Effect of Omalizumab on Symptoms of Seasonal Allergic Rhinitis (2025)

ContextSeasonal allergic rhinitis is a common IgE-mediated disorder that producestroublesome symptoms. A recombinant humanized monoclonal anti-IgE antibody(omalizumab) forms complexes with free IgE, blocking its interaction withmast cells and basophils and lowering free IgE levels in the circulation.

ObjectiveTo assess the efficacy and safety of omalizumab for prophylaxis of symptomsin patients with seasonal allergic rhinitis.

DesignRandomized, double-blind, dose-ranging, placebo-controlled trial conductedfrom July 25 through November 21, 1997.

SettingTwenty-five outpatient centers throughout the United States.

PatientsFive hundred thirty-six patients aged 12 to 75 years with at least a2-year history of moderate to severe ragweed-induced seasonal allergic rhinitisand a baseline IgE level between 30 and 700 IU/mL.

InterventionsPatients were randomly assigned to receive omalizumab, 50 mg (n = 137),150 mg (n = 134), or 300 mg (n = 129), or placebo (n = 136) subcutaneouslyjust prior to ragweed season and repeated during the pollen season every 3weeks in patients with baseline IgE levels of 151 to 700 IU/mL (4 total treatments)and every 4 weeks in patients with baseline IgE levels of 30 to 150 IU/mL(3 total treatments).

Main Outcome MeasuresSelf-assessed daily nasal symptom severity scores (range, 0-3), rescueantihistamine use, and rhinitis-specific quality of life during the 12 weeksfrom the start of treatment.

ResultsNasal symptom severity scores were significantly lower in patients whoreceived 300 mg of omalizumab than in those who received placebo (least squaresmeans, 0.75 vs 0.98, respectively; P = .002). A significantassociation was observed between IgE reduction and nasal symptoms and rescueantihistamine use. Rhinitis-specific quality of life scores were consistentlybetter in patients who received 300 mg of omalizumab than in those who receivedlower dosages or placebo and did not decline during peak season. The frequencyof adverse events was not significantly different among the omalizumab andplacebo groups.

ConclusionOmalizumab decreased serum free IgE levels and provided clinical benefitin a dose-dependent fashion in patients with seasonal allergic rhinitis.

Allergic rhinitis is an IgE-mediated condition manifested by upper respiratorytract, lower respiratory tract, and ocular symptoms.^1-3This disease affects at least 10% to 20% of US and northern European populations,and its prevalence in urban areas is increasing.^4-7It is a common reason for seeking outpatient medical care⁸and frequently complicates concomitant conditions such as allergic asthma,chronic sinusitis, otitis media, and nasal polyposis.^9-11Allergic rhinitis is also associated with diminished quality of life, lostwork productivity, and school absenteeism.^12-14The total economic burden of allergic rhinitis and its complications in theUnited States is estimated at $6 billion per year.¹⁵

Symptoms of allergic rhinitis are triggered by exposure to allergens.Patients who are very sensitive to pollen exhibit symptoms almost as soonas pollination begins, with symptoms becoming more severe when pollen concentrationsare highest and waning with the end of the pollen season.¹⁶Presently, allergen avoidance, pharmacotherapy, and immunotherapy are thetreatments available for allergic rhinitis.^17,18Despite these therapeutic options, there remains a group of patients whosesymptoms are not controlled and for whom alternative therapies are needed.At least 50% of patients are likely to require primary care management withcombined therapies, such as an intranasal corticosteroid and an oral antihistaminefor optimal control throughout the pollen season.¹⁹A survey of 526 patients prescribed these combined therapies showed that only142 (27%) were using both types of drug regularly, and 88 (62%) of those patientsdescribed symptom control as partial or poor.²⁰

A recombinant humanized monoclonal anti-IgE antibody (omalizumab) wasrecently developed.²¹ This antibody binds specificallyto a unique epitope, the Fc∊RI binding site on human IgE, and therebyblocks the binding of IgE to mast cells and basophils. Given the fundamentalrole of IgE in the pathogenesis of seasonal allergic rhinitis, decreasingfree serum IgE in atopic patients was expected to decrease seasonal rhinitissymptoms during the pollen season.

