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Allergic diseases, particularly the atopic diathesis of asthma, allergic rhinoconjunctivitis, and atopic dermatitis, represent an increasing socioeconomic and health burden around the world (1–3). The prevalence of atopic sensitizations, the most important risk factor for asthma and other allergic diseases, is increasing. The morbidity caused by allergic rhinoconjunctivitis due to seasonal or perennial allergens is often not fully appreciated (4), and asthma is associated with a substantial mortality rate (5). It has been estimated that approximately half the cases of asthma may be attributed to atopy (6). In individuals with atopic disease, high allergen loads contribute to the severity of disease, and allergen-avoidance strategies can bring about measurable improvements (7).

Role of IgE in allergic inflammation

  1. Top of page
  2. Role of IgE in allergic inflammation
  3. Mode of action
  4. Update on phase III clinical studies in patients with allergic asthma
  5. Phase III studies in seasonal allergic rhinitis (SAR)
  6. Safety
  7. Concluding remarks
  8. References

Allergic airway inflammation is thought to result from a failure to control an otherwise harmful IgE-mediated immune response. Thus, elevated levels of serum IgE are a hallmark of atopic diseases. The biological activities of IgE are mediated through the high-affinity IgE receptor (FcεRI) and through the low-affinity IgE receptor (FcεRII or CD23). Mast cells have an important role in perpetuating the allergic response. Mast cells in patients with allergic rhinitis express increased numbers of FcεRI receptors, which are associated with increased binding to IgE and subsequent degranulation (8). Other FcεRI+ cells and the likely effects mediated by IgE include monocytes (9) (prolonged survival and differentiation [10]), dendritic cells (11) (enhanced antigen presentation to T-cells [11–13]), eosinophils (14, 15) (cytotoxicity [16]), and epithelial cells (17) (possibly resulting in enhanced chemokine release). The numbers of FcεRI+ cells and the expression of this receptor are increased in atopic subjects (14, 15, 18).

Differentiation of B cells into IgE-secreting plasma cells requires at least two distinct signals. The first is provided by the cytokines IL-4 and IL-13, and the second signal is delivered by the interaction of CD40L on the surface of T cells with CD40, a costimulatory molecule, on the B-cell membrane. However, recent studies have shown that antigen-activated mast cells also are capable of inducing IgE synthesis in B cells (8), indicating the possibility of local IgE synthesis. This could be relevant in patients with intrinsic asthma, where the elevated local production of IL-4 and IL-13 in the bronchial mucosa is compatible with the possibility of local IgE production in the bronchial submucosa (19). Moreover, the numbers of FcεRI+ cells and levels of serum IgE can be increased in asthmatic patients regardless of atopic status (20, 21), suggesting that IgE-mediated mechanisms may be relevant in some forms of “intrinsic” asthma too. Therefore, both some forms of nonatopic and all atopic asthma are associated with production of IgE.

The IgE-mediated type I immediate hypersensitivity reaction is well characterized. IgE binds to high-affinity receptors (FcεRI) on mast cells and basophils to provide an adapter molecule conferring antigen specificity upon the receptor. Cross-linking by allergen is followed by the release of preformed and newly formed mediators and cytokines that implicate the mast cell in both the immediate and longer-term aspects of allergic inflammation (22).

While our knowledge of IgE and its role and function are still far from complete, the development of a humanized monoclonal anti-IgE antibody will assist in research into allergic diseases, and broaden options for treatment. Omalizumab is the first such agent. It has been extensively evaluated in clinical trials in patients with allergic asthma (23–26) and seasonal allergic rhinitis (SAR) (27–29).

Mode of action

  1. Top of page
  2. Role of IgE in allergic inflammation
  3. Mode of action
  4. Update on phase III clinical studies in patients with allergic asthma
  5. Phase III studies in seasonal allergic rhinitis (SAR)
  6. Safety
  7. Concluding remarks
  8. References

Omalizumab is a humanized kappa IgG1 antibody that binds to free IgE at the FcεRI binding site on the c3 domain of the IgE molecule, thereby preventing its interaction with FcεRI receptors on effector cells (30–32). Since the binding site for the low-affinity IgE receptor is located close to the FcεRI binding site, omalizumab probably prevents the binding of IgE to CD23, although it is not known whether all CD23 isoforms are affected.

Levels of serum free IgE decrease by ≥90% from pretreatment values within approximately 24 h of subcutaneous administration of omalizumab. During continued administration, the fall in serum free IgE is accompanied by a reduction in FcεRI expression on effector cells, reduced occupancy of these cellular receptors, and reduced responsiveness of the cells to appropriate antigenic stimuli in sensitive subjects (33).

Anti-IgE: anti-inflammatory?

