Effectiveness of Anti-IL4R Therapy Following Suboptimal Response to Anti-IL5/5R Therapy in Severe Eosinophilic Asthma

Introduction:Dupilumab is an anti-IL4R monoclonal antibody (mAb) with proven efficacy in severe eosinophilic asthma (SEA). We have previously identified that a suboptimal response to the eosinophil targeting anti-IL5/5R mAbs mepolizumab and benralizumab is seen in 27% and 14% of patients with SEA respectively1,2. The mechanism of this is not well-understood. It is unknown whether such patients respond in a clinically meaningful way following a switch to dupilumab. Methods:We performed a retrospective analysis of the clinical effectiveness of dupilumab (minimum 6 months treatment) in patients with SEA at our tertiary severe asthma centre who had failed to adequately respond to at least one of the anti-IL-5/5R mAbs. Change in the annualised exacerbation rate (AER), maintenance oral corticosteroids (mOCS) requirements, ACQ-6 and mAQLQ was recorded. Results:Thirty-two patients (mean age 41.2, 68.8% female, 71.9% atopic) were included in the analysis. 13/32(40.6%) had co-morbid nasal polyposis and 5/32(15.6%) had eczema. The baseline FeNO was 60ppb(IQR 39.6-87.5) and peak eosinophil count prior to any mAb was 0.6(IQR 0.5-0.9). 23/32(71.8%) were switched from benralizumab, of whom, 12/23(52.2%) had also failed to respond to at least one other anti-IL5 mAb previously. At six months, the daily median mOCS dose in those requiring mOCS at baseline (n=18) fell from 10mg(IQR 5-25mg) to 3mg(IQR 0-5mg), p≤0.001. 4/18(22%) were able to stop mOCS completely. Mean(SD) AER improved from 2.34(1.89) to 0.44(0.95), p≤0.001. There were also significant improvements in ACQ6 and mAQLQ that exceeded twice the MCID for both measures: mean (SD) ACQ6 improved from 3.04(1.26) to 1.82(1.28), p≤0.001;mAQLQ improved from 3.90(SD 1.40) to 5.36(SD 1.05), p≤0.001. Due to the COVID-19 pandemic, FEV1 data was only available for 8 patients. However, there was nonetheless a significant rise in FEV1 (%predicted) from 55.6% (9.78) to 68.5%(16.9), p=0.011. One patient discontinued dupilumab during the follow-up period. Conclusion: A minority of individuals with SEA have a suboptimal response to eosinophil targeted therapy with an anti-IL5/5R mAb. In these patients, we report significant clinical improvements following initiation with dupilumab suggesting an important role for the IL-4/-13 pathway in these patients. Further research is required to understand whether these patients represent a distinct subphenotype of T2-high asthma.

COVID-19 in the absence of eosinophils: a case series of confirmed infection whilst on treatment with benralizumab

BackgroundBlood eosinopaenia was one of the earliest reported findings in hospitalised patients with COVID-19, questioning whether eosinophils could have an anti-viral or deleterious role in the immune response against SARS-CoV2. Benralizumab is an anti-IL5R monoclonal antibody licensed for the treatment of severe eosinophilic asthma (SEA) and causes the near-complete depletion of blood and tissue eosinophils. As such, it offers the opportunity to explore the impact of eosinopaenia at the time of infection on outcome with COVID-19.MethodPatients started on treatment with benralizumab (up until April 2021) for SEA at our regional asthma centre were contacted by telephone throughout May and June 2021 to establish whether they had experienced a confirmed (PCR-positive) SARS-CoV2 infection since commencing benralizumab. Clinical and demographic characteristics were recorded along with the outcome of infection, including the need for hospitalisation or intensive care admission. Patients requiring hospitalisation were compared to those experiencing mild infections.ResultsData on 268 patients treated with benralizumab was collected with 24/268 (9%) confirming SARS-CoV2 infection with a positive PCR test. Of these 18/24 (75%) experienced mild infections that did not require hospitalisation. Of the 6/24 requiring hospitalisation, the median (IQR) length of stay was 6 (1–8) days. No patients required ICU admission or mechanical ventilation. There was no significant difference in baseline characteristics between hospitalised and non-hospitalised patients. However, it is noteworthy that a higher proportion of hospitalised patients were male (50.0% vs 38.9%) and had a higher mean BMI (32.1 vs 29.5).DiscussionIn the context of drug-induced eosinopaenia with benralizumab, 75% of patients with severe asthma experienced mild COVID-19 disease. This is likely to be an underestimate given that other patients may have experienced an asymptomatic infection or not pursued PCR testing in the context of mild infection. Although caution is needed due to the small sample size, these results do not support a significant role for eosinophils in SARS-CoV2 infection.

