a reduction in the dose of BDP were analyzed. within 3 months of visit 1; clinically significant abnormalities in Asthma symptom scores, rescue medication use, pulmonary electrocardiogram, chest radiograph, or laboratory values, or ele- function test results, and asthma exacerbations were recorded as vated serum IgE levels for reasons other than atopy. Those chil- follows: dren who would have required omalizumab doses of Ͼ750 mg per 4 weeks, based on total serum IgE and body weight consideration • During both the run-in and stable-steroid phases, patients (0.016 mg/IgE in IU/mL ϫ body weight in kg), were excluded. maintained a daily diary to record nocturnal and daytime asthma symptom score (0–4 scale), morning asthma symptoms (yes ϭ 0, no ϭ 1), number of puffs of rescue medication during Study Protocol day and night, morning peak expiratory flow rate (PEFR) using After a 1-week enrollment and screening period, there were 3 Mini-Wright peak flow meter (Clement Clarke International for phases: 1) run-in phase (4–6 weeks), 2) stable-steroid phase (16 Ferraris Medical Inc, Holland, NY), and number of puffs of weeks), 3) steroid dose-reduction phase (12 weeks). Patients who BDP. completed the study were offered entry into an open-label exten- • Spirometry measurements (FEV-1, forced vital capacity [FVC], sion study to assess long-term safety, which will be reported forced expiratory volume during middle half of forced vital elsewhere. The study was performed in accordance with the Dec- capacity [FEF 25%–75%] were performed before start of the laration of Helsinki and its amendments. Parents or guardians treatment and predose, and 1-hour postdosing throughout both gave written informed consent, and the patients signed an assent the stable-steroid phase and the steroid dose-reduction phase. statement before enrollment. The institutional review board at • Any worsening of asthma that in investigator’s clinical judg- each center approved the study. ment required additional treatment, over and above the main- ␤ In the 4- to 6-week run-in phase, all patients not receiving BDP tenance BDP dose and pro re nata -2 agonist rescue medica- were switched to BDP 42 ␮g/puff for oral inhalation administered tion, was defined as an asthma exacerbation episode. ␮ twice daily (168–420 g/d). Initially, BDP was administered in For early assessment of worsening asthma, patients were in- doses considered to be comparable to the patient’s previous main- structed to contact the investigator for any of the following indi- tenance corticosteroid treatment. Subsequently, at week 2 of the cations: run-in phase, the dose of BDP was adjusted to maintain the previous level of asthma control. Patients whose asthma was • Worsening of asthma requiring an urgent (unscheduled) visit well-controlled with BDP 2 to 5 puffs twice daily (168–420 ␮g/d for medical care; ex mouthpiece equal to 200–500 ␮g/d ex valve, as often reported • PEFR Ͻ50% of patient’s personal best; outside the United States) were maintained on stable doses for 4 • A decrease in morning PEFR of Ն20% on Ն2 of 3 successive weeks before randomization. At the end of the run-in phase, days, compared with baseline (the lowest morning PEFR in the patients who met the criteria were randomized to either omali- week before visit 3 [week 0] and before start of BDP dose- zumab or placebo with a 2:1 randomization ratio. Patients and reduction provided the baseline values for the stable-steroid investigators were blinded to the treatment administered. phase and steroid dose-reduction phase, respectively); Depending on the patient’s body weight and serum IgE at visit •AϾ50% increase in 24-hour rescue medication use on Ն2of3 1, patients randomized to omalizumab were treated with subcu- successive days (Ն8 puffs), compared with baseline; taneous administration of omalizumab 150 mg or 300 mg every 4 • Ն2 of 3 successive nights with awakenings because of asthma weeks or with omalizumab 225 mg, 300 mg, or 375 mg every 2 symptoms requiring rescue medication; weeks, using a dosing chart designed to assure a minimum dose • A decrease in FEV-1 of Ն20% compared with baseline. of 0.016 mg/kg/IgE (IU/mL) per 4 weeks. Patients were main- Patients developing any of the above manifestations were eval- tained on the baseline dose of BDP for the first 16 weeks of the uated