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The efficacy of omalizumab in treating severe asthma

They both had very poor response to preventive treatment, but tended to respond quite well to treatment of acute attacks. The severity and frequency of their asthma attacks were increasing with time, and there was great concern over their long-term prognosis. Fortunately, both had a very gratifying response to omalizumab.

Omalizumab (Xolair) is a novel monoclonal antibody that received FDA approval for treatment of asthma in 2003, in patients over 12 years old. It is indicated for patients with moderate-to-severe, persistent allergic asthma. It is also licensed for use in chronic idiopathic urticaria.

Omalizumab is not indicated for the treatment of other allergies. It is given as a subcutaneous injection and was initially licensed to be given every two weeks, but now a larger dose every four weeks is recommended. The large volume of injection can necessitate up to three injection sites, with a maximum of 150mg in each site (1.2ml). The lyophilised product takes up to 15-to-20 minutes to dissolve and is very viscous. The dosage varies from 150-to-375mg and is determined using a combination of weight and pre-treatment total IgE levels [Tables 1 and 2]. Patients should be given omalizumab for at least 12 weeks before efficacy is assessed.

Table 1: Subcutaneous Xolair doses every four weeks for patients 12 years of age and older with asthma

Individuals who can be considered for omalizumab usually have an elevated total IgE level, but it should be at least 30IU/ml, and they must have a positive skin test or in vitro reactivity to a perennial aeroallergen and be inadequately controlled with inhaled corticosteroids. Specific IgE testing should be done to confirm the diagnosis of allergic asthma and a total IgE level should be done to determine the appropriate dose of omalizumab [Tables 1 and 2].

Table 2: Subcutaneous Xolair doses every two weeks for patients 12 years of age and older with asthma

Omalizumab can be given with caution during pregnancy, but there are no adequate human studies of its use in pregnancy. Animal studies have shown no teratogenic effects. There is a pregnancy exposure registry for women taking omalizumab during pregnancy.

In asthma, omalizumab acts by inhibiting the binding of IgE to the high-affinity IgE receptor on the surface of mast cells and basophils. In CIU, omalizumab binds to IgE and reduces the free levels.

The monitoring of total IgE levels during treatment is not indicated, as total IgE levels actually increase during treatment and can be elevated for up to one year after withdrawal of omalizumab. The reason for this higher IgE level is due to the formation of omalizumab-IgE complexes, which have a slower elimination rate compared to free IgE levels. The average serum levels of total IgE can increase up to five-fold at 16 weeks compared to pre-treatment IgE levels. No other monitoring laboratory tests are indicated during treatment.

It is important to note that IgE levels during treatment cannot be used to determine omalizumab doses. However, if a patient is off omalizumab for a year or more, the total IgE levels can be used to determine dosage.

The majority of patients who will be starting omalizumab will most probably be on some long-term steroid therapy and it is important to gradually reduce the doses rather than reduce abruptly. Omalizumab does not treat acute exacerbation of asthma, thus it is of no benefit if given acutely in acute asthma attacks. There have been cases of Churg-Strauss syndrome being unmasked in patients who are taken off steroids.

The most frequent adverse events are injection site reaction, fever, muscle aches and rash, which may occur a few days later. Viral infections, upper respiratory tract infections, sinusitis, headache and pharyngitis, as well as parasite (worm) infestations, can also occur. Omalizumab is also associated with anaphylaxis. Anaphylaxis is more common after the first few doses (39 per cent of cases after one dose; 19 per cent after two doses; 10 per cent with the third dose) but can occur after more than a year of regular treatment. Patients should be observed for several hours after their injection and resuscitation facilities must be present.

Anaphylaxis may occur up to 24 hours after treatment and patients must be appropriately educated and supplied with an adrenaline pen. There may be a slightly increased risk of certain types of malignancies in omalizumab patients, but this study observed patients for only one year. Longer-term observational studies for up to five years showed no increased incidence of cancer.

There were four main phase III trials prior to FDA approval of omalizumab in 2003. All of these trials showed a decreased requirement for inhaled steroids with the addition of omalizumab to standard asthma therapy in patients with moderate-to-severe asthma. Three of these trials showed a significant reduction in the frequency of exacerbations per patient, as well as less patients having exacerbations compared to placebo. In the fourth trial, patients with more severe asthma who needed high doses of inhaled corticosteroids for symptom control were assessed. In this trial, no significant effect on exacerbation frequency was seen. However, the dose of inhaled corticosteroids needed to control symptoms was significantly lower among patients on omalizumab.

