INTRODUCTION

TOP ABSTRACT INTRODUCTION DOSE JUSTIFICATION ANTI-IgE (OMALIZUMAB) PHASE II... ANTI-IgE (OMALIZUMAB) PHASE III... CONCLUSION REFERENCES

Keywords: asthma; anti-IgE; IgE; omalizumab

Immunoglobulin E (IgE)-mediated events play an important role in the inflammatory processes that are thought to underlie the symptoms of allergic asthma. Earlier studies with the anti-IgE monoclonal antibody, omalizumab, established that it decreased serum-free IgE concentrations and was thus potentially useful in the treatment of allergic diseases without regard to the specific allergen involved (1). These studies also demonstrated that omalizumab therapy reduces wheal and flare reactions, effectively attenuates allergen-induced early and late asthmatic responses and sputum eosinophilia, and increases the dose of allergen needed to provoke an early response to allergen challenge, raising the possibility that this agent may have a long-term anti-inflammatory effect (2). Future studies will further define and confirm its role in modifying this disease process.

The pharmacotherapeutic management of asthma has progressed over time but is still imperfect. Although drug interventions can generally alleviate the symptoms of this disease, they do not necessarily address the underlying mechanisms responsible for the natural history of asthma (5). Inhaled corticosteroids are considered the standard anti-inflammatory agents for allergic asthma (6) and are usually efficacious for mild and moderate asthma. Some patients with moderate or severe asthma, however, remain symptomatic despite treatment with corticosteroids, suggesting persistent inflammation in the airways.

The limitations of existing asthma interventions support continued research into novel therapeutic options, particularly those that may modify the disease process. To this end, omalizumab has been studied for the treatment of allergic asthma. Early double-blind, placebo-controlled clinical trials demonstrated the ability of omalizumab to impede allergen-induced airway responses (3, 4). Specifically, these studies have found that intravenous administration of omalizumab attenuated the early asthmatic response as demonstrated by a significantly smaller reduction in FEV₁ after allergen challenge (3) and significant increases in PC₁₅ and PC₂₀ (the concentration of allergen needed to cause a 15% and 20% drop, respectively, in FEV₁) (4). In line with the Boulet study, Fahy and coworkers found that omalizumab diminished the late-phase response as demonstrated by a significantly smaller decrease in FEV₁ between 2 and 7 h after allergen challenge (3). A more recent study tested whether direct delivery of omalizumab to the airway had the same effect on airway responses to allergen challenge as intravenous administration. The results from this study demonstrated that aerosolized omalizumab was not as effective as intravenous administration in attenuating airway responses to inhaled allergen (7). A possible explanation for the lack of efficacy of aerosolized omalizumab may be the inability of this route of delivery to result in high enough concentrations of omalizumab to neutralize IgE in the lung tissue compartments surrounding IgE effector cells (7).

Based on the foregoing early trial results, intravenous and subcutaneous routes of administration were used to test the clinically meaningful benefits of omalizumab in Phase II and III studies, respectively. Evidence from these clinical trials continues to support the benefits and safety of this therapy in patients with symptomatic, persistent asthma.

	DOSE JUSTIFICATION

TOP ABSTRACT INTRODUCTION DOSE JUSTIFICATION ANTI-IgE (OMALIZUMAB) PHASE II... ANTI-IgE (OMALIZUMAB) PHASE III... CONCLUSION REFERENCES

The doses and dosing regimen necessary to achieve the targeted free IgE suppression were estimated based upon the following: (1) the ratio of serum omalizumab (nM): serum IgE (nM) necessary to maintain suppression (estimated at 16-21:1); (2) the dose of drug necessary to maintain an average serum concentration at or above the minimum drug:IgE ratio; (3) the dosing frequency necessary to ensure adequate serum concentrations with an acceptable number of visits and injections

Early Phase I and II studies used dosing adjusted only for body weight (mg/kg). Dosing on a mg/kg basis ensured that serum levels of omalizumab were comparable across all body weights, but did not ensure that the serum IgE levels would be suppressed to a comparable extent in every subject because allergic subjects have a wide range of baseline serum IgE concentrations. Adjustment of doses based upon baseline serum IgE would therefore ensure a consistent omalizumab:IgE ratio. Doses also still need to include the adjustment by body weight because the target population was to include both children and adults, and the body weight range could extend from approximately 20 to 150 kg.

