Benralizumab for PDGFRA-Negative Hypereosinophilic Syndrome.

BACKGROUND: Hypereosinophilic syndrome is a group of diseases defined by marked eosinophilia in blood or tissue and eosinophil-related clinical manifestations. Benralizumab is a monoclonal antibody against interleukin-5 receptor α, which is expressed on human eosinophils. METHODS: In this randomized, double-blind, placebo-controlled, phase 2 trial, we administered a series of three monthly subcutaneous injections of either benralizumab (at a dose of 30 mg) or placebo in 20 symptomatic patients who had PDGFRA-negative hypereosinophilic syndrome and an absolute eosinophil count of at least 1000 cells per cubic millimeter; all the patients were receiving stable therapy (drugs or dietary changes) for this disease. This regimen was followed by an open-label phase, during which the patient's background therapy could be tapered as tolerated, and an extension phase. The primary end point of the randomized phase was a reduction of at least 50% in the absolute eosinophil count at week 12. RESULTS: During the randomized phase, the primary end point occurred in more patients in the benralizumab group than in the placebo group (9 of 10 patients [90%] vs. 3 of 10 patients [30%], P = 0.02). During the open-label phase, clinical and hematologic responses were observed in 17 of 19 patients (89%) and were sustained for 48 weeks in 14 of 19 patients (74%); in the latter group, in 9 of 14 patients (64%), background therapies could be tapered. Bone marrow and tissue eosinophilia were also suppressed with benralizumab therapy. The most common drug-related adverse events, headache and an elevated lactate dehydrogenase level, occurred in 32% of the patients after the first dose of benralizumab and resolved within 48 hours in all patients. Other adverse events occurred with similar frequency in the two groups. Of the many potential predictors of response that were examined, only clinical disease subtype appeared to be associated with the initial response or relapse. CONCLUSIONS: In this small phase 2 trial, patients with PDGFRA-negative hypereosinophilic syndrome who received benralizumab for 12 weeks had lower absolute eosinophil counts than those who received placebo. During the open-label phase, clinical and hematologic responses were sustained for 48 weeks in 74% of the patients. Adverse events did not limit treatment. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov numbers, NCT00001406 and NCT02130882.).

Benralizumab for the Prevention of COPD Exacerbations.

BACKGROUND: The efficacy and safety of benralizumab, an interleukin-5 receptor alpha-directed cytolytic monoclonal antibody, for the prevention of exacerbations in patients with moderate to very severe chronic obstructive pulmonary disease (COPD) are not known. METHODS: In the GALATHEA and TERRANOVA trials, we enrolled patients with COPD (at a ratio of approximately 2:1 on the basis of eosinophil count [≥220 per cubic millimeter vs. <220 per cubic millimeter]) who had frequent exacerbations despite receiving guideline-based inhaled treatment. Patients were randomly assigned to receive benralizumab (30 or 100 mg in GALATHEA; 10, 30, or 100 mg in TERRANOVA) every 8 weeks (every 4 weeks for the first three doses) or placebo. The primary end point was the treatment effect of benralizumab, measured as the annualized COPD exacerbation rate ratio (benralizumab vs. placebo) at week 56 in patients with baseline blood eosinophil counts of 220 per cubic millimeter or greater. Safety was also assessed. RESULTS: In GALATHEA, the estimates of the annualized exacerbation rate were 1.19 per year (95% confidence interval [CI], 1.04 to 1.36) in the 30-mg benralizumab group, 1.03 per year (95% CI, 0.90 to 1.19) in the 100-mg benralizumab group, and 1.24 per year (95% CI, 1.08 to 1.42) in the placebo group; the rate ratio as compared with placebo was 0.96 for 30 mg of benralizumab (P = 0.65) and 0.83 for 100 mg of benralizumab (P = 0.05). In TERRANOVA, the estimates of the annualized exacerbation rate for 10 mg, 30 mg, and 100 mg of benralizumab and for placebo were 0.99 per year (95% CI, 0.87 to 1.13), 1.21 per year (95% CI, 1.08 to 1.37), 1.09 per year (95% CI, 0.96 to 1.23), and 1.17 per year (95% CI, 1.04 to 1.32), respectively; the corresponding rate ratios were 0.85 (P = 0.06), 1.04 (P = 0.66), and 0.93 (P = 0.40). At 56 weeks, none of the annualized COPD exacerbation rate ratios for any dose of benralizumab as compared with placebo reached significance in either trial. Types and frequencies of adverse events were similar with benralizumab and placebo. CONCLUSIONS: Add-on benralizumab was not associated with a lower annualized rate of COPD exacerbations than placebo among patients with moderate to very severe COPD, a history of frequent moderate or severe exacerbations, and blood eosinophil counts of 220 per cubic millimeter or greater (Funded by AstraZeneca [GALATHEA and TERRANOVA] and Kyowa Hakko Kirin [GALATHEA]; GALATHEA and TERRANOVA ClinicalTrials.gov numbers, NCT02138916 and NCT02155660.).