by the investigator and treated in accordance with the double-blind treatment period (stable-steroid phase), and then the current guidelines for management of asthma exacerbation.29 Each dose was tapered gradually (steroid dose-reduction phase). Over asthma exacerbation episode requiring additional treatment was the first 8 weeks of steroid dose-reduction phase, BDP was re- recorded on the case report form with the start and end date, the duced step-wise, approximately 25% of the baseline dose every 2 cause of asthma exacerbation, the asthma exacerbation criteria weeks, until total elimination or worsening of asthma, to establish met, and the treatment required. Asthma exacerbations that were the minimum effective dose of BDP. If the reduction in the BDP serious enough to require doubling of the BDP dose or systemic dose resulted in development of 1 or more of the criteria associ- corticosteroids were used for the statistical analysis. ated with the worsening of asthma listed below, the corticosteroid tapering was stopped and the BDP dose was increased to a pre- Global Evaluation of Effectiveness viously tolerated level or higher, based on the investigator’s clinical judgment. Participants were maintained on this minimum At the end of the study both patients and investigators per- effective dose of BDP during the last 4 weeks of the steroid formed global evaluations of treatment effectiveness using the dose-reduction phase. following ratings: excellent (complete control of asthma), good (marked improvement), moderate (discernible but limited improvement), poor (no appreciable change), or worsening. Concomitant Medication Throughout the study, albuterol (salbutamol) 2 puffs (90 ␮g/ Pharmacoeconomics ␮ puff ex mouthpiece equal to 100 g/puff ex valve, as often re- Frequency of unscheduled medical contacts (phone consults, ported outside the United States) as needed (maximum 8 puffs office visits, emergency department visits, urgent care center vis- daily) was allowed as rescue medication for symptoms of bron- its, admissions to hospital, additional lab work, additional proce- chospasm. Except for treatment of asthma exacerbation, all other dures) for treatment of asthma and other allergic diseases, fre- ␤ asthma medications, including -adrenergic agonists other than quency of school absence because of asthma, and frequency of albuterol, were prohibited during the study. missed work by the patient’s caregiver were recorded throughout double-blind treatment. Safety Assessments Pharmacodynamics Safety and tolerability were evaluated by gauging the frequency, severity, and seriousness of adverse events (AEs) and the Serum samples were taken at baseline and before dosing at reported relationship to the study drug; clinically significant weeks 16 and 24 for determination of IgE concentrations. In pa- changes in laboratory measures and vital signs; and local reactions tients treated with omalizumab, total serum IgE comprises free at the injection site. IgE (that not bound to omalizumab) and bound IgE (that com- plexed to omalizumab). Serum IgE at baseline (before omalizumab treatment) consists entirely of free IgE. Serum concentrations of Efficacy Assessments both free and total IgE (free IgE ϩ bound IgE) were measured by To evaluate the steroid-sparing effects, the BDP dose main- an enzyme-linked immunoassay27,30 with the use of Fc-receptor– tained constant for the last 4 weeks of the steroid dose-reduction IgG chimeric antibody and monoclonal anti-IgE. Serum samples phase was compared with the baseline dose. The percentage re- were screened for the presence of anti-omalizumab antibodies

Downloaded from www.aappublications.org/newshttp://www.pediatrics.org/cgi/content/full/108/2/ by guest on September 26, 2021 e36 3of10 using an antibody assay based on the method described by Casale RESULTS et al.30 After omalizumab treatment, values of free IgE above 150 Patient Characteristics ng/mL could not be quantified by the assay and were reported as A total of 334 patients were randomized into the Ͼ150 ng/mL. Concentrations of free IgE in ng/mL can be con- double-blind study: 225 to omalizumab (76 dosed verted to IU/mL by dividing by 2.42.31,32 Changes in total and free IgE levels in serum compared with baseline were calculated. every 2 weeks, 149 dosed every 4 weeks) and 109 