Anti-Immunoglobulin E (Omalizumab) Therapy in

Seasonal Allergic Rhinitis

THOMAS B. CASALE

Department of Medicine, Creighton University School of Medicine, Omaha, Nebraska

Anti-immunoglobulin E (anti-IgE) (omalizumab), a humanized mono-

clonal anti-IgE antibody that binds to circulating IgE, has been stud-

ied in several large double-blind, randomized, placebo-controlled

clinical trials to determine its pharmacokinetic characteristics, effi-

cacy, and safety in ragweed- or birch pollen-induced seasonal al-

lergic rhinitis (SAR). The consequences of readministering omalizu-

lab after a lapse of time have also been studied. These studies have

confirmed that serum-free IgE declines in a dose-related manner

with such treatment and that omalizumab-induced declines in IgE

correlate with symptom improvement. Whether omalizumab is

administered intravenously or subcutaneously, its pharmacokinet-

ics do not differ. A Phase II dose-ranging study demonstrated that

the optimum efficacious dose of omalizumab for the treatment of

seasonal allergic rhinitis is 300 mg administered subcutaneously.

The dosing frequency, in terms of whether the antibody is admin-

istered every 3 or 4 wk, is based on the patient's baseline IgE level.

With adequate dosing, nasal and ocular symptoms are signifi-

cantly reduced, and quality of life is significantly improved. Omali-

zumab is safe and well tolerated and can be safely readministered

in subsequent pollen seasons.

Keywords: allergic rhinitis; anti-IgE; ragweed; birch pollen; omalizumab

Seasonal allergic rhinitis (SAR) is the most common atopic dis-

ease in the United States (1), afflicting approximately 40% of

children and 10% to 30% of adults (2). It is responsible for sub-

stantial impairment of quality of life, and it has serious conse-

quences on productivity at the workplace as well as at school.

Studies of children with allergic rhinitis have shown that they

perform certain school tasks less effectively than do their non-

atopic peers (3) and that the disorder has been estimated to be

responsible for more than 820,000 missed school days (4). The

economic burden imposed by allergic rhinitis in terms of both

direct and indirect costs is extremely large (4, 5). Furthermore,

allergic rhinitis is a well-known risk factor for asthma (6-8).

The relationship between allergic rhinitis and asthma is at-

tributed to both a shared immunologic pathogenesis and the

actual physical contiguity between the upper and lower air-

ways (6-8). Many patients with allergic rhinitis who have no

perceived asthma symptoms have bronchial hyperresponsive-

ness to natural stimuli such as exercise or to bronchial chal-

lenge with chemical stimuli (7, 9). In addition, the underlying

pathophysiologic processes, immunoglobulin E (IgE)-dependent

sensitivity and chronic allergic inflammation (10), are similar

in the upper and lower airways (8). Studies have reinforced

the link between allergic rhinitis and asthma, demonstrating

that when the former condition is treated appropriately, the

latter improves as well (11-14).

(Received in original form March 8, 2001; accepted in final form May 1, 2001)

Supported by educational grants from Genentech, Inc., and Novartis Pharma-

ceuticals Corporation.

Correspondence and requests for reprints should be addressed to Thomas B.

Casale, M.D., Creighton University School of Medicine, 601 North 30th Street,

Suite 5850, Omaha, NE 68131. E-mail: [email protected]

Am J Respir Crit Care Med Vol 164. pp S18-S21, 2001

DOI: 10.1164/rccm2103023

Internet address: www.atsjournals.org

The pathophysiologic connection between allergic rhinitis and

asthma has important implications for the development of novel

treatment options for these diseases. In this context, the develop-

ment of the monoclonal anti-IgE antibody (omalizumab), a novel

drug that works in a broader, non-allergen-specific manner and is

designed to block IgE-mediated disease early in the cascade of

biologic events, has merited careful study. Phase II and III stud-

ies of treatment with omalizumab have demonstrated its efficacy

and safety in treating allergic asthma and rhinitis as separate dis-

eases (15, 16). Ongoing studies will elucidate whether treatment

with omalizumab in patients with both asthma and allergic rhini-

tis will attenuate the allergic response and therefore demonstrate

improved control of both diseases.