Omalizumab does not have an acute bronchodilator effect but does provide significant protection against the bronchoconstriction observed during both the early- and late-phase asthmatic responses (EAR, LAR) to allergen challenge in subjects with mild allergic asthma (34, 35). After 9 weeks of treatment, omalizumab provided a 50% reduction in the fall in FEV1 during the LAR while subjects were given a dose of allergen double that used at baseline (35). A significant reduction in associated bronchial responsiveness to methacholine was observed during treatment in both of these small studies (34, 35). Although the precise mechanism by which IgE contributes to the LAR is not clearly defined (36), the attenuation of the LAR by omaluzimab establishes a clear role for IgE in the pathogenesis of the LAR.

The LAR is often considered to reflect the processes of chronic inflammation, and many events of the LAR are more in part attributed to granulocyte influx and activation. Reductions in circulating eosinophils and eosinophil counts in induced sputum have been reported in patients with allergic asthma during treatment with omalizumab (35, 37). A pilot study reported nonsignificant decreases in neutrophils and neutrophil-derived myeloperoxidase in induced sputum of patients with moderate-to-severe allergic asthma (38). A clinical study in patients with moderate-to-severe allergic asthma reported a significant reduction in oral corticosteroid requirement in a subgroup of 35 patients dependent on this form of therapy (23).

Antigenicity

It is appropriate to review some of the features that the design of the omalizumab molecule aimed to achieve. Omalizumab is unable to cross-link cell-bound IgE and trigger effector cell activation (32), since the epitope is buried within the IgE–FcεRI complex and is not available to omalizumab. In addition, the two FcεRI binding sites on the IgE molecule are both occupied in the IgE–FcεRI complex (39). This renders the potential for omalizumab itself to cause an anaphylactic reaction theoretically impossible.

Immune complex formation and immunogenicity

Omalizumab binds to serum free IgE to form complexes made up of trimers (in a 2:1 or 1:2 relationship, depending on which molecule is present in excess concentration) or cyclic hexamers (of omalizumab and IgE in a 3:3 relationship, when the concentrations are approximately equimolar). Studies in vitro and in cynomolgus monkeys showed that these cyclic hexamers were the largest complexes detected, at approximately 1000 kDa in molecular mass (40, 41). This size is similar to that of naturally occurring IgM and is unlikely to present any problems for clearance via the reticuloendothelial system. The omalizumab–IgE complexes were soluble, and larger (e.g., linear) structures were not detected. The cynomolgus monkey studies showed a lack of association of omalizumab or the complexes with any organ system or with red blood cells (41), and neither omalizumab nor the complexes were complement-fixing. The small size, solubility, and lack of ability to fix complement are all desirable features to minimize the risk of clinical complications arising from the precipitation and deposition of large immune complexes. The omalizumab–IgE complexes have a serum half-life of approximately 20 days and are cleared via the Fcγ receptors of the reticuloendothelial system (41). The circulating complexes may have a protective effect by binding to and neutralizing free antigen, since up to six antigen-binding sites are still theoretically available on the complexed IgE molecules.

Update on phase III clinical studies in patients with allergic asthma

  1. Top of page
  2. Role of IgE in allergic inflammation
  3. Mode of action
  4. Update on phase III clinical studies in patients with allergic asthma
  5. Phase III studies in seasonal allergic rhinitis (SAR)
  6. Safety
  7. Concluding remarks
  8. References

Dosing

One of the key aims of the early-phase clinical development programme was to establish the level of suppression of free IgE that was needed for a clinical effect to become apparent. In a dose-ranging study in patients with ragweed-induced SAR (42), a preventive effect on rhinitis symptoms was observed only in those patients whose serum free IgE was sufficiently reduced. The investigators concluded, first, that omalizumab needed to be given at a dose based on a patient's baseline level of serum free IgE; and, second, that omalizumab should be given at a dose providing the drug in a molar excess (approximately 15:1) over free IgE (Fig. 1).

image

Figure 1. Steady-state levels of free IgE plotted against steady-state ratio of omalizumab:total (free plus complexed) IgE in treated subjects. This shows that for consistent suppression of serum free IgE to lowest level of detection, initial ratio of omalizumab:total IgE of approximately 10 to 15:1 is required (from Casale et al. [42]).

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For the phase III clinical studies, omalizumab was reformulated to allow subcutaneous dosing rather than the intravenous formulation that had been used previously. Part of the early clinical research involved a pilot study of aerosol administration topically to the lungs. The results from this study showed instances of anti-omalizumab antibody formation, and the topical route of administration would thus probably not be clinically practicable (43). In the phase III work, patients were assigned to one of the dosing strata according to body weight and baseline free IgE. The resulting omalizumab dose was administered once every 4 weeks or, if necessary because of the volume to be injected, every 2 weeks to achieve an omalizumab dosage of at least 0.016 mg/kg per IU/ml of IgE per 4 weeks. In phase III studies in allergic asthma, 60% of patients received omalizumab by subcutaneous injection once every 2–4 weeks. Levels of serum free IgE achieved with this regimen are shown in Fig. 2.

image

Figure 2. Reduction in serum free IgE after subcutaneous administration of omalizumab given at dose of 300 mg once monthly for 48 weeks in patients with allergic asthma treated in phase III trial (24).

