Omalizumab in the management of asthma

Asthma is one of the most common chronic conditions worldwide, affecting approximately 300 million people of all ages, and which is estimated to account for approximately one of every 250 deaths.(1) GINA (Global Initiative for Asthma)(2) defines asthma as a chronic inflammatory disorder of the airways in which many cells and cellular elements play a role. The chronic inflammation causes an associated increase in airway hyper-responsiveness that leads to recurrent episodes of wheezing, breathlessness, chest tightness and coughing, particularly at night or in the early morning. These episodes are usually associated with widespread, but variable, airflow obstruction that is often reversible, either spontaneously or with treatment.

The majority of people with asthma have mild disease that is readily controlled on low-to-moderate doses of inhaled corticosteroids (ICS), together with a combination of short- and long-acting beta 2 agonists (SABA/LABA).  However, between 5% and 10% have disease that is more difficult to control, experiencing persistent symptoms and frequent exacerbations.(3) Morbidity and health costs are disproportionately high in these patients and they are at greater risk of fatal and near-fatal exacerbations.(4)

In addition, the regular prescribing of both oral and high-dose inhaled corticosteroids to control the asthma increases the risk of corticosteroid-related adverse effects. In some cases, it is likely that the asthma severity may be a result of other factors than asthma itself, such as poor adherence to therapy, incorrect inhaler technique, environmental factors, psychological problems and untreated or undertreated co-existing conditions.(4,5) In contrast, other people with ‘severe refractory asthma’ have disease that remains uncontrolled, despite attention to, and resolution of, all these factors, and additional or new therapies are required.(6) It is estimated that in this severe asthma group >50% have an allergic component resulting in over-production of human immunoglobulin E (IgE) in response to environmental allergens, for example, pollen, house dust mites.(7) Omalizumab is a recombinant humanised monoclonal antibody that binds selectively to IgE. As a result, the release of inflammatory mediators is prevented, and the subsequent allergic reaction and inflammation avoided. In patients with allergic asthma and an elevated IgE level, the administration of omalizumab can result in decreased airway inflammation and improved asthma control and may allow tapering of corticosteroid medications.

IgE is central to the pathophysiology of allergic asthma. There is an exaggerated IgE response to common environmental allergens in allergic asthma; this is referred to as atopy.(8) In people with asthma who are sensitive to a particular allergen, exposure to the allergen causes an early-phase and late-phase allergic response. The early-phase response occurs within minutes of allergen exposure, with the allergen binding to circulating IgE, attaching to IgE receptors on the mast cells and thereby stimulating the rapid release of inflammatory molecules such as histamine, prostaglandin, leukotrienes and cytokines.

These inflammatory molecules can worsen the symptoms of asthma by stimulating contraction of airway smooth muscle and increasing mucus production. This leads to the classic symptoms of asthma; wheezing, coughing, chest tightness and shortness of breath. Release of cytokines from mast cells and other inflammatory cells attracts eosinophils to the site of inflammation, which release a variety of other inflammatory molecules that can damage tissues and cause the late-phase asthma response, such as bronchoconstriction.

Omalizumab is an anti-IgE monoclonal antibody, which binds to the FcεRI binding site on all free circulating IgE, regardless of allergen specificity, and which forms small complexes. As a result, circulating free IgE is reduced and IgE is prevented from attaching to mast cells and basophils. The inflammatory response to allergens and the early and chronic late phases of allergic inflammation are thereby prevented before they can commence. As IgE upregulates IgE receptors on mast cells, the reduced free IgE in the circulation leads to a decrease in the number of IgE receptors on the surface of the mast cells.(9) Both these effects are reversible on discontinuation of the drug.

Two systemic reviews(10,11) and numerous randomised controlled trials (RCTs) have examined the efficacy of omalizumab for the treatment of allergic asthma in adults and children who are not responsive to other therapies. All studies evaluated the effect of omalizumab on asthma exacerbations, among other endpoints. The definition of an asthma exacerbation varied between studies. Further details on the key clinical studies are given in Table 1.

The pivotal study supporting the licensed indication of omalizumab is the INNOVATE trial.(16) This multicentre, double-blind RCT included 419 patients with severe persistent asthma receiving ICS plus LABA and additional controller medication if necessary. After adjustment for an observed imbalance in baseline exacerbations, the mean exacerbation rate during the 28-week treatment period was 0.68 with omalizumab and 0.91 with placebo (p=0.042, rate ratio 0.738; 95% CI: 0.552–0.998). Without adjustment, a similar effect was seen but this did not reach statistical significance.

