An Update on Biologic-based Therapy in Asthma

Garry M Walsh


Immunotherapy. 2013;5(11):1255-1264. 

In This Article

IgE Inhibitors

IgE is central to the pathogenesis of diseases associated with immediate hypersensitivity reactions, such as allergic asthma. IgE binds to high-affinity (FcεRI) receptors on mast cells and basophils, and to low-affinity (FcεRII) receptors on macrophages, dendritic cells and B lymphocytes. Allergens crosslink adjacent cell surface Fab components of IgE thereby activating intracellular signal transduction. This results in mast cell release of preformed mediators and synthesis and release of other mediators that contribute to bronchoconstriction and airway inflammation.

The anti-IgE biologic omalizumab (Xolair®, Genentech/Novartis), is a US FDA/EMEA-approved humanized monoclonal antibody (mAb) to the FcεRI (Cε3)-binding domain of human IgE. Early studies demonstrated inhibition of early- and late-phase allergen-induced asthmatic reactions with serum-free IgE concentrations reduced to less than 5% of baseline;[7] omalizumab may also be able to suppress new IgE production. Furthermore, through inhibition of binding of IgE to FcεRI expressed on dendritic cells, omalizumab can reduce the efficiency of antigen presentation to T lymphocytes.[8]

In clinical studies, positive outcomes were reported in a large Phase II trial that studied fortnightly intravenous (iv.) administration of omalizumab for 20 weeks in 317 patients[9] and also in two Phase III trials, including over 500 patients each, which studied subcutaneous (sc.) omalizumab every 2–4 weeks for 12 months.[10,11] In patients with moderate-to-severe allergic asthma whose symptoms were poorly controlled by high doses of inhaled GCs, 12-month administration of omalizumab resulted in a 50% reduction in their asthma deterioration-related incidents.[12] Another study reported that omalizumab treatment of subjects with both persistent rhinitis and difficult-to-treat asthma resulted in significantly reduced asthma exacerbations and improvement in the Asthma Quality of Life Questionnaire score over the 28-week study period.[13] Omalizumab has also been shown to be beneficial as an add-on therapy in severe persistent asthmatics with inadequately controlled symptoms despite best available treatment, thus reducing the occurrence of disease exacerbations, emergency hospital visits and hospitalizations.[14] A pooled analysis of six controlled clinical trials that evaluated the effect of add-on omalizumab in patients with severe persistent allergic asthma reported significant improvements in quality-of-life indices.[15] These findings support the use of omalizumab as an efficacious therapy for patients with symptomatic moderate-to-severe allergic asthma despite treatment with GCs and rescue medication. Omalizumab reduces the frequency of exacerbations and GC and β2-agonist usage, and improves symptom control, with improved patient quality of life and significant improvements in lung function as measured by peak expiratory flow rate and forced expiratory volume in 1 s (FEV1). Omalizumab has a good risk–benefit profile with few side effects reported in these studies and no reports of circulating antibodies against omalizumab. However, the FDA has a black-box warning on the potential for omalizumab-induced anaphylaxis presenting as bronchospasm, hypotension, syncope, urticaria and/or angioedema of the throat or tongue. The Omalizumab Joint Task Force reported that, out of 39,510 patients receiving omalizumab, 25 had 41 episodes of anaphylaxis. The task force recommends that physicians prescribing omalizumab instigate postadministration wait periods combined with education of patients with regard to an anaphylaxis.[16,17] An analysis of omalizumab-treated patients that examined the incidence of malignancy using comprehensive pooled data from clinical trials concluded that a causal relationship between omalizumab and malignancy was unlikely.[18]