We assessed the efficacy of omalizumab, formerly rhuMAb-E25, for theprophylaxis of symptoms in patients with ragweed-induced seasonal allergicrhinitis, determined the agent's effect on rhinitis-specific quality of life,and evaluated the relationship between free IgE levels (serum IgE not boundup in the IgE-omalizumab complex) and clinical efficacy measures.

Individuals aged 12 to 75 years with no or mild symptoms during thepreceding month but with at least a 2-year history of moderate to severe seasonalallergic rhinitis due to ragweed were eligible for the study. The historyof moderate to severe ragweed-induced allergic rhinitis was defined as havinga score of 2 or more on a 0- to 3-point scale (0, no symptoms and 3, severesymptoms), in 4 of 8 symptom categories (sneezing, itchy nose, running nose,stuffy nose, watery eyes, red eyes, itchy eyes, or itchy throat) based onpatient recall of the previous ragweed season. Skin test sensitivity to ragweedpollen and a baseline total IgE level of between 30 and 700 IU/mL also wererequired. A positive skin test result was defined as presence of both whealand erythema. In the absence of wheal, an erythema response equal to the positivecontrol (1 mg/mL histamine base) and 1 grade larger than the negative control(extract diluent) at 15 to 20 minutes after skin testing was considered apositive skin test result. The erythema response was graded as follows: 0,no erythema; 1, 20 mm or less; or 2, more than 20 mm.²²The lower limit of baseline total IgE level was established to ensure thatserum IgE levels would be sufficiently high to be detectable, and the upperlimit was based on dosing considerations. Prior to drug therapy, total IgEis equivalent to free IgE; after drug therapy, total IgE is equivalent tofree IgE plus IgE bound to omalizumab.

Exclusion criteria included history of severe idiopathic anaphylacticreaction; immunotherapy within 2 years for seasonal ragweed allergic rhinitis;prior exposure to omalizumab; parasitic infection; history of perennial, vasomotor,or structurally related rhinitis; recent history (<3 months) of drug-inducedrhinitis or acute infectious sinusitis; regular treatment with β-adrenergicantagonists, tricyclic antidepressants, or monoamine-oxidase inhibitors; treatmentwith short-acting antihistamines within 3 days, cetirizine hydrochloride orloratadine within 5 days, or astemizole within 3 months; systemic corticosteroidswithin 3 months; inhaled or intranasal corticosteroids within 15 days or anytimeduring the trial; travel for at least 5 consecutive days outside the regionsof the study; current or recent serious systemic disease; clinically significantECG abnormality; and pregnancy or lactation.

The study was performed in accordance with the Declaration of Helsinkiand its amendments. Patients gave written informed consent before enrollment.The institutional review board at each center approved the study.

This was a double-blind, placebo-controlled, dose-ranging trial conductedfrom July 25 through November 21, 1997, at 25 centers in the Northeast, Southeast,Midwest, West, and Great Lakes regions of the United States. Blinded studyparticipants included investigators, patients, and study monitors. At trialcompletion, drug codes were broken and made available for data analysis. Ragweed-inducedseasonal allergic rhinitis was chosen as the study condition because ragweedis the most common cause of seasonal allergic rhinitis in North America,¹⁶ and the timing of ragweed season is uniform in theseregions, usually peaking in late August or early September.²³Daily ragweed pollen counts were used to determine the pollen season (thestart and end defined as the first and last sequence of >10 grains/m³ for ≥2 consecutive days) and the severe pollen season (the startand end defined as the first and last sequence of >100 grains/m³for ≥2 consecutive days) for each center. Pollen data, collected with arotation impaction sampler, were measured locally at each center.

Eligible patients with baseline IgE levels between 151 and 700 IU/mLwere randomly assigned (Figure 1)to receive either 50, 150, or 300 mg of omalizumab or placebo subcutaneouslyat 3-week intervals for a total of 4 treatments administered at baseline andat weeks 3, 6, and 9. Patients with baseline IgE levels between 30 and 150IU/mL were randomly assigned to receive 1 of the 3 omalizumab dosages or placeboevery 4 weeks, for a total of 3 treatments administered at baseline and weeks4 and 8. The treatment schedules were based on data showing the pharmacokineticand pharmacodynamic relationship between baseline IgE levels and omalizumaband the expected suppression of IgE necessary for clinical benefit.^24-26

A computer-generated randomization scheme was used to provide balancedblocks of patient numbers for each of the 4 treatment groups within each baselineIgE stratum, and patients were assigned a sequential randomization number.Placebo was sterile, white, preservative-free lyophilized powder excipientidentical to excipient in the vials that contained study drug. Clinical assessmentswere performed at each visit for study drug administration and at the endof the trial (week 12). Blood levels of anti-omalizumab antibody were determinedapproximately 12 weeks after the final visit.