The number needed to treat (NNT) for one year to prevent one clinically significant exacerbation was 2.2. Among the secondary outcomes, severe exacerbation rate (PEF or FEV1 <60% of personal best requiring treatment with systemic corticosteroids) was halved in the omalizumab group compared with placebo. The total number of emergency visits was significantly reduced in the omalizumab group versus placebo (omalizumab n=50 versus placebo n=93; rate ratio 0.561; 95% CI: 0.325–0.928; p=0.038). There were 13 hospital admissions in omalizumab-treated patients compared with 25 admissions in the placebo group. Using the Juniper Asthma Quality of Life (QoL) questionnaire,(17) a greater percentage of patients receiving omalizumab achieved ≥0.5-point improvement from baseline compared with patients receiving placebo, which is considered clinically meaningful (60.8% versus 47.8%, respectively; p=0.008).

Pooled data from seven studies including the INNOVATE study (omalizumab n=2511 and placebo n=1797) showed a significantly lower annual rate of exacerbations in omalizumab treated patients than in control patients (0.910 versus 1.474, respectively; p<0.0001).(18) Omalizumab also significantly reduced total emergency visits compared with placebo (p<0.0001). Omalizumab reduced hospital admissions by 52%, emergency room visits by 61% and unscheduled doctor visits by 47% (no absolute figures given).

A 2006 Cochrane review of 14 randomised controlled trials in 3143 children and adults with mild-to-severe allergic asthma found that treatment with omalizumab reduced asthma exacerbations (OR 0.52; 95% CI 0.41–0.65) and increased the proportion of patients who were able to reduce or withdraw inhaled corticosteroids.(10) A 2011 systematic review included eight randomised controlled trials in 3429 children and adults with moderate-to-severe asthma showed that patients taking omalizumab were more likely to be able to withdraw from corticosteroids completely, compared with those taking placebo (relative risk (RR=1.80; 95% CI 1.42–2.28; p<0.0001). Omalizumab patients showed a decreased risk of asthma exacerbations (RR=0.57; 95% CI, 0.48–0.66; p=0.0001). A post-hoc analysis suggested that this effect was independent of duration of treatment, age, severity of asthma, and risk of bias.(11)

The most common adverse reactions in patients receiving omalizumab were injection site reactions (for example, pain, swelling, erythema and pruritus) and headache.(19) Most of the reactions were mild or moderate in severity. More serious adverse events included malignancies and anaphylaxis. A variety of malignancies were observed in 0.5% of patients treated with omalizumab compared with 0.18% of control patients.(20) The overall incidence rate of malignancy for omalizumab patients was comparable to that in the general population. Type I local or systemic allergic reactions, including anaphylaxis and anaphylactic shock, can occur with omalizumab.(19,20)

Most of these reactions occurred within two hours of the first and subsequent injections of omalizumab, but some started beyond two hours, and even beyond 24 hours, of the injection.(20) Therefore medicinal products for the treatment of anaphylactic reactions should always be available for immediate use following administration of omalizumab.(21) Patients should be informed that such reactions are possible and prompt medical attention should be sought if allergic reactions occur. Anaphylactic reactions were rare in clinical trials (<1/1000).(21) Preliminary data from a five-year safety study have raised concerns about increased cardiovascular events and a final report is awaited. Prescribers should be vigilant for possible thrombotic adverse reactions.(22)

After being introduced in Australia in 2002 and the US in 2003, the prescribing of omalizumab was approved in 2005 by the European Medicines Agency (EMA) as add-on therapy to improve asthma control in adult and adolescent patients (12 years of age and above) with severe persistent allergic asthma. Patients should have the following characteristics: a positive skin prick test or serum IgE (levels should be in the range of 30–1500IU/ml in adults and children >12 years and <1300IU/ml for children over six years) to a perannial aeroallergen, an impaired lung function (FEV1 <80% predicted) and experience frequent daytime symptoms and/or nocturnal awakenings, associated with multiple severe exacerbations despite daily high doses of ICS and LABAs. More recently, the use of omalizumab has also been approved by the EMA for children six years old and above.(23) Patients with IgE lower than 76IU/ml are less likely to experience benefit.

Prescribing physicians should ensure that adult and adolescent patients with IgE below 76IU/ml and children (six to <12 years of age) with IgE below 200IU/ml have unequivocal in vitro reactivity to a perennial allergen before starting therapy.(22)

The dose of omalizumab and dose frequency is based on the serum total IgE level (IU/ml), measured before the start of treatment, and the person’s body weight (kg). Based on this calculation, omalizumab is given at a dose of 75–600mg by subcutaneous injection every two-to-four weeks. The maximum recommended dose is 600mg omalizumab every two weeks.(22) It remains uncertain when treatment can be discontinued or whether prolonged treatment is required.

