Benralizumab 30mg/1ml solution for injection pre-filled disposable devices

BACKGROUND: Exacerbations of asthma and chronic obstructive pulmonary disease (COPD) are important events and are associated with critical illness. Eosinophilic inflammation is a treatable trait commonly found during acute exacerbations of asthma and COPD. We hypothesised that for patients with eosinophilic exacerbations, a single injection of benralizumab, a humanised monoclonal antibody against interleukin-5 receptor-α, alone or in combination with prednisolone, will improve clinical outcomes compared with prednisolone, the standard of care. METHODS: The Acute exacerbations treated with BenRAlizumab trial (ABRA) was a multicentre, phase 2, double-blind, double-dummy, active placebo-controlled randomised trial completed in the UK at Oxford University Hospitals NHS Foundation Trust and Guy's and St Thomas' NHS Foundation Trust. Patients were recruited from urgent care clinics and emergency departments of these two hospitals. At the time of an acute exacerbation of asthma or COPD, adults with blood eosinophil counts of equal to or more than 300 cells per μL were randomly assigned in a 1:1:1 ratio to receive acute treatment with: prednisolone 30 mg once daily for 5 days and 100 mg benralizumab subcutaneous injection once (BENRA plus PRED group); placebo tablets once daily for 5 days and 100 mg benralizumab subcutaneous injection once (BENRA group); or prednisolone 30 mg once daily for 5 days and placebo subcutaneous injection once (PRED group). Randomisation was performed with a centralised interactive computer randomisation service. All patients and study research staff involved in data collection were masked to study blood results and treatment allocation. The co-primary outcomes were proportion of treatment failures over 90 days and total visual analogue scale (VAS) symptoms at day 28 in the pooled benralizumab groups compared with the prednisolone alone group and analysed in the intention-to-treat population. The trial was registered on Clinicaltrials.govNCT04098718. FINDINGS: Between May 13, 2021, and Feb 5, 2024, 287 patients were screened for study inclusion. 129 were excluded due to not having an exacerbation captured or not meeting the eosinophil exclusion criteria. 158 patients were randomly assigned at acute eosinophilic exacerbation of asthma or COPD where 86 (54%) patients were female and 72 (46%) were male with a mean age of 57 years (range, 18-84). 53 patients were randomly assigned to the PRED group, 53 were randomly assigned to the BENRA group, and 52 were assigned to the BENRA plus PRED treatment group. At 90 days, treatment failures occurred in 39 (74%) of 53 in the PRED group, and 47 (45%) of 105 in the pooled-BENRA group (OR 0·26 [95% CI 0·13-0·56]; p=0·0005). The 28-day total VAS mean difference was 49 mm (95% CI 14-84; p=0·0065), favouring the pooled-BENRA group. There were no fatal adverse events and benralizumab was well tolerated. Notably, hyperglycaemia and sinusitis or sinus infection adverse events were related to the prednisolone study drug only. INTERPRETATION: Benralizumab can be used as a treatment of acute eosinophilic exacerbations and achieves better outcomes than the current standard of care with prednisolone alone. These results offer a new way of treating eosinophilic endotypes of asthma and COPD exacerbations. FUNDING: AstraZeneca.

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BACKGROUND: Chronic spontaneous urticaria (CSU) is a relatively common skin disease associated with hives and angio-oedema. Eosinophils play a role in CSU pathogenesis. Benralizumab, an anti-interleukin-5 receptor-α monoclonal antibody, has been shown to induce nearly complete depletion of eosinophils. OBJECTIVES: To determine the clinical efficacy and safety of benralizumab in patients with CSU who were symptomatic despite H1 antihistamine treatment. METHODS: The 24-week, randomized, double-blind, placebo-controlled, phase IIb portion of the ARROYO trial enrolled adult patients with CSU who were currently on H1 antihistamine treatment. Patients were randomized to one of five treatment groups according to benralizumab dose and regimen for a 24-week treatment period. The primary endpoint was change from baseline in Itch Severity Score (ISS)7 at week 12. The key secondary endpoint was change from baseline in Urticaria Activity Score (UAS)7 at week 12. Additional secondary endpoints included other metrics to assess CSU at week 24, blood eosinophil levels, and pharmacokinetics and immunogenicity assessments. Exploratory subgroup analyses were conducted to explore responses according to demographics, clinical features and biomarkers. Safety was assessed in all treatment groups. RESULTS: Of 155 patients, 59 were randomized to benralizumab 30 mg, 56 to benralizumab 60 mg and 40 to placebo. Baseline and disease characteristics were consistent with what was expected for patients with CSU. There were no significant differences in change from baseline in ISS7 score at week 12 between benralizumab and placebo [benralizumab 30 mg vs. placebo, least-squares mean difference -1.01, 95% confidence interval (CI) -3.28 to 1.26; benralizumab 60 mg vs. placebo, least-squares mean difference -1.79, 95% CI -4.09 to 0.50] nor in change from baseline in UAS7 score at week 12 between benralizumab and placebo (benralizumab 30 mg vs. placebo, P = 0.407; benralizumab 60 mg vs. placebo, P = 0.082). Depletion of blood eosinophil levels was observed at week 24 in patients treated with benralizumab. All other secondary endpoints and exploratory/subgroup analyses indicated no significant differences between benralizumab and placebo. Safety results were consistent with the known profile of benralizumab. CONCLUSIONS: Although benralizumab resulted in near-complete depletion of blood eosinophils, there was no clinical benefit over placebo.