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Phase III study design

Three large studies were conducted in patients with allergic asthma. Protocol 008 was conducted in the USA in adults and adolescents who were symptomatic while receiving standard therapy with inhaled corticosteroids (beclomethasone dipropionate, [BDP]) and a short-acting inhaled β2-agonist (24). Protocol 009 studied a very similar population of patients and was conducted in the EU, South Africa, Australia, and the USA (25). The third study (protocol 010) was conducted in the USA in children who were well controlled on inhaled corticosteroids (26). Patients had a history of positive skin prick sensitivity to house-dust mite, dog, cat, and (in the US studies only) cockroach. The characteristics of the study populations are outlined in Table 1.

Table 1.  Characteristics of randomized patients in phase III allergic asthma studies (24–26)
 Adults and adolescents (protocol 008)Adults and adolescents (protocol 009)Children (protocol 010)
OmalizumabPlaceboOmalizumabPlaceboOmalizumabPlacebo
Number treated268257274272225109
Mean (range) age (years)39 (12–73)39 (12–74)40 (12–76)39 (12–72)9 (5–12)10 (6–12)
Mean (range) duration of asthma (years)21 (1–61)23 (2–60)20 (2–68)19 (1–63)6 (1–12)6 (1–12)
Mean serum total IgE (IU/ml)172186223206348323
Mean (range) FEV1 (% predicted)68 (30–112)68 (32–111)70 (30–112)70 (22–109)84 (49–129)85 (43–116)
Mean (range) BDP dose (μg/day)679 (500–1200)676 (400–1000)769 (500–1600)772 (200–2000)338 (200–800)318 (200–600)
Severe asthma (%)2221222296

The three studies followed largely the same design. During a run-in period, patients were transferred from their previous inhaled corticosteroid to an equivalent dose of BDP. The dose was adjusted to the lowest consistent with control of the patients' asthma. This dose was maintained for at least 4 weeks, the last 2 weeks providing baseline data. Patients were then randomized to active or matching placebo treatment, which in the first (“corticosteroid-stable”) phase of the study was added to standard therapy (BDP and short-acting inhaled β2-agonist) for a period of 16 weeks. In the second, 12-week phase (“corticosteroid-reduction”), the dose of BDP was reduced by 25% every 2 weeks if the asthma remained well controlled. This dosage adjustment took place over 6–8 weeks, and the lowest dose of BDP required for asthma control was maintained for at least 4 weeks. After this core treatment period, patients continued on their assigned double-blind treatment for 5 months (adults and adolescents for protocols 008 and 009) or were switched to active treatment in an open-label manner (paediatric study 010) for this extension phase. The core plus extension phases covered a 1-year treatment period. Patients returned for a single visit 12 weeks later to check for the presence of any anti-omalizumab titres.

The level of asthma control, as reflected in the incidence and frequency of exacerbations, and the level of BDP dose reduction that could be achieved without loss of asthma control were important variables in these studies. Thus, an exacerbation had to fulfil stringent criteria in order to be analysed as such. Patients were instructed to visit their investigator if they had any urgent or unscheduled medical contact for their asthma, if they had a peak expiratory flow (PEF) reading of ≥50% below their personal best, or if they experienced any of the following on two or more of three successive days: PEF of ≥20% of baseline value, nighttime awakenings requiring use of rescue β2-agonist, or over 50% increase in 24-h use of rescue β2-agonist. A further criterion was FEV1 being ≥20% below baseline at a clinic visit. An exacerbation was then defined by the investigator's judgement of the need for additional medication, and was treated as an exacerbation if patients required treatment with systemic corticosteroids or a doubling from baseline in BDP dose.

Additional measures of asthma control included symptom scores, lung function (FEV1, PEF), and requirement for rescue short-acting inhaled β2-agonist.

Efficacy results in pivotal phase III studies in allergic asthma and SAR

The results for incidence of asthma exacerbations and BDP requirement are shown in Table 2. A significantly lower incidence of exacerbations was observed in the actively treated patients in the two studies (008 and 009) in adults and adolescents in both of the core treatment phases. In the paediatric study (010), where the children's asthma was well controlled on entry to the study, the difference with regard to placebo became evident in the corticosteroid-reduction phase. In all studies, a significantly greater reduction in BDP dose was possible in the omalizumab-treated patients. In the two adult studies, approximately twice as many actively treated patients were able to withdraw completely from BDP treatment (40%vs 20%). In the paediatric study, 55% of children were able to discontinue BDP while on omalizumab compared with 39% of the placebo group.