Studies generally have shown that discontinuation of omalizumab treatment results in a return to elevated free IgE levels and associated symptoms.(24,25) Total IgE levels are elevated during treatment and remain elevated for up to one year after the discontinuation of treatment. Therefore, re-testing of IgE levels during omalizumab treatment cannot be used as a guide for dose determination. Doses should be adjusted for significant changes in body weight.(22)

Omalizumab therapy was included in 2006 within step 5 of the GINA guideline as add-on treatment to inhaled and, eventually, oral corticosteroids, LABAs and other controller medications, such as leukotriene modifiers and theophylline.(2) The British guideline on the management of asthma has similar recommendations on the management of chronic asthma.(4)

Clinical trials have demonstrated that it takes at least 12–16 weeks for omalizumab treatment to show effectiveness.(26) At 16 weeks after commencing omalizumab therapy, patients should be assessed by their physician for treatment effectiveness before further injections are administered. The decision to continue omalizumab following the 16-week timepoint, or on subsequent occasions, should be based on whether a marked improvement in overall asthma control is seen. The physician’s overall assessment of response should encompass multiple aspects, including patient interviews, review of medical notes, spirometry, diary of symptoms, rescue medication use and peak expiratory flow recordings.(27)

Analyses of pre-treatment demographic and clinical data from studies of omalizumab have shown that it is difficult to predict which patients derive the greatest benefit from treatment.

Identifying responders in clinical practice and selecting only those who appear to respond for ongoing treatment is critical to ensure the treatment is cost-effective. A number of studies have investigated the cost effectiveness of omalizumab for the treatment of allergic asthma in adults and children who are not responsive to other therapies. A cost effectiveness analysis(28) applied data from the INNOVATE study to Sweden as a reference country and calculated an incremental cost effectiveness ration of €56,091 (slightly higher that the Swedish accepted threshold of €53,384). Another analysis from Canada indicated the cost effectiveness of omalizumab. This ‘real-life’ one-year randomised open-label study using costs in Canada suggested that adding omalizumab to usual care improves quality-adjusted survival (QALYs), but at an increase in direct medical costs.(29)

Owing to the high cost of treatment, individual countries have issued specific criteria for use of omalizumab to maximise benefit in selected populations. For example, the National Institute for Health and Clinical Excellence (NICE) provides guidance for prescribing in England and Wales and recommends that omalizumab should only be used in people over 12 years of age who give a history of two or more severe exacerbations of asthma requiring admission to hospital within the previous year, or three or more severe exacerbations within the previous year, including at least one of which required hospital admission and two emergency visits.(30) NICE does not recommend omalizumab for the treatment of severe persistent allergic asthma in children aged 6–11 years. Updated guidance on prescribing omalizumab from NICE is due to be published during 2013. In Scotland, the Scottish Medicines Consortium (SMC)(31) restricts the use of omalizumab to people with chronic oral corticosteroid-dependent severe allergic asthma.

Omalizumab is a monoclonal antibody that is approved in the US and Europe for the management of people with moderate-to-severe asthma. The clinical effectiveness of omalizumab has been well documented in an extensive programme of clinical trials, showing that it reduces asthma exacerbations, severe asthma exacerbations, inhaled corticosteroid requirements, and emergency visits, as well as significantly improving asthma-related quality of life, morning PEF and asthma symptom scores in patients with severe allergic (IgE-mediated) asthma. Results from clinical trials have also been replicated in routine clinical practice, where considerable reduction in the need for maintenance oral corticosteroid following omalizumab has been reported. Ongoing studies continue to evaluate the treatment benefits of omalizumab and to guide therapy.

• Omalizumab is a recombinant humanised monoclonal antibody. It decreases allergic inflammatory cascade by binding to circulating free immunoglobulin E (IgE).
• International guidelines recommend omalizumab for the treatment of adults and children over 12 years of age with moderate-to-severe persistent allergic asthma, whose symptoms are not controlled with inhaled corticosteroids plus long-acting beta-2 agonists.
• There is evidence from clinical studies of the effectiveness of omalizumab in reducing exacerbations and hospital visits and improving patients’ quality of life.
• As it is not possible to predict reliably which patients will respond to omalizumab, eligible people should be monitored at 16 weeks to ensure a clinical response to the therapy. Omalizumab should only be continued in people judged to have achieved a marked improvement in asthma control.
• The main adverse effect of omalizumab is anaphylaxis, although this occurs infrequently.