Patients could take 4 mg of chlorpheniramine maleate as needed for severeallergic rhinitis symptoms. Patients unable to tolerate chlorpheniramine werepermitted to use alternative antihistamines as rescue medication. Oral ortopical decongestants were allowed on a restricted basis, after consultingwith the study physician, for temporary relief of severe nasal congestion,as were eye drops for ocular symptoms.

The primary efficacy parameter was the average daily nasal symptom severityscore. Secondary efficacy measures included average daily ocular symptom severity,average daily nasal and ocular symptom duration, proportion of days with minimalnasal symptoms, proportion of days with rescue or concomitant antihistamineuse, rescue or concomitant seasonal allergic rhinitis medication use index,number of tablets of rescue medication taken, patient's and investigator'sglobal evaluation of treatment effectiveness, Rhinoconjunctivitis Qualityof Life Questionnaire (RQLQ) scores,²⁷ andpharmacoeconomic assessments.

Each evening, patients recorded self-assessed symptom severity and durationscores in a daily diary. Nasal symptoms included sneezing and itchy, runny,or stuffy nose; ocular symptoms included itchy, watery, or red eyes. Symptomswere scored on a scale from 0 to 3 (for symptom severity, 0, no symptoms;1, mild; 2, moderate; 3, severe; for symptom duration, 0, no symptoms; 1,symptoms present for <3 hours; 2, symptoms present for 3-8 hours; 3, symptomspresent >8 hours). A minimal nasal symptom day was defined as a day when thetotal nasal symptom severity score was 2 or less and no rescue medicationswere taken to alleviate allergic rhinitis symptoms. Concomitant medicationsused for symptomatic relief of allergy symptoms were recorded. The averagenumber of tablets of rescue chlorpheniramine taken per day was calculatedby adding up the number of tablets per day and dividing by the number of dayswithin the pollen season. Alternative rescue antihistamines were equated tochlorpheniramine based on the recommended dosing frequency (every 6 hours)of chlorpheniramine (eg, 1 tablet of loratadine daily equals 4 chlorpheniraminetablets). A rescue antihistamine or concomitant medication use index was calculatedfor each patient by adding the total number of different kinds of rescue antihistaminesor concomitant medications used each day during the pollen season and dividingit by the total number of days in the pollen season.

Using the RQLQ,²⁷ quality of life wasassessed at randomization before receiving the initial treatment, before eachsubsequent treatment, and at the end of the trial, week 12. The RQLQ is a28-item questionnaire assessing an overall quality-of-life score and 7 domainsof rhinitis-related quality of life (activity limitations, sleep impairment,nonnasal or nonocular symptoms, practical problems, nasal symptoms, eye symptoms,and emotional function). The recall period for each question was the previous7 days. Baseline measurements on the day that patients received their firsttreatment represent their status 2 to 3 weeks before the start of the pollenseason. Each domain was scored on a 0- to 6-point scale (0, not troubled to6, extremely troubled).

The number of days missed from work or school, perceived effectivenessat performing daily work or school activities (missing 1 day, 0%-25%; 2, 26%-50%;3, 51%-75%; 4, 76%-100%) and medical resource use (unscheduled health carevisits and contacts, changes in allergy treatments) were also recorded. Atthe end of the 12-week trial, investigators and patients rated global evaluationof treatment effectiveness on a 5-point scale (1, excellent control of symptomsto 5, worsening of symptoms).

Blood samples for measurement of IgE levels were obtained at each treatmentvisit, at week 12, and 12 weeks after the end of the trial (week 24). Assaysto determine total IgE levels were performed at the central laboratory facilityusing Abbott IMX Microparticle Enzyme Immunoassay, MEIA (Abbott Laboratories,Abbott Park, Ill). Assays to determine ragweed-specific IgE levels were performedusing the Pharmacia CAP system RAST FEIA (Pharmacia, Uppsala, Sweden).²⁵ Free IgE levels were measured using a solid-phaseenzyme-linked immunosorbent assay²⁵ with afluorometric technique and human serum as standard. The coefficients of variationof the assay were from 5.4% to 11.2%. The upper limit of quantitation of thisassay was 62.5 IU/mL and the lower limit of quantitation was 0.3 IU/mL.

