CADTH Health Technology Review

The Efficacy and Safety of Biologic Drugs to Treat Severe Asthma

Jason R. Randall, Richard Leigh, Ellen T. Crumley, Sylvia Aponte-Hao, Ngoc Khanh Vu, Karen Martins, Scott Klarenbach

This Rapid Review was conducted by the Alberta Drug and Technology Evaluation Consortium through the Post-Market Drug Evaluation CoLab Network.

Rapid Review

Key Messages

Several biologic drugs have been developed to treat severe asthma, but it is unclear how well they work across different types of asthma.

Comparing the efficacy of biologic drugs for asthma is challenging because of differing definitions of asthma severity and inconsistent application of severity criteria in randomized controlled trials.

The randomized controlled trials and systematic reviews included in this Rapid Review mainly focused on specific severe asthma subtypes (frequently, eosinophilic type 2 asthma). Recruitment and outcome reporting among different asthma subgroups was limited and varied, making it difficult to assess the efficacy of biologic drugs across the specific subgroups of severe asthma.

Determining the efficacy and safety of biologics in the pediatric population is hindered by both the lack of inclusion of children with severe asthma in clinical trials and the lack of outcome reporting specific to this population.

Further synthesis of the existing data is unlikely to provide new insights to further inform the outlined policy questions on biologics in severe asthma.

Introduction and Rationale

Background

Asthma is a spectrum of chronic conditions that exhibit airway inflammation and hyperreactivity.¹ Severe asthma affects approximately 5% to 10% of individuals living with asthma. It is characterized by poorly controlled symptoms despite optimal use of front-line treatments such as high-dose inhaled corticosteroids with an adjuvant controller medication and/or systemic corticosteroids.^2,3 It is estimated that as many as 250,000 people living in Canada have severe asthma. These individuals account for the majority of the morbidity and mortality related to asthma and incur most of the health care costs associated with treatment and management.^4-6 The incremental cost of severe asthma relative to no asthma in Canada is approximately $2,779 per person per year.⁷

Severe asthma has several typologies (Figure 1), and several biologic drugs have been developed to target inflammation in specific subtypes of severe asthma, namely type 2 eosinophilic or allergic. Type 2 inflammatory asthma is predominately caused by type 2 cytokines and lymphocytes. Subtypes include eosinophilic asthma (characterized by increased eosinophil levels in the airways and blood) and allergic asthma (characterized by elevated immunoglobulin E levels and elevated bronchial responsiveness).⁸ There is overlap between the subtypes with crosstalk involving cytokine signalling so some patients may have characteristics of both eosinophilic and allergic asthma. Non–type 2 inflammatory asthma is characterized by the absence of type 2 markers with neutrophilic and paucigranulocytic airway inflammation, for which there is evidence suggesting it might respond to benralizumab and tezepelumab.^9-11 Additionally, structural changes in the lung, such as fixed airflow obstruction caused by remodelling of the airway wall, can occur in severe asthma with or without the presence of type 2 inflammation; there are no current pharmacological treatments for targeting airway remodelling.¹²

Figure 1: Severe Asthma Typologies

Policy Issue

In Canada, reimbursement for biologics has occurred for the following drugs and indications: benralizumab and mepolizumab are indicated specifically for severe eosinophilic asthma, dupilumab is indicated for severe asthma with a type 2–eosinophilic subtype, and omalizumab is indicated for allergic asthma (Appendix 1). A Letter of Intent for tezepelumab (indicated for severe asthma) was issued by the pan-Canadian Pharmaceutical Alliance on September 15, 2023. Reslizumab is not currently covered by public drug plans in Canada and therefore was not considered in this review.^13,14 Biologics have the potential to offer more effective symptom control for 1 or more subtypes of severe asthma with fewer adverse events compared with oral corticosteroids;^13,15 however, there is some evidence of increased adverse events compared with standard care (e.g., inhaled corticosteroids, anticholinergics, and beta agonists).¹⁶

The available biologic therapies for severe asthma currently have disparate criteria for use due to the sequential nature of evaluation and listing, and criteria developed based on available information at the time of consideration. The efficacy of biologic drugs along the spectrum of severe asthma is unclear; similarly, the efficacy and safety in children has not been well characterized. Knowledge of the available evidence within and between biologic drugs by patient population and subtypes of severe asthma, and potential subsequent synthesis of available evidence, may inform listing criteria to optimize health and health care system sustainability.

Policy Questions

1. Is there evidence of comparative efficacy and safety to support harmonization of criteria for use of biologic drugs for patients with severe asthma (compared with current biologic-specific criteria)?

   1. What is the efficacy and safety of each biologic drug by population as defined by specific asthma subtypes (i.e., eosinophilic or allergic with or without specific criteria such as immunoglobulin E levels and eosinophil counts) and age (pediatric: 6 years to 17 years; adult: ≥ 18 years)?

   2. What is the relative efficacy and safety between biologic drugs as defined by specific asthma subtypes and population age?

Objectives

The approach was to conduct the review in 2 parts. Part 1 was a Rapid Review to assess the recent body of evidence available from randomized controlled trials (RCTs) and systematic reviews to determine the feasibility of conducting a more fulsome Health Technology Assessment (HTA).

The aims of the Rapid Review (part 1) were:

• to identify and describe the research examining the comparative efficacy and safety of biologics for severe asthma using clinically important outcomes

• to characterize the patient populations studied

• to determine if further evidence synthesis (systematic review, meta-analysis, indirect treatment comparison) is feasible to address knowledge gaps for specific populations and subgroups with severe asthma.

Part 2 was to be an HTA to provide guidance about the alignment of the drug funding criteria by the public drug plans.

This report presents the findings of the part 1 Rapid Review.

Research Questions

The project identified the literature that addressed the following research questions. It determined whether recent RCTs and systematic reviews addressed these questions, and whether a future systematic review and/or meta-analysis is feasible and needed. Details on the specific interventions and outcomes are included in Table 1.

1. What is the comparative efficacy of biologic drugs for patients with severe asthma by specific population?

   1. Population defined by severe asthma:

      • Type 2 asthma

        • allergic and/or eosinophilic asthma

        • specific criteria for allergic or eosinophilic asthma (e.g., immunoglobulin E level, bronchial responsiveness, sputum or blood eosinophil count)

   2. Population defined by age:

      • pediatric (6 years to 17 years); adult (≥ 18 years)

2. What is the safety of biologic drugs for pediatric populations with severe asthma?

Methods

To inform the conduct of this focused Rapid Review, a review of the existing literature, including RCTs and systematic reviews, was performed. The part 1 study used the CADTH Rapid Review Summary with Critical Appraisal and Peer Review process, with modifications:

• The selection of studies and data extraction were conducted by 2 reviewers.

• The literature search included additional databases and sources, and the literature search strategy was peer reviewed.

• Because it was subsequently decided that part 2 (the HTA) was not required, a decision was made to post the part 1 draft science report for stakeholder feedback.

Literature Search Methods

The literature searches were developed by an experienced librarian with systematic searching experience. A Peer Review of Electronic Search Strategies (PRESS) was performed by a second librarian to optimize the search. Searches were last conducted or updated in May 2023.

The search was restricted to articles published in the past 5 years (2018 onward) and only included those published in English. The search was restricted to RCTs, systematic reviews, meta-analyses, and network meta-analyses conducted using the Ovid interface, and included the following databases and registers: MEDLINE All (1946 to present) via Ovid, Embase (1974 to present) via Ovid, PubMed, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials via Wiley Cochrane Library, preprints via EuropePMC.org, ClinicalTrials.gov, WHO ICTRP, Health Canada’s Clinical Trials Database, EU Clinical Trials Register, International Traditional Medicine Clinical Trial Registry, and PROSPERO. The detailed search strategies are presented in Appendix 2.

Table 1: Selection Criteria

Selection Criteria and Methods

Study Selection

Two reviewers independently screened titles and abstracts for relevance to the clinical research questions. The full text of potentially relevant articles was retrieved and independently assessed for possible inclusion based on the predetermined selection criteria (Table 1). The 2 reviewers then compared their chosen included and excluded studies; disagreements were discussed until consensus was reached. Both the abstract screening and the full-text screening were pilot tested by 2 reviewers with nonconsensus resolved by third reviewer; clarification of inclusion and exclusion criteria was done as required through pilot testing and calibration.

Exclusion Criteria

Articles were excluded if they did not meet selection criteria outlined in Table 1, were duplicate publications, reported duplicate data on the outcomes of interest, or were published before 2018. Studies that focused on niche subpopulations not identified a priori (e.g., severe asthma with nasal polyps or rhinosinusitis), or study populations of asthma with other conditions (e.g., chronic obstructive pulmonary disorder), were excluded. Post hoc analyses of RCTs were included provided that they added new data relevant to the research and policy questions, and reviewers were confident that the new analysis met the inclusion criteria (e.g., population, intervention, comparator, and outcome [PICO] criteria were clearly met after changes to population via filtering). Systematic reviews, meta-analyses, and network meta-analysis were excluded if they contained data from nonrandomized or observational studies.

Data Extraction and Critical Appraisal

Data Extraction

Information from each article was extracted using a standardized data extraction form. Extracted information encompassed characteristics of the study (year of publication, study design, sample size, and general statistics), trial participants (including characteristics that defined asthma subtype and age groups), inclusion and exclusion criteria, type of intervention(s) or control (including dose, duration, and co-medication), relevant outcomes, and broad results of the clinical efficacy or effectiveness and safety. Specific extracted outcomes included hospitalization, mortality, asthma exacerbations (AEXs), changes in force expiratory volume in 1 second (FEV₁), and health-related quality of life (HRQoL). HRQoL was measured using 3 validated questionnaires: the Asthma Control Questionnaire, the Asthma Control Test, and the Asthma Quality of Life Questionnaire.

All data were extracted by 1 reviewer and checked for accuracy by a second independent reviewer. The presence of publications reporting on specific combinations of medications, subgroups, and outcomes was also abstracted. If a recent systematic review or meta-analysis had been conducted for each combination was also captured. Country of origin for each article was not extracted because some studies were conducted across numerous countries to recruit an adequately large sample of participants with severe asthma.

Multiple publications for a unique trial (e.g., supplemental online appendices, companion publications of specific outcomes, or populations from the original study) were handled by extracting the most recently adjudicated data for each outcome specified a priori. Results were presented from the original trial if multiple articles were published based on the same clinical sample and provided unique data relevant to the study question.

Quality Assessment

Risk of bias assessments were conducted on the included RCTs using the second version of the Cochrane Risk of Bias,¹⁷ and the systematic reviews using A Measurement Tool to Assess Systematic Reviews second version (AMSTAR 2).¹⁸

Data Analysis and Synthesis

Extracted data were summarized heuristically; no meta-analysis or new data analysis was conducted. Statistical significance of results were reported as they were described in the included articles, without attempting any adjustment for multiple comparisons. Outcomes such as HRQoL were generally secondary outcomes in these trials and may be more susceptible to bias from multiple testing. Post hoc analyses reported in the articles are reported in this report without any controlling for potential bias from multiple testing.

Operational definitions for subtypes of severe inflammatory asthma, for which biologics have been developed to target, was determined based on available literature and clinical expert opinion (Table 2).¹⁹ Severe inflammatory asthma was characterized as type 2 that was further classified (subtype) based on the presence of eosinophilic and/or allergic markers, or non–type 2. Due to possibility of overlap between type 2 eosinophilic and allergic asthma, characterization by both an eosinophilic and allergic subtype was also included.

Table 2: Operational Definitions for Severe Inflammatory Asthma Subgroups

Eosinophilic status was determined by blood eosinophil count (BEC) (cells/µL of blood). For this review, the criterion for eosinophilic asthma was set at a BEC of 150 cells/µL or higher at enrolment or a history of BEC 300 cells/µL or higher. The criteria for noneosinophilic asthma was set at a BEC less than 150 cells/µL with no previous history of BEC 300 cells/µL or higher. In some trials, cut-offs of BEC 300 cells/µL or higher and less than 300 cells/µL at enrolment were used to define eosinophilic and noneosinophilic asthma, respectively. Trials investigating tezepelumab also assessed enrolled participants with severe asthma by fractional exhaled nitric oxide levels (trials used several cut-offs methods including less than 25 parts per billion and 25 or more parts per billion, 25 parts per billion to 50 parts per billion, and less than 50 parts per billion and greater than or equal to 50 parts per billion).

Trials were heterogeneous in definition of allergic status, and included thresholds based on immunoglobulin E level, radioallergosorbent test, skin prick test, fluoroenzyme immunoassay, and/or other allergy measures. Given this heterogeneity, we assumed trial-specific criteria used to characterize type 2 allergic asthma were appropriate to define this severe asthma subtype. Although the variation in clinical testing used to establish allergic status was considerable, we relied on these trial-based criteria to define this status in the interest of feasibility. We recognize the variation in the underlying condition across studies resulting from this heterogeneity is a limitation of this Rapid Review but is not a major limitation in the context of assessing the breadth of subgroup analysis in recent publications.