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Abstract Background and Objective Several randomized controlled trials (RCTs) have shown that benralizumab is characterized by a good profile of efficacy and safety, thereby being potentially able to elicit clinical remission on‐treatment of severe eosinophilic asthma (SEA). The main goal of this multicentre observational study was to verify the effectiveness of benralizumab in inducing a sustained remission on‐treatment of SEA in patients with or without comorbid chronic rhinosinusitis with nasal polyps (CRSwNP). Methods Throughout 2 years of treatment with benralizumab, a four‐component evaluation of sustained remission of SEA was performed, including the assessment of SEA exacerbations, use of oral corticosteroids (OCSs), symptom control and lung function. Results The present study recruited 164 patients suffering from SEA. After 24 months of add‐on biological therapy with benralizumab, 69 (42.1%) achieved the important target of sustained remission on‐treatment (exacerbation rate = 0, OCS dose = 0, pre‐bronchodilator FEV 1 ≥80% pred., ACT score ≥ 20). During the same period, a persistent improvement of CRSwNP (SNOT‐22 < 30, NP recurrence = 0) was observed in 33 (40.2%) out of 82 subjects with concomitant NP. The latter comorbidity and post‐bronchodilator reversibility of airflow limitation were two independent predictors of sustained remission on‐treatment (OR = 2.32, p < 0.05 and OR = 5.59, p < 0.01, respectively). Conclusion Taken together, the results of this real‐life clinical investigation indicate that benralizumab can induce a sustained remission on‐treatment of SEA, especially in those patients with comorbid CRSwNP and reversible airflow limitation. image

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BACKGROUND: Benralizumab induces rapid and near-complete depletion of eosinophils from blood and lung tissue. We investigated whether benralizumab could attenuate the allergen-induced late asthmatic response (LAR) in participants with allergic asthma. METHODS: Participants with allergic asthma who demonstrated increased sputum eosinophils and LAR at screening were randomised to benralizumab 30 mg or matched placebo given every 4 weeks for 8 weeks (3 doses). Allergen challenges were performed at weeks 9 and 12 when blood, sputum, bone marrow and bronchial tissue eosinophils and LAR were assessed. RESULTS: 46 participants (mean age 30.9 years) were randomised to benralizumab (n=23) or placebo (n=23). Eosinophils were significantly reduced in the benralizumab group compared with placebo in blood at 4 weeks and sputum and bone marrow at 9 weeks after treatment initiation. At 7 h after an allergen challenge at week 9, sputum eosinophilia was significantly attenuated in the benralizumab group compared to placebo (least squares mean difference -5.81%, 95% CI -10.69- -0.94%; p=0.021); however, the LAR was not significantly different (least squares mean difference 2.54%, 95% CI 3.05-8.12%; p=0.363). Adverse events were reported for seven (30.4%) and 14 (60.9%) participants in the benralizumab and placebo groups, respectively. CONCLUSION: Benralizumab administration over 8 weeks resulted in a significant attenuation of blood, bone marrow and sputum eosinophilia in participants with mild allergic asthma; however, there was no change in the LAR, suggesting that eosinophils alone are not a key component of allergen-induced bronchoconstriction.