to placebo (35 dosed every 2 weeks, 74 dosed every 4 Statistical Analysis weeks). Baseline characteristics of the study popula- All randomized patients who received 1 or more doses of the tion are summarized in Table 1. At baseline, patients study medication were included in the efficacy and safety analy- in both treatment groups had minimal asthma symp- ses. toms, with mean rescue albuterol use under 2 The percentage reduction in the dose of BDP and the propor- puffs/d. There were no statistically significant dif- tion of patients who were able to reduce the dose of BDP were analyzed using the generalized Cochran-Mantel-Haenszel (van ferences between the omalizumab and placebo Elteren) test stratified by treatment schedule.33 Patients who did groups with respect to any of the demographic or not enter the steroid dose-reduction phase were included in the background variables. analysis of these 2 variables with 0% BDP reduction. Asthma exacerbations requiring treatment with doubling of the BDP dose Patient Disposition or systemic corticosteroid were expressed as the number of Of the 501 patients screened, 6.8% were excluded asthma exacerbations per patient and the number of patients Ͼ experiencing one or more exacerbation in each phase and ana- because of serum IgE 1300 IU/mL, and 5.4% were lyzed using the generalized van Elteren test stratified by treatment excluded because of serum IgE Ͻ30 IU/mL. Sixteen schedule. The Breslow-Day test was used to determine the homo- (7.1%) omalizumab and 12 (11.0%) placebo partici- geneity of proportions across the dosing frequency strata (q 2 pants did not complete the study. In the omalizumab weeks, q 4 weeks).34 To account for the potential bias introduced by patients who discontinued the study, for the purpose of anal- group, 9 patients (4%) were discontinued during the ysis, the number of asthma exacerbations during a phase for these stable-steroid phase and 7 (3.1%) during the steroid patients was imputed as (number observed ϩ [number of days dose-reduction phase; in the placebo group, 8 pa- between discontinuation and planned end of phase/14]) rounded tients (7.3%) were discontinued during the stable- up to next integer. Patients who permanently discontinued treatment during the double-blind stable-steroid phase were included steroid phase and 4 (3.7%) during the steroid dose- in the analysis of the double-blind steroid dose-reduction phase. reduction phase. Withdrawal of consent was the In the steroid dose-reduction phase, the number of asthma exac- most frequent reason for premature termination in erbations assigned to patients who discontinued during the stable- both omalizumab (3.1%) and placebo (4.6%) groups. steroid phase was the (maximum number of episodes calculated One patient in each treatment group was discontin- during the steroid dose-reduction phase ϩ 1). Differences in the proportion of patients who had an unscheduled physician visit, ued because of lack of efficacy, and 1 patient in each experienced a decrease in morning PEFR Ն20% on 2 or 3 succes- was discontinued because of adverse effects (urticar- sive days, or awakenings on 2 or 3 successive nights that required ia in 1 omalizumab treated patient, hip fracture in 1 rescue medication were analyzed using the Pearson ␹2 test. The placebo patient). patients’ and investigators’ global evaluations of treatment effectiveness were analyzed at the last visit using the generalized Safety and Tolerability Cochran-Mantel-Haenszel test, stratified by treatment schedule. Change from baseline in rescue albuterol use was analyzed using There were no serious treatment-related AEs re- the van Elteren test, stratified by treatment schedule. ported in this study. Serious asthma exacerbations

TABLE 1. Summary of Demographic and Baseline Characteristics by Treatment (All Randomized Patients) Omalizumab Placebo (N ϭ 225) (N ϭ 109) Gender, n (%) Male 158 (70.2) 73 (67.0) Race, n (%) White 168 (74.7) 86 (78.9) Black 38 (16.9) 14 (12.8) Other 19 (8.4) 9 (8.3) Mean age (range, y) 9.4 (5–12) 9.5 (6–12) Mean duration of asthma (range, y) 6.1 (1–12) 6.1 (1–12) Mean BDP dose (range, ␮g/day) 284 (168–672) 267 (168–504) Mean serum total IgE (range, IU/mL) 348 (20–1269) 323 (29–1212) Mean FEV-1, % predicted (range) 84 (49–129) 85 (43–116) Mean FEV-1 reversibility, % 20.39 19.59 Mean morning PEFR (range, L/min) 261 (101–408) 264 (140–407) Number hospitalized for asthma treatment 18 (8.0) 9 (8.0) past y, n (%) Mean number of doctor’s office visits for urgent 1.9 1.6 asthma treatment past y Mean number emergency room visits for asthma 0.6 0.6 past y Mean daytime asthma symptom score (median) 0.52 (0.31) 0.57 (0.38) Mean nocturnal asthma symptom score (median) 0.21 (0) 0.25 (0) Mean morning asthma symptom score (median) 0.17 (0) 0.17 (0) Mean albuterol use (median, puffs/day) 1.1 (0.31) 1.4 (0.43)