Feasibility of a future meta-analysis or network meta-analysis was determined based on assessment of published literature and availability of data to examine efficacy and safety by specific subgroups with severe asthma.

Summary of Evidence

Quantity of Research Available

Of the 1,014 identified articles, 233 underwent full-text screening. Of these, 47 articles were included in this review that consisted of 26 publications from 13 RCTs^9,11,20-43 (2 sets of trials were pooled: MENSA and MUSCA as well as SIROCCO and CALIMA]) and 21 systematic reviews^15,16,44-62 (3 systematic reviews without meta-analyses, 8 meta-analyses, 6 network meta-analyses, and 4 indirect treatment comparisons including matching-adjusted indirect comparisons). Details on study selection and included studies are in Appendix 3 and Appendix 4.

Although most data in the included systematic reviews were from RCTs that met the inclusion criteria for this review, some were from trials published before 2018 (e.g., DREAM for mepolizumab). In addition, 19^{15,16,44-49,51,52,54-62} systematic reviews included in this study contained trials that were outside of the selection criteria (13 included at least 1 trial with moderate to severe asthma^{16,44-48,54,55,57-59,61,62} and others included trials that administered biologics intravenously or studied other biologics). However, these systematic reviews were included based on the following: more than 75% of the trials included in the systematic review only had participants with severe asthma and it provided relevant data and reported results in a manner that allowed for the abstraction of pertinent information. Appendix 5 shows the RCTs included in the systematic reviews.

Supplemental information: A total of 37 articles were excluded because they contained populations with moderate to severe (versus severe only) asthma, of which a number investigated efficacy and safety of biologic drugs for pediatric populations. These studies are listed in Appendix 6 to facilitate future consideration of nonexclusively severe asthma populations. A list of RCTs of biologics for the treatment of asthma comprising the 13 trials included in this review, relevant trials within included SRs, and additional known major trials (compiled with the assistance of a clinical expert) is found in Appendix 7.

Study Characteristics

Patient Population

The population of interest was individuals identified as living with severe asthma.

There are 2 commonly used definitions of severe asthma: the Global Initiative for Asthma definition and the European Respiratory Society and American Thoracic Society definition, with the latter considered the definitive definition by asthma experts.^63,64 These definitions have undergone modifications over the past decade, which introduces the potential for inconsistencies in populations that meet the criteria for severe asthma over time. In general, the trials included in this focused rapid systematic review used the European Respiratory Society and American Thoracic Society definition, which considers a person to have severe asthma if either:

• their controlled asthma worsens on tapering of medium- to high-dose inhaled corticosteroid(s) or systemic corticosteroids (or additional biologics)

• symptoms remain uncontrolled with the use of high-dose inhaled corticosteroid(s) plus a second controller (and/or systemic corticosteroids).

Uncontrolled asthma is defined as at least 1 of the following: at least 1 AEX requiring hospitalization, intensive care unit stay, or mechanical ventilation in the past year; 2 or more short courses of systemic corticosteroids in the past year; reduced lung functioning (FEV₁ < 80% predicted) after appropriate bronchodilator treatment; or an Asthma Control Test score less than 20 or an Asthma Control Questionnaire score of 1.5 or higher.⁶³ Inclusion criteria were frequently poorly described in individual articles. The criteria used to define severe asthma was supplemented by reviewers accessing trial descriptions on clinicaltrials.gov registration records. The inclusion criteria from the registration and/or articles are provided in Table 9.

Randomized Controlled Trials

The number of RCTs by biologic drug and asthma subgroup are presented in Table 3, and the number of participants in these trials by biologic drug and asthma subgroup are presented in Table 4, according to (refer to Appendix 8, Table 10, Table 11, and Table 12 for general information on these RCTs). Characterizing study populations by asthma severity and subtypes was challenging given the changing definitions, evolving understanding of asthma subtypes, and overlap of asthma subtypes. Using available data from included studies, characterization of subtypes was attempted when possible. Trials may have targeted recruitment of a specific subtype and may or may not have reported other information on subtype (e.g., study target population was type 2 eosinophilic asthma, but information on allergic status was or was not reported).

In half the trials, enrolment was open to both adults and children, whereas the other half allowed only adult participants (Table 3). Enrolment of children in the trials was notably limited (Table 4), with a relatively small number of confirmed child participants (229 of a total 7,773 participants; additional children may have been enrolled but not reported).

The largest enrolled asthma subtype was type 2 eosinophilic asthma (Table 4). Trials that targeted patients with this specific subtype of severe asthma investigated the effect of benralizumab (ANDHI, SOLANA) and mepolizumab (MENSA and MUSCA) (Table 9 and Table 10); no data were available on the efficacy of mepolizumab for noneosinophilic patients (Table 13). Although the SIROCCO and CALIMA trial (benralizumab) recruited patients with severe asthma (with no subtype targeted), enrolment was stratified to ensure a large portion of participants had type 2 eosinophilic asthma. RCTs investigating omalizumab targeted enrolment of patients with severe type 2 allergic asthma (EXTRA, NCT01202903, NCT02049294). Although eosinophilic status was reported in some of these trials (Table 14). Trials investigating dupilumab (LIBERTY ASTHMA VENTURE) and tezepelumab (NAVIGATOR, PATHWAY, SOURCE) enrolled patients with severe asthma with no subtype targeted. None of the studies specifically enrolled participants with non–type 2 severe asthma.

Systematic Reviews

Characteristics of the study populations were not well described within the included systematic reviews. Reviews frequently combined trials with varying populations (Table 15) and were classified as type 2 eosinophilic or allergic subtypes. Some systematic reviews did use meta-analysis methods to adjust for differences in populations across the trials.

Table 3: Number of Randomized Controlled Trials by Biologic Drug and Asthma Subgroup

EOS = eosinophilic.

Note: Non–type 2 indicates individuals without markers of either EOS or allergic asthma. “EOS and allergic” indicates individuals with indicators of both EOS and allergic asthma.

Table 4: Number of Participants in Each Randomized Controlled Trial by Biologic Drug and Asthma Subgroup

EOS = eosinophilic; NR = not reported.

Note: Non–type 2 indicates individuals without indication of either eosinophilic or allergic asthma. The method of determining allergic status varied and was based on immunoglobulin E levels, radioallergosorbent tests, skin prick tests, fluoroenzyme immunoassays, and/or other allergy measures. “EOS and allergic” indicates individuals with indicators of both eosinophilic and allergic asthma. Trial information on clinicaltrials.gov was checked to determine or verify these values. Trial-specific criteria for eosinophilic asthma was determined using blood eosinophil count levels (cells/µL).

^aBlood eosinophil of 150 cells/µL or higher at baseline or a history of 300 cells/µL or higher.

^bBlood eosinophil of 300 cells/µL or higher.

^cBlood eosinophil of 260 cells/µL or higher.

^dValues estimated based on 2 of the 4 arms of the PATHWAY study in the pooled analysis by Corren et al.⁹

^eBlood eosinophil of 250 cells/µL or higher.

Interventions and Comparators

Randomized Controlled Trials

In the included trials, the active interventions were benralizumab (4 trials, among which SIROCCO and CALIMA were pooled), dupilumab (1 trial), mepolizumab (2 trials that were pooled), omalizumab (3 trials), and tezepelumab (3 trials) (Table 4, Table 9). In all identified studies, the comparator was a subcutaneous placebo injection that was physically similar to the study drug. In general, “standard-of-care” asthma therapies were allowed in both arms. This is in line with the use of biologic drugs as add-on medications; they are not intended to replace standard asthma therapies (although it is hoped they will reduce the need for oral corticosteroids).

Systematic Reviews

The included systematic reviews compared biologics to placebos. Benralizumab was the most evaluated biologic compared to a placebo (included in 14 SRs), and omalizumab was the least evaluated (included in 4 SRs) (Table 15). Ten of the systematic reviews included a comparative efficacy component — either a network meta-analysis or indirect treatment comparison or matching-adjusted indirect comparison. Mepolizumab (10 systematic reviews), benralizumab (9 systematic reviews), and dupilumab (8 systematic reviews) were evaluated in most of these reviews. Tezepelumab and omalizumab were considered in 3 comparative efficacy reviews each.

Outcome Measures

Randomized Controlled Trials

Main study outcomes are reported in Table 13. AEX was the most common outcome reported (most often as an annualized rate; reported in 11 trials [includes 2 sets of pooled trials]). FEV₁ and/or HRQoL outcomes were reported in 12 trials (includes 2 sets of pooled trials). NCT01202903 did not report FEV₁, and EXTRA did not report HRQoL. Safety outcomes were less commonly reported (included in 5 studies). Safety outcomes may have been previously reported and were not included in articles identified for this Rapid Review. Hospitalization outcomes were reported in 2 trials, and mortality results were not reported separately in any trial.

Outcomes for subgroups are summarized in Appendix 8 in Tables 14, 16, 17, 18, 19, and 20. Although trials that enrolled individuals with a specific subtype of asthma may have also characterized other subtype characteristics (e.g., enrolled a type 2 eosinophilic population but also characterized allergic status of the population), outcomes were infrequently reported for many specific subgroups (Table 14). Outcomes reported by specific subgroups of asthma are shown in Table 14; outcomes for non–type 2 inflammation were rarely reported (i.e., only 2 of 11), and outcomes by characterization of both eosinophilic status and allergic status were infrequent (5 of 11).

Reporting of trial outcome measures by biologic drug (benralizumab, dupilumab, mepolizumab, and tezepelumab) and type 2 eosinophilic asthma subgroups are presented based on characterization by BEC level (Table 17) and fractional exhaled nitric oxide level (Table 18). Only trials that investigated tezepelumab reported type 2 eosinophilic asthma classified by fractional exhaled nitric oxide levels.

Type 2 allergic asthma subgroups were challenging to assess because a standardized method of characterizing allergic status was not consistently used. Therefore, outcomes for type 2 allergic asthma subtypes are presented in 2 different formats of characterization. Omalizumab eligibility criteria subgroups were reported in Table 19, and other allergic marker subgroups were reported in Table 20). AEX was almost always reported (41 of 47 reported subgroups), and FEV₁ and HRQoL were reported for approximately half of extracted 47 subgroup results. No other outcomes were reported for the asthma subgroupings.

Systematic Reviews

Details regarding reported outcomes from the systematic reviews can be found in Appendix 8. Definitions of AEX in the reviews are listed in Table 21. These reviews and meta-analyses reported outcomes on few of the patient subgroups (Table 22) while reporting 20 primary patient population and drug intervention combinations (Table 23). Outcomes were also reported for 23 subgroup and drug intervention combinations (Table 24). Subgroups were stratified primarily by BEC level or fractional exhaled nitric oxide level, by adult and pediatric populations for omalizumab, and by severe asthma type 2 allergic subgroup for tezepelumab. In the primary patient populations, AEX outcomes were consistently reported (95%; 19 of 20 reviews), whereas FEV₁ and HRQoL were reported in 13 reviews (65%). Safety outcomes were reported in 11 out of 20 reviews (55%). In the subgroups, AEX outcomes were consistently reported (100%; 23 of 23 subgroups reported), whereas FEV₁ (26%; 6 of 23 subgroups reported), HRQoL (13%; 3 of 23 subgroups reported), and safety (9%; 2 of 23 subgroups reported) were reported less frequently.

The identified comparative efficacy reviews (network meta-analyses, indirect treatment comparisons, matching-adjusted indirect comparisons) reported outcomes on 27 primary patient population and drug intervention combinations, as well as 50 subgroup and drug intervention combinations. Eosinophilic subgroups (determined by BEC levels in 34 instances, and fractional exhaled nitric oxide levels in 12 instances) were reported in 46 instances, and allergic subgroups (with unclear cut-offs) were reported in 4 instances (Table 25 and Table 26). In the primary patient population, AEX outcomes were consistently reported (88%; 24 of 27 reviews), whereas FEV₁ (44%; 12 instances), HRQoL (30%; 8 of 27 reviews), safety (26%; 7 of 27), and hospitalization (19%; 5 of 27 reviews) outcomes were reported less frequently. Similarly, in the subgroups, AEX outcomes were consistently reported (100%; 50 instances), whereas FEV₁ (36%; 18 of 50 subgroups reported) and HRQoL (16%; 8 of 50 subgroups reported) were reported less frequently. All 10 systematic reviews that included a comparative efficacy component reported AEX outcomes in the primary patient population; FEV₁ was reported in 5 reviews, HRQoL in 4 reviews, safety in 3 reviews, and hospitalizations in 1 review (Table 27). Half the systematic reviews that included a comparative efficacy component also reported outcomes in a combined 17 subgroups (Table 28). Subgroups were stratified primarily by BEC level (9 subgroups reported) or fractional exhaled nitric oxide level (6 subgroups reported); an allergic subgroup (with unclear cut-offs) and a subgroup based on oral corticosteroid use status were also assessed. All subgroups reported AEX outcomes. FEV₁ was reported in 10 subgroups, HRQoL in 8 subgroups, and safety in 1 subgroup; hospitalizations were not reported.