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BACKGROUND: Stepwise intensification of inhaled corticosteroids (ICS) is routine for severe eosinophilic asthma, despite some poor responses to high-dose ICS. Dose reductions are recommended in patients responding to biologics, but little supporting safety evidence exists. METHODS: SHAMAL was a phase 4, randomised, open-label, active-controlled study done at 22 study sites in four countries. Eligible participants were adults (aged ≥18 years) with severe eosinophilic asthma and a five-item Asthma Control Questionnaire score below 1·5 and who received at least three consecutive doses of benralizumab before screening. We randomly assigned patients (3:1) to taper their high-dose ICS to a medium-dose, low-dose, and as-needed dose (reduction group) or continue (reference group) their ICS-formoterol therapy for 32 weeks, followed by a 16-week maintenance period. The primary endpoint was the proportion of patients reducing their ICS-formoterol dose by week 32. The primary outcome was assessed in the reduction group, and safety analyses included all randomly assigned patients receiving study treatment. This study is registered at ClinicalTrials.gov, NCT04159519. FINDINGS: Between Nov 12, 2019, and Feb 16, 2023, we screened and enrolled in the run-in period 208 patients. We randomly assigned 168 (81%) to the reduction (n=125 [74%]) and reference arms (n=43 [26%]). Overall, 110 (92%) patients reduced their ICS-formoterol dose: 18 (15%) to medium-dose, 20 (17%) to low-dose, and 72 (61%) to as-needed only. In 113 (96%) patients, reductions were maintained to week 48; 114 (91%) of patients in the reduction group had zero exacerbations during tapering. Rates of adverse events were similar between groups. 91 (73%) patients had adverse events in the reduction group and 35 (83%) in the reference group. 17 patients had serious adverse events in the study: 12 (10%) in the reduction group and five (12%) in the reference group. No deaths occurred during the study. INTERPRETATION: These findings show that patients controlled on benralizumab can have meaningful reductions in ICS therapy while maintaining asthma control. FUNDING: AstraZeneca.

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ABSTRACT The introduction of biologics, such as benralizumab (an anti‐IL‐5 receptor α humanised monoclonal antibody), has made remission a feasible goal for patients with severe eosinophilic asthma (SEA). However, there are remaining research gaps and no clear consensus on the definition of remission. We consolidated post hoc remission data from clinical trials and real‐world studies of benralizumab in patients with SEA to gather insights on: testing different definitions; predictors of remission; the effect of comorbidities on achieving remission; remission and background medication reduction; long‐term remission patterns with benralizumab; and remission in a real‐life setting. In the SIROCCO and CALIMA Phase 3 randomised studies, patients with remission had higher baseline median blood eosinophil counts, were more likely to have a FEV 1 of ≥ 65% predicted, had fewer exacerbations within 12 months and had lower mean ACQ‐6 scores. Compared with the overall population, patients with a history of nasal polyps were also more likely to achieve remission with benralizumab. Analyses of the BORA and MELTEMI extension studies showed that in the longer term, once remission is achieved with benralizumab, patients are likely to remain in remission with continued treatment. In the open‐label, single‐arm ANDHI‐In Practice and PONENTE studies, patients achieving remission had a shorter median time since asthma diagnosis, higher median age at asthma onset and lower median ACQ‐6 scores. The SHAMAL study and the Phase 3b ANDHI‐In Practice substudy demonstrate that remission is maintained with benralizumab even when patients reduce their background medication. Finally, the XALOC‐1 real‐world study highlights how patients with lower BMI are more likely to achieve remission with benralizumab. These findings demonstrate that achieving remission in patients with SEA is feasible with benralizumab and, in turn, inform future directions for research and treatment that includes a promising shift towards a new era of treat‐to‐target. This manuscript was supported by AstraZeneca, the manufacturer of benralizumab.

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BACKGROUND: Type 2 (T2) inflammation, characterized by blood and airway eosinophilia, underlies severe eosinophilic asthma (SEA) and chronic rhinosinusitis with nasal polyps (CRSwNP). In line with the Global Airways theory, SEA and CRSwNP frequently co-occur, creating a multimorbid phenotype. Separately, SEA and CRSwNP are burdensome: when concomitant, they compound each other, creating a more difficult-to-treat disease with increased complications. BODY: Current management approaches rarely control disease and are associated with substantial side-effects. Several recently developed anti-IL-5 monoclonal antibodies have shown efficacy in treating co-morbid SEA with CRSwNP by targeting T2 inflammation with systemic therapies. Of these, only benralizumab directly targets the IL-5 receptor-α, leading to rapid, sustained, near-complete eosinophil depletion. Analyses in patients with co-morbid SEA with CRSwNP are limited, although data from the ANDHI, XALOC-1, and RANS studies suggest benralizumab can effectively target inflammation underlying co-morbid disease. CONCLUSION: Despite progress toward more effective therapies, treatment approaches remain siloed, with SEA and CRSwNP often managed separately. There is a need for the development of multidisciplinary approaches for treating patients with comorbid SEA with CRSwNP.

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