AIMS To compare the efficacy of tezepelumab with other approved biologics via indirect treatment comparisons (ITCs) in patients aged ≥12 years with severe uncontrolled asthma.MATERIALS AND METHODS Data from randomized controlled trials (RCTs) identified from a systematic literature review were synthesized using two different ITC approaches: network meta-analysis (NMA) and simulated treatment comparison (STC). Outcomes of interest were annualized asthma exacerbation rate (AAER) and AAER for exacerbations leading to hospitalization. To address potential heterogeneity between study populations, various subgroup analyses were performed for the NMA (based on blood eosinophil count [Eos], fractional exhaled nitric oxide level, and presence of allergic asthma), and for the STC, models were adjusted for potential treatment effect modifiers. Sensitivity analyses were performed to assess the impact of study design (exclusion of non placebo-controlled studies and non-phase 3 or 4 studies). Results were reported as rate ratios (RRs) with 95% credible/confidence intervals and ranking statistics were computed for the NMAs.RESULTS Sixteen RCTs were included in at least one of the ITCs. All biologics (tezepelumab, dupilumab, benralizumab, mepolizumab, reslizumab, and omalizumab) had similar efficacy, with no statistically significant RRs for either exacerbation outcome; however, tezepelumab was favorably associated with numerically lower AAERs and was ranked first in the network for both types of exacerbation outcome. This trend was consistent in the subgroup and sensitivity analyses. As with the primary NMA, the STC results did not demonstrate any significant differences between biologics, but point estimates were favorable towards tezepelumab.LIMITATIONS Heterogeneity between trials was observed among eligibility criteria and clinically important patient characteristics; however, impact on findings is expected to be low, based on consistency across analyses.CONCLUSIONS Findings from both ITCs (NMA and STC) support the use of tezepelumab in a broad patient population of severe uncontrolled asthma of any phenotype.
BACKGROUND: The comparative safety and efficacy of the biologics currently approved for asthma is unclear.
OBJECTIVE: To compare the safety and efficacy of mepolizumab, benralizumab, and dupilumab in individuals with severe eosinophilic asthma.
METHODS: Systematic review of peer-reviewed literature from 2000 through 2021, and Bayesian network meta-analyses of exacerbation rates, prebronchodilator FEV1, the Asthma Control Questionnaire (ACQ) and serious adverse events (SAE) in individuals with eosinophilic asthma.
RESULTS: Eight randomized clinical trials (n=6,461) were identified. In individuals with ≥300 eosinophils per microliter (eosin/mcl), in reducing exacerbation rates in comparison to placebo: dupilumab (risk ratio [RR] 0.32; 95% credible interval [CI], 0.23-0.45), mepolizumab (RR, 0.37; 95%CI, 0.30-0.45), and benralizumab (RR, 0.49; 95%CI, 0.43-0.55). In improving FEV1: dupilumab (mean difference in milliliters [MD] 230; [CI], 160-300), benralizumab (MD 150; 95%CI, 100-200), and mepolizumab (MD 150; 95%CI, 66-220); and in reducing ACQ: mepolizumab (MD -0.63; [CI], -0.81 to -0.45), dupilumab (MD -0.48; 95%CI, -0.83 to -0.14), and benralizumab (MD -0.32; 95%CI, -0.43 to -0.21). In individuals with eosinophil counts of 150-299 eosin/mcl, benralizumab (RR, 0.62; 95%CI, 0.52-0.73) and dupilumab (RR, 0.60; 95%CI, 0.38-0.95) were associated with lower exacerbation rates; and only benralizumab (MD 81; 95% CI, 8-150) significantly improved FEV1. These differences were minimal in comparison to clinically important thresholds. For SAE in the overall population, mepolizumab (odds ratio, 0.67; 95% CI, 0.48-0.92) and benralizumab (0.74; 95% CI, 0.59-0.93) were associated with lower odds of a SAE, while dupilumab was not different from placebo (1.0; 95% CI, 0.74-1.4).
CONCLUSIONS: There are minimal differences in the efficacy and safety of mepolizumab, benralizumab, and dupilumab in eosinophilic asthma.