Critical Appraisal

Randomized Controlled Trials

All identified trials had clear study objectives, intervention(s), comparators, and outcomes. Trial registration information was provided, and no significant deviations from the planned studies were noted. However, specific details about the characteristics of enrolled populations were reported inconsistently, and several publications lacked sufficient information about how severe asthma was defined and characterized. In these cases, trial registration information was used to determine enrolment criteria. The variability of the enrolled populations was increased in the included trials because they were conducted during a period when there were shifting standards for the diagnosis of severe asthma.

A Cochrane risk of bias assessment (second version¹⁷) was conducted, and the results are shown in Table 5. Our assessment did not identify any high levels of concern for bias. Overall, 4 trials had a low level of concern for bias (ANDHI, NCT02049294, NAVIGATOR, and PATHWAY), and 9 had some level of concern for bias (CALIMA [domains 3 and 5], SIROCCO [domains 3 and 5], SOLANA [domain 1], LIBERTY ASHTMA VENTURE [domain 4], MENSA [domain 5], MUSCA [domain 5], EXTRA [domains 3 and 5], NCT01202903 [domain 3], and SOURCE [domains 4 and 5]). Most of the potential sources of bias were concentrated in a few domains, particularly domain 3 (bias due to missing outcome data), although it was unlikely that the extent of missing data could offset the reported differences in key outcomes, and domain 5 (bias in selection of overall result) that was related to the selection of results based on the number of planned analyses and what was presented in the final publications. The LIBERTY ASTHMA VENTURE and SOURCE trials had levels of some concern within domain 4 (bias in the measurement of outcomes), and the SOLANA trial had some level of concern within domain 1 (bias arising from the randomization process) due to an unclear description of the randomization process in the manuscript. These concerns were unlikely to significantly bias the results in a way that would negate the observed outcomes for the investigated biologics.

Thirteen of the included systematic reviews also conducted Cochrane risk of bias assessments on the included RCTs.^{15,16,44-46,51,54-56,58,59,61,62} Their findings were similar to our assessment, with the exception of Agache et al. who rated some of the trials (CALIMA, SIROCCO, LIBERTY ASTHMA VENTURE, MENSA, and MUSCA) as having high levels of concern in the domains of attrition, reporting, and/or other bias.^15,16,44 However, the rationale for these ratings was unclear.

The various subtypes of severe asthma were not consistently reported. Various studies defined subtypes (such as type 2 eosinophilic or allergic) differently and used different criteria. For example, there were varying thresholds of eosinophil counts to define type 2 eosinophilic asthma (refer to Appendix 8, Table 17 and Table 18). More recent trials focused on patients with severe asthma without restrictions for asthma subtype, while older trials tended to focus on specific asthma subtypes with broader criteria for asthma severity. The internal validity of these trials appears to be acceptable based on our assessments. However, the variation in trial inclusion criteria and protocols limits generalization across trials and outside of the inclusion criteria.

Table 5: Risk of Bias Assessment for Included Randomized Controlled Trials

NR = not reported.

Note: Overall bias was assessed using “'low,” “'some,” and “high” concerns. Information within published articles was cross-referenced to protocols published on clinicaltrials.gov.

^aDefinitions of risk of bias domains: Domain 1 = Bias arising from the randomization process. Domain 2 = Bias due to deviations from intended intervention. Domain 3 = Bias due to missing outcome data. Domain 4 = Bias in measurement of outcome. Domain 5 = Bias in selection of overall result.

Systematic Reviews

Similar to individual RCTs, many systematic reviews did not provide a clear description of the included patient populations. In many cases, it was unclear whether the reviews included similar populations. Despite the inclusion and exclusion restrictions applied by the systematic reviews, issues with population variation persisted. Some of the biologics were extensively tested among subgroups of asthma patients, but this occurred without complete characterization, such as type 2 eosinophilic asthma without characterization of allergic status. Despite this issue, biologic drugs were compared with one another in some reviews. Some studies recognized this issue and used sample adjustment methods, such as filtering, matching, and/or weighting, to minimize population differences.

All the included systematic reviews underwent an AMSTAR 2 assessment (refer to Table 29). The framework proposed by Shea et al.¹⁸ was used to inform an overall level of confidence (high, moderate, low, critically low) in the results of the systematic reviews based on critical and noncritical domains of weakness. Based on the AMSTAR 2 assessment, the levels of confidence in results of the systematic reviews were considered to be high in 3 reviews,^15,16,44 moderate in 2 reviews,^52,53 and low or critically low in the remaining 16 reviews. A full description of the AMSTAR 2 assessment is detailed subsequently.

Of the critical domains (AMSTAR 2 items 1, 2, 4, 9, 11, 13, and 15), all the 21 included systematic reviews adequately described their PICO criteria (item 1). However, 13 reviews did not provide sufficient justification for their search strategy, such as language restriction justification (item 4).^{45-49,51,54,57-62} Although the majority of reviews published their protocols before commencing the review (item 2), 9 reviews did not follow this practice,^{46,48,49,51,54-56,60,62} which suggests a potential risk of bias due to ad hoc study decisions. In the majority of reviews, a satisfactory approach for assessing the risk of bias was used (item 9). However, 9 did not account for risk of bias when interpreting the results of the review (item 13).^{47-51,54,59,60,62} The application of meta-analytic methods was appropriate (item 11) with the exception of 1 review⁵¹ that employed unsuitable methods (converted rate outcomes into binary outcomes so that odds ratios could be reported). Nine reviews did not report sufficient exploration of potential publication bias (item 15).^{47-50,55-57,59,62} However, this omission may have been due to the small number of included trials, which prevented this assessment.

In the case of noncritical domains (AMSTAR 2 items 3, 5, 6, 7, 8, 10, 12, 14, and 16), numerous reviews did not meet several of these criteria. None of the authors of the systematic reviews explained their rationale for selecting only RCTs for inclusion (item 3). Although study selection was always performed in duplicate (item 5), data extraction was not described as being performed in duplicate in 10 of the reviews (item 6).^{46,48,49,51,54-56,58,60,62} Only systematic reviews performed by Agache et al.^15,16,44 provided a list of excluded studies and the reasons for their exclusion (item 7). Only 1 study failed to describe the included studies in enough detail (item 8).⁵⁹ Furthermore, these were the only reviews that assessed the sources of funding for included studies and whether they might introduce bias (item 10). Eight reviews did not assess possible effects of risk of bias on results (item 12).^{46-51,54,59,60} Heterogeneity observed in the results of the reviews was not sufficiently discussed in 6 reviews.^47-50,54,59 In 9 reviews, potential relevant conflicts of interests were not sufficiently detailed to determine whether safeguards against conflicts were taken (item 16).^{15,16,44,47-51,57}

Findings

Our analysis of the included 47 articles indicated that biologics appeared to be effective across important clinical (AEX, FEV₁) and patient-reported outcomes (HRQoL) for their current indications with similar outcomes for safety. However, there were gaps in the evidence for each of these drugs among the subgroups of severe asthma (type 2 inflammation further characterized by eosinophilic and allergic markers, and non–type 2 asthma). Assessment of the comparative efficacy of biologic drugs was challenging due to heterogenous definitions of asthma severity and inconsistent application of severity criteria in RCTs, and therefore remains uncertain. Evidence on comparative safety is limited. There was also a lack of evidence on the efficacy and safety of these biologics in severe asthma among children.

Included RCTs enrolled primarily a type 2 inflammatory phenotype patient population (Table 3). Further characterization of this study population by subtype was performed in some studies (e.g., reporting on allergic status in a study that targeted enrolment of a type 2 eosinophilic population), although outcome reporting by asthma subgroups was incomplete (Table 14). Table 30 summarizes the main findings and evidence gaps for the 5 biologics of interest, and Table 31 provides a summary of findings for asthma subgroups (severe asthma, type 2 eosinophilic and/or allergic, and non–type 2).

Mepolizumab and omalizumab had the largest evidence gaps due to trials including only 1 specific asthma subtype. Mepolizumab was only evaluated in type 2 eosinophilic severe asthma; evidence for patients with a type 2 eosinophilic and allergic asthma subtype was also reported (Table 16), but results in a type 2 allergic and noneosinophilic subgroup was not available. Omalizumab was exclusively studied in patients with type 2 allergic severe asthma. Efficacy by eosinophilic status (high or low BEC) was not commonly reported (Table 16).

Eosinophilic status in severe asthma was frequently characterized by BEC levels in both the RCTs and systematic reviews. Although the results generally favoured the intervention across BEC levels, the low BEC subgroups were less likely to be statistically significant. Subgroups for type 2 allergic asthma were regularly reported from trial data in eosinophilic and severe asthma populations, however, the classification of this subtype was less consistent. Few systematic reviews examined this subtype.

In the few trials that enrolled individuals with severe asthma who had a non–type 2 inflammatory phenotype, benralizumab, dupilumab, and tezepelumab were investigated. The trials evaluating benralizumab and tezepelumab reported outcomes in this subtype. These biologics consistently demonstrated a statistically significant improvement in AEX compared to placebo (Table 16). A cut-off of less than 300 BEC was used for benralizumab; however, a cut-off of less than 150 BEC would more clearly identify non–type 2 patients. The direction of this effect was maintained for tezepelumab in a recent re-analysis of the PATHWAY and NAVIGATOR trials⁹ within a narrow subgroup (N = 96) that more rigorously classified non–type 2 asthma by also including only those with fractional exhaled nitric oxide less than 25 parts per billion (in addition to < 150 BEC and perennial allergies). The reported between-group difference in AEX in this small sample size was not statistically significant.

Among the included RCTs that evaluated the use of biologics in patients with severe asthma, some studies recruited participants younger than 18 years but only a small portion were confirmed as children (n = 229, 3% of the included trial participants). Reporting of outcomes for participants younger than 18 years was infrequent, with only 1 review¹⁵ reporting outcomes within this population (pediatric patients with type 2 allergic asthma with omalizumab investigated). A number of studies that evaluated efficacy and safety of biologics in moderate to severe asthma among pediatric populations are listed in Appendix 6 for reference.

Included systematic reviews were consistent with our assessment of the current evidence, with main clinical outcomes and HRQoL generally favouring biologics over placebos (Table 23). Reviews also generally did not identify any risk of serious adverse events, with only 1 review finding a statistically significant risk of adverse events for mepolizumab.¹⁶ Assessment of subgroups was more limited in reviews than in published articles on RCTs.

Among the included systematic reviews, 10 reported on comparative efficacy (Table 25). These reviews examined populations that were broadly classified as severe asthma or were based on eosinophilic criteria, without specific characterization of allergic status and limited by a lack of direct comparisons (indirect comparison with attendant limitations). Most comparisons did not reveal significant differences between the included drugs in the targeted patient populations of interest. Although these reviews selected pertinent trials and effectively summarized main study outcomes, they lacked systematic subgroup assessments and often did not fully account for population variations across the trials. In light of these limitations, statistical adjustments were made in some reviews to better compare dissimilar populations (although inconsistencies remained), and some statistically significant differences were found in some of those studies. Benralizumab, mepolizumab, and omalizumab were inferior to tezepelumab and dupilumab in some reviews listed as including trials of type 2 eosinophilic or severe asthma not otherwise. Mepolizumab was superior to benralizumab in HRQoL outcomes and superior to dupilumab in safety outcomes in some reviews of type 2 eosinophilic asthma trials. However, given the underlying heterogeneity across trials, comparative effectiveness between biologics is still uncertain. Subgroup analyses were mostly consistent with overall group results.

Limitations

This was a focused rapid systematic review that searched articles in English that were recently published (from 2018 onward); a more fulsome review may have identified additional studies. Severity of asthma was inconsistently defined. Many trials that studied patients with moderate to severe asthma that were not clearly “severe” asthma were excluded. Handsearching was limited due to the nature of this study; however, PROSPERO and clinical trial registries were checked (including any linked studies listed on the registries). Results of RCTs are reported as simplified positive or negative outcomes with significance noted as a means of simplifying the large volume of complex data, and because of potential variation in effect sizes due to differences in baseline populations. This analysis did not adjust for any potential concerns related to multiple testing or reporting bias due to the substantial number of outcomes that are frequently recorded and published from the included RCTs.

This review was intended to identify and quickly map the available evidence from recent RCTs and systematic reviews. Therefore, an in-depth extraction of specific effect sizes or a meta-analysis or comparative efficacy testing were not performed.

