**3. Biological and other highly specialized therapies for uncontrolled asthma: Phenotype-oriented present and future options**

In the last decade, significant efforts have been made to identify the characteristics of severe asthma, which are different from those described in the mild-to-moderate asthma, setting the stage for the development of new personalized therapies [7, 30]. The most promising options are represented by biological therapies, including mAbs against selective targets [10]. Later, we summarize the evidence of the only mAb that is available today to treat patients with severe asthma (omalizumab) and review those biological treatments that are currently in clinical trials, but in a more advanced stage of development and will be available for the clinical practice in the upcoming years.

#### **3.1 Allergic asthma**

#### *3.1.1 Omalizumab: state of the art on long-term efficacy and safety in real life studies.*

Omalizumab is currently approved as an additional treatment in patients older than 6 years with severe allergic asthma [31]. The antibody is an IgG1 kappa that binds to IgE and prevents it binding to FCεRI and FCεRII (IgE receptors of, respectively, high and low affinity), expressed on mast cells, basophils, and dendritic cells [32]. Several post-marketing studies have been conducted in European countries [33–37] to assess the effectiveness of omalizumab: despite obvious differences between countries, all studies confirmed the usefulness and safety of omalizumab in real-life conditions. The discontinuation rate was variable, but the lack of efficacy was less than 20%, whereas in clinical trials, it was 30–40%. A probable explanation is that the "real" patients are more serious and less selected than those included in clinical trials. In Spain, a multicenter study was conducted within the routine clinical practice, in Pulmo‐ nology and Allergology departments, to evaluate the efficacy and tolerability of omalizumab [38]. With the participation of 30 centers nationwide, 266 patients who had received at least one dose of omalizumab, with 2 years of follow-up at least, were analyzed. The global evaluation of therapeutic efficacy (GETE) was good or excellent in most treated patients: 74.6% at 4 months, reaching 81.6% of the patients after 2 years, with statistically significant differences from baseline. Significant improvements in asthma control test (ACT), lung function, and exacerbation frequency were also demonstrated. In terms of medication, the doses of ICSs were significantly decreased, and the maintenance treatment with oral corticosteroids was sus‐ pended in many patients [38].

#### *3.1.2. Current evidence on omalizumab efficacy in off-label uses: Non-allergic asthma, nasal polyps, and allergic broncopulmonary aspergillosis*

The interaction between IgE and omalizumab prevents a fundamental step in the inflammatory cascade. The rapid decrease in the free circulating IgE leads to a progressive and significant decrease in the expression of IgE receptors on the inflammatory cells, so it is important to take into consideration certain entities in which IgE may also play a part even if the allergic etiology is not well established, such as nasal polyposis (NP) or non-allergic asthma.

While the inflammation in allergic or "extrinsic" asthma is clearly caused by outdoor allergens (such as dust mites and animal dander), in the intrinsic disease, there is no identifiable allergen, at least not by currently available methods. In this case, an unidentified exogenous antigen (without systemic sensitization), an infectious agent, or an endogenous "allergen" might be responsible for triggering the mechanism of atopy or in this case "entopy" [39]. The finding of specific IgEs against *Staphylococcus aureus* enterotoxins in patients with severe asthma, intolerance to NSAIDs and NP allowed to speculate that they were susceptible of having their airways colonized by *S. aureus*, which through the release of superantigens could trigger an inflammatory response with formation of local IgE [40]. NP may be present in asthma with or without concomitant atopy, but it is particularly associated with non-allergic aspirin-sensitive asthma and is one of the most common comorbid conditions in patients with severe asthma. NP is not a life-threatening condition, but the patients see their quality of life severely compromised and must undergo prolonged treatments with topical and systemic corticoste‐ roids and multiple sinus surgeries in most cases. Over time, the lack of effective alternative treatments and the need to respond to these IgE-mediated diseases led professionals to use omalizumab off-label, with very promising results, as discussed later.

In 2010, a multicenter study performed in Spain described the evolution of nasal polyps in 19 patients with NP and severe asthma treated with omalizumab [41]. The average treatment time was 16 (15–28) months. Thirteen patients (68%) had undergone at least one endoscopic surgery. The size of the polyps (assessed by calculating a score of 0–8 points by means of nasal endos‐ copy and confirmed by CT scan) diminished significantly in both nasal cavities after the treatment. Later, Bachart et al assessed the usefulness of anti-IgE in severe or recurrent NP associated with asthma, in a prospective double-blind placebo-controlled study (24 patients) [42]. There was a significant improvement at 16 weeks of treatment in clinical terms: nasal congestion, rhinorrhea, and loss of smell. An overall reduction in polyp size (primary endpoint, assessed using the same above-mentioned score) when compared to baseline was observed [41].

As to non-allergic asthma, in Spain it was first demonstrated, in a retrospective observational study [43], the efficacy of omalizumab in 29 patients with "non-atopic" asthma. GETE, ACT, the number of exacerbations and lung function improved significantly after treatment with omalizumab. There was no statistically significant difference in the response of the non-atopic asthmatics when compared with 266 patients with positive prick tests to usual inhalants. These results were subsequently confirmed in a prospective double-blind placebo-controlled trial [44].