4of10 TREATMENTDownloaded OF CHILDHOOD from www.aappublications.org/news ASTHMA WITH ANTI-IgE by guest on ANTIBODY September 26, 2021 TABLE 2. Number (%) of All Randomized Patients Reporting patient. In all except 2 patients, the urticaria was Most Frequent Adverse Events mild or moderate, resolved spontaneously or with Adverse Event Omalizumab Placebo antihistamine therapy (1 patient required corticoste- (N ϭ 225) (N ϭ 109) roid treatment), and did not recur with subsequent Number (%) Number (%) treatment. The urticaria occurring 1 day after the first Whether or not judged injection of omalizumab in 1 patient was considered study related severe; this resolved spontaneously in 20 minutes Any 201 (89.3) 95 (87.2) and did not recur with subsequent treatment. One Headache 81 (36.0) 33 (30.3) Pharyngitis 58 (25.8) 26 (23.9) omalizumab patient experienced mild to moderate Upper respiratory tract 78 (34.7) 39 (35.8) urticaria on 2 occasions and was discontinued from Infection the study. Viral infection 56 (24.9) 25 (22.9) Study-drug–related AEs occurred more frequently Fever 39 (17.3) 16 (14.7) in the omalizumab group than in the placebo group Sinusitis 38 (16.9) 22 (20.2) ϭ Coughing 30 (13.3) 19 (17.4) (6.2% vs 0.9%; P .029), but these were few in either Abdominal pain 28 (12.4) 13 (11.9) group (Table 2). The drug-related AEs in omali- Rhinitis 24 (10.7) 12 (11.0) zumab treated patients included urticaria (1.3%), Otitis media 19 (8.4) 7 (6.4) rash (0.4%), flushing (0.4%), and pruritus (0.4%). Ur- Trauma 17 (7.6) 3 (2.8) Vomiting 15 (6.7) 9 (8.3) ticaria, dyspepsia, and abnormal vision reported in 1 Ear ache 15 (6.7) 4 (3.7) placebo patient were considered treatment related. Injury 13 (5.8) 1 (0.9) Injection site pain or other local skin reactions (burn- Dyspepsia 13 (5.8) 2 (1.8) ing, itching, warmth, bruising, redness, hive forma- Judged study related Any 14 (6.2) 1 (0.9) tion, rashes) occurred in 37.5% omalizumab and Urticaria 3 (1.3) 0 (0.0) 36.6% placebo-treated patients; the frequency and Rash maculopapular 1 (0.4) 0 (0.0) severity of local reaction tended to decrease over the Flushing 1 (0.4) 0 (0.0) course of the study. Four omalizumab patients (1.7%) Pruritus 1 (0.4) 0 (0.0) and 2 placebo patients (1.8%) withdrew from the Pain, arm 1 (0.4) 0 (0.0) study because of pain and/or fear of injection. There were no clinically meaningful changes from baseline in clinical laboratory measures or vital signs in either requiring hospitalization occurred in 5 patients, all in the omalizumab or placebo group. There were no the placebo group. The frequency and types of all significant differences between the omalizumab and AEs, judged treatment related or not, were similar in placebo group in changes in height and weight dur- the omalizumab group and the placebo group (Table ing the study. 2). The majority of AEs were mild to moderate in One patient (0.4%) in the omalizumab group was severity. The most commonly reported AEs were withdrawn from the study because of urticaria, as headache (36.0% vs 30.3% for placebo), pharyngitis described above, and 1 patient (0.9%) in the placebo (25.8% vs 23.9% for placebo), upper respiratory tract group was withdrawn because of a prolonged hos- infection (34.7% vs 35.8% for placebo), and viral in- pitalization for hip fracture. fection (24.9% vs 22.9% for placebo). No AEs suggestive of serum sickness or immune complex formation BDP Dose Reduction were observed. Urticaria was reported in 9 omali- The median reduction in the dose of BDP from zumab patients (4%) compared with 1 (0.9%) placebo baseline was 100% in the omalizumab group com-

Fig 1. Percentage of patients with reduction in dose of inhaled steroid at end of treatment. The difference between the omalizumab group and the placebo group is statistically significant (P ϭ .002).