Individualized dosing via intravenous bolus administration was used for the pivotal proof of concept Phase II study in allergic asthma (8). The route of administration for the Phase III asthma studies was changed from intravenous to subcutaneous and the dosing interval was extended from every 2 wk to every 4 wk, where possible, to improve patient convenience and compliance. The minimal effective intravenous dose from the Phase II study (0.006 mg/kg/IU/ml) was increased to a SQ equivalent dose of 0.008 mg/kg/IU/ml. Doses were doubled for the every 4-wk dosing intervals to ensure the same steady-state, average total omalizumab serum concentrations as the every 2-wk doses. Doses in excess of 300 mg/mo were split into two equal dose administrations every 2 wk. The split doses were required to reduce injection volumes and numbers of injections at each administration and to ensure that single-dose administrations were within the dose limits.

	ANTI-IgE (OMALIZUMAB) PHASE II TRIAL

TOP ABSTRACT INTRODUCTION DOSE JUSTIFICATION ANTI-IgE (OMALIZUMAB) PHASE II... ANTI-IgE (OMALIZUMAB) PHASE III... CONCLUSION REFERENCES

A large-scale Phase II trial of the efficacy of omalizumab in the treatment of allergic asthma was reported by Milgrom and colleagues in 1999 (8). The double-blind, randomized trial involved 317 patients of mean age 30 yr (range, 11 to 50 yr) with moderate to severe asthma who required daily inhaled or oral corticosteroids, or both, for control of their symptoms. The median baseline dose of daily inhaled beclomethasone dipropionate (BDP) was 800 µg/d, and the median baseline dose of oral corticosteroids, required by approximately 11% of patients, was 10 mg/d. Mean use of ₂-agonists (albuterol) among the subjects was approximately 9 puffs/d for control of ongoing symptoms. Despite these treatments, the baseline mean asthma symptom score was 4.0, and the mean FEV₁ was 71% of predicted value.

After a 4-wk run-in period in which patients' inhaled corticosteroid therapy was maintained, subjects were randomized to receive treatment with low-dose omalizumab (2.5 µg/kg body weight per ng IgE/ml), high-dose omalizumab (5.8 µg/kg body weight per ng IgE/ml), or placebo in addition to their standard therapy of inhaled corticosteroid and as-needed ₂-agonist. Treatment was administered intravenously on Day 0 (half a dose), Day 4 (half a dose), Day 7 (full dose), and then once every 2 wk for a total of 20 wk. During the last 8 wk of the study, the doses of corticosteroids were tapered in an attempt to attain complete discontinuation. The primary outcome measure was a change in the 7-point asthma symptom scale at 12 wk. Other outcomes were corticosteroid requirement, rescue medication use, and quality of life (QOL).

Phase II Trial Results

Omalizumab treatment was associated with a rapid decline in serum-free IgE concentrations, which remained at less than 5% of mean baseline values for the 20-wk treatment period in both low-dose and high-dose omalizumab groups (Figure 1). At Week 12, the mean reduction in overall asthma symptoms scores (mean baseline for all patients, 4.0) was significantly greater with either low-dose (2.8 ± 0.1, p = 0.005) or high-dose (2.8 ± 0.1, p = 0.008) omalizumab than placebo (3.1 ± 0.1). Almost twice as many omalizumab-treated patients experienced reductions in weekly symptom scores of greater than 50% than placebo-treated patients (low-dose, 47% of patients, p < 0.001 and high-dose, 49% of patients, p < 0.001, compared with 24% of patients receiving placebo plus standard therapy). As measured at Week 20, the reductions in symptom scores were maintained (low-dose, 2.7 ± 0.1; high-dose 2.7 ± 0.1; placebo, 2.9 ± 0.1) despite a reduction in corticosteroid dose.

View larger version (11K): [in this window] [in a new window]   Figure 1.   Mean serum concentration of free IgE in subjects given a low dose of omalizumab for 20 wk. Serum-free IgE concentrations decreased rapidly by more than 95% (baseline level, 1,060 ng/ml [441.7 IU/ml]) after omalizumab administration. To convert values to international units per milliliter, divide by 2.4. A log (base 10) scale is shown. Adapted with permission from Milgrom and coworkers (8).

