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Meta-Analysis
. 2017 Sep 21;9(9):CD010834.
doi: 10.1002/14651858.CD010834.pub3.

Anti-IL5 therapies for asthma

Hugo A Farne  1 , Amanda Wilson, Colin Powell, Lynne Bax, Stephen J Milan
Affiliations
Meta-Analysis

Anti-IL5 therapies for asthma

Hugo A Farne et al. Cochrane Database Syst Rev. .

Update in

  • Anti-IL-5 therapies for asthma.
    Farne HA, Wilson A, Milan S, Banchoff E, Yang F, Powell CV. Farne HA, et al. Cochrane Database Syst Rev. 2022 Jul 12;7(7):CD010834. doi: 10.1002/14651858.CD010834.pub4. Cochrane Database Syst Rev. 2022. PMID: 35838542 Free PMC article.

Abstract

Background: This review is the first update of a previously published review in The Cochrane Library (Issue 7, 2015). Interleukin-5 (IL-5) is the main cytokine involved in the activation of eosinophils, which cause airway inflammation and are a classic feature of asthma. Monoclonal antibodies targeting IL-5 or its receptor (IL-5R) have been developed, with recent studies suggesting that they reduce asthma exacerbations, improve health-related quality of life (HRQoL) and lung function. These are being incorporated into asthma 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 qualify 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 the Cochrane Airways Trials Register, clinical trials registries, manufacturers' websites, and reference lists of included studies. The most recent search was March 2017.

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 authors independently extracted data and analysed outcomes using a random-effects model. We used standard methods expected by Cochrane.

Main results: Thirteen studies on 6000 participants met the inclusion criteria. Four used mepolizumab, four used reslizumab, and five used benralizumab. One study in 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. Eight included children over 12 years but these results were not reported separately. We deemed the risk of bias to be low, with all studies contributing data being of robust methodology. We considered the quality of the evidence for all comparisons to be high overall using the GRADE scheme, with the exception of intravenous mepolizumab because this is not currently a licensed delivery route.All of 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 of 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) 1.5 or more). Non-eosinophilic participants treated with benralizumab also showed a significant reduction in exacerbation rates, but no data were available for non-eosinophilic participants, and mepolizumab or reslizumab.We saw modest improvements in validated HRQoL scores with all anti-IL-5 agents in severe eosinophilic asthma. However these did not exceed the minimum clinically important difference for ACQ and Asthma Quality of Life Questionnaire (AQLQ), with St. George's Respiratory Questionnaire (SGRQ) only assessed in two studies. The improvement in HRQoL scores in non-eosinophilic participants treated with benralizumab, the only intervention for which data were available in this subset, was not statistically significant, but the test for subgroup difference was negative.All anti-IL-5 treatments produced a small but statistically significant improvement in mean pre-bronchodilator forced expiratory flow in one second (FEV1) of between 0.08 L and 0.11 L.There were no excess serious adverse events with any anti-IL-5 treatment, and indeed a reduction in favour of mepolizumab that could be due to a beneficial effect on asthma-related serious adverse events. 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 (36/1599 benralizumab versus 9/998 placebo).Mepolizumab, reslizumab and benralizumab all markedly reduced blood eosinophils, but benralizumab resulted in almost complete depletion, whereas a small number remained with mepolizumab and reslizumab. The implications for efficacy and/or adverse events are unclear.

Authors' conclusions: Overall our study supports the use of anti-IL-5 treatments as an adjunct to standard of care in people with severe eosinophilic asthma and poor 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. There were no safety concerns regarding mepolizumab or reslizumab, and no 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), and comparing anti-IL-5 treatments to each other and, in people eligible for both, to anti-immunoglobulin E. For benralizumab, future studies should closely monitor rates of adverse events prompting discontinuation.

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Conflict of interest statement

HF: none known.

AW: none known.

CP: none known.

LB: none known.US Food & Drug Administration

SM: none known.