Conclusions and Implications for Decision- or Policy-Making

Conclusions

• Recent RCTs and systematic reviews (published in 2018 onward) predominately focused on a limited range of severe asthma subtypes. Children were infrequently included. Outcome reporting for biologic drugs by the subtypes of severe asthma and by age was limited.

• In this review, most participants included in RCTs were those with primarily type 2 eosinophilic severe asthma. Biologics indicated for this subtype demonstrated benefit for this patient population (benralizumab, dupilumab, mepolizumab, and tezepelumab) and this benefit may extend to those who also have markers of allergic asthma (type 2 eosinophilic and allergic).

• Included systematic reviews that assessed comparative efficacy primarily included trials on the type 2 eosinophilic asthma population. Although conclusions were heterogenous, most found no significant differences among the biologics assessed. Conclusions were limited by population characterization, power, and method (indirect treatment comparison).

• Biologics studied in type 2 allergic asthma, other than omalizumab (indicated for this patient population), were limited by variable definition of this subtype. Although there was limited evidence, tezepelumab was shown to be effective in a type 2 allergic severe asthma population defined by the same criteria indicated for omalizumab. Dupilumab was shown to be statistically significantly better for some outcomes compared to omalizumab in an indirect treatment comparison conducted in included systematic reviews in which the dupilumab data were adjusted to match the population from omalizumab trials. However, clinical relevance and validity of this result is uncertain.

• There was limited research on the non–type 2 severe asthma population. No trial specifically enrolled individuals with this phenotype. Among a small number of participants with non–type 2 severe asthma, benralizumab and tezepelumab reported positive outcomes (consistently showed a statistically significant reduction in AEXs compared with placebo). However, the benralizumab analysis used a higher than normal BEC level as their cut-off point, which limits clinical interpretation.

• There is evidence from subgroup analyses in the PATHWAY and NAVIGATOR studies on tezepelumab that patients with non–type 2 asthma, defined rigorously as those with BEC less than 150 cells/µL, fractional exhaled nitric oxide less than 25 parts per billion, and negative perennial allergy skin tests, may benefit from treatment with tezepelumab. However, data showing efficacy for the other biologic therapies in this subgroup are lacking.

• There was insufficient evidence to inform efficacy and safety of biologics in pediatric populations with severe asthma. Full assessment of efficacy and safety would require using subject-specific characteristics (to identify age if not reported) but is likely to be challenging given access to data and the small numbers of children enrolled. Studies on the efficacy and safety of biologics in pediatric populations with moderate to severe asthma have been conducted and could contribute to further evidence synthesis.

• Conduct of de novo evidence synthesis would be constrained by incomplete inclusion, characterization, and outcome reporting of study populations by both type 2 allergic and eosinophilic subtypes for each biologic, and small numbers of identified children enrolled in trials. This is unlikely to result in evidence to inform alignment of criteria of biologics in severe asthma.

• Overall, biologic drugs are better than placebo across all outcomes for their respective indications. However, comparative efficacy of biologics for these indications is uncertain, and evidence on comparative safety is limited.

Implications for Decision- or Policy-Making

• In this part 1 Rapid Review, potential comparative efficacy and safety analysis to answer the proposed research and policy questions is limited by lack of similar eligibility criteria and outcome reporting for all asthma subtypes and patient populations, especially pediatric populations.

• Part 2 was to be an HTA to provide guidance concerning the alignment of the drug funding criteria by the public drug plans. Based on the findings of part 1, it is highly unlikely that further evidence synthesis using data from available trials would generate policy-relevant conclusions. As such, CADTH will not proceed with part 2 (the HTA).

References

1.Mayo Clinic. Diseases and conditions. Asthma. 2022; https://www.mayoclinic.org/diseases-conditions/asthma/symptoms-causes/syc-20369653 Accessed 2023 Dec 8.

2.Reihman AE, Holguin F, Sharma S. Management of severe asthma beyond the guidelines. Curr Allergy Asthma Rep. 2020;20(9). PubMed

3.American Academy of Allergy Asthma & Immunology. Severe asthma. 2019; https://www.aaaai.org/tools-for-the-public/conditions-library/asthma/severe-asthma. Accessed 2023 Dec 8.

4.Asthma Canada. Severe asthma. 2022; https://asthma.ca/get-help/severe-asthma/. Accessed 2023 Dec 3.

5.Globe G, Martin M, Schatz M, et al. Symptoms and markers of symptom severity in asthma—content validity of the asthma symptom diary. Health Qual Life Outcomes. 2015;13(1):21. PubMed

6.Ismaila AS, Sayani AP, Marin M, Su Z. Clinical, economic, and humanistic burden of asthma in Canada: a systematic review. BMC Pulm Med. 2013;13(1):70. PubMed

7.Chen W, Safari A, Fitzgerald JM, Sin DD, Tavakoli H, Sadatsafavi M. Economic burden of multimorbidity in patients with severe asthma: a 20-year population-based study. Thorax. 2019;74(12):1113-1119. PubMed

8.Chen M, Shepard K, Yang M, et al. Overlap of allergic, eosinophilic and type 2 inflammatory subtypes in moderate‐to‐severe asthma. Clin Exp Allergy. 2021;51(4):546-555. PubMed

9.Corren J, Menzies-Gow A, Chupp G, et al. Efficacy of tezepelumab in severe, uncontrolled asthma: pooled analysis of PATHWAY and NAVIGATOR studies. Am J Respir Crit Care Med. 2023;04:04.

10.Thomson NC. Novel approaches to the management of noneosinophilic asthma. Ther Adv Respir Dis. 2016;10(3):211-234. PubMed

11.FitzGerald JM, Bleecker ER, Menzies-Gow A, et al. Predictors of enhanced response with benralizumab for patients with severe asthma: pooled analysis of the SIROCCO and CALIMA studies. Lancet Respir Med. 2018;6(1):51-64. PubMed

12.Hsieh A, Assadinia N, Hackett TL. Airway remodeling heterogeneity in asthma and its relationship to disease outcomes. Front Physiol. 2023;14:1113100. PubMed

13.Canonica GW, Blasi F, Paggiaro P, et al. Oral corticosteroid sparing with biologics in severe asthma: a remark of the Severe Asthma Network in Italy (SANI). World Allergy Organ J. 2020;13(10):100464. PubMed

14.pan-Canadian Pharmaceutical Alliance. Cinqair (reslizumab). 2018; https://www.pcpacanada.ca/negotiation/20781. Accessed 2023 Sept 28.

15.Agache I, Rocha C, Beltran J, et al. Efficacy and safety of treatment with biologicals (benralizumab, dupilumab and omalizumab) for severe allergic asthma: A systematic review for the EAACI Guidelines - recommendations on the use of biologicals in severe asthma. Allergy. 2020b;75(5):1043-1057. PubMed

16.Agache I, Beltran J, Akdis C, et al. Efficacy and safety of treatment with biologicals (benralizumab, dupilumab, mepolizumab, omalizumab and reslizumab) for severe eosinophilic asthma. A systematic review for the EAACI Guidelines - recommendations on the use of biologicals in severe asthma. Allergy. 2020a;75(5):1023-1042. PubMed

17.Sterne JAC, Savovic J, Page MJ, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. 2019;366:l4898. PubMed

18.Shea BJ, Reeves BC, Wells G, et al. AMSTAR 2: a critical appraisal tool for systematic reviews that include randomised or non-randomised studies of healthcare interventions, or both. BMJ. 2017;358:j4008. PubMed

19.Brusselle GG, Koppelman GH. Biologic therapies for severe asthma. N Engl J Med. 2022;386(2):157-171. PubMed

20.Albers FC, Licskai C, Chanez P, et al. Baseline blood eosinophil count as a predictor of treatment response to the licensed dose of mepolizumab in severe eosinophilic asthma. Respir Med. 2019;159:105806. PubMed

21.Bleecker ER, Wechsler ME, FitzGerald JM, et al. Baseline patient factors impact on the clinical efficacy of benralizumab for severe asthma. Eur Respir J. 2018;52(4):10. PubMed

22.Brusselle G, Quirce S, Papi A, et al. Dupilumab efficacy in patients with uncontrolled or oral corticosteroid-dependent allergic and nonallergic asthma. J Allergy Clin Immunol Pract. 2023;11(3):873-884 e811. PubMed

23.Chipps BE, Newbold P, Hirsch I, Trudo F, Goldman M. Benralizumab efficacy by atopy status and serum immunoglobulin E for patients with severe, uncontrolled asthma. Ann Allergy Asthma Immunol. 2018;120(5):504-511.e504. PubMed

24.Corren J, Ambrose CS, Griffiths JM, et al. Efficacy of tezepelumab in patients with evidence of severe allergic asthma: results from the phase 3 NAVIGATOR study. Clin Exp Allergy. 2023;53(4):417-428. PubMed

25.Corren J, Ambrose CS, Salapa K, et al. Efficacy of tezepelumab in patients with severe, uncontrolled asthma and perennial allergy. J Allergy Clin Immunol Pract. 2021;9(12):4334-4342.e4336. PubMed

26.Corren J, Chen S, Callan L, Garcia Gil E. The impact of tezepelumab on hospitalization and emergency department visits in patients with severe uncontrolled asthma: results from the pathway phase 2b trial. Am J Respir Crit Care Med. 2019;199(9).

27.Corren J, Garcia Gil E, Griffiths JM, et al. Tezepelumab improves patient-reported outcomes in patients with severe, uncontrolled asthma in PATHWAY. Ann Allergy Asthma Immunol. 2021;126(2):187-193. PubMed

28.Corren J, Pham TH, Garcia Gil E, et al. Baseline type 2 biomarker levels and response to tezepelumab in severe asthma. Allergy. 2022;77(6):1786-1796. PubMed

29.Domingo C, Maspero JF, Castro M, et al. Dupilumab efficacy in steroid-dependent severe asthma by baseline oral corticosteroid dose. J Allergy Clin Immunol Pract. 2022;10(7):1835-1843. PubMed

30.Hanania NA, Fortis S, Haselkorn T, et al. Omalizumab in asthma with fixed airway obstruction: post hoc analysis of EXTRA. J Allergy Clin Immunol Pract. 2022;10(1):222-228. PubMed

31.Harrison TW, Chanez P, Menzella F, et al. Onset of effect and impact on health-related quality of life, exacerbation rate, lung function, and nasal polyposis symptoms for patients with severe eosinophilic asthma treated with benralizumab (ANDHI): a randomised, controlled, phase 3b trial. Lancet Respir Med. 2021;9(3):260-274. PubMed

32.Humbert M, Albers FC, Bratton DJ, et al. Effect of mepolizumab in severe eosinophilic asthma according to omalizumab eligibility. Respir Med. 2019;154:69-75. PubMed

33.Jackson DJ, Humbert M, Hirsch I, Newbold P, Garcia Gil E. Ability of serum IgE concentration to predict exacerbation risk and benralizumab efficacy for patients with severe eosinophilic asthma. Adv Ther. 2020;37(2):718-729. PubMed

34.Lemiere C, Taille C, Lee JK, et al. Impact of baseline clinical asthma characteristics on the response to mepolizumab: a post hoc meta-analysis of two Phase III trials. Respir Res. 2021;22(1):184. PubMed

35.Li J, Wang C, Liu C, et al. Efficacy predictors of omalizumab in Chinese patients with moderate-to-severe allergic asthma: Findings from a post-hoc analysis of a randomised phase III study. World Allergy Organ J. 2020;13(12):100469. PubMed

36.Menzies-Gow A, Corren J, Bourdin A, et al. Tezepelumab in adults and adolescents with severe, uncontrolled asthma. N Engl J Med. 2021;384(19):1800-1809. PubMed

37.Menzies-Gow A, Wechsler ME, Brightling CE, et al. Long-term safety and efficacy of tezepelumab in people with severe, uncontrolled asthma (DESTINATION): a randomised, placebo-controlled extension study. Lancet Respir Med. 2023;23:23. PubMed

38.Mukherjee M, Kjarsgaard M, Radford K, et al. Omalizumab in patients with severe asthma and persistent sputum eosinophilia. Allergy Asthma Clin Immunol. 2019;15:21. PubMed

39.Panettieri RA, Jr., Welte T, Shenoy KV, et al. Onset of effect, changes in airflow obstruction and lung volume, and health-related quality of life improvements with benralizumab for patients with severe eosinophilic asthma: phase iiib randomized, controlled trial (SOLANA). J Asthma Allergy. 2020;13:115-126. PubMed

40.Prazma CM, Idzko M, Douglass JA, et al. Response to mepolizumab treatment in patients with severe eosinophilic asthma and atopic phenotypes. J Asthma Allergy. 2021;14:675-683. PubMed