Total IgE levels are a marker of immune activity in another severe lung disease, often without any effective therapeutic alternative to systemic corticosteroids: allergic bronchopulmonary aspergillosis (ABPA). The anti-IgE treatment was also evaluated in this pathology (also offlabel). In 2011, a multicenter research conducted in Spain included 18 patients with ABPA from 11 hospitals [45]. Patients were followed for a median of 36 (28–42) weeks. In this series, the largest published so far, omalizumab was beneficial in reducing daytime symptoms (44%) and nighttime awakenings (22%), significantly reduced exacerbations and improved FEV1 (*p* = 0.03), allowing a reduction or even discontinuance of systemic corticosteroids.

### *3.1.3. New anti-IgE agents: ligelizumab and quilizumab*

The inverse correlation between free IgE levels and asthma control, found in several studies [46], suggests that a more profound suppression of free IgE could lead to an even more marked clinical improvement, so new, more potent anti-IgE mAbs are currently being assessed in clinical trials.

#### *3.1.3.1. Ligelizumab*

that the "real" patients are more serious and less selected than those included in clinical trials. In Spain, a multicenter study was conducted within the routine clinical practice, in Pulmo‐ nology and Allergology departments, to evaluate the efficacy and tolerability of omalizumab [38]. With the participation of 30 centers nationwide, 266 patients who had received at least one dose of omalizumab, with 2 years of follow-up at least, were analyzed. The global evaluation of therapeutic efficacy (GETE) was good or excellent in most treated patients: 74.6% at 4 months, reaching 81.6% of the patients after 2 years, with statistically significant differences from baseline. Significant improvements in asthma control test (ACT), lung function, and exacerbation frequency were also demonstrated. In terms of medication, the doses of ICSs were significantly decreased, and the maintenance treatment with oral corticosteroids was sus‐

*3.1.2. Current evidence on omalizumab efficacy in off-label uses: Non-allergic asthma, nasal polyps, and*

The interaction between IgE and omalizumab prevents a fundamental step in the inflammatory cascade. The rapid decrease in the free circulating IgE leads to a progressive and significant decrease in the expression of IgE receptors on the inflammatory cells, so it is important to take into consideration certain entities in which IgE may also play a part even if the allergic etiology

While the inflammation in allergic or "extrinsic" asthma is clearly caused by outdoor allergens (such as dust mites and animal dander), in the intrinsic disease, there is no identifiable allergen, at least not by currently available methods. In this case, an unidentified exogenous antigen (without systemic sensitization), an infectious agent, or an endogenous "allergen" might be responsible for triggering the mechanism of atopy or in this case "entopy" [39]. The finding of specific IgEs against *Staphylococcus aureus* enterotoxins in patients with severe asthma, intolerance to NSAIDs and NP allowed to speculate that they were susceptible of having their airways colonized by *S. aureus*, which through the release of superantigens could trigger an inflammatory response with formation of local IgE [40]. NP may be present in asthma with or without concomitant atopy, but it is particularly associated with non-allergic aspirin-sensitive asthma and is one of the most common comorbid conditions in patients with severe asthma. NP is not a life-threatening condition, but the patients see their quality of life severely compromised and must undergo prolonged treatments with topical and systemic corticoste‐ roids and multiple sinus surgeries in most cases. Over time, the lack of effective alternative treatments and the need to respond to these IgE-mediated diseases led professionals to use

In 2010, a multicenter study performed in Spain described the evolution of nasal polyps in 19 patients with NP and severe asthma treated with omalizumab [41]. The average treatment time was 16 (15–28) months. Thirteen patients (68%) had undergone at least one endoscopic surgery. The size of the polyps (assessed by calculating a score of 0–8 points by means of nasal endos‐ copy and confirmed by CT scan) diminished significantly in both nasal cavities after the treatment. Later, Bachart et al assessed the usefulness of anti-IgE in severe or recurrent NP associated with asthma, in a prospective double-blind placebo-controlled study (24 patients)

is not well established, such as nasal polyposis (NP) or non-allergic asthma.

omalizumab off-label, with very promising results, as discussed later.

pended in many patients [38].

*allergic broncopulmonary aspergillosis*

122 Asthma - From Childhood Asthma to ACOS Phenotypes

QGE031B (ligelizumab) is a new anti-IgE mAb (Novartis). It is a humanized IgG1 that binds with higher affinity to the Ce3 region of IgE. QGE031 is designed for greater suppression of IgE, with a dissociation constant (Kd) of 139 pM, representing an increase in almost 50 times of the affinity for IgE when compared with omalizumab (Kd = 6–8 nM). This is hypothesized to overcome some of the limitations associated with the dosage of omalizumab and lead to better clinical outcomes in asthma.

Up to date, December 2015, we have only data from preclinical experiments, and the results of two phase I, randomized, double-blind placebo-controlled studies investigating the pharmacokinetics, pharmacodynamics, and safety of ligelizumab in atopic but otherwise healthy subjects [47]. Ligelizumab was superior to omalizumab in the suppression of free IgE and FceRI expression on surface of basophils. These effects resulted in the almost complete suppression of skin response to allergens, which was higher in extent and duration when compared with omalizumab. In the 156 patients who completed the study, no serious adverse effects were reported, and only one patient developed urticaria accompanied by systemic symptoms. QGE031B's effectiveness is currently being evaluated in patients with allergic asthma (GINA step 4/5) in a phase IIa clinical trial, with omalizumab as an active comparator.