Serum samples were screened for the presence of anti-omalizumab antibodiesbefore patients received their first treatment and 12 weeks after the endof the trial (week 24) using a previously described antibody assay.²⁴

Adverse events were classified at each visit according to modified WorldHealth Organization Adverse Reaction Terminology²⁸and assessed by the investigators as mild, moderate, or severe and relatedor not related to treatment. Patients were instructed to record all skin reactionsat the trial drug injection sites after each treatment, using a 0 (none) to3 (severe) scale for symptoms such as burning, itching, and redness. Laboratoryvalues measured were complete blood cell count with differential, serum chemistrypanel, and urinalysis.

Symptom severity and duration scores were averaged over the 12-weektrial for each patient. In the analyses of average symptom scores and globaleffectiveness evaluations, a step-down method was used to control the typeI error rate of the multiple comparisons. It first tested the highest dosevs placebo and would only test the second highest dose if the first test wassignificant. Each significance test was performed at a .025 level (1-sided).This procedure was adopted because it was valid regardless of the variablesanalyzed and statistical models used. Statistical tests for quality of lifeand minimal symptom days were performed at a .05 significance level (2-sided).

The data were analyzed with SAS software version 6.08 (SAS InstituteInc, Cary, NC). The primary efficacy analysis was based on all patients whoreceived at least 1 dose of trial medication, did not withdraw from the trialprior to the onset of the pollen season, and who had any diary data duringthe pollen season. Average symptom scores and medication use were analyzedusing an analysis of variance model. The factors included in the model weretreatment, center, treatment schedule, as well as treatment by center andtreatment by treatment schedule interactions. In addition, a post hoc analysisof minimal symptom days was conducted. Wilcoxon rank sum test was used tocompare the number of minimal symptom days during the entire pollen seasonin each omalizumab group vs placebo.

The patients' and investigators' global evaluation scores at week 12,as well as change in RQLQ score from baseline to the visit closest to thepeak of the ragweed season, were analyzed using van Elteren test stratifiedby center.²⁹ Each domain of the RQLQ scoreand the overall score were grouped into 3 categories: meaningful improvement(decrease in score ≥0.5), no meaningful change (decrease or increase <0.5),and meaningful deterioration (increase of ≥0.5).³⁰

An analysis of covariance model was used to investigate the relationshipbetween free IgE level and clinical efficacy. This model fitted the averagenasal symptom severity score with covariate baseline total IgE level and factorsbaseline IgE strata (equivalent to treatment schedule) and free IgE category.Four free IgE categories (≤10.4, >10.4-20.8, >20.8-62.5, and >62.5 IU/mL)were defined according to measurements taken at the treatment visit when thepollen count was the highest. According to the Bonferroni rule, an αlevel of .0016 was used to adjust for multiple comparisons of each of thelower free IgE categories to the highest free IgE category.

A sample size of 100 efficacy-evaluable patients per treatment arm wasrequired to detect mean differences in average nasal symptom severity scoreof 0.1, 0.2, and 0.3 between placebo and the low, medium, and high doses ofomalizumab, respectively. Approximately 20% more patients were randomizedin anticipation of dropouts.

Five hundred thirty-six of 959 screened patients from 25 centers metthe eligibility criteria and were randomized as shown in Figure 1. Seven patients were excluded from the analysis becausethey had no data within the pollen season. No statistically significant differenceswere detected among the study groups at baseline (Table 1). Ninety-two percent to 96% of patients were white, 21%to 29% had a history of asthma, and 12% to 15% had a history of atopic dermatitis.Thirty-seven patients either withdrew or were excluded from the study: 10were lost to follow-up; 9 were excluded for noncompliance (failure to meetscheduled appointments or to comply with study procedure); 5 withdrew consent;5 did not meet protocol criteria; 5 failed to respond to treatment (basedon investigator's medical judgment); and 3 withdrew because of adverse events(Figure 1). The 37 patients wereequally distributed across the treatment groups.