A more recent French study showed that discontinuation of omalizumab was not associated with any rebound effect or exacerbation of the disease in nearly half the patients in the study (total of 61 patients). The patient cohort had a mean treatment duration of 22 months. This study suggests it might be worth considering stopping treatment in patients who have had an excellent response to omalizumab after two or more years of treatment. Currently, the manufacturer also advises to reassess the need for continued therapy based on patients’ disease severity and asthma control.

While the role of omalizumab in the treatment of asthma is not precisely defined, it is a very important treatment option in patients with moderate-to-severe allergic asthma whose symptoms are inadequately controlled on standard treatment regimens. However, cost is a major obstacle for its wider use — annual treatment cost is approximately €30,000.

Omalizumab is not approved by the Irish National Pharmacoeconomics Unit and it is not refunded under the High-Tech Drugs Scheme. This means that the drug cost has to be borne by individual hospitals and it cannot be given in the community. Availability for individual patients is thus dependent on hospital drug budgets and many patients who would likely benefit from omalizumab are not currently getting it, with some hospitals not approving its use.

Strategies to reduce cost should always be considered, such as discontinuation of treatment after two or three years of use, and close review of patients on treatment to determine efficacy.

References on request

Case study 1

A 42-year-old African female, in Ireland for five years, is a sickle cell carrier and has had mild asthma since 2006. Her asthma and rhinitis/hay fever symptoms have worsened since 2012, with both the frequency and severity of the attacks increasing. Frequent nocturnal attacks became an increasing problem: these were of acute onset, with severe dyspnoea and wheeze and associated tachycardia.

She was first seen in the OPD in 2012. Treatment was maximised as per GINA guidelines: She was on inhaled formoterol/budesonide 400mcg, two-to-three puffs BD, with extra rescue doses, inhaled salbutamol, montelukast 10mg daily, theophylline 300mg BD. She also had a home nebuliser for emergencies, in which she used salbutamol/ipratropium bromide and she had back-up steroids, which were helpful. During 2013, the frequency of her acute attacks increased: She was commenced on maintenance 5mg prednisolone and provided with an adrenaline pen and a cylinder of oxygen for emergency use. The emergency services were called frequently to her home, but she refused hospitalisation as she is a single parent. She usually responded rapidly to intravenous treatment. By late 2013, she was using the adrenaline pen once-to-twice monthly. She was trialled on sublingual grass immunotherapy (Grazax) for her hay fever, without benefit. Investigations for other causes of her symptoms were negative, including echocardiogram and CT scan of her thorax. Her IgE was mildly elevated at 139IU/ml (NR up to 100) and RAST test was strongly positive for grass pollens. She was initiated on omalizumab (Xolair) 300mg every four weeks in May 2014. Within one month she noted benefit and by November 2014, she had no acute attacks for two months and she was off maintenance steroids. She has remained well since then and her montelukast has been discontinued.

Case study 2

A 47-year-old Caucasian female with a family history of asthma had no asthma symptoms until 2009, when she developed acute episodes of exercise-induced bronchospasm, always of very sudden onset. She had two overnight admissions to hospital in 2010, with very low peak flow, which responded rapidly to nebuliser treatment and IV hydrocortisone. Peak flow was >500 within hours. She was on Seretide 250 Evohaler, salbutamol inhaler PRN and later montelukast was added, however she still had acute asthma attacks. She was admitted in 2012 with acute onset of severe bronchospasm while dancing. She was brought straight to her GP’s surgery nearby, but sustained a respiratory arrest and was resuscitated. She was given adrenaline, IV hydrocortisone and oxygen and nebuliser treatment. Her peak flow was back to 500 on arrival in the emergency department. She had a normal CXR and CT scan of her thorax. She was discharged after two days on the above treatment and obtained a home nebuliser and was advised to carry an adrenaline pen at all times, especially while exercising, and was given back-up steroids and anti-histamines.

She developed another acute episode while hill-walking and had to take her adrenaline injection. She had no history of hay fever or eczema. She was very fit and active and very well between the acute attacks, with normal pulmonary function.

Her IgE level was raised at 369IU/ml and her RAST test showed a positive reaction to grass pollens and moderate reaction to house dust mites. Aspergillus serology was negative and her eosinophil count was normal. She had an admission in 2013 with lip and tongue swelling, with no obvious cause. She developed episodes of cough, wheeze, dyspnoea with large mucous plugs and had to take her adrenaline on several occasions. She commenced omalizumab 600mgs every four weeks in autumn 2013. She has had no asthma attacks since she went on the omalizumab and has no side-effects from it.

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