Molecular Targets for Biological Therapies of Severe Asthma: Focus on Benralizumab and Tezepelumab

Asthma is a heterogeneous respiratory disease characterized by usually reversible bronchial obstruction, which is clinically expressed by different phenotypes driven by complex pathobiological mechanisms (endotypes). In recent years several molecular effectors and signaling pathways have emerged as suitable targets for biological therapies of severe asthma, refractory to standard treatments. Indeed, various therapeutic mono-clonal antibodies currently allow one to intercept at different levels the chain of pathogenic events leading to type 2 (T2) airway inflammation. Pro-allergic immunoglobulin E (IgE) is the first molecule against which an anti-asthma monoclonal antibody (omalizumab) was developed; today other targets are successfully being exploited by biological treatments for severe asthma. In particular, pro-eosinophilic interleukin 5 (IL-5) can be targeted by mepolizumab or reslizumab, whereas benralizumab is a selective blocker of IL-5 receptor, and IL-4 and IL-13 can be targeted by dupilumab. Besides these drugs, which are already available in medical practice, other biologics are under clinical development such as those targeting innate cytokines, including the alarmin thymic stromal lymphopoietin (TSLP), which plays a key role in the pathogenesis of type 2 asthma. Therefore, ongoing and future biological therapies are significantly changing severe asthma management on a global level. These new therapeutic options make it possible to implement phenotype/endotype-specific treatments, which are delineating personalized approaches precisely addressing the individual traits of asthma pathobiology. The aim of the study is to review the immunopathology and treatment efficacy for severe asthma and focused on new biological agents with benralizumab (anti-IL-5) and tezepelumab (anti-TSLP).


Introduction
Based on GINA guidelines, severe asthma is a subset of difficult-to-treat asthma [1]. Difficult-to-treat asthma is uncontrolled asthma despite the following of GINA Step 4 or 5 treatment. Uncontrolled asthma includes one or both of the following: (a) poor symptom control, (b) at least 2 exacerbations requiring oral corticosteroids (OCS) annually, or at least 1 serious exacerbation requiring hospitalization annually.
Current biologics are mainly targeting T2-high severe asthma, which is characterized by increased level of type 2 inflammation in the airway [2]. It manifests clinically with a combination of peripheral eosinophilia, sputum eosinophilia, and/or elevated fractional exhaled nitric oxide (FeNO) [3].
Benralizumab is a humanized, afucosylated, IgG1k isotype monoclonal antibody which specifically binds to interleukin-5 receptor alpha-directed cytolytic (IL-5Rα), which is expressed on eosinophils and basophils [5]. Benralizumab is uniquely engineered to recruit natural killer cells directly to its target, resulting in apoptosis via antibody-dependent cellular cytotoxicity, producing rapid and sustained complete depletion of eosinophils in blood and target tissues [6]. Its efficacy and safety have been confirmed in pivotal randomized clinical trials and long-term extension study (SIRROCO [7], CALIMA [8], BORA [9], and ZONDA [10]). Benralizumab 30 mg every 8 weeks (Q8W); first three doses every 4 weeks (Q4W) is indicated for the add-on-maintained treatment of patients with severe asthma aged 12 years and older, and with an eosinophilic phenotype. Benralizumab treatment enabled patients with severe, uncontrolled OCS-dependent asthma and baseline blood eosinophil counts ≥150 cells/uL to achieve and maintain asthma control while reducing OCS dosages [10]. The ANDHI study increases confidence in the benralizumab mechanism of action for treating patients with severe eosinophilic asthma through further assessment of the onset and maintenance of clinical effects, benefits in health-related quality of life (HRQOL) measures, and the potential to treat symptoms of nasal polyposis for patients with chronic rhinosinusitis with nasal polyposis [11]. Treatment with benralizumab for patients with severe eosinophilic asthma (BEC ≥ 150 cells per µL) significantly reduced the risk of asthma exacerbation, which was primarily driven by patients with efficacy associated with known markers of the eosinophilic phenotype.
Tezepelumab binds to TSLP, which is one of the key drivers of the asthmatic pathophysiology as it is produced by the airway epithelium in response to inhaled allergens and proinflammatory stressors [12]. Because of its upstream activity early in the inflammatory cascade, tezepelumab may have a role in patients with severe, uncontrolled asthma irrespective of patient phenotype or T2 biomarker status. In the phase 2b PATHWAY trial the annualized rate of asthma exacerbations was up to 71% lower with tezepelumab than with placebo among patients with severe, uncontrolled asthma [12]. Furthermore, exacerbations were reduced regardless of baseline levels of inflammatory biomarkers, including fraction of exhaled nitric oxide (FeNO), blood eosinophils, IgE, and allergic status [12][13][14].
The UK Severe Asthma Registry (UKSAR) study demonstrated even though 68.9% were prescribed biologic therapies including mepolizumab (50.3%), benralizumab (26.1%) and omalizumab (22.6%), 51.7% of the UKSAR remain poorly controlled. They continue to have a high exacerbation rate averaging four acute OCS courses/year, with an average ACQ6 of 2.9 at assessment, and on maintenance OCS. Treatment goals in asthma include symptom control and reducing risk of future exacerbations. However, approximately 3% to 5% of asthmatic patients have severe asthma where either symptoms persist or numerous exacerbation occur despite maximal treatment, an estimate that varies by country and may reach ≥10% in the United States [15]. Systemic reviews have been carried out for severe asthma in omalizumab, mepolizumab, reslizumab, benralizumab, and dupilumab from 2017 to 2021 [3,[16][17][18][19]; however, only one of them has been reviewed in both benralizumab and tezepelumab [19]. The study was conducted in 2020, which did not include phase 3 NAVIGATOR study for tezepelumab [20], or phase 3b ANDHI study for benralizumab [11]. An Italian cross-sectional study analyzed real-life descriptions of severe refractory population from June 2017 to June 2019 [21]. Between patients in therapy with omalizuamb, six switched to bronchial thermoplasty, two shifted to mepolizumab, and two to benralizumab [21]. An Australia case report documenting a 68-year-old man revealed refractory airway eosinophilia after treatment with mepolizumab, but he then responded to benralizumab [22]. Another Italian real world study was carried out from January 2019 to November 2019. Forty-two benralizumab patients showed improved asthma control and lung function and a reduced OCS use among those previously treated with either omalizumab (n = 15) or mepolizumab (n = 5) or both omalizumab and mepolizumab (n = 2) [23]. According to a real-world study, physicians may prescribe benralizumab while omalizumab or mepolizumab are not adequately respond in clinical practice. Therefore, this systemic review is focused on benralizumab and tezepelumab.
The objective of this study was to survey and elucidate the efficacy of benralizumab and tezepelumab using literature reviews on the assessment of symptom control, emergency department visits (severe acute exacerbations), lung function, and safety in those with severe uncontrolled asthma.