Recruitment started June 30, 1997. All patients received the first doseof study drug between July 25 and August 4, 1997. The last treatment was administeredbetween October 16 and 24, 1997. The start date of the pollen season was betweenAugust 6 and September 3, 1997, and the end date was between September 5 andOctober 5, 1997. Fifteen of the 25 centers reported a severe pollen seasonbetween August 6 and September 24, 1997. The duration and severity of thepollen season varied among participating study centers, but exposure to thepollen season and severe pollen season was similar across the treatment groups(Table 1). Sixty-four percentof patients in the 300-mg, 63% in the 150-mg, and 64% in the 50-mg omalizumabgroups and 61% in the placebo group were exposed to the severe pollen season.

All patients received the first treatment approximately 2 weeks beforethe ragweed pollen season. The mean (median) number of days before the onsetof the pollen season after the first treatment was 19.8 (19.0) in the 300-mg,19.8 (19.5) in the 150-mg, and 20.0 (20.0) days in the 50-mg omalizumab groupsand 19.9 (19.0) days in the placebo group. Ninety-eight percent of patientsin the 300-mg, 97% in the 150-mg, and 97% in the 50-mg omalizumab groups and97% in the placebo group received treatment more than a week before the startof pollen season. No patient started study drug after the start of the pollenseason.

Average nasal and ocular symptom severity and duration scores over theentire pollen season were consistently and significantly lower in the omalizumab300-mg group than in the placebo group (Table 2). During the severe pollen season, average nasal symptomseverity scores were also significantly lower in the 300-mg (0.84 vs 1.20; P = .001) and 150-mg (0.95 vs 1.20; P = .01) omalizumab groups than in the placebo group. A linear dose-responserelationship was observed (slope for dose −0.001; P<.001) for average daily nasal symptom severity scores (Figure 2). Weekly nasal symptom severityscores over the entire pollen season showed minimal change in the 300-mg omalizumabgroup compared with the other omalizumab groups and with placebo (Figure 3), even when pollen counts increased.Patients in the 300-mg (41% vs 18%, P<.001) andpatients in the 150-mg (29% vs 18%, P = .04) omalizumabgroups had a significantly greater percentage of days with minimal nasal symptomsthan did those in the placebo group (Figure4).

The proportion of days during the pollen season with rescue antihistamineor concomitant medication use was significantly lower in the 300-mg (0.12vs 0.21 days, P = .005) and 150-mg (0.13 vs 0.21days, P = .01) omalizumab groups than in the placebogroup, as was the rescue antihistamine or concomitant medication use index(least squares mean [SD], 0.13 [0.34] for the 300-mg and 150-mg omalizumabgroups vs 0.22 [0.35] for placebo; P = .006 and P = .01, respectively). The corresponding values (leastsquares mean) for the omalizumab 50-mg group were 0.18 days (P = .20) and 0.19 (0.35) rescue medication index (P = .23).

Most patients who used rescue antihistamines other than chlorpheniramineused fexofenadine (10 of 12 in the 300-mg, 21 of 22 in the 150-mg, and 22of 24 in the 50-mg omalizumab groups and 29 of 35 in the placebo group). Thedaily average number of tablets of rescue antihistamine medication taken was0.17 in the 300-mg vs 0.37 for placebo (P = .001)and 0.20 in the 150-mg omalizumab groups vs 0.37 for placebo (P = .004). The difference between the number of tablets taken by thosein the 50-mg omalizumab group vs the placebo group did not reach statisticalsignificance (0.29 vs 0.37 tablets, P = .097). Averagedaily rescue antihistamine use decreased in congruence with average dailynasal symptom severity scores (Figure 5),with the lowest nasal symptom severity scores and daily rescue antihistaminemedication use being obtained with omalizumab 300 mg.

Treatment effectiveness was globally rated as good or excellent by 70.7%in the 300-mg (P<.001), 60.0% in the 150-mg (P<.001), and 51.9% in the 50-mg (P = .007) omalizumab groups compared with 40.8% in the placebo group.The respective values for investigators were 65.3% (P<.001),51.9% (P = .001), and 50% (P= .004) compared with 35.4% for placebo.

