Dupilumab Efficacy and Safety as an Add-On Therapy in Uncontrolled Asthma Patients: A Systematic Review

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INTRODUCTION
Asthma is a heterogeneous chronic inflammatory affecting the airways caused by airway hyperresponsiveness after exposure to triggers or allergens. It results in bronchoconstriction and airflow obstruction. Its symptoms are breathlessness, chest tightness, wheezing, and cough (Farne et al., 2017;Harb and Chatila, 2017;GINA, 2021). Symptoms due to airflow obstruction may resolve either spontaneously or with asthma therapy. However, patients can experience exacerbations, an increase in the severity of a disease or its signs and symptoms in a certain period (Rothe et al., 2018).
Based on World Health Organization (WHO) survey data from 2002 to 2003, the prevalence of asthma patients among young adults (18-45 years old) in 70 countries was 177,496 (Global Asthma Network, 2018;Syfridiana and Herawati, 2021). Furthermore, asthma is still one of Indonesia's top ten diseases causing illness and death. Based on Basic Health Research in 2018, the prevalence of asthma in Indonesia was 2.4% of the total population of Indonesia. The highest asthma prevalence was in DI Yogyakarta (4.59%), East Kalimantan (4.0%), and Bali (3.9%) (Kemenkes RI, 2019 The long-term goals of asthma management are symptom control and risk reduction. The treatment includes medication, risk factors modification, and non-pharmacological therapies. Controller medication is vital in controlling asthma and preventing exacerbation in chronic asthma. There are five steps of treatment for chronic asthma. The higher the step, the more medication to manage chronic asthma ( Fig.1) (GINA, 2021). Standard treatment, a high-dose inhaled corticosteroid (ICS) and long-acting bronchodilator (LABA), effectively manages asthma in most individuals. There were no data in Indonesia, but to the authors' knowledge, 5%-10% of individuals with asthma were ineffective with those treatments.
They require add-on therapy (in step 5; Fig.1). Patients with severe uncontrolled asthma tend to have a poor quality of life (QOL), more extended hospitalization, and impaired lifestyle compared to wellcontrolled asthmatic patients. In addition, they experience adverse effects from oral corticosteroids (Rogliani et al., 2020;Ricciardolo, Bertolini, and Carriero, 2021).
In the last decade, advanced research has led to new asthma treatments. This new therapy is a biological therapy indicated for uncontrolled severe asthma patients. Most of these therapy target inflammation molecules from the type two inflammation pathway (Rogliani et al., 2020). There is currently a limited medication option in step 5 for uncontrolled, moderate to severe asthma patients.
Omalizumab is an anti-IgE available in Indonesia, but only for persistent asthma patients with a positive skin test or reactive to perennial aeroallergen (in vitro) (FDA, 2017b (Harb and Chatila, 2017;Papi et al., 2018) T-helper2 (Th-2) lymphocytes can mediate the Th-2 immune response that precipitates asthma.
Evidence states that elevated expression of Th2 cytokines, such as IL-4, IL-5, and IL-13, can drive allergic asthma (Ricciardolo, Bertolini, and Carriero, 2021). IL-4 promotes the synthesis of IgE and primes blood vessels for eosinophil extravasation by acting on IL-4R (Papi et al., 2018). Meanwhile, IL-13 induces the production of iNOS in airway epithelial cells and metaplasia of goblet cells. In addition, it causes bronchial hyperactivity ( Fig.2) (Papi et al., 2018). Therefore, these molecules are essential for managing T2 allergic asthma (Ricciardolo, Bertolini, and Carriero, 2021). Preliminary simulation of Th-2 lymphocytes with the aid of several inflammatory cytokines, causing the expression of the CCR-4 chemokine receptor and secretion of different inflammatory interleukins, such as IL-4, IL-5, IL-9, and IL-13. As Th-2 lymphocytes migrate from surrounding lymph nodes to the airways, they induce chemotaxis and activation of inflammatory cells. In addition, it causes mast cells and eosinophils production that are liable for bronchial asthma symptoms over a long period (Zayed et al., 2019). The prevalence of eosinophilic asthma is about 50% in asthmatic adults. In addition, recent findings suggest that patients with corticosteroid withdrawal also have eosinophilic inflammation. Therefore an IL-4/IL-13 inhibitor that can lower the eosinophilic levels is essential to target therapy (Papi et al., 2018). Dupilumab is a monoclonal antibody derived from humans, acting as an IL-4/IL-13 inhibitor. It targets the α subunit of the IL-4 and IL-13 receptors. It forms a high affinity to IL-13-and IL-4binding type II heterodimeric complex ( Fig.2) Chatila, 2017, 2020). Thus, it blocks the signal transduction of the Th-2-mediated immune response (Ricciardolo, Bertolini, and Carriero, 2021).
A systematic review and meta-analysis of randomized clinical trials conducted in 2018 supported Dupilumab use in patients with uncontrolled asthma (Zayed et al., 2019). The addition of Dupilumab in moderate-to-severe asthma therapy was associated with a reduced risk of asthma exacerbation and improved FEV1 without an increased risk of an adverse event (Zayed et al., 2019). Dupilumab injection was approved by the US Food and Drug Administration on Mar 28, 2017, to treat adults with uncontrolled moderate-to-severe eczema (atopic dermatitis) (FDA, 2017a). Dupilumab is available in Indonesia. Therefore, updated evidence with more recent trials is required to support its use in uncontrolled asthma therapy.
In this systematic review, we updated published systematic reviews and meta-analyses (Zayed et al., 2019). This paper analyzes the efficacy (the annualized rate of severe asthma exacerbation and increase in FEV1 from baseline) and safety of Dupilumab as an add-on therapy compared to a placebo in patients with moderate-severe uncontrolled asthma.

