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Eosinophilic asthma is characterized by frequent exacerbations, poor symptom control and accelerated lung function decline. It is now recognized that the immune response underlying eosinophilic asthma involves a complex network of interconnected pathways from both the adaptive and innate immune systems. Within this response, interleukin‐5 (IL‐5) plays a central role in eosinophil differentiation, activation and survival and has emerged as a key target for therapies treating severe asthma. The monoclonal antibodies mepolizumab and reslizumab target the ligand IL‐5, preventing its interaction with eosinophils; in contrast, benralizumab binds to the IL‐5 receptor (IL‐5R), preventing IL‐5 from binding and leading to substantially greater eosinophil reduction by enhanced antibody‐dependent cell‐mediated cytotoxicity. Although no direct head‐to‐head clinical trials of asthma have been published to formally evaluate the clinical significance of these different therapeutic approaches, the potential benefits of partial versus complete eosinophil depletion continue to remain an important area of study and debate. Here, we review the existing real‐world and clinical study data of anti‐IL‐5/anti‐IL‐5R therapies in severe eosinophilic asthma. [ABSTRACT FROM AUTHOR]

Background: Eosinophils are key therapeutic targets in severe asthma that are suppressed by IL5 (mepolizumab) and IL5 receptor (benralizumab) blockade. The effect of IL5 pathway biologics on recently described homeostatic (hEOs) and inflammatory (iEOs) eosinophil subsets is unknown. We aimed to determine the relative impact of mepolizumab and benralizumab treatment on eosinophil subset and phenotype, and explore clinical associations of eosinophil subsets with severe asthma characteristics and treatment response. Methods: We performed a cross‐sectional observational study of severe asthma (eosinophilic n = 32, non‐eosinophilic n = 23, mepolizumab‐treated n = 25), with longitudinal follow‐up of 30 eosinophilic participants at two timepoints (4–24 weeks, >24 weeks) post‐commencement of mepolizumab (n = 20) or benralizumab (n = 10). Blood hEOs and iEOs were measured by flow cytometry assessment of surface CD62L protein. Results: iEO proportion was significantly lower in mepolizumab‐treated participants in both the cross‐sectional and longitudinal study. Mepolizumab and benralizumab depleted iEOs to a similar extent, however a significantly greater number of hEOs remained in mepolizumab participants at follow‐up. Greater iEO proportion correlated with poorer asthma control in eosinophilic but not non‐eosinophilic asthma. Higher residual iEO proportion correlated with poorer asthma control in mepolizumab‐treated individuals. Reduced blood eosinophil viability was observed in around half of mepolizumab‐treated participants, which was associated with significantly better asthma control and spirometry. Conclusions: Mepolizumab depletes iEOs and reduces circulating eosinophil viability in severe asthma but preserves a residual population of circulatory hEOs. In contrast benralizumab depleted both iEOs and hEOs. Higher iEO abundance and eosinophil viability are associated with poorer clinical outcomes following mepolizumab‐treatment. Monitoring circulating eosinophil phenotype and viability may be useful to predict biologic treatment response in severe asthma. [ABSTRACT FROM AUTHOR]

This article examines the occurrence of eosinophilic granulomatosis with polyangiitis (EGPA) in patients with severe asthma who are being treated with anti-T2 monoclonal antibodies (mAbs). The study involved 30 EGPA patients from different countries who developed the disease while on anti-T2 therapy for severe asthma. The patients were receiving various mAbs, such as omalizumab, benralizumab, mepolizumab, dupilumab, and reslizumab. The article provides demographic, clinical, and treatment-related information about the study population. The findings suggest that EGPA can still develop in these patients despite the use of anti-T2 mAbs, and monitoring blood eosinophil count may be important in predicting disease progression. However, more research is needed to fully understand the relationship between EGPA and anti-T2 mAbs. [Extracted from the article]