At baseline, the mean overall RQLQ and domain scores did not differamong the 4 treatment groups. The RQLQ scores were consistently lower (indicatingbetter rhinitis-related quality of life) throughout the pollen season in thosereceiving 300 mg of omalizumab (Figure 6).Patients receiving placebo or 50 mg of omalizumab experienced a worseningof quality-of-life scores at the peak of the pollen season compared with baseline.

Significant differences in the proportion of patients with meaningfulchanges (≥0.5 points)³⁰ from baseline topeak season in quality-of-life scores were noted between those receiving 300mg of omalizumab and those receiving placebo in 4 of the 7 domains, includingactivity limitations, sleep impairment, non-nasal symptoms, and emotionalfunction, and in overall quality-of-life scores at the peak of the pollenseason (Table 3). Significantdifferences in quality of life were observed between the 150-mg omalizumabgroup and placebo group in 3 of 7 domains, including sleep impairment, non-nasalsymptoms, and emotional function scores at the peak of the pollen season (Table 3).

There were no statistically significant differences between the 3 activetreatment groups and placebo group with respect to performance effectivenessand the number of additional contacts with health care professionals. Themean (SD) number of days missed from work, school, or both among those receiving300 mg of omalizumab was 0.1 (0.4) compared with 0.4 (1.6) in those receivingplacebo (P = .005).

A dose-dependent decrease in serum free IgE levels (serum IgE not boundup in the IgE-omalizumab complex) occurred after omalizumab treatment (Table 4). Analysis of the relationshipbetween suppression of serum free IgE levels at peak season and efficacy measuresshowed a significant association between free IgE levels and daily nasal symptomseverity and rescue antihistamine use during the pollen season. Patients withthe lowest trough free IgE levels had the lowest symptom scores and leastrescue antihistamine use (Table 5).The proportion of patients achieving a serum free IgE level <10.4 IU/mLafter the first dosing interval was 63% in the 300-mg, 33% in the 150-mg,4% in the 50-mg omalizumab groups and 3% in the placebo group.

Ragweed pollen-specific IgE levels were measured at baseline and 12weeks after the final visit (week 24). At baseline, the levels were comparablebetween all treatment groups (ragweed-short, 8.5-10.7 IU/mL; ragweed-long8.2-9.8 IU/mL). At the 24-week follow-up, concentrations were higher in omalizumab-treatedpatients compared with placebo. The increase was dose related and thoughtto represent ragweed-specific IgE bound up in the IgE-omalizumab complexesas the result of the longer serum half-life of the complexes compared withfree IgE.^25,31-33

Headache, upper respiratory infection, and viral infection were themost frequently reported adverse events in the omalizumab groups but werereported less frequently in the 300-mg omalizumab group than in the otheromalizumab groups (Table 6). Headache,sinusitis, upper respiratory infection, and viral infection were the mostfrequently reported adverse events in the placebo group. Asthma worsened in4 patients (2.9%) in the placebo group compared with 3 patients (1%) in theomalizumab groups. Sinusitis was also more common in the placebo group thanin the omalizumab group (Table 6).The most commonly reported trial drug–related adverse events in alltreatment groups, including placebo, were weight gain (all groups, ≤3.0%)and headache (all groups, ≤2.2%). Trial drug–related urticaria wasreported in 1 patient receiving 150 mg of omalizumab, who was subsequentlywithdrawn from treatment, and in 1 receiving 50 mg of omalizumab. Trial drug-relatedsevere adverse events included sprains and strains (1, 300-mg omalizumab),and nausea (1, 50-mg omalizumab).

Injection site reactions were mild and infrequent. The mean symptomscore for injection site reaction (eg, burning, itching, redness) was thesame in each treatment group (the average frequency of reactions per injectiongiven was 0.2% per patient). There were no clinically significant alterationsin laboratory values in any group, and no reactivity for antibodies to theFab fragment of omalizumab was observed. There was no evidence of immune complex–relatedadverse events.

In a follow-up to the primary study, 287 of 374 patients who completedtreatment with omalizumab were treated with omalizumab during a second ragweedseason.³³ The overall incidence and patternof adverse events were similar to those reported in the primary study. Therewere no severe or serious adverse events related to omalizumab treatment.No anti-omalizumab antibodies were detected in any patient, and no significantimmune-complex mediated disorders were observed.