Oral corticosteroid use was reduced after omalizumab therapy. Among the 35 patients who required oral corticosteroids at baseline, the median dose reduction over the 8-wk steroid-withdrawal phase was 50% for patients taking high-dose omalizumab (p = 0.045) and 65% for patients taking low-dose omalizumab (p = 0.11) versus 0% in the placebo group. Reductions of at least 50% of oral corticosteroid dose were achieved by 78% of patients receiving high-dose omalizumab (p = 0.04) and 57% of patients receiving low-dose omalizumab (p = 0.23) versus 33% of patients receiving placebo.

Inhaled corticosteroid use was also reduced after omalizumab therapy. Reductions in inhaled corticosteroid dose of at least 50% were achieved by 51% of patients in the high-dose omalizumab group (p = 0.07) and 49% of patients in the low-dose omalizumab group (p = 0.12) compared with 38% of patients in the placebo group, demonstrating a trend toward, but not reaching, statistical significance. Similarly, 18% of patients in the high-dose omalizumab group (p = 0.27) and 23% of patients in the low-dose omalizumab group (p = 0.048) were able to discontinue use of inhaled corticosteroids altogether versus 12% of those receiving placebo.

Supporting the improved control induced by omalizumab, decreases in oral or inhaled corticosteroid use did not result in an increased need for rescue ₂-agonist medication. The use of ₂-agonists after 12 wk of treatment was reduced by 1.8 puffs/ day in the high-dose omalizumab group (p = 0.02) and by 1.2 puffs/d in the low-dose omalizumab group (p = 0.24) compared with 0.8 puff/d in the placebo group. These reductions in rescue medication use were maintained at 20 wk in both groups receiving omalizumab.

At Week 12, the increase in morning peak expiratory flow (PEF) rate tended to be greater in the omalizumab groups than placebo (low-dose, 18.6 L/min, p = 0.10; high-dose, 30.7 L/min, p = 0.001; placebo, 11.3 L/min). This effect persisted to Week 20 (low-dose 20.8 L/min, p = 0.046; high-dose, 29.9 L/min, p = 0.02; placebo, 10.2 L/min). Though the absolute improvement in FEV₁ was almost twice as great with active treatment than placebo (low-dose, +2.1%, p = 0.49; high-dose, +1.9%, p = 0.81; placebo, +1.0%), the differences were not statistically significant.

Changes in QOL were also demonstrated in favor of omalizumab treatment using an asthma-specific QOL questionnaire. For adults, after 12 wk of treatment, the overall score had risen by a mean of 1.4 in the high-dose omalizumab group (p < 0.001), 1.2 in the low-dose omalizumab group (p = 0.007), and 0.8 in the placebo group; scores were similar in each of the four areas measured (activities, emotions, symptoms, exposure) (Figure 2A). These differences persisted throughout the 8-wk steroid-withdrawal phase (Figure 2B). Omalizumab therapy was well tolerated. There were no significant differences in adverse events among the groups. Mild to moderate urticaria was reported in 17 patients (8 high-dose, 6 low-dose, and 3 placebo), all of which responded to antihistamines. In addition, no antibodies to anti-IgE (omalizumab) were detected.

View larger version (18K): [in this window] [in a new window]   View larger version (19K): [in this window] [in a new window]   Figure 2.   Increase in scores on the Asthma-Specific Quality-of-Life Questionnaire (AQLQ) for 263 subjects. (Top panel ) Increases in AQLQ scores after the 12-wk stable-steroid phase for each treatment group. *p  0.002, p  0.02. (Bottom panel ) Increases in AQLQ scores after the 8-wk steroid-withdrawal phase. *p  0.002, p  0.05. Figure adapted by permission from data published in H. Milgrom and coworkers (8).

In this study of patients with moderate to severe allergic asthma, omalizumab therapy improved control of this disease by improving symptoms while permitting reductions in oral or inhaled corticosteroid use without increases in ₂-agonist therapy. Though the favorable changes attributed to omalizumab are modest, they occurred despite reductions in corticosteroid and ₂-agonist therapy in patients who were symptomatic on these therapies. Improvements observed with placebo treatment probably reflect stabilization of corticosteroid therapy during the 4-wk run-in period before randomization and continued physician monitoring of placebo-treated patients during the study. Indeed, the effectiveness of the protocol of this study is evidenced by the improvement in symptoms among the placebo-treated patients. Nevertheless, improvements in asthma were greater with omalizumab than placebo.