Benralizumab for adolescent patients with severe, eosinophilic asthma: Safety and efficacy after 3 years of treatment.

BACKGROUND: Adults and adolescents with severe asthma who completed the 48-week SIROCCO and 56-week CALIMA phase III benralizumab trials entered the safety extension study BORA (NCT02258542). The continued safety and efficacy of benralizumab in the first year of BORA (year 2 of treatment) have been reported. OBJECTIVE: We sought to report outcomes for adolescents during years 2 and 3 of treatment in BORA. METHODS: Patients on benralizumab 30 mg every 4 weeks (Q4W) or every 8 weeks (Q8W) in SIROCCO/CALIMA continued their regimens in BORA (Q4W/Q4W and Q8W/Q8W, respectively), whereas placebo patients were rerandomized 1:1 to benralizumab (placebo/Q4W and placebo/Q8W, respectively) for 108 weeks. The primary outcome was safety; secondary outcomes included reduction in annual asthma exacerbation rate and change from baseline in prebronchodilator FEV1. RESULTS: Adolescents (N = 86) were treated with benralizumab Q8W (n = 61) or Q4W (n = 25); 69 completed treatment (Q8W: n = 51; Q4W: n = 18). For Q4W and Q8W regimens, rates of treatment-emergent adverse events were 68% (17 of 25) and 74% (45 of 61), respectively, rates of treatment-emergent adverse events (TEAEs) were 68% (17/25) and 74% (45/61), TEAEs leading to discontinuation were 4% (1/25) and 0%, serious AEs were 8% (2/25) and 7% (4/61), and no deaths occurred. In efficacy analyses, 69% (42 of 61) Q8W patients were exacerbation-free (placebo/Q8W: 62% [18 of 29], Q8W/Q8W: 75% [24 of 32]). Mean ± SD change in FEV1 at week 108 versus BORA baseline was 0.327 ± 0.452 L (placebo/Q8W) and 0.323 ± 0.558 L (Q8W/Q8W). CONCLUSIONS: Safety and efficacy profiles in this 2-year extension study (up to 3 years of benralizumab treatment in adolescents) were consistent with previous findings.

Innovation in Resident Core Oncology Education: Switching from an Inpatient Ward Rotation to a Hybrid Model of Inpatient Consultations and Outpatient Clinics.

Interest in an oncology career has decreased among internal medicine residents completing an inpatient hematology-oncology rotation. Over years, our institutional data at Indiana University School of Medicine reflected lower satisfaction with the oncology inpatient ward rotation as compared to other rotations. We hypothesized that a switch from an inpatient ward rotation to a hybrid model of inpatient consultations and outpatient clinics would improve resident satisfaction with their educational experience in oncology. Over the 6-month periods preceding and following the change in rotation format, residents were asked to complete anonymous rotation evaluations and rate their experiences on a 5-point Likert scale (poor 1 to excellent 5). Areas assessed included patient load, educational value of patient mix, quality of didactics and teaching, quality of patient care delivery, adequacy of time for reading, and overall rotation quality. The hybrid oncology rotation was rated as significantly superior to the traditional ward format in six out of eight areas including patient load, educational value of patient mix, time for study, teaching quality, relevance of material, and overall rating. Improvements in the perceived quality of patient care delivery (p = 0.139) and quality of didactics (p = 0.058) were also observed without reaching statistical significance. The balance of inpatient and outpatient experiences with the hybrid rotation was highly rated (4.5 ± 0.5). The implementation of a hybrid oncology rotation was associated with perceived improvement in educational value, patient mix, and time for reflection and study without apparent compromise in the quality of patient care delivery.

Patient characteristics, biomarkers and exacerbation risk in severe, uncontrolled asthma.