The results of this randomized, placebo-controlled trial provide clinicalevidence that lowering systemic free IgE levels with a specific blocker ofIgE binding provides clinical benefit in patients with seasonal allergic rhinitis.These findings are consistent with the results of a previously published placebo-controlledtrial in 251 adults with birch pollen-induced seasonal allergic rhinitis,in which omalizumab, administered subcutaneously 2 or 3 times during the season(depending on baseline IgE levels) significantly reduced nasal symptom severityscores and use of rescue medication, and improved quality of life scores.³⁴

Treatment with omalizumab was initiated before the onset of the ragweedpollen season to assess whether blocking IgE binding before and during thepollen season could reduce seasonal allergic rhinitis symptoms for an entirepollen season. It was hypothesized that beginning treatment before symptomsdevelop might prevent the priming effect of allergic inflammation in the nasalmucosa that leads to increased reactivity to allergen challenge as the seasonprogresses.³⁵

Average daily nasal symptom severity score, the outcome that measuressome of the most troublesome symptoms of allergic rhinitis, and the primaryefficacy variable for this study, was significantly lower (indicating lesssevere symptoms) in the 300-mg omalizumab group than in the placebo groupover the entire ragweed pollen season (difference in least squares means of–0.23) adjusted for center and treatment schedule. During the severepollen season, the difference in least squares means between the 300-mg omalizumabtreatment group and placebo was 0.36 (0.84 vs 1.20, respectively; P = .001).

Patients reported mild nasal symptoms (<1.0 on a 0- to 3-point scale)on the first day of treatment. Therefore, even though the study investigatorsconsidered patients to be asymptomatic at baseline, background symptoms mayrepresent underlying chronic nasal disease or mild perennial allergic rhinitis.Patients receiving 300 mg of omalizumab experienced almost no difference innasal symptom severity score between the first treatment day and peak season,whereas patients in the placebo group experienced a 50% increase in symptomseverity (0.8 and 1.2, respectively, Figure3). These data suggest that patients generally were protected duringthe pollen season. In addition, patients receiving 300 mg of omalizumab showedmore than a 2-fold difference in proportion of minimal nasal symptom daysduring the entire pollen season compared with patients receiving placebo (median,41% vs 18%, P<.001).

Daily nasal and ocular symptom severity and duration scores were consistentlylower among patients who received 300 mg of omalizumab compared with thosein the placebo group (Table 2),despite significantly greater rescue antihistamine use in the placebo group(Figure 5). This combined effectstrengthens the efficacy results in this study because the greater use ofrescue medication probably reduced symptom severity in the placebo group anddecreased the treatment difference between the omalizumab and placebo groups.The proportion of days with rescue antihistamine or concomitant medicationuse was 43% lower, the rescue antihistamine or concomitant medication useindex was 41% lower, and the number of tablets of rescue antihistamines usedwas 54% lower in those who received 300 mg of omalizumab compared with thosewho received placebo. Regression analysis of daily nasal symptom severityscores over the entire pollen season confirmed a linear dose-response relationshipover the dosages of omalizumab evaluated (Figure 2). The linear dose-response is noteworthy when one considersthe subjective nature of nasal symptom scoring in more than 500 patients andthe inability to control pollen exposure in the ambient environment.

Assessment of quality of life is critical in a study exploring treatmenteffectiveness in allergic rhinitis because these patients experience poorquality of life.¹² Significant differencesin changes from baseline in quality-of-life scores between those taking 300mg of omalizumab and those taking placebo were shown in 4 of 7 domains andin overall quality-of-life score at the peak of the pollen season. Few publishedstudies have reported quality-of-life changes over the course of a pollenseason. However, in a randomized treatment trial that measured quality oflife using the RQLQ questionnaire during a ragweed pollen season, patientswho received antihistamine, nasal corticosteroid, or both, experienced a deteriorationin total RQLQ score between the beginning and height of the ragweed season(P<.001).¹⁹ Inour study, there was no deterioration in RQLQ scores between baseline andthe peak of the pollen season in the 300-mg omalizumab group and in fact,quality of life scores were better at peak season than at study entry.

Pharmacoeconomics outcomes may provide supportive evidence of patientbenefit. In this study, patients treated with omalizumab experienced a 75%reduction in days they missed work, school, or both compared with placebo(0.1 vs 0.4 days, respectively). This result is consistent with the quality-of-lifeimprovements measured by the RQLQ, rhinitis symptom score improvements, andreduction in the use of concomitant rescue medication in the 300-mg omalizumabgroup.