INITIAL CLINICAL INVESTIGATION OF OMALIZUMAB IN

ALLERGIC RHINITIS

The first large clinical trial of omalizumab in allergic rhinitis

was conducted in 1994, with the aim of evaluating the safety

and efficacy of repeated doses of the drug in adults with a his-

tory of significant ragweed-induced disease (17). It also exam-

ined the pharmacodynamic relationship between omalizumab

and blood IgE levels.

The trial was a seven-center, double-blind, placebo-con-

trolled study that enrolled 240 patients, who were randomized

into one of five groups. Altogether, 181 patients received an

intravenous loading dose of omalizumab 1 mo before ragweed

season, followed by one of three additional doses of omali-

zumab, given either subcutaneously or intravenously, in a ra-

tio to body weight of 0.15 mg/kg (subcutaneous), 0.15 mg/kg

(intravenous), or 0.5 mg/kg (intravenous). The other two

groups were given placebo intravenously and placebo subcu-

taneously. The drug was administered every other week dur-

ing the ragweed season for 12 wk, with an 8-wk follow-up pe-

riod added thereafter (17).

The trial findings confirmed that ragweed-specific IgE lev-

els correlated with symptom scores. Omalizumab-treated sub-

jects experienced a rapid dose- and baseline IgE-dependent

decrease in free IgE levels in their serum. The clearance of IgE

bound to omalizumab is slower than the typical clearance of

free IgE in serum. Therefore, there was a simultaneous increase

in total IgE in the omalizumab-treated subjects. Importantly,

it was also observed that omalizumab produced the same

pharmacokinetic effects whether it was administered subcuta-

neously or intravenously. In addition, the study confirmed ear-

lier data regarding the safety and tolerability of omalizumab

(18). Adverse events were mild, and their frequencies did not

differ between the active drug and the placebo groups (17).

Efficacy, however, was not demonstrated, since only 11 pa-

tients achieved IgE levels that were below detectable limits.

Nevertheless, the finding that symptom scores correlated with

IgE and that free IgE in serum declined in a dose-dependent

manner suggested that omalizumab could ameliorate seasonal

allergic rhinitis symptoms if given in adequate doses. In fact,

our analysis of unbound and complexed IgE suggested that

the efficacy of omalizumab would improve if its dosing were

based on the patient's baseline IgE value (17).

Casale: Anti-IgE in SAR

DOSE-RANGING TRIAL

Based on the results of this study, a second large multicenter

study compared three subcutaneous doses of omalizumab: 50 mg,

150 mg, and 300 mg, with placebo (19). The dose-response re-

lationships to symptoms, quality of life, and reduction in the use

of rescue medication were studied in 536 patients with moder-

ate to severe ragweed-induced allergic rhinitis of at least 2-yr

duration.

In the double-blind trial, patients were randomized to pla-

cebo or one of the three doses of omalizumab approximately

2 wk before the onset of the ragweed pollen season. Hypothe-

sizing that baseline IgE levels were important in the dosing

strategy, the investigators established the frequency with

which patients received their assigned treatment according to

baseline IgE levels: those with serum IgE levels of 30 to 150

IU/ml received their assigned treatment at 0, 4, and 8 wk and

those with IgE levels of 151 to 700 IU/ml received treatment

at 0, 3, 6, and 9 wk. Patients were initially followed for 12 wk,

recording nasal and ocular symptom severity scores (on scales

of 0 to 3), the use of rescue medication, and changes in quality

of life. An additional 12-wk observation period was included

in the study design (19).

As anticipated, the mean daily nasal symptom severity

scores (sneezing or itchy, runny, or stuffy nose), rated on a

scale of 0 to 3 depending on the severity of symptoms (0 no

symptoms, 3 severe symptoms) for patients receiving pla-

cebo, rose with the pollen count, but in patients receiving the

300-mg dose of omalizumab, there was no increase in these

scores, not even during the peak ragweed season. The differ-

ence between the placebo and the 300-mg omalizumab groups

was statistically significant throughout the pollen season as

well as the peak season (p 0.001, one-sided t test). Patients

receiving the 150-mg dose of omalizumab had lower mean symp-

tom scores with drug levels, but the difference from the scores

in the placebo group was not statistically significant (19).

