Effect of Omalizumab on Symptoms of Seasonal Allergic Rhinitis:  A Randomized Controlled Trial FREE

Allergic rhinitis is an IgE-mediated condition manifested by upper respiratory tract, lower respiratory tract, and ocular symptoms.^1- 3 This disease affects at least 10% to 20% of US and northern European populations, and its prevalence in urban areas is increasing.^4- 7 It is a common reason for seeking outpatient medical care⁸ and frequently complicates concomitant conditions such as allergic asthma, chronic sinusitis, otitis media, and nasal polyposis.^9- 11 Allergic rhinitis is also associated with diminished quality of life, lost work productivity, and school absenteeism.^12- 14 The total economic burden of allergic rhinitis and its complications in the United 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 soon as pollination begins, with symptoms becoming more severe when pollen concentrations are highest and waning with the end of the pollen season.¹⁶ Presently, allergen avoidance, pharmacotherapy, and immunotherapy are the treatments available for allergic rhinitis.^17- 18 Despite these therapeutic options, there remains a group of patients whose symptoms are not controlled and for whom alternative therapies are needed. At least 50% of patients are likely to require primary care management with combined therapies, such as an intranasal corticosteroid and an oral antihistamine for optimal control throughout the pollen season.¹⁹ A survey of 526 patients prescribed these combined therapies showed that only 142 (27%) were using both types of drug regularly, and 88 (62%) of those patients described symptom control as partial or poor.²⁰

A recombinant humanized monoclonal anti-IgE antibody (omalizumab) was recently developed.²¹ This antibody binds specifically to a unique epitope, the Fc∊RI binding site on human IgE, and thereby blocks the binding of IgE to mast cells and basophils. Given the fundamental role of IgE in the pathogenesis of seasonal allergic rhinitis, decreasing free serum IgE in atopic patients was expected to decrease seasonal rhinitis symptoms during the pollen season.

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

Individuals aged 12 to 75 years with no or mild symptoms during the preceding month but with at least a 2-year history of moderate to severe seasonal allergic rhinitis due to ragweed were eligible for the study. The history of moderate to severe ragweed-induced allergic rhinitis was defined as having a score of 2 or more on a 0- to 3-point scale (0, no symptoms and 3, severe symptoms), in 4 of 8 symptom categories (sneezing, itchy nose, running nose, stuffy nose, watery eyes, red eyes, itchy eyes, or itchy throat) based on patient recall of the previous ragweed season. Skin test sensitivity to ragweed pollen and a baseline total IgE level of between 30 and 700 IU/mL also were required. A positive skin test result was defined as presence of both wheal and erythema. In the absence of wheal, an erythema response equal to the positive control (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 a positive skin test result. The erythema response was graded as follows: 0, no erythema; 1, 20 mm or less; or 2, more than 20 mm.²² The lower limit of baseline total IgE level was established to ensure that serum IgE levels would be sufficiently high to be detectable, and the upper limit was based on dosing considerations. Prior to drug therapy, total IgE is equivalent to free IgE; after drug therapy, total IgE is equivalent to free IgE plus IgE bound to omalizumab.

Exclusion criteria included history of severe idiopathic anaphylactic reaction; 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-induced rhinitis or acute infectious sinusitis; regular treatment with β-adrenergic antagonists, tricyclic antidepressants, or monoamine-oxidase inhibitors; treatment with short-acting antihistamines within 3 days, cetirizine hydrochloride or loratadine within 5 days, or astemizole within 3 months; systemic corticosteroids within 3 months; inhaled or intranasal corticosteroids within 15 days or anytime during the trial; travel for at least 5 consecutive days outside the regions of the study; current or recent serious systemic disease; clinically significant ECG abnormality; and pregnancy or lactation.