Patients receiving 300 mg of omalizumab experienced profound reductionsin serum free IgE levels after the first dosing interval, when 63% of patientshad serum free IgE levels below 10.4 IU/mL. Casale et al²⁵postulated that suppression of serum free IgE levels lower than 17 IU/mL wouldcorrelate with measures of clinical efficacy. In agreement with this hypothesis,this study showed a significant relationship between free IgE level suppressionand clinical response.

Overall, the frequency of adverse events was similar in the active treatmentand placebo groups and included those commonly prevalent in the study population.There was only 1 withdrawal that was related to omalizumab treatment (forurticaria). There was no evidence of a dose-response relationship with anyof the adverse events. Neither adverse events nor laboratory safety analysisdata were suggestive of an immune complex-related disorder.

Elevated IgE is characteristic of the immune response during and afterparasitic infections, suggesting a theoretical drawback of anti-IgE therapy.However, experimental evidence in animal models indicates a neutral or beneficialeffect of low IgE levels on the outcome of parasitic infection and resistanceto reinfection.^36-39

There are several limitations to this study. Despite requiring patientsto have a history of significant seasonal allergic rhinitis to ragweed, thesubjects in this study were not very symptomatic during the course of theragweed season. The reason for the low symptom scores is not clear but couldbe related to the placebo effect of administering parenteral therapy for adisease traditionally treated with topical and oral medications. There isa considerable placebo effect observed in the study, which decreases the differencesobserved among treatment groups. However, a placebo effect is not unusualin allergic rhinitis studies. In most allergic rhinitis studies, therapeuticinterventions with oral or topical medications result in approximately a 30%to 40% placebo effect.⁴⁰ There is also variabilityin ragweed exposure across the different sites. For instance, only about twothirds of patients were exposed to the severe pollen season. Lastly, patientsentering the study were not completely asymptomatic. This could be a resultof carryover from allergic rhinitis symptoms due to the spring allergy season.It would be extremely difficult to find patients who were sensitive to ragweedonly, and thus completely asymptomatic during the enrollment and randomizationperiods.

The majority of clinical pharmacotherapy studies that have evaluatedefficacy in allergic rhinitis have randomized symptomatic patients to showthat the agent is suitable for the treatment of rhinitis symptoms. Few studies,outside of the realm of immunotherapy, report on the outcome of prophylactictreatment, and those that do have failed to show complete prevention of seasonalallergic rhinitis symptoms for the season.^40,41In our study, patients treated with omalizumab generally were protected fromthe seasonal increase in nasal symptoms. It is estimated that only 33% to50% of patients with seasonal allergic rhinitis are symptom-free with antihistaminetherapy.² One study that compared first-linetreatments for seasonal allergic rhinitis (nasal corticosteroid spray andsecond-generation antihistamine) estimated at least 50% of seasonal allergicrhinitis patients needed to take both types of treatment in combination toadequately control symptoms.¹⁹ Despite generalagreement that nasal steroids are only minimally bioavailable, the safetyof these drugs still remains a concern.^42,43

Patients who would most likely benefit from omalizumab would be thosewho have moderate to severe seasonal allergic rhinitis with evidence of specificIgE antibodies to clinically relevant allergens. In addition, candidates wouldlikely include patients not achieving a satisfactory favorable response totherapy with antihistamines plus or minus nasal corticosteroids; patientswho have intolerable adverse effects from these medications; patients whohave difficulty taking daily medications for various compliance reasons; andpatients who are unable to tolerate traditional allergy immunotherapy or areunable to comply with the strict regimen of traditional allergy immunotherapy.Others who might benefit are those with comorbid allergic conditions, suchas allergic rhinitis and asthma. In recent publications, omalizumab was shownto be effective therapy for moderate to severe asthma, suggesting that omalizumabhas the potential to treat multiple comorbid allergic disorders.^44,45

In conclusion, in this 12-week study of patients with seasonal ragweedallergic rhinitis, omalizumab therapy decreased serum free IgE levels andprovided clinical benefit, improving rhinitis-specific quality of life andreducing rescue medication use. Comparative trials will be necessary to definethe exact placement of this agent in the therapeutic armamentarium for seasonalallergic rhinitis.