41.Rabe KF, Nair P, Brusselle G, et al. Efficacy and safety of dupilumab in glucocorticoid-dependent severe asthma. N Engl J Med. 2018;378(26):2475-2485. PubMed

42.Wardlaw A, Howarth PH, Israel E, et al. Fungal sensitization and its relationship to mepolizumab response in patients with severe eosinophilic asthma. Clin Exp Allergy. 2020;50(7):869-872. PubMed

43.Wechsler ME, Menzies-Gow A, Brightling CE, et al. Evaluation of the oral corticosteroid-sparing effect of tezepelumab in adults with oral corticosteroid-dependent asthma (SOURCE): a randomised, placebo-controlled, phase 3 study. Lancet Respir Med. 2022;10(7):650-660. PubMed

44.Agache I, Song Y, Rocha C, et al. Efficacy and safety of treatment with dupilumab for severe asthma: A systematic review of the EAACI guidelines-Recommendations on the use of biologicals in severe asthma. Allergy. 2020c;75(5):1058-1068. PubMed

45.Akenroye A, Lassiter G, Jackson JW, et al. Comparative efficacy of mepolizumab, benralizumab, and dupilumab in eosinophilic asthma: A Bayesian network meta-analysis. J Allergy Clin Immunol. 2022;150(5):1097-1105.e1012. PubMed

46.Ando K, Fukuda Y, Tanaka A, Sagara H. Comparative efficacy and safety of tezepelumab and other biologics in patients with inadequately controlled asthma according to thresholds of type 2 inflammatory biomarkers: A systematic review and network meta-analysis. Cells. 2022;11(5). PubMed

47.Bateman ED, Khan AH, Xu Y, et al. Pairwise indirect treatment comparison of dupilumab versus other biologics in patients with uncontrolled persistent asthma. Respir Med. 2022;191:105991. PubMed

48.Bourdin A, Husereau D, Molinari N, et al. Matching-adjusted comparison of oral corticosteroid reduction in asthma: systematic review of biologics. Clin Exp Allergy. 2020;50(4):442-452. PubMed

49.Busse W, Chupp G, Nagase H, et al. Anti-IL-5 treatments in patients with severe asthma by blood eosinophil thresholds: Indirect treatment comparison. J Allergy Clin Immunol. 2019;143(1):190-200.e120. PubMed

50.Chagas GCL, Xavier D, Gomes L, Ferri-Guerra J, Oquet REH. Effects of tezepelumab on quality of life of patients with moderate-to-severe, uncontrolled asthma: Systematic review and meta-analysis. Curr Allergy Asthma Rep. 2023;23(6):287-298. PubMed

51.Chen C, Wen T, Wei L. Different IL-5 monoclonal antibody agents in treating severe asthma patients: a systemic review and network meta-analysis of randomized controlled trials (RCTs). Int J Clin Exp Med. 2019;12(6):6512-6519.

52.Henriksen DP, Bodtger U, Sidenius K, et al. Efficacy, adverse events, and inter-drug comparison of mepolizumab and reslizumab anti-IL-5 treatments of severe asthma - a systematic review and meta-analysis. Eur Clin Respir J. 2018;5(1):1536097. PubMed

53.Henriksen DP, Bodtger U, Sidenius K, et al. Efficacy of omalizumab in children, adolescents, and adults with severe allergic asthma: a systematic review, meta-analysis, and call for new trials using current guidelines for assessment of severe asthma. Allergy Asthma Clin Immunol. 2020;16:49. PubMed

54.Lee J, Song J-U, Kim YH. The clinical efficacy of type 2 inflammation-specific agents targeting interleukins in reducing exacerbations in severe asthma: a meta-analysis. Yonsei Med J. 2022;63(6):511-519. PubMed

55.Mahdavian M, Brothers C, Asghari S, Mallay S, Pike J. Impact of benralizumab on asthma control, asthma-related quality of life and lung function in patients with poorly controlled eosinophilic asthma: A systematic review and meta-analysis. Can J Respir Crit Care Sleep Med. 2019;3(2):106-111.

56.Mahdavian M, Mallay SA, Asghari S, Voduc N, Pike JC. Effect of benralizumab on asthma exacerbation rates in patients with severe asthma: Systematic review and meta-analysis. Can J Respir Crit Care Sleep Med. 2020;4(2):133-141.

57.Menzies-Gow A, Steenkamp J, Singh S, et al. Tezepelumab compared with other biologics for the treatment of severe asthma: a systematic review and indirect treatment comparison. J Med Econ. 2022;25(1):679-690. PubMed

58.Nopsopon T, Lassiter G, Chen ML, et al. Comparative efficacy of tezepelumab to mepolizumab, benralizumab, and dupilumab in eosinophilic asthma: A Bayesian network meta-analysis. J Allergy Clin Immunol. 2023;151(3):747-755. PubMed

59.Praetorius K, Henriksen DP, Schmid JM, et al. Indirect comparison of efficacy of dupilumab versus mepolizumab and omalizumab for severe type 2 asthma. ERJ Open Res. 2021;7(3). PubMed

60.Ramonell RP, Iftikhar IH. Effect of anti-IL5, anti-IL5R, anti-IL13 therapy on asthma exacerbations: A network meta-analysis. Lung. 2020;198(1):95-103. PubMed

61.Shaban Abdelgalil M, Ahmed Elrashedy A, Awad AK, et al. Safety and efficacy of tezepelumab vs. placebo in adult patients with severe uncontrolled asthma: a systematic review and meta-analysis. Sci Rep. 2022;12(1):20905. PubMed

62.Zoumot Z, Al Busaidi N, Tashkandi W, et al. Tezepelumab for patients with severe uncontrolled asthma: a systematic review and meta-analysis. J Asthma Allergy. 2022;15:1665-1679. PubMed

63.Chung KF, Wenzel SE, Brozek JL, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J. 2014;43(2):343-373. PubMed

64.Reddel HK, Bacharier LB, Bateman E, et al. Global Initiative for Asthma Strategy 2021: executive summary and rationale for key changes. Am J Respir Crit Care Med. 2022;205(1):17-35. PubMed

Authors and Contributors

Jason R. Randall was involved with conception and design and drafted the original project protocol; screening studies, data extraction, and data analysis; and drafting and revising of the report.

Richard Leigh provided content input to analysis and interpretation of data, key messages, and conclusions and provided revisions on the initial draft and on subsequent revisions for important intellectual content.

Ellen T. Crumley conducted all searches, was the second screener of all results, provided details about how to write up searches, and read the final report and suggested edits.

Sylvia Aponte-Hao contributed to the systematic review, data extraction, and data analysis of the study and reviewed the report.

Ngoc Khanh Vu participated in the development of the study protocol and data collection tools, data collection by extracting information from papers, contributed to the contents of the report, and provided comments for report draft and revisions.

Karen Martins provided substantial contributions to interpretation of study results, including the key messages and conclusion, and contributed to revising the report critically for important intellectual content.

Scott Klarenbach was the senior author and investigator and was involved in the conception, study design, oversight of data acquisition and analysis, critical revision of report including policy implications, and oversight of the project.

Contributors

Content Expert

This individual kindly provided comments on this report:

Karen E. Binkley, HBSc MD FRCPC

Associate Professor

Divisions of Clinical Immunology and Allergy and Clinical Pharmacology, University of Toronto

Acknowledgements

CADTH would like to acknowledge the following individuals:

Christine Perras and David Stock reviewed the drafts and final report.

Emily Farrell provided knowledge mobilization support.

Brandy Appleby provided project management support.

Sarah C. McGill conducted a quality check of the references.

Conflicts of Interest

Jason R. Randall disclosed the following:

Current employment

• Real World Evidence Unit, University of Alberta, 2022 to 2024, various drugs and technologies

Ellen T. Crumley disclosed the following:

Payment as advisor or consultant

• Liv Agency – Upadacitinib, 2022: Wrote report from recording of live consultancy meeting.

• Fusion MD Network – Avelumab, 2022: Attended and wrote report from live consultancy meeting.

Scott Klarenbach disclosed the following:

Research funding or grants

• Real World Evidence Consortium (via Bayer) – Outcomes in diabetic kidney disease

• Alberta Drug and Technology Evidence Consortium with funding from CADTH – CoLab PMDE Core Network Partner

• Real World Evidence Unit and Real World Evidence Consortium (RWEU and RWEC) through the University Hospital Foundation (UHF) (funding to UHF from Roche) – Pathways of care for multiple sclerosis; DMT use in patients with multiple sclerosis

• RWEU and RWEC with funding from Allergan – Health care resource use in subjects with migraine; pathways of care post stroke; economic impact of discontinuing or reducing injection frequency of botulinum toxin for the treatment chronic migraine.

• RWEU and RWEC with funding from Purdue – Analgesia use in trauma

• RWEU and RWEC with funding from GSK and in Partnership with Respiratory Strategic Clinical Network (AB) – Treatment patterns in patients with COPD

• RWEU and RWEC with funding from CSL – Immunoglobulin use in AB; treatment patterns in dermatomyositis; incremental cost of SCIg versus IVIg

• RWEU and RWEC with funding from Lundbeck – Health care resource use and treatment in depression

• RWEU and RWEC with funding from University Hospital Foundation (funding to UHF from NovoNordisk) – Health care resources use in patients with obesity

• RWEU and RWEC with funding from UHF (funding from UHF from Jansen) – Health care resource use in patients starting long-acting antipsychotics in schizophrenia

• RWEU and RWEC with funding through the University Hospital Foundation (UHF – funding originated from Novartis) – Economic burden of Multiple Sclerosis in Alberta

• RWEC funding through Ferring – Budesonide MMX treatment in ulcerative colitis

• RWEC funding through IQVIA – Completed a feasibility questionnaire related to data availability for evaluating the cost of cadaver islet cell transplant

• RWEC funding through RTI – Completed a feasibility questionnaire related to data availability for evaluating the risk/benefit of a particular drug among those with CKD and cardiovascular morbidity and mortality

• RWEU and RWEC funding through Janssen – Evaluating the feasibility of health system data to generate decision-grade real world evidence in Canada – under review

• RWEU and RWEC funding through Intuitive – Comparative outcomes between different surgical approaches

Karen Martins disclosed the following:

Member of the Alberta Real World Evidence consortium that conducts investigator-initiated research projects and receives funding from industry.

Richard Leigh disclosed the following:

Speaking engagements

• AstraZeneca – Alarmins: 2022–2023

• GlaxoSmithKline – Asthma, Precision Medicine: 2022–2023

• Sanofi – Asthma, Dupilumab: 2022–2023

• Vale – Asthma, inhalers: 2022–2023

Other

• Attendee – Advisory board meetings for AstraZeneca, GlaxoSmithKline, and Sanofi

Payment as advisor or consultant

• AstraZeneca – Asthma, Alarmins: 2018 to 2023

• GlaxoSmithKline – Asthma, precision medicine; biologics: 2018 to 2023

• Sanofi – Asthma, Dupilumab: 2019 to 2023

Research funding or grants

• AstraZeneca – Asthma, Alarmins: 2018 to 2023

• Sanofi – Asthma, Dupilumab: 2019 to 2023

Payment for academic appointments (endowed chairs)

• GlaxoSmithKline - Asthma, Precision Medicine; biologics: 2018 to 2023

• Received honorariums as advisor from AZ, GSK, and Sanofi. University of Calgary has received funding from AZ, GSK, and Sanofi for clinical trials where Richard Leigh is the Site Principal Investigator. The University of Calgary received an endowment from GSK for a Professorship in Inflammatory Lung Disease – Richard Leigh is the current holder of that Professorship but does not benefit from any personal payments from the Professorship (all funds channelled into Operations).

Karen Binkley disclosed the following:

Speaking engagement and educational lecture

• Takeda – Firazyr, Takzhyra

Other – Advisory board member

• Takeda – Firazyr, Takzhyra

• Biocryst – Orladeo

Payment as advisor or consultant

• Medexus – Rupall. Speaker – education lectures on angioedema and urticaria

No other conflicts of interest were declared.

Appendix 1: Approved Indications for Biologics

Note that this appendix has not been copy-edited.

Table 6: Product Information

ICS = inhaled corticosteroids; LABA = long-acting beta agonist; SC = subcutaneous.

Appendix 2: Literature Search Strategy

Note that this appendix has not been copy-edited.