The study was performed in accordance with the Declaration of Helsinki and 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 conducted from July 25 through November 21, 1997, at 25 centers in the Northeast, Southeast, Midwest, West, and Great Lakes regions of the United States. Blinded study participants included investigators, patients, and study monitors. At trial completion, drug codes were broken and made available for data analysis. Ragweed-induced seasonal allergic rhinitis was chosen as the study condition because ragweed is the most common cause of seasonal allergic rhinitis in North America,¹⁶ and the timing of ragweed season is uniform in these regions, usually peaking in late August or early September.²³ Daily ragweed pollen counts were used to determine the pollen season (the start and end defined as the first and last sequence of >10 grains/m³ for ≥2 consecutive days) and the severe pollen season (the start and end defined as the first and last sequence of >100 grains/m³ for ≥2 consecutive days) for each center. Pollen data, collected with a rotation impaction sampler, were measured locally at each center.

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

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

Patients could take 4 mg of chlorpheniramine maleate as needed for severe allergic rhinitis symptoms. Patients unable to tolerate chlorpheniramine were permitted to use alternative antihistamines as rescue medication. Oral or topical decongestants were allowed on a restricted basis, after consulting with 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 severity score. Secondary efficacy measures included average daily ocular symptom severity, average daily nasal and ocular symptom duration, proportion of days with minimal nasal symptoms, proportion of days with rescue or concomitant antihistamine use, rescue or concomitant seasonal allergic rhinitis medication use index, number of tablets of rescue medication taken, patient's and investigator's global evaluation of treatment effectiveness, Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) scores,²⁷ and pharmacoeconomic assessments.

Each evening, patients recorded self-assessed symptom severity and duration scores in a daily diary. Nasal symptoms included sneezing and itchy, runny, or stuffy nose; ocular symptoms included itchy, watery, or red eyes. Symptoms were 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, symptoms present >8 hours). A minimal nasal symptom day was defined as a day when the total nasal symptom severity score was 2 or less and no rescue medications were taken to alleviate allergic rhinitis symptoms. Concomitant medications used for symptomatic relief of allergy symptoms were recorded. The average number of tablets of rescue chlorpheniramine taken per day was calculated by adding up the number of tablets per day and dividing by the number of days within the pollen season. Alternative rescue antihistamines were equated to chlorpheniramine based on the recommended dosing frequency (every 6 hours) of chlorpheniramine (eg, 1 tablet of loratadine daily equals 4 chlorpheniramine tablets). A rescue antihistamine or concomitant medication use index was calculated for each patient by adding the total number of different kinds of rescue antihistamines or concomitant medications used each day during the pollen season and dividing it by the total number of days in the pollen season.

Using the RQLQ,²⁷ quality of life was assessed at randomization before receiving the initial treatment, before each subsequent treatment, and at the end of the trial, week 12. The RQLQ is a 28-item questionnaire assessing an overall quality-of-life score and 7 domains of 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 previous 7 days. Baseline measurements on the day that patients received their first treatment represent their status 2 to 3 weeks before the start of the pollen season. Each domain was scored on a 0- to 6-point scale (0, not troubled to 6, extremely troubled).

The number of days missed from work or school, perceived effectiveness at 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 care visits and contacts, changes in allergy treatments) were also recorded. At the end of the 12-week trial, investigators and patients rated global evaluation of treatment effectiveness on a 5-point scale (1, excellent control of symptoms to 5, worsening of symptoms).

Blood samples for measurement of IgE levels were obtained at each treatment visit, at week 12, and 12 weeks after the end of the trial (week 24). Assays to determine total IgE levels were performed at the central laboratory facility using Abbott IMX Microparticle Enzyme Immunoassay, MEIA (Abbott Laboratories, Abbott Park, Ill). Assays to determine ragweed-specific IgE levels were performed using the Pharmacia CAP system RAST FEIA (Pharmacia, Uppsala, Sweden).²⁵ Free IgE levels were measured using a solid-phase enzyme-linked immunosorbent assay²⁵ with a fluorometric technique and human serum as standard. The coefficients of variation of the assay were from 5.4% to 11.2%. The upper limit of quantitation of this assay 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 antibodies before patients received their first treatment and 12 weeks after the end of the trial (week 24) using a previously described antibody assay.²⁴

Adverse events were classified at each visit according to modified World Health Organization Adverse Reaction Terminology²⁸ and assessed by the investigators as mild, moderate, or severe and related or not related to treatment. Patients were instructed to record all skin reactions at the trial drug injection sites after each treatment, using a 0 (none) to 3 (severe) scale for symptoms such as burning, itching, and redness. Laboratory values measured were complete blood cell count with differential, serum chemistry panel, and urinalysis.

