Mepolizumab for chronic rhinosinusitis with nasal polyps (SYNAPSE): in-depth sinus surgery analysis

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

Mepolizumab improves clinical outcomes in patients with severe asthma and comorbid conditions

Abstract Background Comorbidities can complicate the management of severe asthma; therefore, the presence of comorbid conditions or traits often need to be considered when considering treatment options for patients with severe asthma. The aim of this analysis is to investigate the efficacy of mepolizumab in patients with severe eosinophilic asthma and comorbidities. Methods This was a post hoc analysis (GSK ID:209140) of data from the Phase IIb/III studies DREAM, MENSA, SIRIUS, and MUSCA. Patients aged ≥ 12 years with severe eosinophilic asthma were randomized to: mepolizumab 750, 250, or 75 mg intravenously or placebo (DREAM); mepolizumab 75 mg intravenously or 100 mg subcutaneously or placebo (MENSA); or mepolizumab 100 mg subcutaneously or placebo (SIRIUS and MUSCA) every 4 weeks for 24 weeks in SIRIUS and MUSCA, 32 weeks in MENSA or 52 weeks in DREAM. In this analysis the primary endpoint was the annual rate of clinically significant exacerbations; secondary endpoints were Asthma Control Questionnaire-5 score, St George’s Respiratory Questionnaire total score, and pre-bronchodilator forced expiratory volume in 1 s at study end. Subgroups were based on comorbidities at baseline. Results Overall, 1878 patients received placebo (n = 689) or mepolizumab (n = 1189). Across all comorbidity subgroups mepolizumab reduced the rate of clinically significant exacerbations by 44–68% versus placebo, improved Asthma Control Questionnaire-5 score by 0.27–0.59 points, and improved St George’s Respiratory Questionnaire total score by 5.0–11.6 points. Pre-bronchodilator forced expiratory volume in 1 s was improved by 27.1–286.9 mL in all but one comorbidity subgroup, the diabetes mellitus subgroup. Conclusions Mepolizumab reduces exacerbations, and improves asthma control, health-related quality of life, and lung function in patients with severe eosinophilic asthma despite comorbid conditions, including upper respiratory conditions, psychopathologies, cardiovascular conditions, gastroesophageal reflux disease, diabetes mellitus, and obesity. Trial registration: https://clinicaltrials.gov/ DREAM, MEA112997/NCT01000506; MENSA, MEA115588/NCT01691521; SIRIUS, MEA115575/NCT01842607; MUSCA, 200862/NCT02281318

Mepolizumab reduces the need for surgery in patients with chronic rhinosinusitis with nasal polyps

Background: For patients with chronic rhinosinusitis with nasal polyps (CRSwNP), endoscopic sinus surgery (ESS) can be associated with high recurrence rates despite intranasal corticosteroids (as part of standard of care [SoC]). We assessed the impact of mepolizumab, a humanized anti-interleukin-5 antibody, on the need for repeat ESS in patients with CRSwNP. Methods: SYNAPSE, a randomized, double-blind, placebo-controlled, multicenter study, enrolled patients with CRSwNP uncontrolled with SoC. All patients had ≥1 ESS in the past 10 years and were eligible for repeat ESS. Patients received 4-weekly subcutaneous (SC) mepolizumab 100 mg or placebo, plus SoC, for 52 Weeks. We assessed the proportion of patients with a need for ESS (visual analog scale overall symptom score >7; endoscopic bilateral NP score ≥5), time to inclusion on a waiting list for ESS (Kaplan–Meier [KM] estimate), and the proportion of patients included on a waiting list, by Week 52. Results: Data from 407 patients (placebo n=201; mepolizumab n=206) were analyzed. Mean (SD) duration of CRSwNP was 11.4 (8.4) years; 218 (54%) patients had ≥2 ESS in the past 10 years. After 52 weeks, more patients using mepolizumab vs placebo were identified as not needing ESS (72% vs 51%, respectively; odds ratio [95% confidence interval] 2.46 [1.59, 3.79]; P<0.001). KM estimates indicated a ~50% lower risk of inclusion on a waiting list for ESS with mepolizumab than placebo. Up to Week 52, 16% vs 30% of patients using mepolizumab vs placebo were due for ESS on a waiting list. Conclusions: Mepolizumab 100 mg SC reduces the need for repeat surgery compared with placebo for patients with recurrent CRSwNP despite SoC therapy

Discovering hidden material properties of MgCl\u3csub\u3e2\u3c/sub\u3e at atomic resolution with structured temporal electron illumination of picosecond time resolution

\u3cp\u3eA combination of atomic resolution phase contrast electron microscopy and pulsed electron beams reveals pristine properties of MgCl\u3csub\u3e2\u3c/sub\u3e at 1.7 Å resolution that were previously masked by air and beam damage. Both the inter- and intra-layer bonding in pristine MgCl\u3csub\u3e2\u3c/sub\u3e are weak, which leads to uncommonly large local orientation variations that characterize this Ziegler–Natta catalyst support. By delivering electrons with 1–10 ps pulses and ≈160 ps delay times, phonons induced by the electron irradiation in the material are allowed to dissipate before the subsequent delivery of the next electron packet, thus mitigating phonon accumulations. As a result, the total electron dose can be extended by a factor of 80–100 to study genuine material properties at atomic resolution without causing object alterations, which is more effective than reducing the sample temperature. In conditions of minimal damage, beam currents approach femtoamperes with dose rates around 1 eÅ\u3csup\u3e−2\u3c/sup\u3e s\u3csup\u3e−1\u3c/sup\u3e. Generally, the utilization of pulsed electron beams is introduced herein to access genuine material properties while minimizing beam damage.\u3c/p\u3