Regression analysis of the daily nasal symptom scores con-

firmed a linear dose-response relationship (p 0.001). The

mean daily ocular symptom severity scores were 0.41, 0.45,

0.49, and 0.67 for the 300-mg omalizumab, 150-mg omali-

zumab, 50-mg omalizumab, and placebo groups, respectively,

for the entire season. The reduction in ocular symptoms for all

three omalizumab groups as compared with the placebo group

was significant (p 0.012) (19).

The Rhinoconjunctivitis Quality-of-Life Questionnaire

(RQLQ), a disease-specific measuring instrument with seven

domains consisting of 28 items relating to activities, sleep,

non-nose/eye-associated symptoms, practical problems, nasal

and ocular symptoms, and emotional concerns was used to as-

sess changes in quality of life. In the placebo group, increases

in pollen count correlated with a deterioration of quality of

life as manifested by higher RQLQ scores. At the highest dose

of omalizumab, RQLQ scores during the peak pollen season

were lower (20).

Patients who experienced unrelieved symptoms were permit-

ted to use antihistamines as rescue medication. The proportion of

days on which rescue medication was taken and the number of

tablets ingested were reduced by approximately 50% in the

300-mg omalizumab group as compared with the placebo group.

These parameters were also significantly reduced in the 150-mg

omalizumab group, but not in the 50-mg omalizumab group (19).

The relationship between the dose of omalizumab and free

IgE in serum was linear. At the 300-mg dose of omalizumab,

the percentage of patients with serum IgE levels below the de-

tectable level of 25 ng/ml was approximately 65%; at the 150-mg

dose, only half as many patients reached such low serum IgE

S19

levels. A similar relationship existed between IgE levels and

nasal symptom severity scores. Patients with IgE levels from

50 ng/ml to 150 ng/ml had higher symptom scores that did pa-

tients with IgE levels below 50 ng/ml (21). Changes in the use

of rescue medication in relation to IgE were noteworthy. Pa-

tients with the lowest IgE levels had a striking reduction in the

use of rescue medication during the pollen season (21).

The overall incidence of adverse events across all three

doses of omalizumab and placebo was similar. The adverse

events thought to be drug-related and which occurred in more

than 2% of patients were weight increase and headache, and

this was also similar in the placebo group. Drug-related urti-

caria was reported in 0.5% of patients (two of 400), a number

smaller than would be expected with traditional immunother-

apy. There were no drug-related serious adverse events, and

no anti-omalizumab antibodies were detected (19).

OMALIZUMAB IN BIRCH POLLEN ALLERGIC RHINITIS

A Scandanavian group subsequently studied the efficacy of

omalizumab in treating seasonal allergic rhinitis caused by

birch pollen (16). The double-blind, multicenter, placebo-con-

trolled, parallel-group trial involved 251 patients who were

randomized to receive omalizumab at 300 mg subcutane-

ously-the maximum effective dose determined by the previ-

ous study-or placebo in a two-to-one ratio. The study design

was similar to that of the earlier trial, with dosing frequency

dependent on the patients' baseline IgE levels: if levels were

150 IU/ml or lower, patients received omalizumab or placebo

twice, at monthly intervals; if their baseline IgE levels were

greater than 150 IU/ml, they were treated three times at 3-wk

intervals. The study design was also similar to that of the ear-

lier trial in that the first dose was intended to be given a week

or two before the onset of the pollen season, but the season

started early, and some patients received their initial medica-

tion at the beginning of the season or after it had begun (16).

The primary efficacy variable was the patients' average

daily nasal symptom severity score. Secondary efficacy vari-

ables included the average number of rescue antihistamine

tablets taken per day, the proportion of days on which any

medication for seasonal allergic rhinoconjunctivitis was used,

and responses to the RQLQ (16).

In all parameters of efficacy, omalizumab was superior to

placebo. The average daily nasal severity score in the omali-

zumab group was 0.71 at baseline, varying little throughout

the trial period (final value: 0.70), whereas it increased in the

placebo group from 0.78 to 0.98, a significant difference from

the baseline value (p 0.001) (Figure 1). Treatment was also

evaluated for efficacy in preventing eye symptoms, using the

daily ocular symptom severity scale score. Treatment with

omalizumab conferred significant improvement over placebo

(p 0.031). It should be noted that the late start of omali-

zumab treatment in relation to the start of the pollen season in

some individuals may have blunted some of these already fa-

vorable results of omalizumab treatment (16).