Symptom severity and duration scores were averaged over the 12-week trial for each patient. In the analyses of average symptom scores and global effectiveness evaluations, a step-down method was used to control the type I error rate of the multiple comparisons. It first tested the highest dose vs placebo and would only test the second highest dose if the first test was significant. Each significance test was performed at a .025 level (1-sided). This procedure was adopted because it was valid regardless of the variables analyzed and statistical models used. Statistical tests for quality of life and minimal symptom days were performed at a .05 significance level (2-sided).

The data were analyzed with SAS software version 6.08 (SAS Institute Inc, Cary, NC). The primary efficacy analysis was based on all patients who received at least 1 dose of trial medication, did not withdraw from the trial prior to the onset of the pollen season, and who had any diary data during the pollen season. Average symptom scores and medication use were analyzed using an analysis of variance model. The factors included in the model were treatment, center, treatment schedule, as well as treatment by center and treatment by treatment schedule interactions. In addition, a post hoc analysis of minimal symptom days was conducted. Wilcoxon rank sum test was used to compare the number of minimal symptom days during the entire pollen season in 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 the peak of the ragweed season, were analyzed using van Elteren test stratified by center.²⁹ Each domain of the RQLQ score and 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 relationship between free IgE level and clinical efficacy. This model fitted the average nasal symptom severity score with covariate baseline total IgE level and factors baseline 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 the pollen count was the highest. According to the Bonferroni rule, an α level of .0016 was used to adjust for multiple comparisons of each of the lower free IgE categories to the highest free IgE category.

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

Five hundred thirty-six of 959 screened patients from 25 centers met the eligibility criteria and were randomized as shown in Figure 1. Seven patients were excluded from the analysis because they had no data within the pollen season. No statistically significant differences were 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: 10 were lost to follow-up; 9 were excluded for noncompliance (failure to meet scheduled appointments or to comply with study procedure); 5 withdrew consent; 5 did not meet protocol criteria; 5 failed to respond to treatment (based on investigator's medical judgment); and 3 withdrew because of adverse events (Figure 1). The 37 patients were equally distributed across the treatment groups.

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

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

Average nasal and ocular symptom severity and duration scores over the entire pollen season were consistently and significantly lower in the omalizumab 300-mg group than in the placebo group (Table 2). During the severe pollen season, average nasal symptom severity 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-response relationship was observed (slope for dose −0.001; P<.001) for average daily nasal symptom severity scores (Figure 2). Weekly nasal symptom severity scores over the entire pollen season showed minimal change in the 300-mg omalizumab group 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) and patients in the 150-mg (29% vs 18%, P = .04) omalizumab groups had a significantly greater percentage of days with minimal nasal symptoms than did those in the placebo group (Figure 4).

The proportion of days during the pollen season with rescue antihistamine or concomitant medication use was significantly lower in the 300-mg (0.12 vs 0.21 days, P = .005) and 150-mg (0.13 vs 0.21 days, P = .01) omalizumab groups than in the placebo group, 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 omalizumab groups vs 0.22 [0.35] for placebo; P = .006 and P = .01, respectively). The corresponding values (least squares 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 chlorpheniramine used fexofenadine (10 of 12 in the 300-mg, 21 of 22 in the 150-mg, and 22 of 24 in the 50-mg omalizumab groups and 29 of 35 in the placebo group). The daily average number of tablets of rescue antihistamine medication taken was 0.17 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 those in the 50-mg omalizumab group vs the placebo group did not reach statistical significance (0.29 vs 0.37 tablets, P = .097). Average daily rescue antihistamine use decreased in congruence with average daily nasal symptom severity scores (Figure 5), with the lowest nasal symptom severity scores and daily rescue antihistamine medication 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 differ among the 4 treatment groups. The RQLQ scores were consistently lower (indicating better rhinitis-related quality of life) throughout the pollen season in those receiving 300 mg of omalizumab (Figure 6). Patients receiving placebo or 50 mg of omalizumab experienced a worsening of quality-of-life scores at the peak of the pollen season compared with baseline.