CLINICAL IMPLICATION: In individuals with eosinophilic asthma, mepolizumab, benralizumab, and dupilumab are similar in their effect on exacerbations, FEV1, or ACQ.
The anti-thymic stromal lymphopoietin antibody (tezepelumab) has therapeutical potential for inadequately controlled asthma. However, evidence comparing tezepelumab with other biologics is scarce. To address this issue, we performed a network meta-analysis to compare and rank the efficacy of five treatments (tezepelumab, dupilumab, benralizumab, mepolizumab, and placebo) in overall participants and in subgroups stratified by the thresholds of type 2 inflammatory biomarkers, including peripheral blood eosinophil count (PBEC) and fractional exhaled nitric oxide (FeNO). The primary endpoints were annualized exacerbation rate (AER) and any adverse events (AAEs). In the ranking assessment using surface under the cumulative ranking curve (SUCRA) of AER, tezepelumab ranked the highest overall and across subgroups (based on PBEC and FeNO level thresholds). A significant difference was observed between tezepelumab and dupilumab in the patient subgroup with PBEC < 150, and between tezepelumab and benralizumab in overall participants and the patient subgroup with PBEC ≥ 300 and ≥150, respectively. There was no significant difference in the incidence of AAEs in the overall participants between each pair of five treatment arms. These results provide a basis for the development of treatment strategies for asthma and may guide basic, clinical, or translational research.
PURPOSE: Monoclonal antibodies against type 2 inflammatory pathways are currently promising therapeutics for severe asthma. The aim of this study was to determine how well type 2 (T2) inflammation-specific agents targeting interleukins reduce the rate of asthma exacerbations (AE) in patients with severe asthma.
MATERIALS AND METHODS: We performed a systematic review and meta-analysis in accordance with PRISMA guidelines. A systematic literature search was conducted in PubMed, Embase, and the Cochrane Central Register. The primary outcome was the reduction rate of annualized AEs.
RESULTS: We analyzed 17 studies comprising 11800 subjects. A total of 6197 patients received T2-specific agents (benralizumab, dupilumab, lebrikizumab, mepolizumab, reslizumab, and tralokinumab). Overall, T2-specific agents were significantly associated with a lower risk of AE, compared with placebo [rate ratio (RR) 0.58, 95% confidence interval (CI) 0.51 to 0.66]. Among all studied agents, only tralokinumab did not demonstrate a reduction in AE. The efficacy of T2-specific agents in reducing AE was maintained regardless of the pathway used. A subgroup analysis indicated that T2-specific agents further reduced the risk of AE in patients with eosinophil counts of ≥300 cells/µL (RR 0.41, 95% CI 0.32 to 0.53).
CONCLUSION: Our findings suggest that T2-specific agents are significantly associated with a reduced rate of AE, compared with placebo. Their efficacy appears to be enhanced in patients with eosinophil counts of ≥300 cells/µL.
BACKGROUND: This is the second update of previously published reviews in the Cochrane Library (2015, first update 2017). Interleukin-5 (IL-5) is the main cytokine involved in the proliferation, maturation, activation and survival of eosinophils, which cause airway inflammation and are a classic feature of asthma. Studies of monoclonal antibodies targeting IL-5 or its receptor (IL-5R) suggest they reduce asthma exacerbations, improve health-related quality of life (HRQoL) and lung function in appropriately selected patients, justifying their inclusion in the latest guidelines.
OBJECTIVES: To compare the effects of therapies targeting IL-5 signalling (anti-IL-5 or anti-IL-5Rα) with placebo on exacerbations, health-related quality-of-life (HRQoL) measures and lung function in adults and children with chronic asthma, and specifically in those with eosinophilic asthma refractory to existing treatments.
SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, and two trials registers, manufacturers' websites, and reference lists of included studies. The most recent search was 7 February 2022.
SELECTION CRITERIA: We included randomised controlled trials comparing mepolizumab, reslizumab and benralizumab versus placebo in adults and children with asthma.
DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and analysed outcomes using a random-effects model. We used standard methods expected by Cochrane.