Table 2.  Patients (%) with ≥1 exacerbation and BDP reduction achieved in phase III studies in allergic asthma (24–26)
 Adults and adolescents (protocol 008)Adults and adolescents (protocol 009)Children (protocol 010)
OmalizumabPlaceboOmalizumabPlaceboOmalizumabPlacebo
Number treated268257274272225109
Corticosteroid-stable phase (%) with ≥1 exacerbation14.623.312.830.515.622.9
 P=0.009P<0.001P=0.095
Corticosteroid-withdrawal phase (%) with ≥1 exacerbation21.332.315.729.818.238.5
 P=0.004P<0.001P<0.001
Median % reduction in BDP dose7550835010067
 P<0.001P<0.001P=0.001

Modest but statistically significant improvements were observed in asthma symptoms in the two studies in adults and adolescents. At the end of the corticosteroid-stable phase, the median total asthma symptom scores in the active and placebo groups, respectively, were 2.5 and 2.8 (P=0.005; study 008) and 2.5 and 3.1 (P=0.001, study 009). Statistically significant differences were also noted for the nocturnal asthma symptom score. Corresponding figures for the median daily number of puffs of rescue medication were 3.2 and 3.7 (P=0.029, study 008) and 2.0 and 3.7 (P<0.001, study 009). Similarly, for mean PEF, a significant advantage of 12–14 l/min over placebo was observed in the two studies. The results for FEV1 in study 009 were recently reported (44). Absolute values for FEV1 were significantly different between the omalizumab and placebo groups at all but one time point during the corticosteroid-stable phase, the period for which these secondary variables were prospectively analysed. Additional post hoc analysis showed that the significant difference was maintained at week 28, the end of the corticosteroid-reduction phase (44).

Among the children in paediatric study 010, who were asymptomatic and well controlled on entry to the study, no statistical differences were seen in these secondary variables during the corticosteroid-stable phase.

Quality of life (QoL)

Asthma-specific QoL was assessed in all three studies with the questionnaires developed by Juniper et al. for adults and children (45, 46), in which an increase from baseline score of 0.5 or greater is considered to be clinically significant (47). At the end of the corticosteroid-reduction phase, clinically and statistically significant improvements (vs placebo) were observed in all domains in the two studies in adults and adolescents (studies 008 and 009). In the active treatment groups, mean changes from baseline across both studies and all domains were approximately 1.0, and approximately 64% of these patients achieved improvements of ≥0.5 in the QoL scores (48). In the paediatric study 010, statistically significant improvements were observed in the activities, symptoms, and overall domains, but not the emotional domain, and 46% of the children achieved a ≥0.5 improvement in the overall QoL domain (49).

Responder analysis

As a possible guide to the future clinical use of anti-IgE, it was of interest to assess whether patients could be characterized by severity of disease on the basis of their response to treatment. Three definitions were used in the manner of a sensitivity analysis. Definition 1 for “mild”, “moderate”, and “severe” was that baseline per cent predicted FEV1 were >80%, >60 to ≤80%, and ≤60%, respectively. In definition 2, “moderate” and “severe” corresponded to FEV1 >65% and ≤65%. In definition 3, “moderate” was FEV1 >65% with a mean total symptom score of ≤4, while “severe” was FEV1≤65% and symptom score >4 (out of a possible total score of 9). For one of the important variables in the two adult studies, the reduction in BDP dose, omalizumab appeared to be effective across the range of asthma severities (Table 3) (50).

Table 3.  Median % BDP reduction according to disease severity (see text for definition of categories): pooled results of studies in adults and adolescents (50)
Disease severityOmalizumab (n=542)Placebo (n=529)
  1. P≤0.001 for between-group comparison in all categories.

Definition 1
Mild10067
Moderate8050
Severe6033
Definition 2
Moderate8360
Severe6733
Definition 3
Moderate8357
Severe6028

Phase III studies in seasonal allergic rhinitis (SAR)

  1. Top of page
  2. Role of IgE in allergic inflammation
  3. Mode of action
  4. Update on phase III clinical studies in patients with allergic asthma
  5. Phase III studies in seasonal allergic rhinitis (SAR)
  6. Safety
  7. Concluding remarks
  8. References

Omalizumab has been investigated in two double-blind, placebo-controlled studies in patients with SAR. The dosing of omalizumab in SAR differed slightly from that used in asthma. In SAR, a fixed dose of omalizumab (300 mg) was administered every 3 or 4 weeks, depending on whether the patient's baseline free IgE level was above or below 150 IU/ml. The first dose was given before the start of the pollen season. The standard dose of 300 mg was determined from a study conducted in the USA in 536 patients with ragweed-sensitive SAR (28, 29). It assessed three doses of omalizumab (50, 150, and 300 mg). Efficacy variables were the severity of nasal symptoms, ocular symptoms, use of rescue antihistamines, and rhinoconjunctivitis-specific QoL. The patients receiving the 300-mg dose fared better for all variables, and more patients in this group achieved serum free IgE concentrations of <25 ng/ml.

A second study was conducted at centres across Scandinavia in 251 patients with birch pollen-induced SAR (27). A dose of 300 mg or matching placebo was given two or three times during the season, as described above. Although the birch-pollen season was early during the year of the study and many patients did not commence treatment until the start of the season, omalizumab was highly effective in preventing the increased nasal and ocular symptoms associated with pollen exposure. The significant difference in these variables compared with placebo was achieved, while the intake of rescue tablets of antihistamine was significantly reduced.