Prescribing patterns and treatment adherence in patients with asthma during the COVID-19 pandemic

Introduction and ObjectiveThe COVID-19 pandemic has witnessed a reduction in asthma exacerbations in the UK. Several factors may underpin this, including reduced transmission of seasonal viruses and improved use of or adherence to inhaled corticosteroids (ICS). This study aims to investigate whether ICS use has changed during the pandemic for patients with asthma.MethodsUsing the OpenPrescribing database, we analysed prescribing patterns of ICS, salbutamol and peak flow meters from January 2019 to January 2021 across England. Additionally, using a sample asthma cohort from 3 primary care practices, we assessed individual prescription patterns and ICS adherence across the two-year period. ICS adherence has been defined according to the medication possession (MPR) ratio: good (≥75%), sub-optimal (50–74%), poor (25–49%) and non-adherence (<25%).ResultsA sharp increase in national ICS prescriptions was observed at the start of the pandemic in March 2020 representing a 50% increase compared to February 2020. Thereafter national ICS prescription rates appear to have returned to normal levels. The sample asthma cohort included 1132 patients (762 patients treated with ICS across 2019 and 2020). Overall, adherence to ICS improved in 2020 (P<0.001), with the proportion of patients meeting ‘good adherence’ (≥75%) increasing from 34% to 42% (P<0.001). Analysis of this cohort suggested the March 2020 spike predominantly reflected improved adherence rather than a hoarding effect of multiple inhalers or new prescriptions for ICS-naïve individuals. Increasing age was associated with higher levels of ICS adherence. A similar spike in salbutamol occurred in March 2020, however, an overall reduction in salbutamol prescriptions was seen in 2020 (P=0.039). National figures highlighted a progressive increase in prescription of peak flow meters over 2020.ConclusionA marked spike in national ICS prescriptions occurred in March 2020. This increase appears to reflect improved adherence in patients with low levels of adherence rather than a hoarding effect or large-scale initiation in ICS-naïve patients. Despite a comparable spike in salbutamol prescriptions, 2020 saw an overall reduction in salbutamol prescriptions. Prescription of peak flow meters steadily increased over 2020 in keeping with the need for more remote monitoring.

Does asthma control change when patients transition to home administration of mepolizumab?

Introduction: Mepolizumab is a biologic agent targeting interleukin (IL)-5 which is currently licensed as add-on therapy for severe eosinophilic asthmatic (SEA). It is usually administered in a hospital setting but with the option of homecare being introduced in 2019, the 4-weekly subcutaneous injections can be self-administered at home. We investigated whether there was a change in asthma control following the transition to home administration and whether a differential response to treatment exists following transition to homecare before and after the onset of the COVID-19 pandemic. Methods: Patients receiving mepolizumab via home care were stratified according to those who had a planned transition to homecare prior to 1st Feb 2020 versus those who had an unplanned transition after this date necessitated by the COVID-19 pandemic. The last Asthma Control Questionnaire-6 (ACQ6) measured in clinic ('baseline') was compared with that collected by telephone consultation 6-8 weeks after transition ('homecare'). Patients were excluded if both values were not available. Results: Of 87 mepolizumab patients included in the analysis, 46 were planned transitions. There was no significant (Figure presented) difference in the pre-biologic ACQ6 (p=0.07) between groups. Immediately prior to transition to homecare (baseline), the planned group had a lower mean ACQ6 than those in the unplanned group (1.19 vs 1.90, P=0.004). The ACQ6 on homecare decreased significantly in both groups (-0.47 in the planned group vs -0.56 in the unplanned group, both P<0.001). The ACQ6 for the planned cohort during homecare was significantly lower than that for the unplanned group (0.72 vs 1.34, P=0.012) (figure 1). (Table presented) Conclusions: We found a significant improvement in ACQ6 for all SEA patients established on Mepolizumab who transitioned to home mepolizumab administration. This improvement occurred irrespective of whether the transition was 'planned' or 'unplanned'. Further research is required to understand the potential influence of shielding during lockdown and the method of ACQ assessment (telephone vs face-to-face ACQ reporting in clinic) on this improvement.

Does asthma control change following transition to home benralizumab administration?

Introduction: The COVID-19 pandemic necessitated the rapid transition of large numbers of patients onto homecare to facilitate on-going therapy in a cohort of patients who were 'shielding'. Alongside this, patients continued to need to be initiated on biologic therapy in spite of the pandemic. The impact of administering biologic therapy at home is largely unknown, yet crucial to optimise patient outcome and minimise steroid burden. We investigated whether there was a differential response following transition to homecare of established patients versus those newly started. Methods: Patients with severe eosinophilic asthma receiving home benralizumab were stratified according to those who had received ≥3 doses prior to COVID-19 lockdown on the 15th March 2020 ('established' patients) versus those who were initiated after this date ('new' patients). We compared the last Asthma Control Questionnaire-6 (ACQ6) measured in clinic with that collected by telephone consultation 8-12 weeks after transition to homecare. Patients were excluded if both values were not available. Results: 246 benralizumab patients were included in the analysis, of whom 49 (20%) were new. There was no significant difference in pre-biologic ACQ6, pre-homecare (baseline) (Figure presented) ACQ6 or post-homecare ACQ6 between the new and established patient groups. Both cohorts exhibited a similar magnitude of improvement in their ACQ6 following the transition to homecare (-0.73 in the established group vs -0.73 in the new group, both P<0.0001) (figure 1). Conclusions: We have demonstrated that early transition to homecare in patients treated with benralizumab is not associated with worse clinical outcomes as assessed by ACQ6. The improvements in ACQ6 were seen irrespective of whether they were 'established' on therapy at time of transition or 'new'. Further research is required to understand the potential influence of lockdown and/or telephone vs face-to-face ACQ reporting.