Materials and Methods:
The study followed the Preferred Reporting Items for Systemic Reviews and Meta-Analysis (PRISMA) guidelines.

Search Strategy
The systemic review is performed through independent searches of the MEDLINE, and the Cochrane Library database using free text search terms from inception to April 2021 and evaluated the title and abstract for eligibility. By performing a systemic literature review, 32 studies were identified. Among these, 30 studies were identified based on patients, interventions comparisons, outcomes, and study design (PICOs) criteria.

Study Selection
Studies that met following criteria were excluded: 1.
Review articles, case reports, and conference abstracts; and 2.
Articles where the full texts were unavailable.

Data Extraction
The reviewer read the full text, supplementary, and appendix and extracted the data independently and meticulously. The following descriptive data were obtained from all included studies: first author, publication year, study phase, study locations, patient characteristics, methods, duration, and intervention. The reviewer checked the accuracy of data extraction.

Summary Measures and Synthesis Results
Main results are described narratively and tabulated as a summary of findings. Binary outcomes were presented at risk ratio (RR) and confidence interval, whereas continuous outcomes were presented at mean difference (MD) and 95% CI. For each outcome, the change from baseline to the end of treatment vs. placebo were assessed (Tables S6-S11).

Study Selection
A total of 382 publications were identified from PubMed, while using the filters stated in study design, 32 studies remained. The search strategy is in Table S2, with search date on 10 April 2021. Of these, three were excluded for study populations. One study was added as it was published on May 13. There are 12 clinical trials and four observational studies (Table S3), 14 post-analysis (Table S4). The total 30 studies are listed in Table S5.

