Anti‐IL‐5 treatments are a useful adjunct for treatment of chronic severe asthma

https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD010834.pub4/full?highlightAbstract=asthma%7Casthm Farne HA, Wilson A, Milan S, Banchoff E, Yang F, Powell CVE. Anti-IL-5 therapies for asthma. Cochrane Database Syst. Rev. 2022; Issue 7: Art. No.: CD010834. DOI: 10.1002/14651858.CD010834.pub4. Accessed 23 December 2022. The efficacy and safety of monoclonal anti-interleukin (IL)-5 antibodies (mepolizumab, reslizumab and benralizumab) for the treatment of chronic asthma, including both adults and children.1 These treatments target IL-5 (mepolizumab and reslizumab) or the IL-5 receptor found on eosinophils and basophils (benralizumab), affecting the proliferation, maturation, activation, recruitment and survival of eosinophils. Seventeen randomised controlled trials of anti-IL-5 therapy compared to placebo were included, six for mepolizumab (total of 2294 participants), five for reslizumab (2232 participants) and six for benralizumab (3888 participants). Seven included adult participants only, one (presented only in abstract form) included only children aged 6 to 17 years2 and the remaining nine included adolescents aged over 12 years and adults. The majority of studies were considered to be at low risk of bias (15 studies), unclear in one study (the paediatric study presented only in abstract form)2 and high in only one study of benralizumab that was terminated due to sponsor decision after randomising 13 participants. Using the GRADE system, evidence for all comparisons was considered to be high overall except for mepolizumab IV and reslizumab SC, which are not currently licensed delivery routes. The following summary is therefore limited to subcutaneous mepolizumab and benralizumab, the agents and routes currently funded for use in Australia and New Zealand. Participants had asthma, typically but not exclusively moderate or severe eosinophilic asthma, with eosinophilia variously defined on blood (typically greater than 150 or 300 cells/μL) or sputum (≥3%) cell counts. Participants typically required medium to high dose inhaled corticosteroids plus a second controller medication, and a history of inadequate symptom control and/or frequent exacerbations at baseline. Studies including people with respiratory comorbidities were excluded, including current smokers. Concurrent other treatments for asthma were allowed as long as these treatments were not randomised or subject to a planned change over the course of the study (such as steroid weaning studies). Data were only included for monoclonal antibody doses likely to be used clinically, mirroring the licensed doses. Only studies with treatment periods of 16 weeks or longer were included. Monoclonal antibody therapy was compared to placebo. The primary outcome was asthma exacerbations requiring systemic corticosteroids, and secondary outcomes were asthma exacerbations requiring emergency department treatment or admission, health related quality of life (HRQoL), lung function (FEV1), serious and clinically significant adverse events, and blood eosinophil counts. In people with severe eosinophilic asthma, subcutaneous mepolizumab resulted in a large reduction in the rate of asthma exacerbations requiring systemic corticosteroids (rate ratio 0.45 (95% CI 0.36–0.55); 2 studies; 936 participants) (Fig. 1). The rate of emergency department presentation or admission was also reduced (rate ratio 0.36, 95% CI 0.2–0.66). Significant improvements in HRQoL were found, above the minimum clinically important difference in most cases. There was a small increase in FEV1 (90 mL, 95% CI 50–140 mL), which was felt to be less than the variability typically seen in a single testing session. There was slight evidence for reduced serious adverse events in the mepolizumab SC group, likely mainly related to a reduction in asthma-related events. There was no difference in adverse events prompting treatment discontinuation. There was insufficient data to analyse the response of blood eosinophil levels, but individual studies consistently showed lower eosinophil counts. Benralizumab SC reduced clinically significant exacerbations requiring systemic corticosteroids in all studies (rate ratio 0.59, 95% CI 0.52–0.66). This effect was present for both eosinophilic and non-eosinophilic participants, with a stronger effect for the eosinophilic participants. When this analysis was limited to exacerbations requiring ED presentation or admission, the effect was also likely decreased but there was considerable heterogeneity in the exacerbation history of the participants, meaning that those with less exacerbations had less scope for a reduction. One study noted that participants with three or more exacerbations in the previous year saw the greatest effects of benralizumab treatment.3 In general, measures of HRQoL improved, and one study found higher rates of response (proportion above the minimum clinically important difference) in the active treatment group versus placebo. Modest improvement was also seen in FEV1. Serious adverse events were lower in the benralizumab groups (due to a reduction in asthma-related outcomes), but the clinically significant adverse event rate pooled across all studies was higher in the benralizumab group (risk ratio 2.04, 95% CI 1.03–4.03) whereas no difference was reported in the individual studies. There were more discontinuations with benralizumab versus placebo (2.1% vs. 0.9%). A separate meta-analysis of all benralizumab placebo controlled randomised studies in asthma has shown this