BACKGROUND: Greater precision in asthma exacerbation risk prediction may improve outcomes. We sought to identify clinical characteristics and biomarkers associated with elevated exacerbation risk in patients with severe, uncontrolled asthma. METHODS: Data were pooled from seven similarly designed phase II and III randomised controlled clinical trials of biologic therapies for the treatment of severe, uncontrolled asthma that enrolled comparable patient populations. Annualised asthma exacerbation rates (AAERs) for patients randomised to placebo were assessed by baseline clinical characteristics, and by biomarker concentrations at baseline and over the study duration. RESULTS: The AAER for the 2016 patients in the combined placebo group was 0.91 (95% CI 0.84‒0.98). Baseline characteristics associated with greater AAER were frequent or severe exacerbations within the prior 12 months, nasal polyposis, maintenance oral corticosteroid use, Asian race and Asian or Western European region. AAER increased with baseline blood eosinophil counts and exhaled nitric oxide fraction (F ENO) concentration, with the greatest AAER occurring for patients with eosinophils ≥300 cells·µL-1 and F ENO ≥50 ppb. No relationship was observed between baseline serum IgE concentration and AAER. Combining type 2 inflammation criteria for eosinophils and F ENO had greater prognostic value than either biomarker alone. Persistent eosinophil and F ENO elevations throughout the study period were associated with greater AAER. CONCLUSIONS: Exacerbation history, maintenance corticosteroid use, nasal polyposis, Asian race, geographic region, and elevations in blood eosinophil counts and F ENO concentrations (particularly when combined and/or persistently achieving type 2 inflammation criteria) were associated with increased exacerbation risk in patients with severe, uncontrolled asthma.

Oral Glucocorticoid-Sparing Effect of Benralizumab in Severe Asthma.

BACKGROUND: Many patients with severe asthma rely on oral glucocorticoids to manage their disease. We investigated whether benralizumab, a monoclonal antibody directed against the alpha subunit of the interleukin-5 receptor that significantly reduces the incidence of asthma exacerbations, was also effective as an oral glucocorticoid-sparing therapy in patients relying on oral glucocorticoids to manage severe asthma associated with eosinophilia. METHODS: In a 28-week randomized, controlled trial, we assessed the effects of benralizumab (at a dose of 30 mg administered subcutaneously either every 4 weeks or every 8 weeks [with the first three doses administered every 4 weeks]) versus placebo on the reduction in the oral glucocorticoid dose while asthma control was maintained in adult patients with severe asthma. The primary end point was the percentage change in the oral glucocorticoid dose from baseline to week 28. Annual asthma exacerbation rates, lung function, symptoms, and safety were assessed. RESULTS: Of 369 patients enrolled, 220 underwent randomization and started receiving benralizumab or placebo. The two benralizumab dosing regimens significantly reduced the median final oral glucocorticoid doses from baseline by 75%, as compared with a reduction of 25% in the oral glucocorticoid doses in the placebo group (P<0.001 for both comparisons). The odds of a reduction in the oral glucocorticoid dose were more than 4 times as high with benralizumab as with placebo. Among the secondary outcomes, benralizumab administered every 4 weeks resulted in an annual exacerbation rate that was 55% lower than the rate with placebo (marginal rate, 0.83 vs. 1.83, P=0.003), and benralizumab administered every 8 weeks resulted in an annual exacerbation rate that was 70% lower than the rate with placebo (marginal rate, 0.54 vs. 1.83, P<0.001). At 28 weeks, there was no significant effect of either benralizumab regimen on the forced expiratory volume in 1 second (FEV1), as compared with placebo. The effects on various measures of asthma symptoms were mixed, with some showing significant changes in favor of benralizumab and others not showing significant changes. Frequencies of adverse events were similar between each benralizumab group and the placebo group. CONCLUSIONS: Benralizumab showed significant, clinically relevant benefits, as compared with placebo, on oral glucocorticoid use and exacerbation rates. These effects occurred without a sustained effect on the FEV1. (Funded by AstraZeneca; ZONDA ClinicalTrials.gov number, NCT02075255 .).

Rapid onset of effect of benralizumab on morning peak expiratory flow in severe, uncontrolled asthma.