Downloaded from www.aappublications.org/newshttp://www.pediatrics.org/cgi/content/full/108/2/ by guest on September 26, 2021 e36 5of10 pared with 66.7% in the placebo group (P ϭ .001). A ening on 2 or 3 successive nights that required rescue significantly greater proportion of patients treated medication (21.1% vs 11.6%, P ϭ .002). with omalizumab reduced the inhaled steroid dose compared with patients in the placebo group (P ϭ Asthma Symptom Score, Rescue Beta-Agonist Use, and .002; Fig 1). BDP was withdrawn completely in 55% Pulmonary Function of the omalizumab group versus 39% of the placebo There was little change in asthma symptom scores, ϭ group (P .004). morning PEFR, FEV-1, FVC, or FEF 25%–75% during the course of either stable-steroid or steroid dose- reduction phase, with minimal difference between Asthma Exacerbations the treatment groups. Median nocturnal asthma Table 3 summarizes the asthma exacerbations re- symptom score was zero in both the omalizumab ported during the stable-steroid and steroid dose- and placebo groups at week 0 and remained at or reduction phases. The majority of the asthma exac- close to zero throughout the study. Mean nocturnal erbations required treatment with doubling of BDP asthma symptom score was lower in the omalizumab dose or systemic corticosteroids. During both phases, group at all evaluations. No notable treatment group the incidence (percentage of patients with exacerba- differences were seen in daytime asthma symptom tion) and the frequency (number of episodes per score until week 22, when the omalizumab group patient) of asthma exacerbations requiring treatment had a mean symptom score of 0.36, compared with with doubling of BDP dose or systemic corticoste- 0.54 in the placebo group. A similar difference per- roids were lower in the omalizumab group; the treat- sisted until the end of the study. Mean morning ment differences were statistically significant during PEFR was 261.3 L/min in the omalizumab group and the steroid dose-reduction phase (18.2% vs 38.5%, 264.0 L/min in the placebo group at week 0; it was P Ͻ .001; 0.42 vs 2.72, P Ͻ .001, respectively). The 269.8 L/min vs 265.0 L/min at the end of the study mean duration of asthma exacerbation episodes was (week 28). Mean FEV-1 was 1797.1 mL in the omali- similar in the 2 treatment groups during both phases zumab group and 1855.2 mL in the placebo group at (range: 10–14 days). week 0; it was 1891.0 mL versus 1883.5 mL at week The most frequently reported reason for asthma 28. Mean FVC was 2272.2 mL in the omalizumab group and 2334.4 mL in the placebo group at week 0; exacerbation was infection, including upper respira- it was 2404.9 mL versus 2422.0 mL at week 28. Mean tory tract infection, pharyngitis, bronchitis, and in- FEF 25%–75% was 1711.7 mL/s in the omalizumab fluenza (50% omalizumab, 41% placebo) followed by group and 1752.5 mL/s in the placebo group at week allergen exposure, including allergic rhinitis (13.2% 0; it was 1774.8 mL/s versus 1691.5 mL/s at week 28. omalizumab, 14.8% placebo). Steroid reduction was The dosage of rescue medication (puffs of albuterol considered the cause of asthma exacerbation in only taken daily) was consistently lower than baseline 1 patient (omalizumab group). during both the stable-steroid and steroid dose-re- A markedly higher proportion of patients in the duction phases in the omalizumab group. At week placebo group than in the omalizumab group re- 28, the median number of puffs of rescue medication quired an urgent, unscheduled physician visit (30.3% taken daily was 0 in the omalizumab group and 0.46 placebo vs 12.9% omalizumab, P ϭ .001), or experi- in the placebo group. The change from baseline was enced a decrease in morning PEFR Ն20%on2or3 statistically significant in favor of omalizumab (P ϭ successive days (17.4% vs 6.7%, P ϭ .002) or awak- .004).

TABLE 3. Summary of Asthma Exacerbations by Treatment Phase Asthma Exacerbations Stable Steroid Phase Steroid Reduction Phase Omalizumab Placebo Omalizumab Placebo n ϭ 225 n ϭ 109 n ϭ 216 n ϭ 101 Number (%) patients with exacerbations Treated with ␤-agonists or CS 45 (20.0) 30 (27.5) 46 (21.3) 49 (48.5) Treated with CS* 34 (15.1) 21 (19.3) 20 (9.3) 29 (28.7) Treated with systemic CS 28 (12.4) 20 (18.3) 20 (9.3) 27 (26.7) Mean number of episodes per patient Treated with ␤-agonists or CS 0.26 0.36 0.29 0.60 Treated with CS* 0.18 0.24 0.13 0.34 Treated with systemic CS 0.14 0.23 0.11 0.32 Analysis of exacerbations requiring doubling of BDP dose or systemic CS* Number (%) patients with exacerbation (imputed value) 35 (15.6) 25 (22.9) 41 (18.2)† 42 (38.5)† P Value .095 Ͻ.001 Mean number of episodes per patient (imputed value) 0.3 0.4 0.42 0.72 P Value .093 Ͻ.001 Mean number of days per exacerbation 10.2 14.0 9.9 10.8 P Value .967 .329 * CS indicates corticosteroids. † Percentages based on the number of randomized patients.