Baseline Demographics and Clinical Characteristics
Baseline demographics are presented in Table S5. Patient characteristics, such as age, race, gender, and BMI were included. Clinical characteristics, such as forced expiratory volume in 1 s (FEV1) on dosing date, Asthma control questionnaire 6 (ACQ-6), Asthma Quality of Life questionnaire for persons 12 years of age or older (AQLQ+12 score) were included.

Tezepelumab
Nominally significant improvements in prebronchodilator FEV1 versus placebo were observed in all tezepelumab groups from Week 4 through to the end of the study (120-150 mL at Week 52) [12]. At Week 52, differences in improvements from baseline in key secondary endpoints versus placebo in the overall population were: Prebronchodilator FEV1: 130 mL (95% CI, 80-180 mL; p < 0.001) [20], Improvements in prebronchodilator FEV1 versus placebo were observed at 2 weeks (first post baseline assessment) and were sustained throughout the treatment period. (Table 4).

Emergency Room Visits/Unscheduled Physician Visits Benralizumab
The Cochrane review which included Bleeker 2016, and Fitzgerald 2016 indicated in eosinophilic participants, benralizumab had fewer exacerbations requiring department treatment or admission by 0.68 (95% CI 0.47 to 0.98) [16]. The reduction rate was statistically significant in Bleeker et al. study [7], but not in FitzGerald et al. study [8]. Chipps [28]. (Table 7).  [13,20]. Tezepelumab 70 mg Q4W led to a relative rate reduction in asthma exacerbations that required hospitalizations of up to 73% and all-cause ED of up to 56% compared with placebo [13]. Menzies-Gow et al. demonstrated fewer rate of exacerbations that were associated with hospitalization or an emergency in tezepelumab (rate ratio, 0.21; 95% CI, 0.12 to 0.37) vs. placebo over a period of 52 weeks [20]. Among patients admitted to the hospital or the ED, those treated with tezepelumab reported fewer mean days in the hospital and ED compared with those who received placebo (hospital: 10 days vs. 23 days; ED: 1.4 days vs. 3.6 days). (Table 8).

Benralizumab
The most common serious adverse events associated with benralizumab were worsening asthma (3-4%), pneumonia (<1% to 1%), and pneumonia caused by bacterial infection (0-1%). The percentages of patients who had any on-treatment adverse event, any serious adverse event, or any adverse event leading to treatment discontinuation during BORA were similar between patients originally assigned benralizumab and those originally assigned placebo and between benralizumab treatment regimens. The percentage of patients who had any adverse event was similar between SIROCCO or CALIMA (71-75%; benral-izumab group only) and BORA (65-71%), as was the percentage of patients who had an adverse event that led to treatment discontinuation (2% in SIROCCO and CALIMA vs. 2-3% in BORA). Goldman et al. found the overall adverse events frequency was similar between treatment groups and eosinophil count cohorts [24]. Busse et al. assessed the long-term safety and efficacy of benralizumab between 19 November 2014 and 6 July 2016, [9] The most common adverse events in all groups were viral upper respiratory tract infection (14-16%) and worsening asthma (7-10%) [9].  [12], two (pneumonia and stroke) occurred in the same patient using tezepelumab 70 mg Q4W, and one (the Guillain-Barre syndrome) using tezepelumab 210 mg Q4W. The discontinuation rates due to adverse events were 1.2% among patients receiving tezepelumab (five patients, including two in tezepelumab 210 mg Q4W, and three in tezepelumab 280 mg Q2W) and 0.7% in the placebo group (one patient). In Menzies-Gow et al's. study, the discontinuation rates was 2.1% in the tezepelumab group and 3.6% in the placebo group [20]. The most common adverse events were nasopharyngitis, upper respiratory tract infection, headache, and asthma (which was more frequently observed in the placebo group than in the tezepelumab group).

Conclusions
Benralizumab significantly reduced exacerbations, improved lung function, and increased patient report outcomes versus placebo. These clinical benefits were sustained long term (2 years). The annual exacerbation profile with benralizumab was similar to that with placebo in the 1-year pivotal studies. Long-term depletion of eosinophils with benralizumab was not associated with new safety risks after 2 years of exposure. Tezepelumab reduced annual exacerbations regardless of baseline levels of several type 2 inflammation biomarkers, including FeNO, blood eosinophils, IL 5, IL-13, and IgE. Lung function and health-related quality of life are both improved in tezepelumab among severe uncontrolled asthma patients, including those with low blood eosinophil counts.