Long-term safety and pharmacodynamics of mepolizumab in children with severe asthma with an eosinophilic phenotype

Background Mepolizumab is approved for patients with severe asthma with an eosinophilic phenotype aged 12 or more (United States) or 6 or more (European Union) years, but its long-term use in children aged 6 to 11 years has not yet been assessed. Objective We sought to assess the long-term safety, efficacy, and pharmacodynamics of mepolizumab in children aged 6 to 11 years with severe asthma with an eosinophilic phenotype. Methods In this open-label, uncontrolled, repeat-dose extension study (NCT02377427), children aged 6 to 11 years with severe asthma with an eosinophilic phenotype (blood eosinophil counts ≥150 cells/μL at screening or ≥300 cells/μL in the previous year) received a body weight–dependent dose of subcutaneous mepolizumab of 40 mg ( Results Over 52 weeks, 30 children received mepolizumab; 27 (90%) and 7 (23%) experienced on-treatment AEs and serious AEs, respectively. No serious AEs were treatment related. There were no fatal AEs. No specific patterns of AEs were evident, and no anti-drug antibody or neutralizing antibody responses were reported. Compared with baseline values, mepolizumab treatment reduced blood eosinophil counts and asthma exacerbations and improved asthma control across all treatment groups. Conclusion Long-term safety, pharmacodynamic, and efficacy data from this study support a positive benefit-risk profile for mepolizumab in children with severe asthma with an eosinophilic phenotype and were similar to data in studies in adults and adolescents

Evaluation of clinical benefit from treatment with mepolizumab for patients with eosinophilic granulomatosis with polyangiitis.

BACKGROUND: In a recent phase III trial (NCT02020889) 53% of mepolizumab-treated versus 19% of placebo-treated patients with eosinophilic granulomatosis with polyangiitis (EGPA) achieved protocol-defined remission. OBJECTIVE: We sought to investigate post hoc the clinical benefit of mepolizumab in patients with EGPA using a comprehensive definition of benefit encompassing remission, oral glucocorticoid (OGC) dose reduction, and EGPA relapses. METHODS: The randomized, placebo-controlled, double-blind, parallel-group trial recruited patients with relapsing/refractory EGPA receiving stable OGCs (prednisolone/prednisone, ≥7.5-50 mg/d) for 4 or more weeks. Patients received 300 mg of subcutaneous mepolizumab or placebo every 4 weeks for 52 weeks. Clinical benefit was defined post hoc as follows: remission at any time (2 definitions used), 50% or greater OGC dose reduction during weeks 48 to 52, or no EGPA relapses. The 2 remission definitions were Birmingham Vasculitis Activity Score of 0 plus OGC dose of 4 mg/d or less (remission 1/clinical benefit 1) or 7.5 mg/d or less (remission 2/clinical benefit 2). Clinical benefit was assessed in all patients and among subgroups with a baseline blood eosinophil count of less than 150 cells/μL, baseline OGC dosage of greater than 20 mg/d, or weight of greater than 85 kg. RESULTS: With mepolizumab versus placebo, 78% versus 32% of patients experienced clinical benefit 1, and 87% versus 53% of patients experienced clinical benefit 2 (both P < .001). Significantly more patients experienced clinical benefit 1 with mepolizumab versus placebo in the blood eosinophil count less than 150 cells/μL subgroup (72% vs 43%, P = .033) and weight greater than 85 kg subgroup (68% vs 23%, P = .005); in the OGC greater than 20 mg/d subgroup, results were not significant but favored mepolizumab (60% vs 36%, P = .395). CONCLUSION: When a comprehensive definition of clinical benefit was applied to data from a randomized controlled trial, 78% to 87% of patients with EGPA experienced benefit with mepolizumab