Background: Asthma remission has emerged as a potential treatment goal. This study evaluated the effectiveness of two biologics (mepolizumab/omalizumab) in achieving asthma remission. Methods: This observational study included 453 severe asthma patients (41% male; mean age ± SD 55.7 ± 14.7 years) from two real‐world drug registries: the Australian Mepolizumab Registry and the Australian Xolair Registry. The composite outcome clinical remission was defined as zero exacerbations and zero oral corticosteroids during the previous 6 months assessed at 12 months and 5‐item Asthma Control Questionnaire (ACQ‐5) ≤1 at 12 months. We also assessed clinical remission plus optimization (post‐bronchodilator FEV1 ≥80%) or stabilization (post‐bronchodilator FEV1 not greater than 5% decline from baseline) of lung function at 12 months. Sensitivity analyses explored various cut‐offs of ACQ‐5/FEV1 scores. The predictors of clinical remission were identified. Results: 29.3% (73/249) of AMR and 22.8% (37/162) of AXR cohort met the criteria for clinical remission. When lung function criteria were added, the remission rates were reduced to 25.2% and 19.1%, respectively. Sensitivity analyses identified that the remission rate ranged between 18.1% and 34.9% in the AMR cohort and 10.6% and 27.2% in the AXR cohort. Better lung function, lower body mass index, mild disease and absence of comorbidities such as obesity, depression and osteoporosis predicted the odds of achieving clinical remission. Conclusion: Biologic treatment with mepolizumab or omalizumab for severe asthma‐induced asthma remission in a subgroup of patients. Remission on treatment may be an achievable treatment target and future studies should consider remission as an outcome measure. [ABSTRACT FROM AUTHOR]

Background: Eosinophils have been divided into different subpopulations with distinct phenotypes based on CD62L expression. No data are available regarding the correlation between eosinophils subphenotypes and clinical severity of asthma, as well as the effect of anti‐IL‐5 therapy on these cells. The study investigates the correlation between blood CD62Llow inflammatory eosinophils (iEos) and clinical severity of severe eosinophilic asthma (SEA) and evaluates the impact of mepolizumab on iEos. Methods: 112 patients were screened and were divided in two groups: biological‐naive (n = 51) and biological‐treated patients (n = 61). The Biological‐naive patients were analyzed before treatment (Group A) and 19 out of 51 patients, were longitudinally analyzed before and after treatment with mepolizumab 100 mg s.c/4 weeks (Group B); 32 patients were excluded because they were being treated with other biological therapies. Blood eosinophils were analyzed by FACS and correlated with clinical scores. In vitro effect of IL‐5 and mepolizumab on CD62L expression was assessed. Results: A significant correlation between blood CD62Llow cells and clinical scores of asthma and nasal polyps, as well as the number of asthma exacerbations in the last year was shown in untreated patients. In longitudinally studied patients we observed a marked reduction of CD62Llow cells paralleled by an increase in the proportion of CD62Lbright cells, associated with clinical improvement of asthma control. In vitro, CD62L expression on eosinophils is modulated by IL‐5 and anti‐IL‐5. Conclusion: A positive correlation between CD62Llow iEos and the baseline clinical features of SEA with CRSwNP was shown. Furthermore mepolizumab restores the healthy balance among eosinophils sub‐phenotypes in SEA patients. [ABSTRACT FROM AUTHOR]

Background: Patients with severe chronic rhinosinusitis with nasal polyps (CRSwNP) often require repeat sinus surgery. Mepolizumab reduced the need for sinus surgery in the SYNAPSE trial; this analysis sought to provide a more in‐depth assessment of surgery endpoints in SYNAPSE. Methods: SYNAPSE was a double‐blind Phase III trial (NCT03085797) in adults with recurrent, refractory, severe, CRSwNP eligible for repeat sinus surgery despite standard of care treatments and previous surgery. Patients were randomized (1:1) to mepolizumab 100 mg subcutaneously or placebo, plus standard of care, every 4 weeks for 52 weeks. Time to first inclusion on a waiting list for sinus surgery and time to first actual sinus surgery (both up to week 52) were assessed; the latter endpoint was also analyzed post hoc according to time since last sinus surgery before study screening and baseline blood eosinophil count. Results: Among 407 patients (mepolizumab: 206; placebo: 201), mepolizumab versus placebo reduced the risk of being included on a waiting list for sinus surgery (week 52 Kaplan–Meier probability estimate [95% confidence interval]: 13.9% [9.8%, 19.5%] vs. 28.5% [22.7%, 35.4%]). Mepolizumab versus placebo reduced the risk of sinus surgery irrespective of time (<3 vs ≥3 years) since patients' last sinus surgery prior to study screening (hazard ratios [95% confidence intervals] 0.28 [0.09, 0.84] and 0.50 [0.26, 0.98], respectively) and baseline blood eosinophil count. Conclusions: Mepolizumab reduced the risk of further sinus surgery in patients with recurrent, refractory, severe CRSwNP, irrespective of the patient baseline characteristics assessed. [ABSTRACT FROM AUTHOR]