6of10 TREATMENTDownloaded OF CHILDHOOD from www.aappublications.org/news ASTHMA WITH ANTI-IgE by guest on ANTIBODY September 26, 2021 Global Evaluation of Treatment Effectiveness was the upper limit of quantification of the free IgE At the end of the study, investigators’ global eval- assay during the treatment period), and it is plotted uation of effectiveness favored the omalizumab in Fig 2 as the baseline value. group over the placebo group (P Ͻ .001). Effective- Total IgE (free ϩ bound IgE) increased in omali- ness was rated excellent for 31.5% of the omalizumab zumab treated patients (Fig 3). The median of the group versus 16.3% of the placebo group; it was percentage increases ranged from 168% (375 mg q 2 rated good for 44.7% of the omalizumab group ver- weeks) to 431% (150 mgq4weeks) at week 16 and sus 32.7% of the placebo group. The patients’ global from 160% (375 mgq2weeks) to 372% (150 mg q 4 evaluation of effectiveness was virtually identical to weeks) at week 24. For the placebo group, total IgE the investigators’; it was significantly better for oma- was close to baseline at weeks 16 and 24. lizumab as compared with placebo (P Ͻ .001). DISCUSSION Pharmacoeconomics Worldwide, 5% to 10% of children suffer from Over 28 weeks of the double-blind treatment pe- asthma.35 Atopy, the genetic predisposition to de- riod, patients in the omalizumab group missed a velop IgE-mediated responses to common allergens, mean of 0.65 school days, compared with a mean of and elevated IgE concentrations are the strongest 1.21 days in the placebo group (P ϭ .040). The mean identifiable factors for the development of asthma in number of missed work days by the patient’s care- young children.29,36 The recently developed recom- giver was 0.29 days in the omalizumab group com- binant humanized monoclonal anti-IgE antibody, pared with 0.49 days in the placebo group, but the omalizumab, has been found to be safe and effective difference did not achieve statistical significance in adult and adolescent patients with seasonal aller- (P ϭ .097). gic rhinitis30,37 and allergic asthma.28 The present The mean number of unscheduled medical con- study was undertaken to assess the safety and ste- tacts attributable to asthma-related medical prob- roid-sparing effects of omalizumab in children (aged lems was significantly smaller in the omalizumab 6–12 years) with moderate to severe allergic asthma. group than in the placebo group throughout the Omalizumab was well tolerated, with no evidence treatment period (0.15 vs 5.35; P ϭ .001). of clinically significant drug toxicity or serious treatment-related AEs. It is noteworthy that serious Pharmacodynamics asthma exacerbations requiring hospitalization oc- Serum free IgE decreased in omalizumab treated curred in 5 (4.6%) of 109 placebo patients but in none patients (Fig 2). Across the 5 dosage subgroups (150 of the omalizumab group. No immunologic or im- mg q 4 weeks, 300 mg q 4 weeks, 225 mg q 2 weeks, mune complex-related AEs were noted except for 300mgq2weeks, and 375 mgq2weeks), median several generally mild or moderate cases of urticaria. free IgE ranged from 133 to 790 IU/mL at baseline, The adverse events reported in the omalizumab from 6 to 9 IU/mL predose at the end of the stable- group were similar to those in the placebo group. steroid phase, and from 7 to 9 IU/mL predose at The most frequently reported adverse events in both week 24 of the treatment period. This corresponded groups consisted of commonly occurring medical to a reduction in free serum IgE ranging from 95% in complaints (headache, respiratory infection). Reac- the150mgq4weeks subgroup to 99% in the q 2 tions at the injection site occurred infrequently and weeks subgroups. Greater reductions were observed decreased with continued therapy. during the first few days after dosing. For the pla- The study was conducted in children whose cebo group during the treatment period, median free asthma was well controlled with ICS, and the ability IgE was greater than 62 IU/mL (150 ng/mL, which of omalizumab to replace ICS was evaluated to as-

Fig 2. Serum free IgE during the study by dosage subgroups. The free IgE measured at baseline is plotted as a reference value. Values Ͼ62 IU/mL could only be determined at baseline, not after omalizumab treatment.