BACKGROUND: Benralizumab is a unique eosinophil-depleting monoclonal antibody that significantly reduces asthma exacerbations, improves lung function and asthma symptoms, and permits the reduction of maintenance oral corticosteroid dosage for patients with severe, uncontrolled eosinophilic asthma. OBJECTIVE: To assess benralizumab's onset of action and efficacy by examining change in morning peak expiratory flow (PEF) after initiation of treatment in the phase 3 clinical trials SIROCCO, CALIMA, and ZONDA. METHODS: Mixed-model repeated-measures analysis was used to calculate PEF using daily least squares mean changes from baseline in morning PEF as well as differences between the benralizumab every 8 weeks (first 3 doses every 4 weeks) and placebo groups. A Bayesian nonlinear mixed-effects approach with an exponential relationship was used to model trial data to determine time to clinically meaningful improvement in morning PEF (defined as ≥25 L/min). RESULTS: Least squares mean morning PEF improvement from baseline was numerically greater by Day 2 after initiation of benralizumab therapy in all 3 trials. The Bayesian nonlinear mixed-effects model indicated that PEF improvement reached the clinically meaningful threshold within 3 weeks in SIROCCO and CALIMA and 2 weeks in ZONDA. CONCLUSION: In 3 phase 3 randomized clinical trials, benralizumab provided notable improvement in morning PEF 2 days after initiation and clinically meaningful improvements within 3 weeks for patients with severe, uncontrolled eosinophilic asthma. The rapid improvement in PEF demonstrated in these trials suggests that benralizumab's unique mechanism of action rapidly improves lung function for patients with severe, eosinophilic asthma. TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT01928771 (SIROCCO), NCT01914757 (CALIMA), and NCT02075255 (ZONDA).

Baseline patient factors impact on the clinical efficacy of benralizumab for severe asthma.

Benralizumab is an anti-eosinophilic monoclonal antibody that reduces exacerbations and improves lung function for patients with severe, uncontrolled asthma with eosinophilic inflammation. We evaluated the impact of baseline factors on benralizumab efficacy for patients with severe asthma.This analysis used pooled data from the SIROCCO (ClinicalTrials.gov identifier NCT01928771) and CALIMA (ClinicalTrials.gov identifier NCT01914757) Phase III studies. Patients aged 12-75 years with severe, uncontrolled asthma receiving high-dosage inhaled corticosteroids plus long-acting ß2-agonists received benralizumab 30 mg subcutaneously every 8 weeks (Q8W, first three doses every 4 weeks (Q4W)), Q4W or placebo. Baseline factors that influenced benralizumab efficacy were evaluated, including oral corticosteroid (OCS) use, nasal polyposis, pre-bronchodilator forced vital capacity (FVC), prior year exacerbations and age at diagnosis. Efficacy outcomes included annual exacerbation rate and change in pre-bronchodilator forced expiratory volume in 1 s at treatment end relative to placebo.Benralizumab Q8W treatment effect was enhanced with each baseline factor for all patients and those with ≥300 eosinophils·µL-1 relative to the overall population. OCS use, nasal polyposis and FVC <65% of predicted were associated with greater benralizumab Q8W responsiveness for reduced exacerbation rate for patients with <300 eosinophils·µL-1Baseline clinical factors and blood eosinophil counts can help identify patients potentially responsive to benralizumab.

Benralizumab efficacy by atopy status and serum immunoglobulin E for patients with severe, uncontrolled asthma.

BACKGROUND: Patients with severe asthma can have eosinophilic inflammation and/or allergen sensitization. Benralizumab is an anti-eosinophilic monoclonal antibody indicated for add-on maintenance treatment of patients with severe asthma aged 12 years and older, and with an eosinophilic phenotype. OBJECTIVE: To investigate the efficacy of benralizumab by atopic status and serum immunoglobulin E (IgE) concentrations. METHODS: We analyzed pooled results from the SIROCCO (NCT01928771) and CALIMA (NCT01914757) phase III studies. Patients 12 to 75 years old with severe, uncontrolled asthma on high-dosage inhaled corticosteroids plus long-acting ß2-agonists received 30 mg of subcutaneous benralizumab every 4 weeks or every 8 weeks (first 3 doses every 4 weeks) or placebo every 4 weeks. The analysis stratified patients who did and did not meet similar omalizumab-qualifying criteria of atopy and serum IgE levels 30 to 700 kU/L. Patients also categorized as having high serum IgE (≥150 kU/L) or low serum IgE (<150 kU/L) and as having atopy or no atopy. Efficacy outcomes were for all patients and by blood eosinophil counts and included annual exacerbation rate ratio and pre-bronchodilator forced expiratory volume in 1 second change at treatment end vs placebo. RESULTS: Benralizumab every 8 weeks decreased exacerbations by 46% (95% confidence interval 26-61, P = .0002) and increased forced expiratory volume in 1 second by 0.125 L (95% confidence interval 0.018-0.232, P = .0218) vs placebo for patients with at least 300 eosinophils/µL who met the atopy and IgE criteria. For patients with eosinophilia and high or low IgE, treatment with benralizumab every 8 weeks resulted in 42% and 43% decreases in exacerbation rate (P ≤ .0004) and 0.123- and 0.138-L increases in forced expiratory volume in 1 second (P ≤ .0041) vs placebo, respectively. CONCLUSION: Benralizumab treatment decreased exacerbations and improved lung function for patients with severe, uncontrolled eosinophilic asthma regardless of serum IgE concentrations and atopy status.