excess of non-severe adverse events to be related to headache and pyrexia.4 All studies included in the Cochrane review found marked reductions in blood eosinophil levels, attributed to the ability of benralizumab to induce apoptosis of eosinophils. Although children over 12 years were included in many of the studies in this review, results in adolescents were not reported separately and so a sub-group analysis could not be performed. This resulted in the review finding that there is insufficient data to reach a conclusion about efficacy and safety in this population. However, the single study exclusively in children and adolescents that was included in the review, with results only in abstract form, was consistent with the findings in adults.2 That study has since been published and confirmed the efficacy of SC mepolizumab for 52 weeks in reducing asthma exacerbations requiring systemic corticosteroids (rate ratio 0.73; 95% CI 0.56–0.96; P = 0.027).5 Treatment-emergent adverse events occurred in 42 (29%) of 146 participants in the mepolizumab group versus 16 (11%) of 144 participants in the placebo group.5 Long-term safety of mepolizumab in 6–11 year old children with severe eosinophilic asthma has also been supported by an open label study (n = 30) which showed no treatment-related serious adverse events and improved asthma exacerbations and control compared to baseline.6 There are increasing concerns about the safety of lifetime exposure to systemic corticosteroids with an increased risk of chronic adverse effects after only four lifetime short (5 day) courses7 and recent calls for improved steroid stewardship.8 Excess corticosteroid use places patients at risk of increased infection, gastrointestinal events, type 2 diabetes, fractures and cardiovascular and psychiatric complications.7 Biologic agents will play a crucial role in reducing steroid exposure, particularly long-term use. The use of biologic agents for the management of asthma sits in Step 5 of the latest Global Initiative for Asthma treatment algorithm.9 Adolescents with eosinophilic asthma and at least two exacerbations requiring systemic corticosteroids per year despite at least medium dose inhaled corticosteroids, or poor control demonstrated by an Asthma Control Questionnaire10 of ≥1.5, are likely to benefit from treatment with one of these agents. In practice, many of these young people are taking high dose inhaled corticosteroids and often using other agents. Currently mepolizumab and benralizumab for subcutaneous use are funded by the Pharmaceutical Benefits Scheme (PBS) in Australia for adolescents who are aged over 12 years with uncontrolled severe asthma despite optimised asthma therapy and who have eosinophilia. Eosinophilia is defined as a blood eosinophil count in the last 12 months greater than or equal to 300 cells per microlitre, or greater than or equal to 150 cells per microlitre whilst receiving treatment with oral corticosteroids. Funding is available for mepolizumab and benralizumab on the Pharmac community schedule in New Zealand with similar requirements apart from a higher eosinophil count of 500 cells per microlitre. Pharmac NZ funding requires application from a respiratory specialist or immunologist whilst PBS Australia requires the patients be treated by a respiratory physician, clinical immunologist, allergist or general physician experienced in the management of patients with severe asthma. Reslizumab is not currently funded in Australia or New Zealand. Other 'biologic' agents for asthma, dupilumab (anti-IL-4 and IL-13 monoclonal antibody) and omalizumab (anti-IgE monoclonal antibody), are funded under the PBS for severe asthma in Australia, and omalizumab is funded in New Zealand. Many patients may qualify for more than one monoclonal antibody therapy and there are no head-to-head studies to guide the first choice of biologic agent. However, patients who are only partially responsive to one treatment may respond to a change in agent even within a receptor class.11, 12 The decision on the choice of agent should be shared between physician and patient, considering patient age (only omalizumab is funded at the current time for use in the 6–12 years age group), availability, co-morbid severe atopic dermatitis (dupilumab), IgE and eosinophil counts, need for maintenance oral corticosteroids (best steroid sparing evidence for mepolizumab, benralizumab and dupilumab13) and the preferred dosing regimen (2 weekly for dupilumab, 2–4 weekly variable dose for omalizumab, 4 weekly for mepolizumab and 8 weekly after the first 3 doses for benralizumab). Administrative requirements for use of these agents are relatively arduous, with strict eligibility criteria. Continuation of treatment beyond 6 months requires documentation of improvement in symptomatology in both New Zealand and Australia, and a reduction of at least 50% in systemic corticosteroid use in New Zealand. Only one biological agent is allowed at a time, and a break of 4 weeks is required between agents. Whilst the large majority of children with asthma will be successfully managed with inhaled treatments, biologic agents are an important tool for the control of asthma exacerbations in those with the most severe disease, improving quality of life and reducing steroid exposure. Use of these agents is likely to become more common with new agents, changing criteria and emerging evidence in younger patients. Whilst of great benefit to patients, these treatments will have implications for services in terms of administrative requirements and accessing day-stay facilities for treatment.