Downloaded from www.aappublications.org/newshttp://www.pediatrics.org/cgi/content/full/108/2/ by guest on September 26, 2021 e36 7of10 Fig 3. Serum total IgE during the study by dosage subgroups. sess the drug efficacy. After 16 weeks of treatment Fc portion of the molecule is blocked. They are with omalizumab, BDP dose was gradually reduced cleared by low-avidity interaction with the Fc-␥ re- to the lowest effective dose level. The reduction in ceptors of leukocytes and the reticuloendothelial sys- BPD dose was significantly greater in the omali- tem.38 They do not fix complement or accumulate in zumab group than the placebo group, and a signifi- renal glomeruli and do not pose a risk for immuno- cantly greater percentage of omalizumab treated pathogenicity.38 patients could reduce their BDP dose. BDP could Overall, the outcome among omalizumab-treated be withdrawn completely in 55% of omalizumab patients was better than the placebo group as evalu- patients. Daily asthma symptom scores, rescue ␤-ag- ated by reduction in BDP dosage, percentage of pa- onist requirement, and pulmonary function assess- tients who discontinued BDP, incidence and fre- ment showed that asthma control was well main- quency of asthma exacerbations, participants’ and tained despite significant reduction in BDP dose. investigators’ global evaluations of treatment effec- During the steroid dose-reduction phase, asthma ex- tiveness, dosage of rescue medication, missed school acerbations requiring doubling of the ICS dose or days, and unscheduled medical contacts attributable addition of oral corticosteroid therapy occurred 42% to asthma-related medical problems. The frequency less frequently among omalizumab patients, and and types of all adverse events, judged treatment 53% fewer patients had 1 or more asthma exacerba- related or not, were similar in the omalizumab group tions. and the placebo group. The majority of adverse Acute asthma exacerbations requiring additional events were mild to moderate in severity. Study- ␤-agonist and/or corticosteroid treatment occurred drug–related adverse events occurred more fre- more frequently during the steroid dose-reduction quently in the omalizumab group than in the placebo phase compared with stable-steroid phase; the dif- group, but were relatively infrequent in both groups. ference in exacerbation rates between the 2 phases The several cases of urticaria were nearly all mild or was much greater for the placebo group. The in- moderate. crease in exacerbation rate during the steroid dose- Early aggressive therapy is needed to maximize reduction phase is related to the loss of anti-inflam- control of asthma in all age groups.40–43 Despite the matory effects of ICS. The lower exacerbation rate in effectiveness of ICS, there is a continuing reluctance omalizumab-treated patients reflects its ability to to use these agents, especially in younger pa- provide similar protection. tients.44,45 Anti-IgE therapy is a promising alterna- Treatment with omalizumab resulted in a reduc- tive treatment for those children who fail to respond tion from baseline in mean serum free IgE that to corticosteroid therapy, require unacceptably high ranged from 95% to over 99% across all dosing reg- doses of ICS or systemic corticosteroids, have fre- imens, indicating that the dosing scheme used in the quent exacerbations, or suffer unacceptable side ef- trial effectively reduces serum IgE in patients with fects of corticosteroid therapy. Because of serious initial concentrations as high as 1300 IU/mL. At the limitations in the adherence to daily ICS therapy, a same time there was an increase in total IgE, ranging long-acting treatment is especially desirable. Because from 167% to 431% of baseline serum IgE level, de- imperfect effort or technique limit efficacy of inhaled pending on baseline IgE and omalizumab dose. This medication, the introduction of an effective agent increase in total IgE represents the persistence in that can be administered parenterally at long inter- circulation of biologically inactive omalizumab-IgE vals is a propitious development. complexes.38,39 These low molecular weight com- Omalizumab is a novel monoclonal antibody that plexes lack the biological activity of IgE because the binds to IgE and may interfere with the pathogenesis

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Downloaded from www.aappublications.org/news by guest on September 26, 2021 Treatment of Childhood Asthma With Anti-Immunoglobulin E Antibody (Omalizumab) Henry Milgrom, William Berger, Anjuli Nayak, Niroo Gupta, Stephen Pollard, Margaret McAlary, Angel Fowler Taylor and Patricia Rohane Pediatrics 2001;108;e36 DOI: 10.1542/peds.108.2.e36

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