Efficacy and safety of benralizumab in Japanese patients with severe, uncontrolled eosinophilic asthma.

BACKGROUND: In the Phase III CALIMA trial, benralizumab significantly reduced asthma exacerbations, increased lung function, and alleviated symptoms for patients with severe, uncontrolled eosinophilic asthma. The aim of this subgroup analysis was to evaluate the efficacy and safety of benralizumab for Japanese patients in the CALIMA trial. METHODS: CALIMA was a randomised, controlled trial of 1306 patients (aged 12-75 years; registered at ClinicalTrials.gov: NCT01914757) with severe asthma uncontrolled by medium- to high-dosage inhaled corticosteroids and long-acting ß2-agonists (ICS/LABA). Patients received 56 weeks' benralizumab 30 mg either every 4 weeks (Q4W) or every 8 weeks (Q8W; first three doses Q4W), or placebo Q4W. The primary analysis population was patients receiving high-dosage ICS/LABA with blood eosinophils ≥300 cells/µL. This subgroup analysis covered Japanese patients from this group. RESULTS: Of 83 patients randomised in Japan, 46 were receiving high-dosage ICS/LABA and had blood eosinophils ≥300 cells/µL. Compared with placebo, benralizumab reduced the annual rate of asthma exacerbations by 66% (Q4W; rate ratio 0.34, 95% CI, 0.11-0.99) and 83% (Q8W; rate ratio 0.17, 95% CI, 0.05-0.60); increased prebronchodilator FEV1 by 0.334 L (Q4W; 95% CI, 0.020-0.647) and 0.198 L (Q8W; 95% CI, -0.118 to 0.514); and decreased total asthma symptom score by 0.17 (Q4W; 95% CI, -0.82 to 0.48) and 0.24 (Q8W; 95% CI, -0.87 to 0.40). Percentages of adverse events were consistent with the overall CALIMA group. CONCLUSIONS: Benralizumab reduced annual asthma exacerbations and symptoms, increased lung function, and was well-tolerated by Japanese patients with severe, uncontrolled eosinophilic asthma.

Efficacy and safety of benralizumab for patients with severe asthma uncontrolled with high-dosage inhaled corticosteroids and long-acting ß2-agonists (SIROCCO): a randomised, multicentre, placebo-controlled phase 3 trial.