	ANTI-IgE (OMALIZUMAB) PHASE III TRIALS

TOP ABSTRACT INTRODUCTION DOSE JUSTIFICATION ANTI-IgE (OMALIZUMAB) PHASE II... ANTI-IgE (OMALIZUMAB) PHASE III... CONCLUSION REFERENCES

The results of the Phase II trial of omalizumab supported the initiation of two Phase III clinical trials. These randomized, double-blind, parallel-group, placebo-controlled, multicenter studies were conducted in symptomatic adolescent and adult patients with moderate to severe allergic asthma (9, 10). One trial was conducted in international and United States centers (9) and the other was conducted in United States centers exclusively (10). At baseline, all patients were receiving standard therapy of inhaled corticosteroids and as-needed ₂-agonists as recommended in the National Heart, Lung, and Blood Institute guidelines. The two pivotal trials were identical in study design and included four distinct phases: run-in, stable-steroid, steroid-withdrawal, and double-blind extension (Figure 3). During the run-in phase, 4 to 6 wk before randomization, patients' standard therapy was switched to BDP and stabilized. Stabilization required the investigator to adjust the BDP dose to balance the symptoms (patients had to be symptomatic).

View larger version (19K): [in this window] [in a new window]   Figure 3.   Study design of pivotal trials of omalizumab. The adult pivotal trials were identical in terms of study design and included four distinct phases: run-in, steroid-stable, steroid-withdrawal, and double-blind extension. During the run-in phase, patients' standard therapy was switched to BDP and stabilized, which required the investigator to adjust the BDP dose so that patients entered the core study period (steroid-stable phase) symptomatic yet exacerbation-free (9, 10).

The design of the Phase III trials was generally similar to the Phase II trial with some exceptions. The Phase III trials used subcutaneous rather than intravenous administration of omalizumab because subcutaneous administration is more convenient and less invasive. Rather than using a low or high dose of omalizumab, patients in the Phase III trials received a dose of omalizumab that was tailored to their individual body weight and total serum IgE level. Patients received at least 0.016 mg per kg body weight per concentration of total serum IgE in IU/ml every 4 wk. (For patients requiring 450 to 750 mg of omalizumab, the monthly dose was divided into two equal portions administered every 2 wk to minimize the number of injections at one time while maintaining adequate drug levels.) Compared with the Phase II trial, the durations of the stable-steroid (8 wk versus 12 wk), steroid-withdrawal (8 wk versus 12 wk), and double-blind extension phases (10 wk versus 24 wk) were lengthened in the Phase III trials. Patient age range was extended in the Phase III trials, range 12 to 75 yr (mean, approximately 40 yr), compared with the Phase II trial, range 11 to 50 yr (mean, 30 yr), in order to include an older group of patients.

The primary end points of these studies differed. The primary end points of the Phase II study were daytime and nocturnal asthma symptom scores, whereas the primary end points of the Phase III studies were the number of asthma exacerbations experienced per patient during the stable-steroid phase and the steroid-withdrawal phase of the study. The number of exacerbations was selected as one of the primary efficacy variables because exacerbations are a marker of disease control with a strong impact on disease morbidity and mortality (9), QOL (11), and total cost of illness (12). The number of exacerbations also reflects the degree of control of airway inflammation. Additional outcomes in the Phase III trials included the effect of anti-IgE (omalizumab) on corticosteroid requirement, symptoms, rescue medication use, lung function, and QOL.

Phase III Trial Results

The findings of the two Phase III trials were quite similar and confirmed the results of the Phase II trial (9, 10). Considering the primary efficacy outcome measure of asthma exacerbations, statistically significant differences were observed in favor of the anti-IgE (omalizumab)-treated patients in both the stable-steroid and the steroid-withdrawal phases of the trials (Table 1). It should be noted that the analysis of exacerbations was restricted to those episodes severe enough to require either a doubling of baseline BDP dose or a course of systemic corticosteroid. This conservative approach considerably strengthens the clinical relevance of the results.

The reduction in asthma exacerbations in the omalizumab group occurred despite the significantly greater reduction of BDP dose from baseline to the end of treatment in the omalizumab group compared with the placebo group (Figures 4A and 4B) (9, 10). In addition, significantly more subjects in the omalizumab group achieved complete withdrawal of BDP than patients treated with placebo and standard therapy. The reduction in BDP dose was achieved without precipitating asthma exacerbations, worsening symptoms and lung function, or increasing the use of rescue medication. These results indicate that treatment with omalizumab is able to control the disease process sufficiently to permit reduction in corticosteroid use.