MAIN RESULTS: Seventeen studies on about 7600 participants met the inclusion criteria. Six used mepolizumab, five used reslizumab, and six used benralizumab. One study using benralizumab was terminated early due to sponsor decision and contributed no data. The studies were predominantly on people with severe eosinophilic asthma, which was similarly but variably defined. One was in children aged 6 to 17 years; nine others included children over 12 years but did not report results by age group separately. We deemed the overall risk of bias to be low, with all studies contributing data of robust methodology. We considered the certainty of the evidence for all comparisons to be high overall using the GRADE scheme, except for intravenous (IV) mepolizumab and subcutaneous (SC) reslizumab because these are not currently licensed delivery routes. The anti-IL-5 treatments assessed reduced rates of 'clinically significant' asthma exacerbation (defined by treatment with systemic corticosteroids for three days or more) by approximately half in participants with severe eosinophilic asthma on standard care (at least medium-dose inhaled corticosteroids (ICS)) with poorly controlled disease (either two or more exacerbations in the preceding year or Asthma Control Questionnaire (ACQ) score of 1.5 or more), except for reslizumab SC. The rate ratios for these effects were 0.45 (95% confidence interval (CI) 0.36 to 0.55; high-certainty evidence) for mepolizumab SC, 0.53 (95% CI 0.44 to 0.64; moderate-certainty evidence) for mepolizumab IV, 0.43 (95% CI 0.33 to 0.55; high-certainty evidence) for reslizumab IV, and 0.59 (95% CI 0.52 to 0.66; high-certainty evidence) for benralizumab SC. Non-eosinophilic participants treated with benralizumab also showed a significant reduction in exacerbation rates, an effect not seen with reslizumab IV, albeit in only one study. No data were available for non-eosinophilic participants treated with mepolizumab. There were improvements in validated HRQoL scores with all anti-IL-5 agents in severe eosinophilic asthma. This met the minimum clinically important difference (MCID) for the broader St. George's Respiratory Questionnaire (SGRQ; 4-point change) for benralizumab only, but the improvement in the ACQ and Asthma Quality of Life Questionnaire (AQLQ), which focus on asthma symptoms, fell short of the MCID (0.5 point change for both ACQ and AQLQ) for all of the interventions. The evidence for an improvement in HRQoL scores in non-eosinophilic participants treated with benralizumab and reslizumab was weak, but the tests for subgroup difference were negative. All anti-IL-5 treatments produced small improvements in mean pre-bronchodilator forced expiratory flow in one second (FEV1) of between 0.08 L and 0.15 L in eosinophilic participants, which may not be sufficient to be detected by patients. There were no excess serious adverse events with any anti-IL-5 treatment; in fact, there was a reduction in such events with benralizumab, likely arising from fewer asthma-related hospital admissions. There was no difference compared to placebo in adverse events leading to discontinuation with mepolizumab or reslizumab, but significantly more discontinued benralizumab than placebo, although the absolute numbers were small (42/2026 (2.1%) benralizumab versus 11/1227 (0.9%) placebo). The implications for efficacy or adverse events are unclear.
AUTHORS' CONCLUSIONS: Overall this analysis supports the use of anti-IL-5 treatments as an adjunct to standard care in people with severe eosinophilic asthma and poor symptom control. These treatments roughly halve the rate of asthma exacerbations in this population. There is limited evidence for improved HRQoL scores and lung function, which may not meet clinically detectable levels. The studies did not report safety concerns for mepolizumab or reslizumab, or any excess serious adverse events with benralizumab, although there remains a question over adverse events significant enough to prompt discontinuation. Further research is needed on biomarkers for assessing treatment response, optimal duration and long-term effects of treatment, risk of relapse on withdrawal, non-eosinophilic patients, children (particularly under 12 years), comparing anti-IL-5 treatments to each other and, in patients meeting relevant eligibility criteria, to other biological (monoclonal antibody) therapies. For benralizumab, future studies should closely monitor rates of adverse events prompting discontinuation.
BACKGROUND: Severe asthma is a major cause of morbidity. Some patients may benefit from biological therapies. Most evaluations of these treatments are derived from randomised controlled trials (RCTs), but few patients are eligible for these trials. Studies involving more diverse groups of participants exist but there is a lack of precise pooled estimates.