BACKGROUND: Eosinophilia is associated with worsening asthma severity and decreased lung function, with increased exacerbation frequency. We assessed the safety and efficacy of benralizumab, a monoclonal antibody against interleukin-5 receptor α that depletes eosinophils by antibody-dependent cell-mediated cytotoxicity, for patients with severe, uncontrolled asthma with eosinophilia. METHODS: We did a randomised, double-blind, parallel-group, placebo-controlled phase 3 study at 374 sites in 17 countries. We recruited patients (aged 12-75 years) with a physician-based diagnosis of asthma for at least 1 year and at least two exacerbations while on high-dosage inhaled corticosteroids and long-acting ß2-agonists (ICS plus LABA) in the previous year. Patients were randomly assigned (1:1:1) by an interactive web-based voice response system to benralizumab 30 mg either every 4 weeks (Q4W) or every 8 weeks (Q8W; first three doses every 4 weeks) or placebo Q4W for 48 weeks as add on to their standard treatment. Patients were stratified 2:1 according to blood eosinophil counts of at least 300 cells per µL and less than 300 cells per µL. All patients and investigators involved in patient treatment or clinical assessment were masked to treatment allocation. The primary endpoint was annual exacerbation rate ratio versus placebo, and key secondary endpoints were prebronchodilator forced expiratory volume in 1 s (FEV1) and total asthma symptom score at week 48, for patients with blood eosinophil counts of at least 300 cells per µL. Efficacy analyses were by intention to treat (based on the full analysis set); safety analyses included patients according to study drug received. This study is registered with ClinicalTrials.gov, number NCT01928771. FINDINGS: Between Sept 19, 2013, and March 16, 2015, 2681 patients were enrolled, 1205 of whom met the study criteria and were randomly assigned: 407 to placebo, 400 to benralizumab 30 mg Q4W, and 398 to benralizumab 30 mg Q8W. 267 patients in the placebo group, 275 in the benralizumab 30 mg Q4W group, and 267 in the benralizumab 30 mg Q8W group had blood eosinophil counts at least 300 cells per µL and were included in the primary analysis population. Compared with placebo, benralizumab reduced the annual asthma exacerbation rate over 48 weeks when given Q4W (rate ratio 0·55, 95% CI 0·42-0·71; p<0·0001) or Q8W (0·49, 0·37-0·64; p<0·0001). Both benralizumab dosing regimens significantly improved prebronchodilator FEV1 in patients at week 48 compared with placebo (least-squares mean change from baseline: Q4W group 0·106 L, 95% CI 0·016-0·196; Q8W group 0·159 L, 0·068-0·249). Compared with placebo, asthma symptoms were improved by the Q8W regimen (least-squares mean difference -0·25, 95% CI -0·45 to -0·06), but not the Q4W regimen (-0·08, -0·27 to 0·12). The most common adverse events were worsening asthma (105 [13%] of 797 benralizumab-treated patients vs 78 [19%] of 407 placebo-treated patients) and nasopharyngitis (93 [12%] vs 47 [12%]). INTERPRETATION: These results confirm the efficacy and safety of benralizumab for patients with severe asthma and elevated eosinophils, which are uncontrolled by high-dosage ICS plus LABA, and provide support for benralizumab to be an additional option to treat this disease in this patient population. FUNDING: AstraZeneca and Kyowa Hakko Kirin.

Benralizumab, an anti-interleukin-5 receptor α monoclonal antibody, as add-on treatment for patients with severe, uncontrolled, eosinophilic asthma (CALIMA): a randomised, double-blind, placebo-controlled phase 3 trial.

BACKGROUND: Benralizumab is a humanised, afucosylated, anti-interleukin-5 receptor α monoclonal antibody that induces direct, rapid, and nearly complete depletion of eosinophils. We aimed to assess the efficacy and safety of benralizumab as add-on therapy for patients with severe, uncontrolled asthma and elevated blood eosinophil counts. METHODS: In this randomised, double-blind, parallel-group, placebo-controlled, phase 3 study (CALIMA) undertaken at 303 sites in 11 countries, we enrolled patients aged 12-75 years with severe asthma uncontrolled by medium-dosage to high-dosage inhaled corticosteroids plus long-acting ß2-agonists (ICS plus LABA) and a history of two or more exacerbations in the previous year. Patients were randomly assigned (1:1:1) to receive 56 weeks of benralizumab 30 mg every 4 weeks (Q4W), benralizumab 30 mg every 8 weeks (Q8W; first three doses 4 weeks apart), or placebo (all subcutaneous injection). Patients were stratified (2:1) by baseline blood eosinophil counts 300 cells per µL or greater and less than 300 cells per µL, respectively. Patients and study centre staff were masked to treatment allocation. The primary endpoint was annual exacerbation rate ratio versus placebo for patients receiving high-dosage ICS plus LABA with baseline blood eosinophils 300 cells per µL or greater (intention-to-treat analysis). Key secondary endpoints were pre-bronchodilator forced expiratory volume in 1 s (FEV1) and total asthma symptom score. This study is registered with ClinicalTrials.gov, number NCT01914757. FINDINGS: Between Aug 21, 2013, and March 16, 2015, 2505 patients were enrolled, of whom 1306 patients were randomised; 425 patients were randomly assigned to and received benralizumab 30 mg Q4W, 441 to benralizumab 30 mg Q8W, and 440 to placebo. 728 patients were included in the primary analysis population. Benralizumab resulted in significantly lower annual exacerbation rates with the Q4W regimen (rate 0·60 [95% CI 0·48-0·74], rate ratio 0·64 [95% CI 0·49-0·85], p=0·0018, n=241) and Q8W regimen (rate 0·66 [95% CI 0·54-0·82], rate ratio 0·72 [95% CI 0·54-0·95], p=0·0188, n=239) compared with placebo (rate 0·93 [95% CI 0·77-1·12], n=248). Benralizumab also significantly improved pre-bronchodilator FEV1 (Q4W and Q8W) and total asthma symptom score (Q8W only) in these patients. The most common adverse events were nasopharyngitis (90 [21%] in the Q4W group, 79 [18%] in the Q8W group, and 92 [21%] in the placebo group) and worsening asthma (61 [14%] in the Q4W group, 47 [11%] in the Q8W group, and 68 [15%] in the group). INTERPRETATION: Benralizumab significantly reduced annual exacerbation rates and was generally well tolerated for patients with severe, uncontrolled asthma with blood eosinophils 300 cells per µL or greater. Our data further refine the patient population likely to receive the greatest benefit from benralizumab treatment. FUNDING: AstraZeneca and Kyowa Hakko Kirin.