The average number of tablets of rescue medication taken

per day was significantly lower in the omalizumab group than

in the placebo group (0.59 and 1.37 tablets per day, respec-

tively; p 0.001), and the proportion of days on which any

rescue medication was taken was almost twice as high in the

placebo group as in the omalizumab group (49% and 28%, re-

spectively; p 0.001).

Statistically significant differences in favor of omalizumab

were observed in all of the RQLQ domains and in the total

RQLQ score (Figure 2). Differences from placebo of more

than 0.5 units are clinically meaningful (20). Twenty-one per-

S20

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 164 2001

Figure 1. Average daily nasal symptom severity

scores (with SEs) over the entire postrandomization

period (all randomized subjects in an intent-to-treat

analysis). Nasal symptom scores were rated on a

scale of 0 to 3, depending on the severity of symp-

toms (0 no symptoms, 3 severe symptoms).

Adapted by permission from Ädelroth E, Rak S, Haahtela

T, Assand G, Rosenhall L, Zetterstrom O, Byrne A,

Champain K, Thirlwell J, Cioppa GD, et al. Recombi-

nant humanized mAb-E25, an anti-IgE mAb, in birch

pollen-induced allergic rhinitis. J Allergy Clin Immunol

2000;106:253-259.

cent of patients in the omalizumab group considered their

symptoms completely controlled, as compared with 2% of pla-

cebo-treated patients, and a further 59% receiving omali-

zumab reported improvement, as compared with 35% in the

placebo group (16).

Omalizumab was also well tolerated, and no significant dif-

ferences were found in either the overall incidence of adverse

events or in the incidence of drug-related adverse events be-

tween the omalizumab and placebo groups. Injection-site re-

actions were similar in both groups, and three patients re-

ported a total of four episodes of urticaria after administration

of omalizumab, but these were mild and required no treat-

ment. No drug-related serious adverse events were noted, and

no anaphylactic reactions or serum sickness occurred. No anti-

omalizumab antibodies were detected (16).

READMINISTERING OMALIZUMAB AFTER A LAPSE

IN TREATMENT

One concern about omalizumab treatment that remained un-

resolved after these trials was whether omalizumab could be

safely readministered after treatment had been discontinued

for a prolonged period. This question was addressed in an ex-

tension of our dose-ranging study of omalizumab in patients

with ragweed-induced seasonal allergic rhinitis.

Of the 374 patients treated with omalizumab in the original

trial, 287 participated in the 12-wk open-label extension trial

(22). The maximum effective dose of omalizumab from the

dose-ranging study, 300 mg, was administered subcutaneously

every 3 wk to subjects with baseline serum IgE levels above

150 IU/ml (37% of patients), or every 4 wk to those with base-

line IgE levels of 150 IU/ml or lower (63% of patients). No

placebo arm was involved, and no efficacy parameters were

studied.

The incidence of adverse events was similar in both treat-

ment groups (43% and 50%, respectively). The incidence of

drug-related adverse events was also similar in both treatment

groups (1.9% and 2.7%, respectively). The most frequent ad-

verse events were headache and upper respiratory tract infec-

tion, and five patients withdrew prematurely because of ad-

verse events, only two of which were considered drug-related,

and both of which involved rashes. No adverse events were

considered serious. Injection-site reactions were few and mild.

No antibodies against omalizumab were detected (21).

CONCLUSION

The use of the humanized monoclonal anti-IgE antibody oma-

lizumab, administered subcutaneously, appears to be clinically

valuable in the treatment of seasonal allergic rhinitis. Nasal

Figure 2. RQLQ scores at Week 3 or 4. Quality of life was assessed with the RQLQ (16). *p 0.5.

Casale: Anti-IgE in SAR

and ocular symptoms are effectively controlled by this agent,

and it substantially improves quality of life for patients with

seasonal allergic rhinitis. Treatment with omalizumab is safe

and well tolerated. Because omalizumab treatment is not al-

lergen specific, it might be expected to help patients with sea-

sonal allergic rhinitis caused by multiple allergens. Furthermore,

because omalizumab also has proven efficacy in allergic asthma,

patients with the comorbid conditions of allergic rhinitis and

asthma might benefit from this novel therapeutic agent.

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