The Juniper questionnaire was used to assess rhinoconjunctivitis-specific QoL (51). Omalizumab was significantly more effective than placebo across all the domains: activities, sleep, non-nose/eye symptoms, practical problems, emotional impact, and nose and eye symptoms. When asked for a global evaluation of treatment effectiveness, patients rated omalizumab significantly higher than placebo, with 60% of patients rating omalizumab as excellent or good (vs 23% of placebo patients). Investigators' opinions were similarly in favour of omalizumab (ratings of excellent/good in 60% of cases, compared with 19% for placebo) (27).

Safety

  1. Top of page
  2. Role of IgE in allergic inflammation
  3. Mode of action
  4. Update on phase III clinical studies in patients with allergic asthma
  5. Phase III studies in seasonal allergic rhinitis (SAR)
  6. Safety
  7. Concluding remarks
  8. References

The patients in these phase III studies in asthma and SAR provided the key safety data, covering 1331 patients (767 with asthma, 564 with SAR) treated with omalizumab and 860 (638 with asthma, 222 with SAR) who received placebo. The overall pattern of adverse events (AEs) was unremarkable and showed little discernible difference between active and placebo treatments. Serious AEs occurred at a low level of 2% in both active and placebo groups and appeared to follow a random pattern. Six patients (0.5%) withdrew from omalizumab treatment and nine (1%) from placebo treatment owing to an AE.

Certain events were addressed specifically as being relevant to the mode of action of omalizumab. Type I hypersensitivity reactions (e.g., anaphylaxis, anaphylactoid reactions, or angioedema/urticaria) occurred in 1.7% omalizumab patients and 2.7% placebo patients (23). Most of these cases were of urticaria: 1.4% (19) of the omalizumab group and 2.3% (18) of the placebo group. Only one anaphylactic reaction was reported after administration of levofloxacin in one patient who had a history of sensitivity to the antibiotic. There were no type II antibody-mediated hypersensitivity reactions such as might arise from circulating immune complexes, nor any laboratory abnormalities suggesting impaired organ function resulting from serum sickness. Parasitic infection occurred in one omalizumab patient (head lice) and in three placebo patients.

Reactions to the subcutaneous injection were reported in similar proportions of omalizumab and placebo patients, and most were reported for fewer than 1% of patients in either group. A local reaction (redness, itching, etc.) occurred in 21% and 17% of active and placebo patients, respectively, after the first dose, and was less common after the second dose (15% and 11%). In the entire clinical programme, encompassing earlier-phase studies, there were no positive antio-malizumab titres in patients receiving omalizumab administered intravenously or subcutaneously, including an extension of the US study in ragweed-sensitive SAR in which 287 patients were readministered omalizumab during the following pollen season (52). In a pilot study of aerosolized administration to the lungs mentioned previously (43), one patient developed serum IgG and IgA antibodies to omalizumab. The clinical safety database shows that omalizumab has an excellent safety profile and was well tolerated in the asthma and SAR patients studied.

Future investigations

Several large studies have recently been completed, and the results are being analysed at the time of writing. These include a study in 246 patients with severe asthma receiving treatment with high-dose inhaled fluticasone propionate and/or oral corticosteroids and/or long-acting β2-agonists. Patients in selected studies (e.g., the phase III paediatric study) will continue treatment for an additional follow-up period in order to amass further safety data. The phase IIIb programme of clinical studies will also assess the use of omalizumab in a setting that more closely resembles everyday clinical practice.

To broaden the experience with omalizumab in different allergic manifestations, a placebo-controlled study in 289 patients with perennial allergic rhinitis (PAR) has been conducted, and the results were recently reported by Chervinsky et al. (53). The primary efficacy variable, the average daily (24-h) nasal severity score, was significantly lower in omalizumab-treated patients during each 4-week period of the 16-week study (P<0.001). Again, as in the SAR studies, patients required less rescue antihistamine compared with the placebo group, and rhinoconjunctivitis-specific QoL scores were significantly higher. As a potential long-term therapy for PAR, omalizumab was administered in this study according to the dosing schedule used in allergic asthma studies, to provide at least 0.016 mg/kg per IU/ml of IgE per 4-week period.

Concluding remarks

  1. Top of page
  2. Role of IgE in allergic inflammation
  3. Mode of action
  4. Update on phase III clinical studies in patients with allergic asthma
  5. Phase III studies in seasonal allergic rhinitis (SAR)
  6. Safety
  7. Concluding remarks
  8. References

Until now, it has been difficult to prove the contribution of IgE to the development and clinical manifestation of allergic disease. Now, for the first time, we have a means of inhibiting IgE-mediated events in the clinical setting. The phase III clinical development programme for omalizumab in asthma included over 1400 children, adolescents, and adults with moderate or severe allergic asthma. The results demonstrate that IgE has an important role in allergic asthma and that clinical benefits can be achieved by blocking IgE-mediated pathways. Compared with placebo, patients on omalizumab were able to substantially reduce their requirement for inhaled corticosteroids, while at the same time experiencing improved asthma control in terms of fewer exacerbations. In the two studies in adults and adolescents, these benefits were observed in patients who were symptomatic at entry to the study. Asthma symptoms improved and patients used less rescue medication while receiving omalizumab. These results suggest that omalizumab should prove to be a valuable addition to current asthma treatments, and may be particularly useful in patients with poorly controlled asthma.