Literature search, data source, and selection of study
Electronic literature searching was performed independently and separately by two authors (EE and PBD) using PUBMED and ScienceDirect with keywords (Asthma) AND (Dupilumab). The authors searched studies conducted from January 2013 to Feb 15, 2022. Collected studies were screened, and duplicates were removed using Mendeley Reference Manager. All included studies met the inclusion criteria: RCTs that compare the efficacy and safety of Dupilumab with a placebo in uncontrolled asthma patients with inhaled ICS and LABA or requiring oral glucocorticoids to control their symptoms. We excluded post hoc analysis and non-RCT studies.

Article quality assessment
Two authors (EE and PBD) assessed the studies' quality using the Critical Appraisal Program (CASP) tools (CASP, 2020) and journal reputation. The CASP checklist contains three parts consisting of several questions. Part A assesses the validation of research results. In addition, part B assesses research results. Furthermore, part C assesses whether the research results can be applied or used by readers. For the CASP checklist, articles were considered good quality because there were at least ten "yes" answers.

Outcomes
The primary efficacy outcome was the annualized rate of severe asthma exacerbations with criteria: a reduction of ≥30% in morning peak expiratory flow (PEF) from baseline on two consecutive days, at least six additional reliever inhalations (salbutamol or albuterol or levalbuterol) in 24 hours relative to baseline on two consecutive days, asthma exacerbation requiring systemic glucocorticoid treatment, an increase in inhaled glucocorticoids of at least four times the most recent dose, or hospitalization for asthma. The secondary outcome was the change in forced expiratory volume at 1s (FEV1) between baseline and the most prolonged follow-up duration (12-24 weeks).
The authors also assessed safety outcomes and adverse events. Furthermore, we analyzed descriptively and narratively all included studies.

Statistical Analysis
We conducted a meta-analysis to calculate the pooled risk ratio (RR). In addition, we used Mantel-Haenszel with 95% confidence intervals for dichotomous data. Furthermore, we used a randomeffects model to count for interstudy heterogeneity. Then, we processed data using Revman 5.4.

Ethical Clearance
This systematic review extracted data from accessible published articles, so ethical clearance is not applicable.

RESULT
A keyword search of two electronic databases, PubMed and ScienceDirect, resulted in 497 articles.
The first screening based on title and abstract resulted in 52 relevant articles. Then, 52 papers were further reviewed and assessed for eligibility. Finally, this paper reviewed five RCT papers that compared Dupilumab with placebo in patients with severe uncontrolled asthma ( Fig.3) (Wenzel et al., 2013(Wenzel et al., , 2016Castro et al., 2018;Rabe et al., 2018;Bacharier et al., 2021). Table 1

Quality of Articles
Assessment of articles with the CASP checklist showed that all five RCTs (Wenzel et al., 2013(Wenzel et al., , 2016Castro et al., 2018;Rabe et al., 2018;Bacharier et al., 2021) in included studies had good quality (5; 100%) ( Fig.4). All studies were randomized, double-blind, and analyzed based on the intention-to-treat principle. All outcomes were mentioned and measured statistically with p and confidence intervals (CI).