Failure of human rhombic lip differentiation underlies medulloblastoma formation

Medulloblastoma (MB) comprises a group of heterogeneous paediatric embryonal neoplasms of the hindbrain with strong links to early development of the hindbrain 1–4. Mutations that activate Sonic hedgehog signalling lead to Sonic hedgehog MB in the upper rhombic lip (RL) granule cell lineage 5–8. By contrast, mutations that activate WNT signalling lead to WNT MB in the lower RL 9,10. However, little is known about the more commonly occurring group 4 (G4) MB, which is thought to arise in the unipolar brush cell lineage 3,4. Here we demonstrate that somatic mutations that cause G4 MB converge on the core binding factor alpha (CBFA) complex and mutually exclusive alterations that affect CBFA2T2, CBFA2T3, PRDM6, UTX and OTX2. CBFA2T2 is expressed early in the progenitor cells of the cerebellar RL subventricular zone in Homo sapiens, and G4 MB transcriptionally resembles these progenitors but are stalled in developmental time. Knockdown of OTX2 in model systems relieves this differentiation blockade, which allows MB cells to spontaneously proceed along normal developmental differentiation trajectories. The specific nature of the split human RL, which is destined to generate most of the neurons in the human brain, and its high level of susceptible EOMES +KI67 + unipolar brush cell progenitor cells probably predisposes our species to the development of G4 MB

Development of methodology for assessing steroid-tapering in clinical trials for biologics in asthma

BACKGROUND: Long-term use of oral corticosteroids (OCS) is associated with a risk of adverse events and comorbidities. As such, a goal in assessing the efficacy of biologics in severe asthma is often to monitor reduction in OCS usage. Importantly, however, OCS dose reductions must be conducted without loss of disease control. MAIN BODY: Herein, we describe the development of OCS-sparing study methodologies for biologic therapies in patients with asthma. In particular, we focus on four randomized, placebo-controlled, parallel-group studies of varying sizes (key single-center study [n = 20], SIRIUS [n = 135], ZONDA [n = 220], VENTURE [n = 210]) and one open-label study (PONENTE [n = 598]), which assessed the effect of asthma biologics (mepolizumab, benralizumab or dupilumab) on OCS use using predefined OCS-tapering schedules. In particular, we discuss the evolution of study design elements in these studies, including patient eligibility criteria, the use of tailored OCS dose reduction schedules, monitoring of outcomes, the use of biomarkers and use of repetitive assessments of adrenal function during OCS tapering. CONCLUSION: Taken together, these developments have improved OCS-sparing asthma studies in recent years and the lessons learned may help with optimization of further OCS-sparing studies, and potentially clinical practice in the future

The roles of eosinophils and interleukin-5 in the pathophysiology of chronic rhinosinusitis with nasal polyps

Chronic rhinosinusitis with nasal polyps (CRSwNP) is generally associated with eosinophilic tissue infiltration linked to type 2 inflammation and characterized by elevated levels of interleukin (IL)-5 and other type 2 inflammatory mediators. Although distinct and overlapping contributions of eosinophils and IL-5 to CRSwNP pathology are still being explored, they are both known to play an important role in NP inflammation. Eosinophils secrete numerous type 2 inflammatory mediators including granule proteins, enzymes, cytokines, chemokines, growth factors, lipids, and oxidative products. IL-5 is critical for the differentiation, migration, activation, and survival of eosinophils but is also implicated in the biological functions of mast cells, basophils, innate lymphoid cells, B cells, and epithelial cells. Results from clinical trials of therapeutics that target type 2 inflammatory mediators (including but not limited to anti-IL-5, anti-immunoglobulin-E, and anti-IL-4/13) may provide further evidence of how eosinophils and IL-5 contribute to CRSwNP. Finally, the association between eosinophilia/elevated IL-5 and greater rates of NP recurrence after endoscopic sinus surgery (ESS) suggests that these mediators may have utility as biomarkers of NP recurrence in diagnosing and assessing the severity of CRSwNP. This review provides an overview of eosinophil and IL-5 biology and explores the literature regarding the role of these mediators in CRSwNP pathogenesis and NP recurrence following ESS. Based on current published evidence, we suggest that although eosinophils play a key role in CRSwNP pathophysiology, IL-5, a cytokine that activates these cells, also represents a pertinent and effective treatment target in patients with CRSwNP.</p