Search Strategies – Final

Updated May 12, 2023

Clinical Trials Registries

Biomed Central. ISRCTN Registry

https://www.isrctn.com/

Searched March 20, 2023, Tezepelumab searched April 13, 2023

Narrowed results to: Condition Category: Respiratory

1. Xolair

2. Omalizumab

3. Nucala

4. Mepolizumab

5. Fasenra

6. Benralizumab

7. Dupilumab

8. Dupixent

Searched April 13, 2023

1. Tezepelumab

2. Tezspire

3. Severe asthma

US National Institutes of Health. ClinicalTrials.gov

https://classic.clinicaltrials.gov/ct2/search/advanced

Searched March 20, 2023

1. (Xolair or omalizumab) and Interventional Studies and severe asthma

2. (Nucala or mepolizumab) and Interventional Studies and severe asthma

3. (Fasenra or benralizumab) and Interventional Studies and severe asthma

4. (Dupilumab or Dupixent) and Interventional Studies and severe asthma

5. (Tezepelumab or Tezspire) and Interventional Studies and severe asthma

Searched April 13, 2023

EU Clinical Trials Register

https://www.clinicaltrialsregister.eu/ctr-search/search

Searched 20 March 2023, Tezepelumab searched 13 April 2023

1. (xolair OR omalizumab OR Nucala OR mepolizumab OR Fasenra OR benralizumab OR Dupilumab OR Dupixent) AND severe asthma

2. (Tezepelumab or Tezspire) AND severe asthma

Searched April 13, 2023

WHO. International Clinical Trials Registry Platform Search Portal (ICTRP)

https://trialsearch.who.int/Default.aspx

Searched April 13, 2023

Narrowed to 2018+

1. (xolair OR omalizumab) AND severe asthma

2. (Nucala OR mepolizumab) AND severe asthma

3. (Fasenra OR benralizumab) AND severe asthma

4. (Dupilumab OR Dupixent) AND severe asthma

5. (Tezepelumab or Tezspire) AND severe asthma

PROSPERO: International prospective register of systematic reviews https://www.crd.york.ac.uk/prospero/

Searched 20 March 2023, Tezepelumab searched 13 April 2023

1. (omalizumab OR xolair OR Nucala OR mepolizumab OR Fasenra OR benralizumab OR Dupilumab OR Dupixent) AND severe asthma AND (Systematic Review OR Meta-Analysis OR Network meta-analysis):RT NOT Animal:DB

2. (Tezepelumab or Tezspire) AND severe asthma AND (Systematic Review OR Meta-Analysis OR Network meta-analysis):RT NOT Animal:DB

Searched April 13, 2023

MEDLINE

Ovid MEDLINE(R) and Epub Ahead of Print, In-Process, In-Data-Review and Other Non-Indexed Citations and Daily 1946 to May 4, 2023

Searched May 8, 2023

1. (nucala* or mepolizumab* or bosatria* or SB240563 or SB-240563 or 90Z2UFOE52).ti,ab,ot,rn,hw,nm,kf. 1323

2. 196078-29-2.rn,nm. 0

3. (Xolair* or omalizumab* or rhuMab-E25 or rhuMabE25 or HSDB 5742 or HSDB5742 or 2P471X1Z11 or UNII2P471X1Z11 or hu 901 or hu901).ti,ab,ot,sh,hw,rn,nm. 3464

4. exp Omalizumab/ 2308

5. (“242138 07 4” or “242138074” or 24213807 4 or “242318 074” or 2421380 74).rn,nm. 0

6. (dupilumab* or dupixent* or regn668 or regn 668 or sar231893 or sar 231893 or 420K487FSG).ti,ab,kf,ot,hw,rn,nm. 2290

7. (Fasenra* or benralizumab* or BIW 8405 or BIW8405 or medi563 or medi 563 or 71492GE1FX).ti,ab,kf,ot,hw,rn,nm. 719

8. (tezepelumab* or Tezspire* or amg-157 or amg157 or medi-9929 or medi9929 or medi-19929 or medi19929 or GTPL-8933 or GTPL8933 or RJ1IW3B4QX).ti,ab,kf,ot,hw,nm,rn. 147

9. or/1-8 6743

10. exp asthma/ 141601

11. asthma*.ti,ab,kf. 180248

12. 10 or 11 200291

13. (severe or eosinophil* or allerg* or type 2 or T2).ti,ab,kf. 1761191

14. exp Eosinophilia/ 27256

15. 13 or 14 1765364

16. 12 and 15 78179

17. 9 and 16 2752

18. (Randomized Controlled Trial or Controlled Clinical Trial or Pragmatic Clinical Trial or Clinical Study or Adaptive Clinical Trial or Equivalence Trial).pt. 689435

19. (Clinical Trial or Clinical Trial, Phase I or Clinical Trial, Phase II or Clinical Trial, Phase III or Clinical Trial, Phase IV or Clinical Trial Protocol).pt. 609848

20. Multicenter Study.pt. 333420

21. Clinical Studies as Topic/ 782

22. exp Clinical Trial/ or exp Clinical Trials as Topic/ or Clinical Trial Protocol/ or Clinical Trial Protocols as Topic/ or exp “Clinical Trial (topic)”/ 1271981

23. Multicenter Study/ or Multicenter Studies as Topic/ or “Multicenter Study (topic)”/ 352706

24. Randomization/ 106927

25. Random Allocation/ 106927

26. Double-Blind Method/ 175065

27. Double Blind Procedure/ 0

28. Double-Blind Studies/ 175065

29. Single-Blind Method/ 32682

30. Single Blind Procedure/ 0

31. Single-Blind Studies/ 32682

32. Placebos/ 35926

33. Placebo/ 0

34. Control Groups/ 1936

35. Control Group/ 1936

36. Cross-Over Studies/ or Crossover Procedure/ 55047

37. (random* or sham or placebo*).ti,ab,hw,kf. 1798183

38. ((singl* or doubl*) adj (blind* or dumm* or mask*)).ti,ab,hw,kf. 266193

39. ((tripl* or trebl*) adj (blind* or dumm* or mask*)).ti,ab,hw,kf. 1582

40. (control* adj3 (study or studies or trial* or group*)).ti,ab,hw,kf. 1911610

41. (clinical adj3 (study or studies or trial*)).ti,ab,hw,kf.1422796

42. (Nonrandom* or non random* or non-random* or quasi-random* or quasirandom*).ti,ab,hw,kf. 54080

43. (phase adj3 (study or studies or trial*)).ti,ab,hw,kf. 176614

44. ((crossover or cross-over) adj3 (study or studies or trial*)).ti,ab,hw,kf. 76401

45. ((multicent* or multi-cent*) adj3 (study or studies or trial*)).ti,ab,hw,kf. 405419

46. allocated.ti,ab,hw. 82977

47. ((open label or open-label) adj5 (study or studies or trial*)).ti,ab,hw,kf. 44243

48. ((equivalence or superiority or non-inferiority or noninferiority) adj3 (study or studies or trial*)).ti,ab,hw,kf. 11909

49. (pragmatic study or pragmatic studies).ti,ab,hw,kf. 596

50. ((pragmatic or practical) adj3 trial*).ti,ab,hw,kf. 7616

51. ((quasiexperimental or quasi-experimental) adj3 (study or studies or trial*)).ti,ab,hw,kf. 11997

52. trial.ti,kf. 304877

53. or/18-52 3769161

54. exp animals/ 26345052

55. exp animal experimentation/ 10316

56. exp models animal/ 639361

57. exp animal experiment/ 10316

58. nonhuman/ 0

59. exp vertebrate/ 25603896

60. or/53-59 26851439

61. exp humans/ 21226470

62. exp human experiment/ 0

63. or/61-62 21226470

64. 60 not 63 5624969

65. 53 not 64 2867628

66. (systematic review or meta-analysis).pt. 309498

67. meta-analysis/ or systematic review/ or systematic reviews as topic/ or meta-analysis as topic/ or “meta analysis (topic)”/ or “systematic review (topic)”/ or exp technology assessment, biomedical/ or network meta-analysis/ 347491

68. ((systematic* adj3 (review* or overview*)) or (methodologic* adj3 (review* or overview*))).ti,ab,kf. 313818

69. ((quantitative adj3 (review* or overview* or synthes*)) or (research adj3 (integrati* or overview*))).ti,ab,kf. 15390

70. ((integrative adj3 (review* or overview*)) or (collaborative adj3 (review* or overview*)) or (pool* adj3 analy*)).ti,ab,kf. 38315

71. (data synthes* or data extraction* or data abstraction*).ti,ab,kf. 39741

72. (handsearch* or hand search*).ti,ab,kf. 11067

73. (mantel haenszel or peto or der simonian or dersimonian or fixed effect* or latin square*).ti,ab,kf. 35193

74. (met analy* or metanaly* or technology assessment* or HTA or HTAs or technology overview* or technology appraisal*).ti,ab,kf. 12007

75. (meta regression* or metaregression*).ti,ab,kf. 14284

76. (meta-analy* or metaanaly* or systematic review* or biomedical technology assessment* or bio-medical technology assessment*).mp,hw. 459513

77. (medline or cochrane or pubmed or medlars or embase or cinahl).ti,ab,hw. 335574

78. (cochrane or (health adj2 technology assessment) or evidence report).jw. 21358

79. (comparative adj3 (efficacy or effectiveness)).ti,ab,kf. 17358

80. (outcomes research or relative effectiveness).ti,ab,kf. 11151

81. ((indirect or indirect treatment or mixed-treatment or bayesian) adj3 comparison*).ti,ab,kf. 4290

82. (multi* adj3 treatment adj3 comparison*).ti,ab,kf. 291

83. (mixed adj3 treatment adj3 (meta-analy* or metaanaly*)).ti,ab,kf. 178

84. umbrella review*.ti,ab,kf. 1420

85. (multi* adj2 paramet* adj2 evidence adj2 synthesis).ti,ab,kf. 13

86. (multiparamet* adj2 evidence adj2 synthesis).ti,ab,kf. 18

87. (multi-paramet* adj2 evidence adj2 synthesis).ti,ab,kf. 11

88. or/66-87 672747

89. 65 or 88 3298948

90. 17 and 89 1078

91. limit 90 to (english language and yr=”2018 -Current”) 528

92. 91 not conference abstract.pt. 528

Embase

OVID Embase 1974 to May 12, 2023

Searched May 12, 2023

1. (nucala* or mepolizumab* or bosatria* or SB240563 or SB-240563 or 90Z2UFOE52).ti,ab,kw,dq. 2533

2. *mepolizumab/ 1422

3. *dupilumab/ 3135

4. (dupilumab* or dupixent* or regn668 or regn 668 or sar231893 or sar 231893).ti,ab,kw,dq. 4338

5. *benralizumab/ 863

6. (Fasenra* or benralizumab* or BIW 8405 or BIW8405 or medi563 or medi 563).ti,ab,kw,dq. 1412

7. *omalizumab/ 4294

8. (Xolair* or omalizumab* or rhuMab-E25 or rhuMabE25 or HSDB 5742 or HSDB5742 or 2P471X1Z11 or UNII2P471X1Z11 or hu 901 or hu901).ti,ab. 6698

9. *tezepelumab/ or (tezepelumab* or Tezspire* or amg-157 or amg157 or medi-9929 or medi9929 or medi-19929 or medi19929 or GTPL-8933 or GTPL8933).ti,ab,kf,dq. 294

10. or/1-9 13479

11. exp asthma/ 301745

12. asthma*.ti,ab,kw,dq. 267302

13. 11 or 12 341205

14. (severe or eosinophil* or allerg* or type 2 or T2).ti,ab,kw,dq. 2583236

15. exp Eosinophilia/ 66689

16. exp Eosinophil count/ 21990

17. or/14-16 2604229

18. 13 and 17 146121

19. 10 and 18 6866

20. randomized controlled trial/ 783392

21. randomization/ 99019

22. controlled clinical study/ 469226

23. (meta-anal$ or metaanal$).mp. 449740

24. ((systematic$ adj3 review$) or (systematic adj3 overview$)).mp. 566702

25. or/20-24 1767760

26. 19 and 25 1137

27. limit 26 to english language 1124

28. limit 27 to yr=”2018 -Current” 723

29. 28 not conference abstract.pt. 336

Europe PMC

https://europepmc.org

Searched May 1, 2023

((TITLE:”nucala*” OR TITLE:”mepolizumab*” OR TITLE:”bosatria*” OR TITLE:”Xolair*” OR TITLE:”omalizumab*” OR TITLE:”dupilumab*” OR TITLE:”dupixent*” OR TITLE:”Fasenra*” OR TITLE:”benralizumab*” OR TITLE:”Tezepelumab” OR TITLE:”Tezspire”) AND (TITLE:asthma* AND (TITLE:”severe” OR TITLE:”eosinophil*” OR TITLE:”allerg*” OR TITLE:”type 2” OR TITLE:”T2”))) AND (((SRC:MED) NOT (PUB_TYPE:”Review”))) AND (FIRST_PDATE:[2018 TO 2023])

Cochrane Library

Searched March 24, 2023, Tezepelumab searched April 13, 2023

Cochrane Reviews

(nucala* or mepolizumab* or bosatria* or Xolair* or omalizumab* or dupilumab* or dupixent* or Fasenra* or benralizumab*) AND (asthma* AND (severe or eosinophil* or allerg* or type 2 or T2))

Year: 2018 to 2023

Language: English

(Tezepelumab or Tezspire) AND (asthma* AND (severe or eosinophil* or allerg* or type 2 or T2)

Year: 2018 to 2023

Language: English

Cochrane Central Register of Controlled Trials

Issue 2 of 12, February 2023

Year: 2018 to 2023

Language: English

(nucala* or mepolizumab* or bosatria* or Xolair* or omalizumab* or dupilumab* or dupixent* or Fasenra* or benralizumab*) in Title Abstract Keyword AND asthma* in Title Abstract Keyword AND (severe or eosinophil* or allerg* or type 2 or T2) in Title Abstract Keyword NOT post-hoc or posthoc or post hoc in Title Abstract Keyword - (Word variations have been searched)

(Tezepelumab or Tezspire) in Title Abstract Keyword AND asthma* AND (severe or eosinophil* or allerg* or type 2 or T2) in Title Abstract Keyword NOT post-hoc or posthoc or post hoc in Title Abstract Keyword - with Publication Year from 2018 to 2023, with Cochrane Library publication date Between Jan 2018 and Jan 2023, in Trials (Word variations have been searched)

Appendix 3: Selection of Included Studies

Note that this appendix has not been copy-edited.