Evaluating treatment response to mepolizumab in patients with severe CRSwNP*

Background: The SYNAPSE study (NCT03085797) demonstrated that mepolizumab decreased nasal polyp (NP) size and nasal obstruction in patients with chronic rhinosinusitis with NP (CRSwNP). Methods: SYNAPSE, a randomized, double-blind study, included patients with recurrent, refractory, severe CRSwNP, eligible for repeated surgery despite receiving standard of care (SoC). Patients received 4-weekly mepolizumab 100 mg or placebo subcuta-neously plus SoC for 52 weeks. This post hoc analysis further characterized treatment responses and association with patient cha-racteristics. The proportion of patients meeting any and each of five response criteria indicating improvement in disease-specific quality of life, NP size, nasal obstruction, loss of smell, and overall symptoms at Weeks 24 and 52, were assessed in subgroups: 1) no surgery; 2) neither surgery nor systemic corticosteroids (SCS). Results: Of 407 patients in the intention-to-treat population, 381 and 343 patients had no sinus surgery by Weeks 24 and 52, res-pectively. More mepolizumab-versus placebo-treated patients without surgery by Weeks 24 and 52 met each response criteria. Of the mepolizumab-treated patients without surgery by Week 24, 109 (55%) responded across ≥ 3 criteria, increasing to 126 (67%) by Week 52. Similar response trends were seen for patients with neither surgery nor SCS by Weeks 24 and 52. At either timepoint, there were no major differences in baseline characteristics between mepolizumab-treated full-(5/5 categories) and non-respon-ders (0/5 categories). Conclusions: Most patients who completed SYNAPSE required neither surgery nor SCS use and in addition achieved a progres-sive and sustained clinical response to mepolizumab underscoring the therapeutic benefits of mepolizumab in severe CRSwNP

Mepolizumab for chronic rhinosinusitis with nasal polyps:Treatment efficacy by comorbidity and blood eosinophil count

Background: In the phase III SYNAPSE study, mepolizumab reduced nasal polyp (NP) size and nasal obstruction in chronic rhinosinusitis with NP.Objective: We sought to assess the efficacy of mepolizumab in patients from SYNAPSE grouped by comorbid asthma, aspirin-exacerbated respiratory disease (AERD), and baseline blood eosinophil count (BEC).Methods: SYNAPSE, a randomized, double-blind, 52-week study (NCT03085797), included patients with severe bilateral chronic rhinosinusitis with NP eligible for surgery despite intranasal corticosteroid treatment. Patients received 4-weekly subcutaneous mepolizumab 100 mg or placebo plus standard of care for 52 weeks. Coprimary end points were change in total endoscopic NP score (week 52) and nasal obstruction visual analog scale score (weeks 49-52). Subgroup analyses by comorbid asthma and AERD status, and post hoc by BEC, were exploratory.Results: Analyses included 407 patients (289 with asthma; 108 with AERD; 371 and 278 with BEC counts >150 or >300 cells/mL, respectively). The proportion of patients with greater than or equal to 1-point improvement from baseline in NP score was higher with mepolizumab versus placebo across comorbid diseases (asthma: 52.9% vs 29.5%; AERD: 51.1% vs 20.6%) and baseline BEC subgroups (150 cells/mL: 49.5% vs 28.1%; 300 cells/mL: 50.4% vs 28.1%). A similar trend was observed in patients without comorbid asthma or AERD. More patients had more than 3-point improvement in nasal obstruction VAS score with mepolizumab versus placebo across comorbid subgroups.Conclusions: Mepolizumab reduced polyp size and nasal obstruction in chronic rhinosinusitis with NP regardless of the presence of comorbid asthma or AERD.Background: In the phase III SYNAPSE study, mepolizumab reduced nasal polyp (NP) size and nasal obstruction in chronic rhinosinusitis with NP.Objective: We sought to assess the efficacy of mepolizumab in patients from SYNAPSE grouped by comorbid asthma, aspirin-exacerbated respiratory disease (AERD), and baseline blood eosinophil count (BEC).Methods: SYNAPSE, a randomized, double-blind, 52-week study (NCT03085797), included patients with severe bilateral chronic rhinosinusitis with NP eligible for surgery despite intranasal corticosteroid treatment. Patients received 4-weekly subcutaneous mepolizumab 100 mg or placebo plus standard of care for 52 weeks. Coprimary end points were change in total endoscopic NP score (week 52) and nasal obstruction visual analog scale score (weeks 49-52). Subgroup analyses by comorbid asthma and AERD status, and post hoc by BEC, were exploratory.Results: Analyses included 407 patients (289 with asthma; 108 with AERD; 371 and 278 with BEC counts >150 or >300 cells/mL, respectively). The proportion of patients with greater than or equal to 1-point improvement from baseline in NP score was higher with mepolizumab versus placebo across comorbid diseases (asthma: 52.9% vs 29.5%; AERD: 51.1% vs 20.6%) and baseline BEC subgroups (150 cells/mL: 49.5% vs 28.1%; 300 cells/mL: 50.4% vs 28.1%). A similar trend was observed in patients without comorbid asthma or AERD. More patients had more than 3-point improvement in nasal obstruction VAS score with mepolizumab versus placebo across comorbid subgroups.Conclusions: Mepolizumab reduced polyp size and nasal obstruction in chronic rhinosinusitis with NP regardless of the presence of comorbid asthma or AERD.A