Background: Biomarkers of eosinophilic disease activity, especially in the context of novel therapies that reduce blood eosinophil counts, are an unmet need. Absolute eosinophil count (AEC) does not accurately reflect tissue eosinophilia or eosinophil activation. Therefore, the aims of this study were to compare the reliability of plasma and urine eosinophil major basic protein 1, eosinophil cationic protein, eosinophil‐derived neurotoxin (EDN), and eosinophil peroxidase measurement and to evaluate the usefulness of eosinophil granule protein (EGP) measurement for the assessment of disease activity in patients with eosinophil‐associated diseases treated with mepolizumab, benralizumab, or dexpramipexole. Methods: Eosinophil granule protein concentrations were measured in serum, plasma, and urine from healthy volunteers and patients with hypereosinophilic syndrome (HES), eosinophilic granulomatosis with polyangiitis (EGPA), and eosinophilic asthma using a multiplex assay. Results: Urine EGP concentrations remained stable, whereas serum and plasma EGP concentrations increased significantly with delayed processing. Plasma (p) EDN, but not urine (u) EDN, concentration correlated with AEC and negatively correlated with prednisone dose. Both pEDN and uEDN decreased significantly following treatment of HES patients with benralizumab and EGPA patients with mepolizumab. uEDN appeared to increase with clinical relapse in both patient groups. Conclusions: Measurement of EGP in urine is noninvasive and unaffected by cellular lysis. Although plasma and urine EDN concentrations showed a similar pattern following benralizumab and mepolizumab treatment, the lack of correlation between AEC or prednisone dose and uEDN concentrations suggests that measurement of uEDN may provide a potential biomarker of disease activity in patients with HES and EGPA. [ABSTRACT FROM AUTHOR]

Effective treatment of inflammatory diseases is often challenging owing to their heterogeneous pathophysiology. Understanding of the underlying disease mechanisms is improving and it is now clear that eosinophils play a complex pathophysiological role in a broad range of type 2 inflammatory diseases. Standard of care for these conditions often still includes oral corticosteroids (OCS) and/or cytotoxic immune therapies, which are associated with debilitating side effects. Selective, biological eosinophil‐reducing agents provide treatment options that improve clinical symptoms associated with eosinophilic inflammation and reduce OCS use. Mepolizumab is a humanized monoclonal antibody that binds to and neutralizes interleukin‐5, the major cytokine involved in eosinophil proliferation, activation, and survival. Mepolizumab is approved for the treatment of severe eosinophilic asthma, eosinophilic granulomatosis with polyangiitis and hypereosinophilic syndrome. Additionally, the efficacy of add‐on mepolizumab has been observed in patients with severe chronic rhinosinusitis with nasal polyposis and chronic obstructive pulmonary disease with an eosinophilic phenotype. Here, we review the development, approval, and real‐world effectiveness of mepolizumab for the treatment of patients with severe eosinophilic asthma, from the DREAM to REALITI‐A studies, and describe how knowledge from this journey extended to the use of mepolizumab and other biologics across a broad spectrum of eosinophilic diseases. [ABSTRACT FROM AUTHOR]

