Effects of Reslizumab on Asthma Outcomes in a Subgroup of Eosinophilic Asthma Patients with Self-Reported Chronic Rhinosinusitis with Nasal Polyps.

An estimated 7% of patients with asthma have chronic rhinosinusitis with nasal polyps (CRSwNP), and more than 80% have at least some radiographic evidence of sinonasal inflammation. Aspirin sensitivity is strongly associated with elevated blood eosinophil levels and increased asthma severity. Intravenous (IV) reslizumab has been shown to improve asthma control in patients with nasal polyps. These post hoc analyses of pooled data from 2 BREATH phase 3 clinical trials, studies 1 and 2 (NCT01287039 and NCT01285323), examined asthma-related outcomes in patients with comorbid, self-reported CRSwNP with and without aspirin sensitivity. Patients aged 12-75 years with elevated blood eosinophils (≥400 cells/μL) and inadequately controlled asthma were randomized to receive placebo or reslizumab (3 mg/kg IV) every 4 weeks for 52 weeks. Patients continued their background asthma maintenance therapy during the study. Information regarding the presence of CRSwNP was obtained through patient-reported medical history. Add-on reslizumab treatment reduced the frequency of clinical asthma exacerbations by 83% versus placebo among patients with CRSwNP. Among patients with and without aspirin sensitivity, reductions of 79% and 84%, respectively, were observed. Patients with CRSwNP (with and without aspirin sensitivity) treated with reslizumab add-on therapy also had significant improvements in lung function, as measured by forced expiratory volume in 1 second, compared with placebo. Among patients with CRSwNP, reslizumab was also associated with improvements in patient-reported asthma control and asthma quality of life. Patients with eosinophilic asthma and self-reported CRSwNP, with and without aspirin sensitivity, are highly responsive to treatment with reslizumab for asthma-related outcomes. These findings suggest that prospective investigation of reslizumab in this patient population is warranted.

Weinstein SF ，Katial RK ，Bardin P ，Korn S ，McDonald M ，Garin M ，Bateman ED ，Hoyte FCL ，Germinaro M ... -  《-》

Benralizumab effect on severe chronic rhinosinusitis with nasal polyps (CRSwNP): A randomized double-blind placebo-controlled trial.

Chronic rhinosinusitis with nasal polyps (CRSwNP) can be a severe and debilitating disease associated with significant morbidity, loss of smell, sinus pressure and asthma exacerbations. Eosinophils play a role in the majority (85%) of patients. Benralizumab, an afucosylated monoclonal antibody directed against the IL-5 receptor, has powerful apoptotic effects on eosinophils. We sought to investigate the therapeutic benefit of inhibiting the IL-5 receptor using benralizumab to treat severe rhinosinusitis with nasal polyps. Patients with severe NP (defined by endoscopic grade 5 or more out of 8) with elevated eosinophils and a history of previous surgical or endoscopic polypectomy met entry criteria and were randomized in a double-blind fashion to receive 30 mg benralizumab SC or placebo. Endoscopic NP score was assessed at baseline and at treatment week 20. CT scan, SNOT-22 survey and UPSIT smell test score changes were also evaluated. Thirty-three patients were screened, and twenty-four (n = 24) were enrolled in the study. Compared with baseline, benralizumab significantly improved NP score (-0.9 ± 0.2, P = 0.004) whereas placebo did not (-0.3 ± 0.3, P = 0.166). Benralizumab induced polyp size reduction compared with placebo did not reach statistical significance (P = 0.103). Five of 12 benralizumab-treated patients (42%) had improvements in all major outcomes (polyp score, CT, SNOT-22 and smell test) versus 2 out of 12 placebo (17%). The ratio of blood eosinophil count to allergen skin test positivity correlated with polyp reduction. Benralizumab was well-tolerated and compared with baseline achieved a statistically significant reduction in nasal polyp size, sinus occupancy, symptoms and improved sensation of smell for most patients (83%).

Tversky J ，Lane AP ，Azar A 《-》

Efficacy and safety of dupilumab in patients with severe chronic rhinosinusitis with nasal polyps (LIBERTY NP SINUS-24 and LIBERTY NP SINUS-52): results from two multicentre, randomised, double-blind, placebo-controlled, parallel-group phase 3 trials.