Figures

Figure 1
Figure 1
Study flow diagram
Figure 2
Figure 2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies
Figure 3
Figure 3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study
Analysis 1.1
Analysis 1.1
Comparison 1 Mepolizumab (SC) versus placebo, Outcome 1 Rate of exacerbations requiring systemic corticosteroids.
Analysis 1.2
Analysis 1.2
Comparison 1 Mepolizumab (SC) versus placebo, Outcome 2 Rate of exacerbations requiring emergency department treatment or admission.
Analysis 1.3
Analysis 1.3
Comparison 1 Mepolizumab (SC) versus placebo, Outcome 3 Rate of exacerbations requiring admission.
Analysis 1.4
Analysis 1.4
Comparison 1 Mepolizumab (SC) versus placebo, Outcome 4 Health‐related quality of life (ACQ).
Analysis 1.5
Analysis 1.5
Comparison 1 Mepolizumab (SC) versus placebo, Outcome 5 Health‐related quality of life (SGRQ).
Analysis 1.6
Analysis 1.6
Comparison 1 Mepolizumab (SC) versus placebo, Outcome 6 Pre‐bronchodilator FEV1 (litres).
Analysis 1.7
Analysis 1.7
Comparison 1 Mepolizumab (SC) versus placebo, Outcome 7 Serious adverse events.
Analysis 1.8
Analysis 1.8
Comparison 1 Mepolizumab (SC) versus placebo, Outcome 8 Adverse events leading to discontinuation.
Analysis 2.1
Analysis 2.1
Comparison 2 Mepolizumab (IV) versus placebo, Outcome 1 Rate of clinically significant exacerbations.
Analysis 2.2
Analysis 2.2
Comparison 2 Mepolizumab (IV) versus placebo, Outcome 2 Rate of exacerbations requiring emergency department treatment or admission.
Analysis 2.3
Analysis 2.3
Comparison 2 Mepolizumab (IV) versus placebo, Outcome 3 Rate of exacerbations requiring admission.
Analysis 2.4
Analysis 2.4
Comparison 2 Mepolizumab (IV) versus placebo, Outcome 4 People with one or more exacerbations.
Analysis 2.5
Analysis 2.5
Comparison 2 Mepolizumab (IV) versus placebo, Outcome 5 Health‐related quality of life (AQLQ).
Analysis 2.6
Analysis 2.6
Comparison 2 Mepolizumab (IV) versus placebo, Outcome 6 Health‐related quality of life (ACQ).
Analysis 2.7
Analysis 2.7
Comparison 2 Mepolizumab (IV) versus placebo, Outcome 7 Health‐related quality of life (SGRQ).
Analysis 2.8
Analysis 2.8
Comparison 2 Mepolizumab (IV) versus placebo, Outcome 8 Pre‐bronchodilator FEV1 (litres).
Analysis 2.9
Analysis 2.9
Comparison 2 Mepolizumab (IV) versus placebo, Outcome 9 Serious adverse events.
Analysis 2.10
Analysis 2.10
Comparison 2 Mepolizumab (IV) versus placebo, Outcome 10 Adverse events leading to discontinuation.
Analysis 2.11
Analysis 2.11
Comparison 2 Mepolizumab (IV) versus placebo, Outcome 11 Serum eosinophil level (cells/microlitre).
Analysis 3.1
Analysis 3.1
Comparison 3 Reslizumab (IV) versus placebo, Outcome 1 Rate of exacerbations requiring systemic corticosteroids.
Analysis 3.2
Analysis 3.2
Comparison 3 Reslizumab (IV) versus placebo, Outcome 2 Rate of exacerbations requiring emergency department treatment or admission.
Analysis 3.3
Analysis 3.3
Comparison 3 Reslizumab (IV) versus placebo, Outcome 3 Health‐related quality of life (AQLQ).
Analysis 3.4
Analysis 3.4
Comparison 3 Reslizumab (IV) versus placebo, Outcome 4 Health‐related quality of life (ACQ).
Analysis 3.5
Analysis 3.5
Comparison 3 Reslizumab (IV) versus placebo, Outcome 5 Pre‐bronchodilator FEV1 (litres).
Analysis 3.6
Analysis 3.6
Comparison 3 Reslizumab (IV) versus placebo, Outcome 6 Serious adverse events.
Analysis 3.7
Analysis 3.7
Comparison 3 Reslizumab (IV) versus placebo, Outcome 7 Adverse events leading to discontinuation.
Analysis 3.8
Analysis 3.8
Comparison 3 Reslizumab (IV) versus placebo, Outcome 8 Serum eosinophil level (cells/microlitre).
Analysis 4.1
Analysis 4.1
Comparison 4 Benralizumab (SC) versus placebo, Outcome 1 Rate of exacerbations requiring systemic corticosteroids.
Analysis 4.2
Analysis 4.2
Comparison 4 Benralizumab (SC) versus placebo, Outcome 2 Rate of exacerbations requiring emergency department treatment or admission.
Analysis 4.3
Analysis 4.3
Comparison 4 Benralizumab (SC) versus placebo, Outcome 3 Health‐related quality of life (AQLQ mean difference).
Analysis 4.4
Analysis 4.4
Comparison 4 Benralizumab (SC) versus placebo, Outcome 4 Health‐related quality of life (ACQ mean difference).
Analysis 4.5
Analysis 4.5
Comparison 4 Benralizumab (SC) versus placebo, Outcome 5 Pre‐bronchodilator FEV1 (litres).
Analysis 4.6
Analysis 4.6
Comparison 4 Benralizumab (SC) versus placebo, Outcome 6 Serious adverse events.
Analysis 4.7
Analysis 4.7
Comparison 4 Benralizumab (SC) versus placebo, Outcome 7 Adverse events leading to discontinuation.
Analysis 4.8
Analysis 4.8
Comparison 4 Benralizumab (SC) versus placebo, Outcome 8 Serum eosinophil level (% change from baseline).
See this image and copyright information in PMC