One of the important causes of poor asthma control is inadequate intake of medication due to the patient's lack of adherence to medical recommendations. Whether omalizumab will improve adherence to other asthma medications, such as inhaled corticosteroids, is unknown. Administering an effective medication at least once a month when patients visit their general practitioner may be regarded as a useful objective of anti-IgE treatment. In children particularly, anti-IgE treatment may prove useful as a means of decreasing the burden of inhaled corticosteroid treatment, although the threshold for what constitutes a “safe” dose of inhaled corticosteroid remains a subject for debate.

Allergic rhinitis is the most prevalent allergic disease. Although it is not life-threatening, allergic rhinitis has a high socioeconomic cost, and patients suffer a high burden of troublesome symptoms, general malaise, and reduced QoL. Omalizumab has been proven effective in treating patients with SAR, with significant reductions compared with placebo in both nasal and ocular symptoms, and a marked improvement in rhinoconjunctivitis-specific QoL. SAR and PAR are recognized as IgE-mediated diseases, and anti-IgE treatment clearly affects the clinical expression of the disease.

The use of a systemic anti-IgE agent may be especially useful in patients with concomitant allergic diseases, such as asthma and SAR. In the phase III clinical trials of omalizumab in allergic asthma, 90% of patients had a history of SAR. A monthly injection that improves control of allergic asthma while reducing the symptoms of allergic rhinitis may prove attractive to such comorbid patients. In addition, omalizumab should offer a universal approach to allergy treatment, since its mechanism of action is independent of the specific allergic sensitivity of the patient. Many patients with allergic disease are polysensitized, and effective allergen avoidance measures are hard to put into practice.

Among the populations of allergic asthma and SAR patients treated in clinical trials, the subcutaneous delivery of omalizumab was well tolerated, with a safety profile similar to that of placebo. The patient population was scrutinized for any adverse events that might be relevant to antibody treatment, and it is reassuring that there were no cases of immune complex disease (or similar syndromes), life-threatening immediate hypersensitivity reactions, or anti-omalizumab antibodies.

While it is probably too early to speculate on where omalizumab will fit into the treatment guidelines for the management of asthma and rhinitis, omalizumab treatment has been shown to confer clinical benefits that suggest that this agent will be an important step forward in managing allergic diseases.