Patients with chronic rhinosinusitis with nasal polyps (CRSwNP) generally have a high symptom burden and poor health-related quality of life, often requiring recurring systemic corticosteroid use and repeated sinus surgery. Dupilumab is a fully human monoclonal antibody that inhibits signalling of interleukin (IL)-4 and IL-13, key drivers of type 2 inflammation, and has been approved for use in atopic dermatitis and asthma. In these two studies, we aimed to assess efficacy and safety of dupilumab in patients with CRSwNP despite previous treatment with systemic corticosteroids, surgery, or both. LIBERTY NP SINUS-24 and LIBERTY NP SINUS-52 were two multinational, multicentre, randomised, double-blind, placebo-controlled, parallel-group studies assessing dupilumab added to standard of care in adults with severe CRSwNP. SINUS-24 was done in 67 centres in 13 countries, and SINUS-52 was done in 117 centres in 14 countries. Eligible patients were 18 years or older with bilateral CRSwNP and symptoms despite intranasal corticosteroid use, receiving systemic corticosteroids in the preceding 2 years, or having had sinonasal surgery. Patients in SINUS-24 were randomly assigned (1:1) to subcutaneous dupilumab 300 mg or placebo every 2 weeks for 24 weeks. Patients in SINUS-52 were randomly assigned (1:1:1) to dupilumab 300 mg every 2 weeks for 52 weeks, dupilumab every 2 weeks for 24 weeks and then every 4 weeks for the remaining 28 weeks, or placebo every 2 weeks for 52 weeks. All patients were randomly assigned centrally with a permuted block randomisation schedule. Randomisation was stratified by asthma or non-steroidal anti-inflammatory drug-exacerbated respiratory disease status at screening, previous surgery at screening, and country. Patients with or without comorbid asthma were included. Coprimary endpoints were changes from baseline to week 24 in nasal polyp score (NPS), nasal congestion or obstruction, and sinus Lund-Mackay CT scores (a coprimary endpoint in Japan), done in an intention-to-treat population. Safety was assessed in a pooled population of both dupilumab groups in SINUS-52 up to week 24 and the dupilumab group in SINUS-24 and the placebo groups in both studies until week 24. The trials are complete and registered at ClinicalTrials.gov, NCT02912468 and NCT02898454. Between Dec 5, 2016, and Aug 3, 2017, 276 patients were enrolled in SINUS-24, with 143 in the dupilumab group and 133 in the placebo group receiving at least one study drug dose. Between Nov 28, 2016, and Aug 28, 2017, 448 patients were enrolled in SINUS-52, with 150 receiving at least one dose of dupilumab every 2 weeks, 145 receiving at least one dose of dupilumab every 2 weeks for 24 weeks and every 4 weeks until week 52, and 153 receiving at least one dose of placebo. Dupilumab significantly improved the coprimary endpoints in both studies. At 24 weeks, least squares mean difference in NPS of dupilumab treatment versus placebo was -2·06 (95% CI -2·43 to -1·69; p<0·0001) in SINUS-24 and -1·80 (-2·10 to -1·51; p<0·0001) in SINUS-52; difference in nasal congestion or obstruction score was -0·89 (-1·07 to -0·71; p<0·0001) in SINUS-24 and -0·87 (-1·03 to -0·71; p<0·0001) in SINUS-52; and difference in Lund-Mackay CT scores was -7·44 (-8·35 to -6·53; p<0·0001) in SINUS-24 and -5·13 (-5·80 to -4·46; p<0·0001) in SINUS-52. The most common adverse events (nasopharyngitis, worsening of nasal polyps and asthma, headache, epistaxis, and injection-site erythema) were more frequent with placebo. In adult patients with severe CRSwNP, dupilumab reduced polyp size, sinus opacification, and severity of symptoms and was well tolerated. These results support the benefits of adding dupilumab to daily standard of care for patients with severe CRSwNP who otherwise have few therapeutic options. Sanofi and Regeneron Pharmaceuticals.

Bachert C ，Han JK ，Desrosiers M ，Hellings PW ，Amin N ，Lee SE ，Mullol J ，Greos LS ，Bosso JV ，Laidlaw TM ，Cervin AU ，Maspero JF ，Hopkins C ，Olze H ，Canonica GW ，Paggiaro P ，Cho SH ，Fokkens WJ ，Fujieda S ，Zhang M ，Lu X ，Fan C ，Draikiwicz S ，Kamat SA ，Khan A ，Pirozzi G ，Patel N ，Graham NMH ，Ruddy M ，Staudinger H ，Weinreich D ，Stahl N ，Yancopoulos GD ，Mannent LP ... -  《-》

Reslizumab in patients with inadequately controlled late-onset asthma and elevated blood eosinophils.

Asthma with adult onset and elevated blood eosinophils is a difficult-to-treat subgroup. This post hoc analysis evaluated reslizumab, an anti-interleukin-5 monoclonal antibody, in patients with late-onset eosinophilic asthma. Data from two 52-week placebo-controlled trials of reslizumab IV 3 mg/kg every 4 weeks in patients aged 12-75 years with inadequately controlled asthma, ≥1 asthma exacerbation within 12 months, and screening blood eosinophils ≥400/μL (NCT01287039/NCT01285323) were stratified by age of asthma onset (<40 or ≥40 years). Annual clinical asthma exacerbation rates, change in lung function, and patient-reported outcomes were analyzed. 273 patients with late-onset asthma (placebo, n = 130; reslizumab, n = 143) and 658 with early-onset asthma (placebo, n = 336; reslizumab, n = 322) were included. Baseline demographics were similar between groups. The interaction between age at onset of asthma and effect of reslizumab on asthma exacerbations was statistically significant (p = 0.0083). Compared with placebo, reslizumab produced a 75% relative reduction in asthma exacerbations in patients with late-onset asthma (rate ratio [RR] 0.25; 95% confidence interval [CI], 0.16, 0.40), substantially larger than the reduction in earlier onset patients (RR 0.58; 95% CI, 0.44, 0.76). Similar findings were observed for other measures of asthma, including forced expiratory volume in 1 s (FEV1). The adverse event profile of reslizumab was similar in patients with early- or late-onset asthma. Compared with placebo, reslizumab produced larger reductions in asthma exacerbations and larger improvements in lung function in patients with late versus early-onset asthma.

Brusselle G ，Germinaro M ，Weiss S ，Zangrilli J ... -  《-》

Decreased nasal polyp eosinophils but increased mast cells in a patient with aspirin-exacerbated respiratory disease treated with reslizumab.

Staudacher AG ，Peters AT ，Carter RG ，Welch KC ，Stevens WW ... -  《-》