Efficacy of Dupilumab as add-on therapy in uncontrolled asthma patients
The first RCT by Wenzel et al. (2013) showed that a subcutaneous injection of Dupilumab 300 mg once a week lowered annualized rate of severe asthma exacerbation compared to placebo in adult patients with persistent, moderate, and severe asthma (odds ratio 0.08; 95% confidence interval [CI], 0.02 to 0.28; p<0.001) (Wenzel et al., 2013). Furthermore, Wenzel et al. (2016)  weeks but in a more extended follow-up period (52 weeks). That study showed a significant reduction of annualized exacerbation by 47.7% and 46.0%, respectively (Castro et al., 2018). Another RCT in 2018 also assessed the efficacy of Dupilumab 300 mg with a loading dose of 600 mg on day one. The study also showed a reduction in severe asthma exacerbations by 59% (95% CI, 37 to 74) (Rabe et al., 2018).
Moreover, the newest RCT by Bacharier et al. (2021) also focused on evaluating the efficacy of Dupilumab in children (6-11 years old), with dosage varied based on the child's weight. A child with ≤30 kg body weight received 100 mg of Dupilumab every two weeks, while samples >30 kg received 200 mg every two weeks for 52 weeks. This systematic review and meta-analysis found that the annualized rate of severe asthma exacerbations in the Dupilumab group was lower than in the placebo group (RR 0.46; 95% CI 0.36-0.58; p=0.007). Previous systematic review and meta-analysis in 2018 also showed a similar result to this paper, despite not including the children population (aged 6-11 years old) (Zayed et al., 2019).
Dupilumab has a complex mechanism and is associated with eosinophil count in reducing severe asthma exacerbation, as mentioned by Zayed et al. (2018). Dupilumab can potentially suppress asthma exacerbation by blocking both IL-4 and IL-13, reducing eosinophil production (IL-4 mediated), mucous production, and preventing airway remodeling (IL-3 mediated, unrelated to the eosinophilia-associated Th-2 response) (Zayed et al., 2019). This notion is supported by findings of a significant reduction of severe asthma exacerbations annual rate and an improvement in FEV1 in asthma patients receiving Dupilumab compared to placebo, regardless of their eosinophil count.
The effect of Dupilumab may be dose-dependent, as demonstrated by Castro et al. (2018), one of the RCTs included in this systematic review. Higher and more frequent Dupilumab doses, either 200 mg every two weeks or 300 mg every two weeks, are required to prevent the annualized rate of severe asthma exacerbations (Castro et al., 2018). However, there is still too little RCT conducted to assess the dosing effect on the Dupilumab efficacy. Therefore, we conducted a meta-analysis in this current study that includes all doses given in the RCT studies.
The secondary outcome of this meta-analysis was the change in FEV1. Dupilumab 300 mg once a week, 200 mg every two weeks, and 300 mg every two weeks significantly showed the consistent result in the increase of FEV1 (Wenzel et al., 2013(Wenzel et al., , 2016Castro et al., 2018;Rabe et al., 2018;Bacharier et al., 2021) (5;100%). However, Dupilumab 200 mg or 300 mg every four weeks showed no significant increase in FEV1 (Wenzel et al., 2016). It might be due to the low frequency of doses.

CONCLUSION
Dupilumab as add-on therapy in patients with uncontrolled asthma significantly lowered the annualized rate of severe asthma exacerbations and increased FEV1 in all five included studies. The most common adverse effects of using Dupilumab were injection site reaction, upper respiratory tract infections, and eosinophilia. Thus, this review concludes that using Dupilumab in uncontrolled asthma patients is beneficial and well-tolerated.
Although all studies included in this systematic review have a low risk of bias, it still can't point out the best dose of Dupilumab for add-on therapy in moderate-to-severe uncontrolled asthma patients. Moreover, RCT studies assessing Dupilumab efficacy and safety in the Indonesian population are still lacking. Thus, there should be more RCT studies (with more samples for achieving generality), especially in Indonesia, to determine the optimal dose.