References

  1. Top of page
  2. Role of IgE in allergic inflammation
  3. Mode of action
  4. Update on phase III clinical studies in patients with allergic asthma
  5. Phase III studies in seasonal allergic rhinitis (SAR)
  6. Safety
  7. Concluding remarks
  8. References
  • 1
    International Study of Asthma and Allergies in Childhood (ISAAC) Steering Committee. Worldwide variation in prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and atopic eczema: ISAAC. Lancet 1998;351:12251232.DOI: 10.1016/s0140-6736(97)07302-9
  • 2
    Beasley R, Crane J, Lai CKW, Pearce N. Prevalence and etiology of asthma. J Allergy Clin Immunol 2000;105:S466S472.
  • 3
    Sly RM. Changing prevalence of allergic rhinitis and asthma. Ann Allergy Asthma Immunol 1999;82:233252.
  • 4
    Van Cauwenberge P, Bachert C, Passalacqua G, et al. Consensus statement on the treatment of allergic rhinitis. Allergy 2000;55:116134.DOI: 10.1034/j.1398-9995.2000.00526.x
  • 5
    World Health Organization. Bronchial asthma. WHO Fact Sheet no. 206. Revised Jan 2000.
  • 6
    Pearce N, Pekkanen J, Beasley R. How much asthma is really attributable to atopy? Thorax 1999;55:268272.
  • 7
    Platts-Mills TAE, Vaughan JW, Carter MC, Woodfolk JA. The role of intervention in established allergy: avoidance of indoor allergens in the treatment of chronic allergic disease. J Allergy Clin Immunol 2000;106:787804.
  • 8
    Pawankar R, Okuda M, Yssel H, Okumura K, Ra C. Nasal mast cells in perennial allergic rhinitics exhibit increased expression of the Fc epsilonRI, CD40L, IL-4, and IL-13, and can induce IgE synthesis in B cells. J Clin Invest 1997;99:14921499.
  • 9
    Tunon-de-Lara JM, Redington AE, Bradding P, et al. Dendritic cells in normal and asthmatic airways: expression of the α subunit of the high affinity immunoglobulin E receptor (FcεRI-α). Clin Exp Allergy 1996;26:648655.
  • 10
    Katoh N, Kraft S, Wessendorf JH, Bieber T. The high-affinity IgE receptor (FcepsilonRI) blocks apoptosis in normal human monocytes. J Clin Invest 2000;105:183190.
  • 11
    Van Den Heuvel MM, Vanhee DD, Postmus PE, Hoefsmit EC, Beelen RH. Functional and phenotypic differences of monocyte-derived dendritic cells from allergic and nonallergic patients. J Allergy Clin Immunol 1998;101:9095.
  • 12
    Maurer D, Ebner C, Reininger B, et al. The high affinity IgE receptor (FcεRI) mediates IgE-dependent allergen presentation. J Immunol 1995;154:62856290.
  • 13
    Shibaki A. FcεRI on dendritic cells: a receptor which links IgE mediated allergic reaction and T cell mediated cellular response. J Dermatol Sci 1998;20:2938.DOI: 10.1016/s0923-1811(99)00003-1
  • 14
    Rajakulasingam K, Durham SR, O'Brien F, et al. Enhanced expression of high-affinity IgE receptor (FcεRI) α chain in human allergen-induced rhinitis with co-localization to mast cells, macrophages, eosinophils, and dendritic cells. J Allergy Clin Immunol 1997;100:7886.
  • 15
    Rajakulasingam K, Till S, Ying S, et al. Increased expression of high affinity IgE (FcεRI) receptor-α chain mRNA and protein-bearing eosinophils in human allergen-induced atopic asthma. Am J Respir Crit Care Med 1998;158:233240.
  • 16
    Dombrowicz D, Woerly G, Capron M. IgE receptors on human eosinophils. In: MaroneG, editors. Human eosinophils. Biological and clinical aspects. Chem Immunol 2000;76:6376.
  • 17
    Campbell AM, Vachier I, Chanez P, et al. Expression of the high-affinity receptor for IgE on bronchial epithelial cells of asthmatics. Am J Respir Cell Mol Biol 1998;19:9297.
  • 18
    Sihra BS, Kon OM, Grant JA, Kay AB. Expression of high-affinity IgE receptors (FcεRI) on peripheral blood basophils, monocytes, and eosinophils in atopic and nonatopic subjects: relationship to total serum IgE concentrations. J Allergy Clin Immunol 1997;99:699706.
  • 19
    Menz G, Ying S, Durham SR, et al. Molecular concepts of IgE-initiated inflammation in atopic and nonatopic asthma. Allergy 1998;53 Suppl 45:1521.
  • 20
    Humbert M, Grant JA, Taborda-Barata L, et al. High-affinity IgE receptor (FcεRI)-bearing cells in bronchial biopsies from atopic and nonatopic subjects. Am J Respir Crit Care Med 1996;153:19311937.
  • 21
    Beeh KM, Ksoll M, Buhl R. Elevation of total serum immunoglobulin E is associated with asthma in nonallergic individuals. Eur Respir J 2000;16:609614.
  • 22
    Bradding P & Holgate ST. Immunopathology and human mast cell cytokines. Crit Rev Oncol Hematol 1999;31:119133.DOI: 10.1016/s1040-8428(99)00010-4
  • 23
    Milgrom H, Fick RB, Su JQ, et al. Treatment of allergic asthma with monoclonal anti-IgE antibody. N Engl J Med 1999;341:19661973.
  • 24
    Busse W, Corren J, Lanier BQ, et al. rhuMAb-E25 (E25), a novel therapy for the treatment of allergic asthma [Abstract]. J Allergy Clin Immunol 2000;105(6, pt 1):5.
  • 25
    Solèr M, Matz J, Townley RG, et al. The anti-IgE antibody omalizumab reduces exacerbations and steroid requirement in allergic asthmatics. Eur Respir J 2001 (in press).