Figure 2: PRISMA Diagram

ITC = indirect treatment comparison; MA = meta-analysis; NMA = network meta-analysis; RCT = randomized controlled trial; SR = systematic review.

Appendix 4: Included Reports

Note that this appendix has not been copy-edited.

Included RCTs

Albers FC, Licskai C, Chanez P, et al. Baseline blood eosinophil count as a predictor of treatment response to the licensed dose of mepolizumab in severe eosinophilic asthma. Respir Med. 2019;159:105806. PubMed

Bleecker ER, Wechsler ME, FitzGerald JM, et al. Baseline patient factors impact on the clinical efficacy of benralizumab for severe asthma. European Respiratory Journal. 2018;52(4):10. PubMed

Brusselle G, Quirce S, Papi A, et al. Dupilumab efficacy in patients with uncontrolled or oral corticosteroid-dependent allergic and nonallergic asthma. J Allergy Clin Immunol Pract. 2023;11(3):873-884 e811. PubMed

Chipps BE, Newbold P, Hirsch I, Trudo F, Goldman M. Benralizumab efficacy by atopy status and serum immunoglobulin E for patients with severe, uncontrolled asthma. Ann Allergy Asthma Immunol. 2018;120(5):504-511.e504. PubMed

Corren J, Ambrose CS, Griffiths JM, et al. Efficacy of tezepelumab in patients with evidence of severe allergic asthma: Results from the phase 3 NAVIGATOR study. Clin Exp Allergy. 2023;53(4):417-428. PubMed

Corren J, Ambrose CS, Salapa K, et al. Efficacy of tezepelumab in patients with severe, uncontrolled asthma and perennial allergy. J Allergy Clin Immunol Pract. 2021;9(12):4334-4342.e4336. PubMed

Corren J, Chen S, Callan L, Garcia Gil E. The impact of tezepelumab on hospitalization and emergency department visits in patients with severe uncontrolled asthma: results from the pathway phase 2b trial. Am J Resp Crit Care Med. 2019;199(9).

Corren J, Garcia Gil E, Griffiths JM, et al. Tezepelumab improves patient-reported outcomes in patients with severe, uncontrolled asthma in PATHWAY. Ann Allergy Asthma Immunol. 2021;126(2):187-193. PubMed

Corren J, Menzies-Gow A, Chupp G, et al. Efficacy of tezepelumab in severe, uncontrolled asthma: pooled analysis of PATHWAY and NAVIGATOR Studies. Am J Resp Crit Care Med. 2023;04:04.

Corren J, Pham TH, Garcia Gil E, et al. Baseline type 2 biomarker levels and response to tezepelumab in severe asthma. Allergy. 2022;77(6):1786-1796. PubMed

Domingo C, Maspero JF, Castro M, et al. Dupilumab efficacy in steroid-dependent severe asthma by baseline oral corticosteroid dose. J Allergy Clin Immunol Pract. 2022;10(7):1835-1843. PubMed

FitzGerald JM, Bleecker ER, Menzies-Gow A, et al. Predictors of enhanced response with benralizumab for patients with severe asthma: pooled analysis of the SIROCCO and CALIMA studies. Lancet Respir Med. 2018;6(1):51-64. PubMed

Hanania NA, Fortis S, Haselkorn T, et al. Omalizumab in asthma with fixed airway obstruction: post hoc analysis of EXTRA. J Allergy Clin Immunol Pract. 2022;10(1):222-228. PubMed

Harrison TW, Chanez P, Menzella F, et al. Onset of effect and impact on health-related quality of life, exacerbation rate, lung function, and nasal polyposis symptoms for patients with severe eosinophilic asthma treated with benralizumab (ANDHI): a randomised, controlled, phase 3b trial. Lancet Respir Med. 2021;9(3):260-274. PubMed

Humbert M, Albers FC, Bratton DJ, et al. Effect of mepolizumab in severe eosinophilic asthma according to omalizumab eligibility. Respir Med. 2019;154:69-75. PubMed

Jackson DJ, Humbert M, Hirsch I, Newbold P, Garcia Gil E. Ability of serum IgE concentration to predict exacerbation risk and benralizumab efficacy for patients with severe eosinophilic asthma. Adv Ther. 2020;37(2):718-729. PubMed

Lemiere C, Taille C, Lee JK, et al. Impact of baseline clinical asthma characteristics on the response to mepolizumab: a post hoc meta-analysis of two Phase III trials. Respir Res. 2021;22(1):184. PubMed

Li J, Wang C, Liu C, et al. Efficacy predictors of omalizumab in Chinese patients with moderate-to-severe allergic asthma: Findings from a post-hoc analysis of a randomised phase III study. World Allergy Organization Journal. 2020;13(12):100469. PubMed

Menzies-Gow A, Corren J, Bourdin A, et al. Tezepelumab in adults and adolescents with severe, uncontrolled asthma. New Engl J Med. 2021;384(19):1800-1809. PubMed

Menzies-Gow A, Wechsler ME, Brightling CE, et al. Long-term safety and efficacy of tezepelumab in people with severe, uncontrolled asthma (DESTINATION): a randomised, placebo-controlled extension study. Lancet Respir Med. 2023;23:23. PubMed

Mukherjee M, Kjarsgaard M, Radford K, et al. Omalizumab in patients with severe asthma and persistent sputum eosinophilia. Allergy Asthma Clin Immunol. 2019;15:21. PubMed

Panettieri RA, Jr., Welte T, Shenoy KV, et al. Onset of effect, changes in airflow obstruction and lung volume, and health-related quality of life improvements with benralizumab for patients with severe eosinophilic asthma: phase IIIb randomized, controlled trial (SOLANA). J Asthma Allergy. 2020;13:115-126. PubMed

Prazma CM, Idzko M, Douglass JA, et al. Response to mepolizumab treatment in patients with severe eosinophilic asthma and atopic phenotypes. J Asthma Allergy. 2021;14:675-683. PubMed

Rabe KF, Nair P, Brusselle G, et al. Efficacy and safety of dupilumab in glucocorticoid-dependent severe asthma. New Engl J Med. 2018;378(26):2475-2485. PubMed

Wardlaw A, Howarth PH, Israel E, et al. Fungal sensitization and its relationship to mepolizumab response in patients with severe eosinophilic asthma. Clin Exp Allergy. 2020;50(7):869-872. PubMed

Wechsler ME, Menzies-Gow A, Brightling CE, et al. Evaluation of the oral corticosteroid-sparing effect of tezepelumab in adults with oral corticosteroid-dependent asthma (SOURCE): a randomised, placebo-controlled, phase 3 study. Lancet Respir Med. 2022;10(7):650-660. PubMed

Included Systematic Reviews

Agache I, Beltran J, Akdis C, et al. Efficacy and safety of treatment with biologicals (benralizumab, dupilumab, mepolizumab, omalizumab and reslizumab) for severe eosinophilic asthma. A systematic review for the EAACI Guidelines - recommendations on the use of biologicals in severe asthma. Allergy. 2020a;75(5):1023-1042. PubMed

Agache I, Rocha C, Beltran J, et al. Efficacy and safety of treatment with biologicals (benralizumab, dupilumab and omalizumab) for severe allergic asthma: a systematic review for the EAACI Guidelines - recommendations on the use of biologicals in severe asthma. Allergy. 2020b;75(5):1043-1057. PubMed

Agache I, Song Y, Rocha C, et al. Efficacy and safety of treatment with dupilumab for severe asthma: a systematic review of the EAACI guidelines-Recommendations on the use of biologicals in severe asthma. Allergy. 2020c;75(5):1058-1068. PubMed

Akenroye A, Lassiter G, Jackson JW, et al. Comparative efficacy of mepolizumab, benralizumab, and dupilumab in eosinophilic asthma: A Bayesian network meta-analysis. J Allergy Clin Immunol. 2022;150(5):1097-1105.e1012. PubMed

Ando K, Fukuda Y, Tanaka A, Sagara H. comparative efficacy and safety of tezepelumab and other biologics in patients with inadequately controlled asthma according to thresholds of type 2 inflammatory biomarkers: a systematic review and network meta-analysis. Cells. 2022;11(5). PubMed

Bateman ED, Khan AH, Xu Y, et al. Pairwise indirect treatment comparison of dupilumab versus other biologics in patients with uncontrolled persistent asthma. Respir Med. 2022;191:105991. PubMed

Bourdin A, Husereau D, Molinari N, et al. Matching-adjusted comparison of oral corticosteroid reduction in asthma: systematic review of biologics. Clinical & Experimental Allergy. 2020;50(4):442-452. PubMed

Busse W, Chupp G, Nagase H, et al. Anti-IL-5 treatments in patients with severe asthma by blood eosinophil thresholds: Indirect treatment comparison. J Allergy Clin Immunol. 2019;143(1):190-200.e120. PubMed

Chagas GCL, Xavier D, Gomes L, Ferri-Guerra J, Oquet REH. Effects of tezepelumab on quality of life of patients with moderate-to-severe, uncontrolled asthma: systematic review and meta-analysis. Curr Allergy Asthma Rep. 2023;23(6):287-298. PubMed

Chen C, Wen T, Wei L. Different IL-5 monoclonal antibody agents in treating severe asthma patients: a systemic review and network meta-analysis of randomized controlled trials (RCTs). nt J Clin Exp Med. 2019;12(6):6512-6519.

Henriksen DP, Bodtger U, Sidenius K, et al. Efficacy, adverse events, and inter-drug comparison of mepolizumab and reslizumab anti-IL-5 treatments of severe asthma - a systematic review and meta-analysis. Eur Clin Respir J. 2018;5(1):1536097. PubMed

Henriksen DP, Bodtger U, Sidenius K, et al. Efficacy of omalizumab in children, adolescents, and adults with severe allergic asthma: a systematic review, meta-analysis, and call for new trials using current guidelines for assessment of severe asthma. Allergy Asthma Clin Immunol. 2020;16:49. PubMed

Lee J, Song J-U, Kim YH. The clinical efficacy of type 2 inflammation-specific agents targeting interleukins in reducing exacerbations in severe asthma: a meta-analysis. Yonsei Med Jl. 2022;63(6):511-519. PubMed

Mahdavian M, Brothers C, Asghari S, Mallay S, Pike J. Impact of benralizumab on asthma control, asthma-related quality of life and lung function in patients with poorly controlled eosinophilic asthma: A systematic review and meta-analysis. Canadian Journal of Respiratory, Critical Care, and Sleep Medicine. 2019;3(2):106-111.

Mahdavian M, Mallay SA, Asghari S, Voduc N, Pike JC. Effect of benralizumab on asthma exacerbation rates in patients with severe asthma: Systematic review and meta-analysis. Can J Respir Crit Care Sleep Med. 2020;4(2):133-141.

Menzies-Gow A, Steenkamp J, Singh S, et al. Tezepelumab compared with other biologics for the treatment of severe asthma: a systematic review and indirect treatment comparison. J Med Econ. 2022;25(1):679-690. PubMed

Nopsopon T, Lassiter G, Chen ML, et al. Comparative efficacy of tezepelumab to mepolizumab, benralizumab, and dupilumab in eosinophilic asthma: A Bayesian network meta-analysis. J Allergy Clin Immunol. 2023;151(3):747-755. PubMed

Praetorius K, Henriksen DP, Schmid JM, et al. Indirect comparison of efficacy of dupilumab versus mepolizumab and omalizumab for severe type 2 asthma. ERJ Open Res. 2021;7(3). PubMed

Ramonell RP, Iftikhar IH. Effect of anti-IL5, anti-IL5R, anti-IL13 therapy on asthma exacerbations: a network meta-analysis. Lung. 2020;198(1):95-103. PubMed

Shaban Abdelgalil M, Ahmed Elrashedy A, Awad AK, et al. Safety and efficacy of tezepelumab vs. placebo in adult patients with severe uncontrolled asthma: a systematic review and meta-analysis. Sci Rep. 2022;12(1):20905. PubMed

Zoumot Z, Al Busaidi N, Tashkandi W, et al. Tezepelumab for patients with severe uncontrolled asthma: a systematic review and meta-analysis. J Asthma Allergy. 2022;15:1665-1679. PubMed

Appendix 5: Co-Occurrence of Included RCTs

Table 7: Co-Occurrence of Included RCTs in This Review Within the Included Systematic Reviews

Notes: This table has not been copy-edited.