OBJECTIVE: This systematic review aims to evaluate the real-world efficacy of recently and nearly licensed biological therapies for severe asthma to assess the generalisability of the RCT data.
METHODS: Clinical outcomes including exacerbation rate, oral corticosteroid (OCS) usage, forced expiratory volume in 1 second (FEV1 ) and fractional exhaled nitric oxide (FeNO) were examined. Studies were assessed for risk of bias using the Critical Appraisal Skills Programme (CASP) checklist tool. The certainty of evidence was assessed using GRADE.
RESULTS: A total of 21 studies examining biologicals in real-world settings were identified, they mostly focused on benralizumab and mepolizumab. The introduction of biologicals reduced the annualised exacerbation rate significantly by -3.79 (95% CI -4.53, -3.04), -3.17 (95% CI -3.74, -2.59) and -6.72 (95% CI -8.47, -4.97) with benralizumab, mepolizumab and reslizumab respectively. Likewise, improvements were observed in FEV1 (0.17 L 95% CI 0.11, 0.24) and FeNO (-14.23 ppb 95% CI -19.71, -8.75) following treatment with mepolizumab. After treatment with benralizumab there was an increase in FEV1 (0.21 L 95% CI 0.08, 0.34).
CONCLUSIONS: These data demonstrate that anti-IL5 biologicals may improve the clinical outcomes of patients with severe asthma in a clinic environment with similar effect sizes to RCTs. The data were mainly retrospective and unadjusted, so estimated effect sizes may not be reliable. More data is needed to acquire accurate effect estimates in different subpopulations of patients.
Airway hyperresponsiveness (AHR) represents a central pathophysiological hallmark of asthma, with airway smooth muscle (ASM) being the effector tissue implicated in the onset of AHR. ASM also exerts pro-inflammatory and immunomodulatory actions, by secreting a wide range of cytokines and chemokines. In asthma pathogenesis, the overexpression of several type 2 inflammatory mediators including IgE, IL-4, IL-5, IL-13, and TSLP has been associated with ASM hyperreactivity, all of which can be targeted by humanized monoclonal antibodies (mAbs). Therefore, the aim of this review was to systematically assess evidence across the literature on mAbs for the treatment of asthma with respect to their impact on the ASM contractile tone. Omalizumab, mepolizumab, benralizumab, dupilumab, and tezepelumab were found to be effective in modulating the contractility of the ASM and preventing the AHR, but no available studies concerning the impact of reslizumab on the ASM were identified from the literature search. Omalizumab, dupilumab, and tezepelumab can directly modulate the ASM in asthma, by specifically blocking the interaction between IgE, IL-4, and TSLP, and their receptors are located on the surface of ASM cells. Conversely, mepolizumab and benralizumab have prevalently indirect impacts against AHR by targeting eosinophils and other immunomodulatory effector cells promoting inflammatory processes. AHR has been suggested as the main treatable trait towards precision medicine in patients suffering from eosinophilic asthma, therefore, well-designed head-to-head trials are needed to compare the efficacy of those mAbs that directly target ASM contractility specifically against the AHR in severe asthma, namely omalizumab, dupilumab, and tezepelumab.
Asthma is one of the most common chronic diseases characterized by sex disparities. Gender bias is a well-documented issue detected in the design of published clinical trials (CTs). International guidelines encourage researchers to analyze clinical data by sex, gender, or both where appropriate. The objective of this work was to evaluate gender bias in the published CTs of biological agents for the treatment of severe asthma. A systematic review of randomized controlled CTs of the biological agents (omalizumab, benralizumab, reslizumab, mepolizumab or dupilumab) for the treatment of severe asthma was conducted. The literature search was performed using PubMed and EMBASE without language restrictions. This study followed the corresponding international recommendations. We identified a total of 426 articles, of which 37 were finally included. Women represented 60.4% of patients included. The mean percentage of women in these trials was 59.9%, ranged from 40.8% to 76.7%. The separate analysis by sex of the main variable was only performed in 5 of the 37 publications included, and none of the trials analyzed secondary variables by sex. Only 1 of the articles discussed the results separately by sex. No study included the concept of gender in the text or analyzed the results separately by gender. The proportion of women included in CTs was higher compared to publications of other disciplines, where women were under-represented. The analysis of the main and secondary variables by sex or gender, even the discussion separately by sex, was insufficient. This gives rise to potential gender bias in these CTs.