The roles of eosinophils and interleukin‐5 in the pathophysiology of chronic rhinosinusitis with nasal polyps

Chronic rhinosinusitis with nasal polyps (CRSwNP) is generally associated with eosinophilic tissue infiltration linked to type 2 inflammation and characterized by elevated levels of interleukin (IL)‐5 and other type 2 inflammatory mediators. Although distinct and overlapping contributions of eosinophils and IL‐5 to CRSwNP pathology are still being explored, they are both known to play an important role in NP inflammation. Eosinophils secrete numerous type 2 inflammatory mediators including granule proteins, enzymes, cytokines, chemokines, growth factors, lipids, and oxidative products. IL‐5 is critical for the differentiation, migration, activation, and survival of eosinophils but is also implicated in the biological functions of mast cells, basophils, innate lymphoid cells, B cells, and epithelial cells. Results from clinical trials of therapeutics that target type 2 inflammatory mediators (including but not limited to anti‐IL‐5, anti‐immunoglobulin‐E, and anti‐IL‐4/13) may provide further evidence of how eosinophils and IL‐5 contribute to CRSwNP. Finally, the association between eosinophilia/elevated IL‐5 and greater rates of NP recurrence after endoscopic sinus surgery (ESS) suggests that these mediators may have utility as biomarkers of NP recurrence in diagnosing and assessing the severity of CRSwNP. This review provides an overview of eosinophil and IL‐5 biology and explores the literature regarding the role of these mediators in CRSwNP pathogenesis and NP recurrence following ESS. Based on current published evidence, we suggest that although eosinophils play a key role in CRSwNP pathophysiology, IL‐5, a cytokine that activates these cells, also represents a pertinent and effective treatment target in patients with CRSwNP

Economic analysis of the phase III MENSA study evaluating mepolizumab for severe asthma with eosinophilic phenotype

Severe eosinophilic asthma patients are at risk of exacerbations, which are associated with substantial costs. Mepolizumab lowers eosinophil levels and reduces exacerbation risk in severe eosinophilic asthma. We evaluated asthma-related exacerbation costs in mepolizumab-treated patients (versus placebo)

Oral corticosteroid dose changes and impact on peripheral blood eosinophil counts in patients with severe eosinophilic asthma: A post hoc analysis

Background: An inverse relationship between oral corticosteroid (OCS) dose and peripheral blood eosinophil (PBE) count is widely recognized in patients with severe eosinophilic asthma; however, there are limited data available to quantify this relationship. This post hoc analysis of the SIRIUS study (NCT01691508) examined the impact of weekly incremental OCS dose reductions on PBE counts during the 3-8-week optimization phase of the study. Methods: SIRIUS was a randomized, double-blind study involving patients with severe asthma (≥12 years old), which included an initial OCS dose optimization phase prior to randomization. Regression analysis assuming a linear relationship between change in OCS dose and change in log (PBE count) during the optimization phase was used to estimate the changes in PBE count following specific decreases in OCS dose. Results: All 135 patients from the SIRIUS intent-to-treat population were included in this analysis. During the optimization period, 44% (60/135) of patients reduced their OCS dose, with an increase in geometric mean PBE count of 110 cells/μL (200 to 310 cells/μL; geometric mean ratio from beginning to end of the optimization phase: 1.52) recorded in these patients. The model estimated that reduction of daily OCS dose by 5 mg/day led to a 41% increase in PBE count (mean ratio to beginning of optimization phase: 1.41 [95% confidence interval (CI); 1.22, 1.63]). Conclusion: These data confirmed and quantified the inverse association between OCS dose and PBE count. These insights will help to inform clinicians when tapering OCS doses in patients with severe eosinophilic asthma