Update of

References

References to studies included in this review

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    4. NCT01287039. A study to evaluate the efficacy and safety of reslizumab (3.0 mg/kg) in the reduction of clinical asthma exacerbations in patients (12‐75 years of age) with eosinophilic asthma. clinicaltrials.gov/ct2/show/NCT01287039 (first received 28 January 2011).
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References to ongoing studies

    1. EUCTR2005‐001932‐61‐GB. Mepolizumab and exacerbation frequency in refractory eosinophilic asthma. A randomised, double blind, placebo controlled, parallel group trial. clinicaltrialsregister.eu/ctr‐search/search?query=EUCTR2005‐001932‐61‐GB (first received 16 November 2005).
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    1. NCT02452190. Study of reslizumab in patients with uncontrolled asthma and elevated blood eosinophils. clinicaltrials.gov/show/NCT02452190 (first received 13 May 2015). [CRS: 4900132000027647]
    1. NCT02555371. Cessation versus continuation of long‐term mepolizumab in severe eosinophilic asthma patients. clinicaltrials.gov/show/NCT02555371 (first received 17 September 2015). [CRS: 4900132000027646]
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    1. Cabon Y, Molinari N, Marin G, Vachier I, Gamez AS, Chanez P, et al. Comparison of anti‐interleukin‐5 therapies in patients with severe asthma: global and indirect meta‐analyses of randomized placebo‐controlled trials. Clinical and Experimental Allergy 2017;47(1):129‐38. [PUBMED: 27859832] - PubMed
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    1. Custovic A, Johnston SL, Pavord I, Gaga M, Fabbri L, Bel EH, et al. EAACI position statement on asthma exacerbations and severe asthma. Allergy 2013;68(12):1520‐31. [PUBMED: 24410781] - PMC - PubMed

References to other published versions of this review

    1. Powell C, Milan SJ, Dwan K, Walters N. Mepolizumab versus placebo for asthma. Cochrane Database of Systematic Reviews 2013, Issue 11. [DOI: 10.1002/14651858.CD010834] - DOI - PubMed
    1. Powell C, Milan SJ, Dwan K, Bax L, Walters N. Mepolizumab versus placebo for asthma. Cochrane Database of Systematic Reviews 2015, Issue 7. [DOI: 10.1002/14651858.CD010834.pub2] - DOI - PubMed

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