Omalizumab is a humanized monoclonal antibody produced by recombinant DNA techniques. More specifically, it is an immunoglobulin G1 (IgG1) antibody which is able to bind the free circulating IgE (anti-IgE mAb) [
9‐
11]. (Table
1) This biological drug has a series of molecular effects that justify its effectiveness from a clinical point of view. In particular, omalizumab can reduce the level of circulating IgE by binding to the IgE constant Cε3 region, averting any interaction between free IgE and high, low affinity IgE receptors – respectively Fc epsilon RI receptor (FcεRI) and Fc epsilon RII receptor (FcεRII) on basophils, mast cells and other cells. This prevents any release of inflammatory agents, in association with a FcεRI down-regulation expression on basophils and mast cells [
12]. In addition, it has been shown that omalizumab can also reduce the in-vivo expression of FcεRI on dendritic cells, a factor that can lead to a reduction in the allergens presentation to T cells and, consequently, to a decrease in the T helper 2 (TH2)-mediated allergic pathway activity [
13]. Thanks to all these effects, omalizumab can down-regulate the production of mediators that are responsible for allergic inflammation by reducing the activation of mast cells and eosinophils [
14,
15]. This biological drug is administered subcutaneously, with a dosage and a frequency (every 2 or 4 weeks) set consistently with a nomogram whose fundamental parameters are the total serum IgE level (30–1500 kU/L) and the weight of the individual patient [
16]. This drug is usually administered in a hospital setting and patients must be monitored after the drug administration. However, some geographical differences among countries due to specific national policies exist, and omalizumab may also be administered by a caregiver, approved by a pediatric allergist or a pulmonologist, with an appropriate training.
Table 1
Treatments with biological drugs currently being approved for severe asthma with their target, age of registration, effects and relevant reference studies
omalizumab | anti-IgE mAb | ≥ 6 years (EMA) ≥ 6 years (FDA) | ↓ asthma exacerbations ↓ asthma hospitalizations ↑ asthma control ↓ oral corticosteroids ↑ quality of life | |
mepolizumab | anti-IL-5 mAb | ≥ 12 years (EMA) ≥ 6 years (FDA) | ↓ asthma exacerbations ↑ asthma control ↓ systemic corticosteroids ↑ pulmonary function | |
reslizumab | anti-IL-5 mAb | ≥ 18 years (EMA) ≥ 18 years (FDA) | ↓ asthma exacerbations ↑ asthma control ↑ pulmonary function ↑ quality of life | |
benralizumab | anti-IL-5Rα mAb | ≥ 18 years (EMA) ≥ 12 years (FDA) | ↓ asthma exacerbations ↑ asthma control ↓ oral corticosteroids | |
dupilumab | anti-IL-4Rα mAb | ≥ 12 years (EMA) ≥ 12 years (FDA) | ↓ asthma exacerbations ↑ pulmonary function | |
Omalizumab is registered by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) [
16,
17]. It is indicated as an add-on therapy for 6-year or older children with moderate to severe persistent asthma, in association with positive skin prick test or specific serum IgE to a perennial aeroallergen and asthma sign/symptoms that cannot be controlled with inhaled corticosteroids and a long-acting inhaled β2-agonist. It is also designed for children with documented severe asthma exacerbations, frequent daytime symptoms or night-time awakenings and, if aged 12 or above, reduced lung function (forced expiratory volume in the first second, FEV1, < 80%) [
16]. Many studies show the safety and efficacy of omalizumab [
16‐
24], which have been specifically demonstrated in pediatric patients through clinical trials or real-life experiences published in the literature [
19,
21,
22,
24]. Apart from the specific clinical indications for which it is prescribed, in the scientific literature there is much evidence showing that this biological drug has also proved effective in the treatment of seasonal asthmatic exacerbations during spring and autumn [
25,
26], in patients with total IgE values > 2000 kU/L [
27] and even in the treatment of intrinsic severe asthma [
28]. Besides, omalizumab has proved to be capable of reducing the anatomopathological alterations induced at a bronchial level by asthma in adults [
29]. It is important to underline that if patients do not clinically respond within 16 weeks from the start of therapy, e.g. showing improvement in terms of disease signs/symptoms or drugs use reduction, it is unlikely that a continuation of treatment with omalizumab will result in a positive response [
3]. Therefore, it is reasonable to re-evaluate them at this time interval to decide whether or not to continue with the omalizumab therapy. The main adverse effects of omalizumab on patients aged 12 years and above undergoing asthma treatments include headache and injection site reactions such as redness, swelling, pain and itching (observed in 1 to 10 patients out of 100). In patients aged 6–12, they are headache and fever, as observed in more than 1 out of 10 patients [
16,
17]. Furthermore, a recent systematic review has shown that omalizumab has a good safety profile and a good tolerability. In the analysis carried out by the authors, this biological drug showed no substantial differences, compared to placebo, in terms of adverse or serious adverse effects [
19]. Even if the vast majority of adverse reactions are represented by mild reactions manageable with a pharmacological treatment of the specific signs and symptoms, severe reactions such as a systemic one or anaphylaxis are sporadic. In these cases, a proper therapy should be given to the patient: intramuscular adrenaline is the most important drug in case of anaphylaxis, and the administration of omalizumab should be interrupted according to a benefit/risk balance principle. There is evidence that patients with a high risk of helminths infestations are slightly more exposed under omalizumab treatment. This could be explained considering the role that IgE plays in the immune response against parasites. The discontinuation of the drug administration should be taken into account in patients not responding to proper anti-helminth therapies [
16]. One of the main problems in omalizumab treatments – albeit common to all treatments with biological drugs – is represented by its direct as well as indirect costs related to the inevitable use of public and family health resources to carry out the periodic follow-up. Uncertainty about the optimal therapy duration is another issue. Some evidence in the literature seems to indicate a direct proportionality between the duration of the therapy and the increase in positive effects, also in the long term. This highlights the need to continue with the treatment for at least a year, in case of clinical response [
30,
31].