This systematic review evaluates the efficacy and safety of biologicals for chronic rhinosinusitis with nasal polyps (CRSwNP) compared with the standard of care. PubMed, Embase, and Cochrane Library were searched for RCTs. Critical and important CRSwNP‐related outcomes were considered. The risk of bias and the certainty of the evidence were assessed using GRADE. RCTs evaluated (dupilumab‐2, omalizumab‐4, mepolizumab‐2, and reslizumab‐1) included 1236 adults, with follow‐up of 20–64 weeks. Dupilumab reduces the need for surgery (NFS) or oral corticosteroid (OCS) use (RR 0.28; 95% CI 0.20–0.39, moderate certainty) and improves with high certainty smell evaluated with UPSIT score (mean difference (MD) +10.54; 95% CI +9.24 to +11.84) and quality of life (QoL) evaluated with SNOT‐22 (MD −19.14; 95% CI −22.80 to −15.47), with fewer treatment‐related adverse events (TAEs) (RR 0.95; 95% CI 0.89–1.02, moderate certainty). Omalizumab reduces NFS (RR 0.85; 95% CI 0.78–0.92, high certainty), decreases OCS use (RR 0.38; 95% CI 0.10–1.38, moderate certainty), and improves high certainty smell (MD +3.84; 95% CI +3.64 to +4.04) and QoL (MD −15.65; 95% CI −16.16 to −15.13), with increased TAE (RR 1.73; 95% CI 0.60–5.03, moderate certainty). There is low certainty for mepolizumab reducing NFS (RR 0.78; 95% CI 0.64–0.94) and improving QoL (MD −13.3; 95% CI −23.93 to −2.67) and smell (MD +0.7; 95% CI −0.48 to +1.88), with increased TAEs (RR 1.64; 95% CI 0.41–6.50). The evidence for reslizumab is very uncertain. [ABSTRACT FROM AUTHOR]

Targeting interleukin-5 with benralizumab: A novel treatment for drug rash with eosinophilia and systemic symptoms Keywords: benralizumab; drug rash with eosinophilia and systemic symptoms; IL-5; mepolizumab; reslizumab EN benralizumab drug rash with eosinophilia and systemic symptoms IL-5 mepolizumab reslizumab 2287 2289 3 08/09/22 20220801 NES 220801 Abbreviations ADCC antibody-dependent cellular cytotoxicity C1q complement component C1q CDC complement-dependent cytotoxicity FcR Fc receptor IL-5 interleukin-5 IL-5R interleukin-5 receptor Drug rash with eosinophilia and systemic symptoms (DRESS) is a potentially fatal systemic adverse drug hypersensitivity reaction that presents with fever, lymphadenopathy, rash, and multiple organ involvement.1 Despite carrying a mortality rate of 10% and a complication rate of 30%, there is a lack of effective evidence-based therapy for DRESS.1 Although systemic corticosteroids are the current mainstay of treatment, their use is based on case reports and series, with no evidence from clinical trials.1 Furthermore, both corticosteroids and current second-line therapies (e.g., immunosuppressants such as cyclosporine) frequently result in high failure rates, relapses upon discontinuation, and high rates of adverse events such as severe infections.1 Thus, there is a pressing need to better define the most appropriate therapeutic targets in DRESS so that targeted therapies can be evaluated in clinical trials. Its administration results in a more potent and rapid drop in eosinophils and IL-5 in comparison with IL-5 binding antibodies and thus might be the more favorable option in acute DRESS. [Extracted from the article]

Enrolled patients presented with either a newly diagnosed disease or a relapse of BP.[1] The primary endpoint was the cumulative rate of relapse-free patients after initiating therapy. Despite the fact that mepolizumab did not significantly affect the clinical outcome, we found significantly lower peripheral blood eosinophil levels in patients treated with mepolizumab compared to patients receiving placebo (Table). (b) Since we could not estimate the effect of mepolizumab in these elderly patients in advance, for ethical reasons, we chose an add-on therapy, that is, mepolizumab or placebo were administered in addition to the standardized therapy with OCS. Even after therapy, eosinophils were detectable in the skin both in patients with and without relapse of BP. [Extracted from the article]

Background: Mepolizumab and omalizumab are treatments for distinct but overlapping severe asthma phenotypes. Objective: To assess if patients eligible for both biologics but not optimally controlled with omalizumab experience improved asthma control when switched directly to mepolizumab. Methods: OSMO was a multicenter, open‐label, single‐arm, 32‐week trial in patients with ≥2 asthma exacerbations in the year prior to enrollment, despite receiving high‐dose inhaled corticosteroids and other controller(s), plus omalizumab (≥4 months). At baseline, patients with blood eosinophil counts ≥150 cells/µL (or ≥300 cells/µL in the prior year) and an Asthma Control Questionnaire (ACQ)‐5 score ≥1.5 discontinued omalizumab and immediately commenced mepolizumab 100 mg subcutaneously every 4 weeks. Endpoints included change from baseline in ACQ‐5 score (primary), St George's Respiratory Questionnaire (SGRQ) score and the proportions of ACQ‐5 and SGRQ responders, all at Week 32, and the annualized exacerbation rate over the study period. Results: At Week 32 (intent‐to‐treat population [n = 145]), the least squares (LS) mean changes (standard error [SE]) in ACQ‐5 and SGRQ total scores were −1.45 (0.107) and −19.0 (1.64) points; with 77% and 79% of patients achieving the minimum clinically important differences (ACQ‐5: ≥0.5 points; SGRQ: ≥4 points), respectively. The annualized rate of clinically significant exacerbations was 1.18 events/year, a 64% reduction from 3.26 events/year during the previous year. Safety and immunogenicity profiles were consistent with previous trials. Conclusion: After directly switching from omalizumab to mepolizumab, patients with uncontrolled severe eosinophilic asthma experienced clinically significant improvements in asthma control, health status, and exacerbation rate, with no tolerability issues reported. [ABSTRACT FROM AUTHOR]