  • 26
    Milgrom H, Nayak A, Berger W, et al. The efficacy and safety of rhuMAb-E25 in children with allergic asthma [Abstract]. l 2000;105(6, pt 1):4.
  • 27
    Ädelroth E, Rak S, Haahtela T, et al. Recombinant humanized mAb-E25, an anti-IgE mAb, in birch pollen-induced seasonal allergic rhinitis. J Allergy Clin Immunol 2000;106:253259.
  • 28
    Casale T, Condemi J, Miller SD, et al. rhuMAb-E25 in the treatment of seasonal allergic rhinitis (SAR) [Abstract]. Ann Allergy Asthma Immunol 1999;82:75.
  • 29
    Casale TB, Racine A, Sallas W, et al. Relationship between the clinical efficacy of rhuMAb-E25 (E25) and serum free IgE in seasonal allergic rhinitis. J Allergy Clin Immunol 2000;105(1, pt 2):Abstract 1052.
  • 30
    Presta LG, Lahr SJ, Shields RL, et al. Humanization of an antibody directed against IgE. J Immunol 1993;151:26232632.
  • 31
    Presta L, Shields R, O'Connell L, et al. The binding site on human immunoglobulin E for its high affinity receptor. J Biol Chem 1994;269:2636826373.
  • 32
    Shields RL, Whether WR, Zioncheck K, et al. Inhibition of allergic reactions with antibodies to IgE. Int Arch Allergy Immunol 1995;107:308312.
  • 33
    MacGlashan DW, Bochner BS, Adelman DC, et al. Down-regulation of FcεRI expression on human basophils during in vivo treatment of atopic patients with anti-IgE antibody. J Immunol 1997;158:14381445.
  • 34
    Boulet L-P, Chapman KR, Côté J, et al. Inhibitory effects of an anti-IgE antibody E25 on allergen-induced early asthmatic response. Am J Respir Crit Care Med 1997;155:18351840.
  • 35
    Fahy JV, Fleming EH, Wong HH, et al. The effect of an anti-IgE monoclonal antibody on the early- and late-phase responses to allergen inhalation in asthmatic subjects. Am J Respir Crit Care Med 1997;155:18281834.
  • 36
    Babu KS & Arshad SH. IgE – a marker of the late asthmatic response? Clin Exp Allergy 2001;31:182185.
  • 37
    Fick RB, Rohane PW, Gupta N, et al. Anti-inflammatory effects of a recombinant monoclonal anti-IgE (E25) in asthma [Abstract]. Am J Respir Crit Care Med 2000;161:A199.
  • 38
    Busse WW, Fahy JV, Fick RB. A pilot study of the effects of an anti-IgE antibody (E25) on airway inflammation in moderate-severe asthma [Abstract]. Am J Respir Crit Care Med 1998;157:A456.
  • 39
    Garman SC, Wurzburg BA, Tarchevskaya SS, Kinet J-P, Jardetzky TS. Structure of the Fc fragment of human IgE bound to its high-affinity receptor FcεRIα. Nature 2000;406:259266.
  • 40
    Liu J, Lester P, Builder S, Shire SJ. Characterization of complex formation by humanized anti-IgE monoclonal antibody and monoclonal human IgE. Biochemistry 1995;34:1047410482.
  • 41
    Fox JA, Hotaling TE, Struble C, Ruppel J, Bates DJ, Schoenhoff MB. Tissue distribution and complex formation with IgE of an anti-IgE antibody after intravenous administration in cynomolgus monkeys. J Pharmacol Exp Ther 1996;279:10001008.
  • 42
    Casale TB, Bernstein IL, Busse WW, et al. Use of an anti-IgE humanized monoclonal antibody in ragweed-induced allergic rhinitis. J Allergy Clin Immunol 1997;100:110121.
  • 43
    Fahy JV, Cockcroft DW, Boulet L-P, et al. Effect of aerosolized anti-IgE (E25) on airway responses to inhaled allergen in asthmatic subjects. Am J Respir Crit Care Med 1999;160:10231027.
  • 44
    Matz J, Fox H, Thirlwell J. Omalizumab (Xolair®) increased FEV1 in asthma patients compared to placebo. J Allergy Clin Immunol 2001;107(2, pt 2):Abstract 1028.
  • 45
    Juniper EF, Guyatt GH, Ferrie PJ, et al. Measuring quality of life in asthma. Am Rev Respir Dis 1993;147:832838.
  • 46
    Juniper EF, Guyatt GH, Feeny DH, et al. Measuring quality of life in children with asthma. Qual Life Res 1996;5:3546.
  • 47
    Juniper EF, Guyatt GH, Willan A, Griffith LE. Determining a minimal important change in a disease-specific quality of life questionnaire. J Clin Epidemiol 1994;47:8187.
  • 48
    Buhl R, Kunkel G, Solèr M, et al. rhuMAb-E25 improves asthma-specific quality of life in patients with allergic asthma [Abstract]. Eur Respir J 2000;16 (Suppl 31):465s.
  • 49
    Nayak A, Milgrom H, Berger W, et al. rhuMAb-E25 (E25) improves quality of life (QoL) in children with allergic asthma [Abstract]. Am J Respir Crit Care Med 2000;161:A504.
  • 50
    Wolfe JD, Fox H, Thirlwell J. Omalizumab demonstrates inhaled corticosteroid (ICS) sparing in asthma across a range of disease severities. J Allergy Clin Immunol 2001;107(2, pt 2):Abstract 357.
  • 51
    Juniper EF & Guyatt GH. Development and testing of a new measure of health status for clinical trials in rhinoconjunctivitis. Clin Exp Allergy 1991;21:7783.
  • 52
    Casale T, Condemi J, Bernstein JA, et al. Safety of readministration of rhuMAb-E25 in seasonal allergic rhinitis (SAR). Ann Allergy Asthma Immunol 2000;Jan (abstract presented at ACAAI November 1999).
  • 53
    Chervinsky P, Busse W, Casale T, et al. Xolair® in the treatment of perennial allergic rhinitis. J Allergy Clin Immunol 2001;107(2, pt 2):Abstract 513.