Yes indicates RCT is included in listed review. No indicates RCT is not included in that review.

Appendix 6: Studies Conducted in Moderate to Severe Asthma

Note that this appendix has not been copy-edited.

Systematic Reviews

Ando K, Tanaka A, Sagara H. Comparative efficacy and safety of dupilumab and benralizumab in patients with inadequately controlled asthma: a systematic review. Int J of Mol Sci. 2020;21(3):30. PubMed

Edris A, Lahousse L. Monoclonal antibodies in type 2 asthma: an updated network meta-analysis. Minerva Medica. 2021;112(5):573-581. PubMed

Farne HA, Wilson A, Milan S, Banchoff E, Yang F, Powell CV. Anti-IL-5 therapies for asthma. Cochrane Database Syst Rev. 2022;7:CD010834. PubMed

Fenu G, La Tessa A, Calogero C, Lombardi E. Severe pediatric asthma therapy: omalizumab-a systematic review and meta-analysis of efficacy and safety profile. Front Ped. 2022;10:1033511. PubMed

Fu Z, Xu Y, Cai C. Efficacy and safety of omalizumab in children with moderate-to-severe asthma: a meta-analysis. J Asthma. 2021;58(10):1350-1358. PubMed

Iftikhar IH, Schimmel M, Bender W, Swenson C, Amrol D. Comparative efficacy of anti IL-4, IL-5 and IL-13 drugs for treatment of eosinophilic asthma: a network meta-analysis. Lung. 2018;196(5):517-530. PubMed

Li J, Yang J, Kong L, et al. Efficacy and safety of omalizumab in patients with moderate-to-severe asthma: An analytic comparison of data from randomized controlled trials between Chinese and Caucasians. Asian Pac J Allergy Immunol. 2022;40(3):223-231. PubMed

Liu L, Zhou P, Wang Z, Zhai S, Zhou W. Efficacy and safety of omalizumab for the treatment of severe or poorly controlled allergic diseases in children: a systematic review and meta-analysis. Front Pediatr. 2022;10:851177. PubMed

Liu W, Ma X, Zhou W. Adverse events of benralizumab in moderate to severe eosinophilic asthma: A meta-analysis. Medicine. 2019;98(22):e15868. PubMed

Meng X, Gan J, Liu G, Qin E, Ning H. Efficacy and safety of mepolizumab in patients with severe eosinophilic asthma: A meta-analysis. Int J Clin Exp Med. 2018;11(3):1483-1489.

Pitre T, Jassal T, Angjeli A, et al. A comparison of the effectiveness of biologic therapies for asthma: a systematic review and network meta-analysis. Ann Allergy Asthma Immunol. 2022. PubMed

Tian BP, Zhang GS, Lou J, Zhou HB, Cui W. Efficacy and safety of benralizumab for eosinophilic asthma: a systematic review and meta-analysis of randomized controlled trials. J Asthma. 2018;55(9):956-965. PubMed

Xiong XF, Zhu M, Wu HX, Fan LL, Cheng DY. Efficacy and safety of dupilumab for the treatment of uncontrolled asthma: a meta-analysis of randomized clinical trials. Respiratory Research. 2019;20(1):108. PubMed

Yan K, Balijepalli C, Sharma R, et al. Reslizumab and mepolizumab for moderate-to-severe poorly controlled asthma: an indirect comparison meta-analysis. Immunotherapy. 2019;11(17):1491-1505. PubMed

Zaazouee MS, Alwarraqi AG, Mohammed YA, et al. Dupilumab efficacy and safety in patients with moderate to severe asthma: A systematic review and meta-analysis. Front Pharmacol. 2022;13:992731. PubMed

Randomized Controlled Trials

Bacharier LB, Maspero JF, Katelaris CH, et al. Dupilumab in children with uncontrolled moderate-to-severe asthma. New Engl J Med. 2021;385(24):2230-2240. PubMed

Bansal A, Simpson E, L. Paller ASS, E. C. Blauvelt, A., et al. Conjunctivitis in dupilumab clinical trials for adolescents with atopic dermatitis or asthma. Am J Clin Dermatol. 2021;22(1):101-115. PubMed

Bourdin A, Papi AA, Corren J, et al. Dupilumab is effective in type 2-high asthma patients receiving high-dose inhaled corticosteroids at baseline. Allergy: Eur J Allergy Clin Immunol. 2021;76(1):269-280. PubMed

Busse WW, Humbert M, Haselkorn T, et al. Effect of omalizumab on lung function and eosinophil levels in adolescents with moderate-to-severe allergic asthma. Ann Allergy Asthma Immunol. 2020;124(2):190-196. PubMed

Canonica GW, Bourdin A, Peters AT, et al. Dupilumab demonstrates rapid onset of response across three type 2 inflammatory diseases. J Allergy Clin Immunol Pract. 2022;10(6):1515-1526. PubMed

Castro M, Corren J, Pavord ID, et al. Dupilumab efficacy and safety in moderate-to-severe uncontrolled asthma. N Engl J Med. 2018;378(26):2486-2496. PubMed

Castro M, Rabe KF, Corren J, et al. Dupilumab improves lung function in patients with uncontrolled, moderate-to-severe asthma. Erj Open Research. 2020;6(1). PubMed

Cheng L, Yang T, Ma X, Han Y, Wang Y. Effectiveness and safety studies of omalizumab in children and adolescents with moderate-to-severe asthma. J Pharm Pract. 2021:8971900211038251. PubMed

Corren J, Castro M, Chanez P, et al. Dupilumab improves symptoms, quality of life, and productivity in uncontrolled persistent asthma. Ann Allergy Asthma Immunol. 2019;122(1):41-49.e42. PubMed

Corren J, Castro M, O'Riordan TH, et al. Dupilumab efficacy in patients with uncontrolled, moderate-to-severe allergic asthma. J Allergy Clin Immunol Pract. 2020;8(2):516-526. PubMed

Corren J, Katelaris CH, Castro M, et al. Effect of exacerbation history on clinical response to dupilumab in moderate-to-severe uncontrolled asthma. Eur Resp J. 2021;58(4):10. PubMed

Diver S, Khalfaoui L, Emson C, et al. Effect of tezepelumab on airway inflammatory cells, remodelling, and hyperresponsiveness in patients with moderate-to-severe uncontrolled asthma (CASCADE): a double-blind, randomised, placebo-controlled, phase 2 trial. Lancet Resp Med. 2021;9(11):1299-1312. PubMed

Hanania NA, Castro M, Bateman E, et al. Efficacy of dupilumab in patients with moderate-to-severe asthma and persistent airflow obstruction. Ann Allergy Asthma Immunol. 2023;130(2):206-214.e202. PubMed

Jackson DJ, Bacharier LB, Gergen PJ, et al. Mepolizumab for urban children with exacerbation-prone eosinophilic asthma in the USA (MUPPITS-2): a randomised, double-blind, placebo-controlled, parallel-group trial. Lancet. 2022;400(10351):502-511. PubMed

Rogers L, Holweg CT, Pazwash H et al. Age of asthma onset does not impact the response to omalizumab. Chron Respir Dis. 2023:20(5):14799731231159673. PubMed

Maspero JF, Cardona G, Schonffeldt P, et al. Dupilumab efficacy and safety in Latin American patients with uncontrolled, moderate-to-severe asthma: phase 3 LIBERTY ASTHMA QUEST study. J Asthma. 2022:1-10. PubMed

Maspero JF, Katelaris CH, Busse WW, et al. Dupilumab Efficacy in Uncontrolled, Moderate-to-Severe Asthma with Self-Reported Chronic Rhinosinusitis. J Allergy Clin Immunol Pract. 2020;8(2):527-539.e529. PubMed

Papi A, Corren J, Castro M, et al. Dupilumab reduced impact of severe exacerbations on lung function in patients with moderate-to-severe type 2 asthma. Allergy: Eur J Allergy Clin Immunol. 2023;78(1):233-243. PubMed

Rabe KF, FitzGerald JM, Bateman ED, et al. Dupilumab is effective in patients with moderate-to-severe uncontrolled GINA-defined type 2 asthma irrespective of an allergic asthma phenotype. J Allergy Clin Immunol Pract. 2022;10(11):2916-2924. PubMed

Rhee CK, Park JW, Park HW, Cho YS. Effect of dupilumab in Korean patients with uncontrolled moderate-to-severe asthma: a LIBERTY ASTHMA QUEST Sub-analysis. Allergy Asthma Immunol Res. 2022;14(2):182-195. PubMed

Szefler SJ, Casale TB, Haselkorn T, et al. Treatment benefit with omalizumab in children by indicators of asthma severity. J Allergy Clin Immunol Pract. 2020;8(8):2673-2680.e2673. PubMed

Wechsler ME, Ruddy MK, Pavord ID, et al. Efficacy and safety of itepekimab in patients with moderate-to-severe asthma. New Engl J Med. 2021;385(18):1656-1668. PubMed

Appendix 7: List of Major Trials for Biologics and Trials

Note that this appendix has not been copy-edited.

Table 8: List of Major Trials for Biologics and Trials Included in the Systematic Reviews, Including Out-of-Scope Trials, and Their Broad Inclusion Criteria

OCS = oral corticosteroids.

^aAsthma type is the target study population of the trial. “None” indicates that a specific subtype of asthma was not specifically recruited.

^bTrial included in randomized controlled trial portion of this report.

^cTrial included in 1 or more systematic reviews included in this report.

Appendix 8: Supplementary Tables and Figures

Note that this appendix has not been copy-edited.

Table 9: Inclusion Criteria of the Included RCTs

ACQ = Asthma Control Questionnaire; BD = bronchodilator; BID = medication taken twice a day; FEV₁ = forced expiratory volume in 1 second; FVC = forced vital capacity; GINA = Global Initiative for Asthma; ICS = inhaled corticosteroids; IU = international unit; LABA = long-acting beta agonist; LAMA = long-acting antimuscarinics; LTRA = Leukotriene receptor agonist; OCS = oral corticosteroid; PEF = peak expiratory flow.

^aPopulation determined by whether trial required participants to have biomarkers for allergic asthma (allergic), eosinophilic asthma (eosinophilic), or were admitted solely based on having severe asthma (severe asthma).

Table 10: RCT Intervention Characteristics by Biologic, RCT, Enrolled Asthma Subtype, and Patient Subgroup

IgE = immunoglobulin E; NOS = not otherwise specified; Q2W = every 2 weeks; Q4W = every 4 weeks; Q8W = every 8 weeks; SC = subcutaneous.

^aEosinophilic asthma studies recruited patients based on a minimum eosinophil biomarker level, but may also include patients with concurrent allergic asthma.

^bSevere asthma NOS patients recruited based on the severity of asthma without additional requirements for biomarkers of allergic or eosinophilic asthma.

^cAllergic asthma studies included patients with a minimum classification of allergic asthma determined by allergic biomarkers, but may also include other subtypes that are not mutually exclusive.

Table 11: Concomitant Medications in RCTs Described in Clinical Trials Registry and/or Publications

GINA = Global Initiative for Asthma; ICS = inhaled corticosteroids; LABA = long-acting beta agonist; LAMA = long-acting antimuscarinics; OCS = oral corticosteroid.

Table 12: RCT-Specific Asthma Exacerbation Definitions From Clinical Trial Registry and/or Publication

Table 13: Main Study Outcomes

ACQ = Asthma Control Questionnaire; ACT = Asthma Control Test; AEX = asthma exacerbation; AQLQ = Asthma Quality of Life Questionnaire; FEV₁ = forced expiratory volume in 1 second; HRQoL = Health-related quality of life; NOS = not otherwise specified; NR = not reported.

Note: Asthma enrolment criteria indicates whether a specific type of asthma patients was sampled. + indicates effect favouring treatment, - indicates effect favouring control, = indicates exact equality of outcome, and an additional + or - indicates whether this effect was statistically significant. All RCTs compared biologics as an add-on to standard of care against standard of care plus a placebo.

Table 14: Outcomes Reported for Each Asthma Subgroup