Background We performed post hoc analyses to evaluate the effect of humanized monoclonal antibody mepolizumab in patients with severe eosinophilic asthma previously treated with omalizumab. Methods Data were collected from two randomized double-blind, placebo-controlled studies: MENSA (NCT01691521: 32-week treatment phase) and SIRIUS (NCT01691508: 24-week treatment phase). Active treatment was 75 mg intravenous mepolizumab (MENSA) or 100 mg subcutaneous mepolizumab (MENSA, SIRIUS). Patients had evidence of eosinophilic inflammation ≥150 cells/μl (at screening) or ≥300 cells/μl (during the previous year). Primary outcomes were the rate of exacerbations (MENSA) and the percentage reduction in oral corticosteroid (OCS) dose (SIRIUS). Other outcomes included lung function (forced expiratory volume in 1 s and morning peak expiratory flow), Asthma Control Questionnaire (ACQ-5), St George's Respiratory Questionnaire (SGRQ) scores, and safety. Results Overall, 576 patients were included from MENSA and 135 from SIRIUS, with 13% and 33% previously receiving omalizumab, respectively. In MENSA, mepolizumab reduced the rate of exacerbations by 57% (prior omalizumab) and 47% (no prior omalizumab) vs placebo. In SIRIUS, reductions in OCS use were comparable regardless of prior omalizumab use. Despite reducing chronic OCS use, mepolizumab also resulted in similar reductions in exacerbation rate relative to placebo in both subgroups. Asthma control and quality of life improved with mepolizumab vs placebo in both studies independent of prior omalizumab use, as shown by ACQ-5 and SGRQ scores. Adverse events were also comparable irrespective of prior omalizumab use. Conclusions These post hoc analyses indicate that patients with severe eosinophilic asthma respond positively to mepolizumab regardless of prior use of omalizumab. [ABSTRACT FROM AUTHOR]

Eosinophils may play an important role in the pathogenesis of atopic dermatitis (AD). Interleukin-5 is essential for eosinophil growth, differentiation and migration. A monoclonal antibody to human interleukin-5 (mepolizumab) was developed for atopic diseases. This study was designed to study the effect of mepolizumab in AD.Two single doses of 750 mg mepolizumab, given 1 week apart, were studied in patients with moderate to severe AD using a randomized, placebo-controlled parallel group design. The primary endpoint of‘success’ to treatment was defined as the percentage of patients with at least‘marked improvement’ after 2 weeks as assessed by the Physician's Global Assessment of Improvement (PGA). Furthermore, SCORing AD (SCORAD), pruritus scoring, number of blood eosinophils and serum thymus and activation-regulated chemokine (TARC) values served as secondary endpoints. Fluticason propionate cream 0.05%, once daily could be used as rescue medication from day 16 if no improvement was recorded.Eighteen patients received mepolizumab and 22 placebo treatment. Peripheral blood eosinophil numbers were significantly reduced in the treatment group compared with placebo (P < 0.05). No clinical success was reached by PGA assessment (P = 0.115), SCORAD (P = 0.293), pruritus scoring and TARC values in the mepolizumab-treated group compared with placebo. However, modest improvement (<50% improvement) assessed by PGA was scored significantly more in the mepolizumab-treated group compared with placebo (P < 0.05).Two single doses of 750 mg mepolizumab did not result in clinical success in patients with AD, despite a significant decrease in peripheral blood eosinophils. [ABSTRACT FROM AUTHOR]