View larger version (16K): [in this window] [in a new window]   View larger version (15K): [in this window] [in a new window]   Figure 4.   Significant reduction in BDP dose with omalizumab therapy; percent reduction in inhaled BDP dose, and percentage of patients with complete BDP reduction at the end of the treatment period (Week 28). Top panel illustrates data from the U.S. sites only trial [adapted by permission from Busse and coworkers (10)] and bottom panel illustrates data from the U.S. and international sites trial. *p  0.001 (9).

Symptom control was also superior in the omalizumab group despite BDP reduction, with significant differences favoring omalizumab during the stable-steroid phase. Control was maintained during the steroid-withdrawal phase (Figure 5) (10). Notably, symptom control improved despite a reduction in rescue medication. For example, the mean number of puffs of rescue medication was also significantly lower in the omalizumab group than in the placebo group during the stable-steroid phase, and this improved control continued during the steroid-withdrawal phase despite the greater reduction in BDP dose in the omalizumab group than in the placebo group. Interestingly, placebo-treated patients took significantly more puffs of rescue medication than did those receiving omalizumab, which might normally improve symptom scores and FEV₁.

View larger version (23K): [in this window] [in a new window]   Figure 5.   U.S. Phase III study: symptom control with omalizumab was maintained during the steroid-withdrawal phase. Mean change from baseline in total asthma symptom scores and the number of puffs of rescue medication (albuterol) per day. Data were derived from the U.S. trial. Adapted by permission from Busse and coworkers (10).

Respiratory function improved significantly for patients receiving omalizumab throughout the stable-steroid phase as measured by PEF. There was also a small, but significant, improvement in FEV₁ in patients receiving omalizumab. The improvements in respiratory function were maintained during the steroid-withdrawal phase (Figures 6A and 6B) (9). These findings suggest that improvements in lung function were sustained with omalizumab despite the withdrawal of corticosteroid medication and the reduction of rescue medication use.

View larger version (8K): [in this window] [in a new window]   View larger version (7K): [in this window] [in a new window]   Figure 6.   U.S. and international pivotal study: respiratory function improved significantly with omalizumab therapy. (Top panel ) Mean morning PEF values during the stable-steroid and steroid-reduction phases. *p < 0.001. (Bottom panel ) Mean FEV1 values as percentage of predicted during the stable-steroid and steroid-reduction phases. *p = 0.025, **p = 0.001 versus placebo. NI = no inferential analysis performed. The vertical dotted line marks the end of the stable-steroid phase. Adapted by permission from Soler and coworkers (9).

The principal efficacy outcomes of fewer exacerbations and reduced BDP dose, as well as the additional outcomes of improved asthma symptom scores, improved and maintained lung function, and concomitant reduction in rescue medication also were reflected in clinically meaningful improvements in QOL. QOL was assessed using the self-administered Asthma-Specific Quality-of-Life Questionnaire (AQLQ). A clinically meaningful change in QOL was defined as a change from baseline of greater than 0.5 in AQLQ scores, and a positive change means improvement in QOL. Omalizumab-treated patients improved significantly compared with placebo-treated patients in all domains of the AQLQ (13). The safety of omalizumab treatment was also supported by this study. The incidence of adverse events was similar between the treatment groups, and no drug-related serious adverse events were reported. In addition, antibodies against omalizumab were not detected.

	CONCLUSION

TOP ABSTRACT INTRODUCTION DOSE JUSTIFICATION ANTI-IgE (OMALIZUMAB) PHASE II... ANTI-IgE (OMALIZUMAB) PHASE III... CONCLUSION REFERENCES

Consistent findings in Phase II and Phase III trials of omalizumab confirm that it is effective therapy for patients with symptomatic, moderate to severe allergic asthma despite treatment of corticosteroids and rescue medication. Omalizumab reduced the frequency and occurrence of exacerbations and improved symptom control while allowing for a reduction in the use of corticosteroids and ₂-agonists. Omalizumab is also

safe and well tolerated and improved patient QOL. Collectively, these results provide convincing evidence that omalizumab is efficacious and safe for the treatment of asthma. Future clinical trials will continue to define the role of omalizumab, including comparative efficacy and safety with standard therapies and use in patients with severe allergic asthma.