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

There were no statistically significant differences between the 3 active treatment groups and placebo group with respect to performance effectiveness and the number of additional contacts with health care professionals. The mean (SD) number of days missed from work, school, or both among those receiving 300 mg of omalizumab was 0.1 (0.4) compared with 0.4 (1.6) in those receiving placebo (P = .005).

A dose-dependent decrease in serum free IgE levels (serum IgE not bound up in the IgE-omalizumab complex) occurred after omalizumab treatment (Table 4). Analysis of the relationship between suppression of serum free IgE levels at peak season and efficacy measures showed a significant association between free IgE levels and daily nasal symptom severity and rescue antihistamine use during the pollen season. Patients with the lowest trough free IgE levels had the lowest symptom scores and least rescue antihistamine use (Table 5). The proportion of patients achieving a serum free IgE level <10.4 IU/mL after 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 12 weeks after the final visit (week 24). At baseline, the levels were comparable between all treatment groups (ragweed-short, 8.5-10.7 IU/mL; ragweed-long 8.2-9.8 IU/mL). At the 24-week follow-up, concentrations were higher in omalizumab-treated patients compared with placebo. The increase was dose related and thought to represent ragweed-specific IgE bound up in the IgE-omalizumab complexes as the result of the longer serum half-life of the complexes compared with free IgE.^25,31- 33

Headache, upper respiratory infection, and viral infection were the most frequently reported adverse events in the omalizumab groups but were reported less frequently in the 300-mg omalizumab group than in the other omalizumab groups (Table 6). Headache, sinusitis, upper respiratory infection, and viral infection were the most frequently reported adverse events in the placebo group. Asthma worsened in 4 patients (2.9%) in the placebo group compared with 3 patients (1%) in the omalizumab groups. Sinusitis was also more common in the placebo group than in the omalizumab group (Table 6). The most commonly reported trial drug–related adverse events in all treatment groups, including placebo, were weight gain (all groups, ≤3.0%) and headache (all groups, ≤2.2%). Trial drug–related urticaria was reported in 1 patient receiving 150 mg of omalizumab, who was subsequently withdrawn from treatment, and in 1 receiving 50 mg of omalizumab. Trial drug-related severe 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 symptom score for injection site reaction (eg, burning, itching, redness) was the same in each treatment group (the average frequency of reactions per injection given was 0.2% per patient). There were no clinically significant alterations in laboratory values in any group, and no reactivity for antibodies to the Fab fragment of omalizumab was observed. There was no evidence of immune complex–related adverse events.

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

The results of this randomized, placebo-controlled trial provide clinical evidence that lowering systemic free IgE levels with a specific blocker of IgE binding provides clinical benefit in patients with seasonal allergic rhinitis. These findings are consistent with the results of a previously published placebo-controlled trial 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 severity scores and use of rescue medication, and improved quality of life scores.³⁴

Treatment with omalizumab was initiated before the onset of the ragweed pollen season to assess whether blocking IgE binding before and during the pollen season could reduce seasonal allergic rhinitis symptoms for an entire pollen season. It was hypothesized that beginning treatment before symptoms develop might prevent the priming effect of allergic inflammation in the nasal mucosa that leads to increased reactivity to allergen challenge as the season progresses.³⁵

Average daily nasal symptom severity score, the outcome that measures some of the most troublesome symptoms of allergic rhinitis, and the primary efficacy variable for this study, was significantly lower (indicating less severe symptoms) in the 300-mg omalizumab group than in the placebo group over the entire ragweed pollen season (difference in least squares means of –0.23) adjusted for center and treatment schedule. During the severe pollen season, the difference in least squares means between the 300-mg omalizumab treatment 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 investigators considered patients to be asymptomatic at baseline, background symptoms may represent underlying chronic nasal disease or mild perennial allergic rhinitis. Patients receiving 300 mg of omalizumab experienced almost no difference in nasal symptom severity score between the first treatment day and peak season, whereas patients in the placebo group experienced a 50% increase in symptom severity (0.8 and 1.2, respectively, Figure 3). These data suggest that patients generally were protected during the pollen season. In addition, patients receiving 300 mg of omalizumab showed more than a 2-fold difference in proportion of minimal nasal symptom days during 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 consistently lower among patients who received 300 mg of omalizumab compared with those in the placebo group (Table 2), despite significantly greater rescue antihistamine use in the placebo group (Figure 5). This combined effect strengthens the efficacy results in this study because the greater use of rescue medication probably reduced symptom severity in the placebo group and decreased the treatment difference between the omalizumab and placebo groups. The proportion of days with rescue antihistamine or concomitant medication use was 43% lower, the rescue antihistamine or concomitant medication use index was 41% lower, and the number of tablets of rescue antihistamines used was 54% lower in those who received 300 mg of omalizumab compared with those who received placebo. Regression analysis of daily nasal symptom severity scores over the entire pollen season confirmed a linear dose-response relationship over the dosages of omalizumab evaluated (Figure 2). The linear dose-response is noteworthy when one considers the subjective nature of nasal symptom scoring in more than 500 patients and the inability to control pollen exposure in the ambient environment.