BACKGROUND: Monoclonal antibody therapies have a growing role in treating refractory airway disease.
OBJECTIVE: The review aimed to summarise the response of respiratory mucosa to monoclonal antibody treatments in inflammatory airway conditions.
DESIGN: We conducted a systematic review including risk of bias assessment.
DATA SOURCES: MEDLINE, Embase and Pubmed from 1 January 2000 to 16 November 2019 were searched.
ELIGIBILITY CRITERIA: Eligible studies assessed the immunological and histological response of airway mucosa to monoclonal antibody therapy compared with baseline or a comparison group in patients with respiratory diseases (asthma, chronic rhinosinusitis and allergic rhinitis). Any prospective interventional studies, including randomized controlled trials (RCTs) and single-arm trials, were eligible.
RESULTS: There were 4195 articles screened, and full-text analysis produced n=11 studies with extractable data. Nine were RCTs and two were single-arm trials. These studies focused on asthma (n=9 articles), chronic rhinosinusitis (n=1) and allergic rhinitis (n=1). Five monoclonal antibody drugs were assessed (omalizumab, mepolizumab, dupilumab, benralizumab and tralokinumab). Risk of bias was low (n=6) or unclear (n=3) in the RCTs and moderate in the single-arm trials. Omalizumab reduced the mucosal concentration of its target, IgE. Dupilumab reduced the concentration of one of its targets, IL-13, but not IL-4. Omalizumab, mepolizumab and benralizumab reduced tissue eosinophil cell density. Dupilumab decreased mucosal eosinophil granule proteins. Tralokinumab did not affect airway mucosa.
CONCLUSIONS: Knowledge of the expected biological response of monoclonal antibody therapy on biomarkers in disease tissue provides an important supplement to data about clinical outcomes. An understanding of the biological effect is essential to identify likely responders, reasons for treatment failure and necessary adjustments to monoclonal antibody treatment. Further investigation into the effect of monoclonal antibody therapy on disease mucosa and more precise endotyping are required to move closer to achieving personalized medicine.
AIMS To compare the efficacy of tezepelumab with other approved biologics via indirect treatment comparisons (ITCs) in patients aged ≥12 years with severe uncontrolled asthma.MATERIALS AND METHODS Data from randomized controlled trials (RCTs) identified from a systematic literature review were synthesized using two different ITC approaches: network meta-analysis (NMA) and simulated treatment comparison (STC). Outcomes of interest were annualized asthma exacerbation rate (AAER) and AAER for exacerbations leading to hospitalization. To address potential heterogeneity between study populations, various subgroup analyses were performed for the NMA (based on blood eosinophil count [Eos], fractional exhaled nitric oxide level, and presence of allergic asthma), and for the STC, models were adjusted for potential treatment effect modifiers. Sensitivity analyses were performed to assess the impact of study design (exclusion of non placebo-controlled studies and non-phase 3 or 4 studies). Results were reported as rate ratios (RRs) with 95% credible/confidence intervals and ranking statistics were computed for the NMAs.RESULTS Sixteen RCTs were included in at least one of the ITCs. All biologics (tezepelumab, dupilumab, benralizumab, mepolizumab, reslizumab, and omalizumab) had similar efficacy, with no statistically significant RRs for either exacerbation outcome; however, tezepelumab was favorably associated with numerically lower AAERs and was ranked first in the network for both types of exacerbation outcome. This trend was consistent in the subgroup and sensitivity analyses. As with the primary NMA, the STC results did not demonstrate any significant differences between biologics, but point estimates were favorable towards tezepelumab.LIMITATIONS Heterogeneity between trials was observed among eligibility criteria and clinically important patient characteristics; however, impact on findings is expected to be low, based on consistency across analyses.CONCLUSIONS Findings from both ITCs (NMA and STC) support the use of tezepelumab in a broad patient population of severe uncontrolled asthma of any phenotype.