Assessment of quality of life is critical in a study exploring treatment effectiveness in allergic rhinitis because these patients experience poor quality of life.¹² Significant differences in changes from baseline in quality-of-life scores between those taking 300 mg of omalizumab and those taking placebo were shown in 4 of 7 domains and in overall quality-of-life score at the peak of the pollen season. Few published studies have reported quality-of-life changes over the course of a pollen season. However, in a randomized treatment trial that measured quality of life using the RQLQ questionnaire during a ragweed pollen season, patients who received antihistamine, nasal corticosteroid, or both, experienced a deterioration in total RQLQ score between the beginning and height of the ragweed season (P<.001).¹⁹ In our study, there was no deterioration in RQLQ scores between baseline and the 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 patient benefit. 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-life improvements measured by the RQLQ, rhinitis symptom score improvements, and reduction in the use of concomitant rescue medication in the 300-mg omalizumab group.

Patients receiving 300 mg of omalizumab experienced profound reductions in serum free IgE levels after the first dosing interval, when 63% of patients had serum free IgE levels below 10.4 IU/mL. Casale et al²⁵ postulated that suppression of serum free IgE levels lower than 17 IU/mL would correlate with measures of clinical efficacy. In agreement with this hypothesis, this study showed a significant relationship between free IgE level suppression and clinical response.

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

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

There are several limitations to this study. Despite requiring patients to have a history of significant seasonal allergic rhinitis to ragweed, the subjects in this study were not very symptomatic during the course of the ragweed season. The reason for the low symptom scores is not clear but could be related to the placebo effect of administering parenteral therapy for a disease traditionally treated with topical and oral medications. There is a considerable placebo effect observed in the study, which decreases the differences observed among treatment groups. However, a placebo effect is not unusual in allergic rhinitis studies. In most allergic rhinitis studies, therapeutic interventions with oral or topical medications result in approximately a 30% to 40% placebo effect.⁴⁰ There is also variability in ragweed exposure across the different sites. For instance, only about two thirds of patients were exposed to the severe pollen season. Lastly, patients entering the study were not completely asymptomatic. This could be a result of carryover from allergic rhinitis symptoms due to the spring allergy season. It would be extremely difficult to find patients who were sensitive to ragweed only, and thus completely asymptomatic during the enrollment and randomization periods.

The majority of clinical pharmacotherapy studies that have evaluated efficacy in allergic rhinitis have randomized symptomatic patients to show that the agent is suitable for the treatment of rhinitis symptoms. Few studies, outside of the realm of immunotherapy, report on the outcome of prophylactic treatment, and those that do have failed to show complete prevention of seasonal allergic rhinitis symptoms for the season.^40- 41 In our study, patients treated with omalizumab generally were protected from the seasonal increase in nasal symptoms. It is estimated that only 33% to 50% of patients with seasonal allergic rhinitis are symptom-free with antihistamine therapy.² One study that compared first-line treatments for seasonal allergic rhinitis (nasal corticosteroid spray and second-generation antihistamine) estimated at least 50% of seasonal allergic rhinitis patients needed to take both types of treatment in combination to adequately control symptoms.¹⁹ Despite general agreement that nasal steroids are only minimally bioavailable, the safety of these drugs still remains a concern.^42- 43

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

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