Overlap of atopic, eosinophilic, and TH2-high asthma phenotypes in a general population with current asthma.

BACKGROUND: Atopic, eosinophilic, and TH2-high asthma phenotypes may overlap, but the extent is unknown. Understanding the overlap across these phenotypes may be useful in guiding asthma patient care. OBJECTIVE: To examine the frequency and overlap of atopic, eosinophilic, and TH2-high asthma phenotypes. METHODS: We analyzed 2005 to 2006 data from the National Health and Nutrition Examination Survey. Patients with asthma were identified based on the participant self-report. Eosinophilic asthma was defined as a blood eosinophil cutoff point of ≥150, 300, or 400/µL. Atopic asthma was defined as having an allergen-specific IgE level of ≥0.35 IU/mL for any of the 9 perennial allergens tested. TH2-high asthma was defined as a total serum IgE of ≥100 IU/mL and a blood eosinophil count of ≥140/µL. RESULTS: The study included 269 children and 310 adults. Depending on the eosinophil cutoff used, 31% to 78% of children and 21% to 69% of adults with asthma were classified as having eosinophilic asthma. In addition, 63% of children and 61% of adults were classified as having atopic disease and 48% of children and 37% of adults as having TH2-high asthma. At a higher eosinophil cutoff point, a greater proportion of eosinophilic asthma can be classified as atopic or TH2 high, but a lower proportion of atopic or TH2-high asthma can be classified as eosinophilic. Approximately 70% or more of children and adults with asthma were 1 of these 3 phenotypes. CONCLUSION: A considerable overlap among eosinophilic, atopic, and TH2-high asthma phenotypes exists in a general asthma population.

Comparative analysis of polymers for short interfering RNA delivery in vascular smooth muscle cells.

UNLABELLED: The use of short interfering RNA (siRNA) to degrade messenger RNA in the cell cytoplasm and transiently attenuate intracellular proteins shows promise in the inhibition of vascular pathogenesis. However, a critical obstacle for therapeutic application is a safe and effective delivery system. Biodegradable polymers are promising alternative molecular carriers for genetic material. Here, we aim to perform a comparative analysis of poly(B-amino ester) (PBAE) and polyethylenimine (PEI) polymers in their efficacy for vascular smooth muscle cell transfection using siRNA against the glyceraldehyde 3-phosphate dehydrogenase (GAPDH) housekeeping gene as our test target. METHODS: Human aortic smooth muscle cells (HASMC) were transfected in vitro with polymers conjugated to GAPDH or negative control (NC) siRNAs. Increasing siRNA:polymer ratios were tested for optimal transfection efficiency. DharmaFECT2 chemical transfection complexes were used for comparative analysis. Live/dead dual stain was used to measure cell viability, and GAPDH gene silencing was measured by quantitative polymerase chain reaction normalized to 18S. RESULTS: The highest rate of PEI-mediated silencing was achieved with a 9µL polymer:220 pmol/mL siRNA conjugate (16 ± 2% expression versus NC; n = 6). Comparable PBAE-mediated silencing could be achieved with a 1.95µL polymer:100 pmol/mL siRNA conjugate (10 ± 1% expression versus NC; n = 5). Transfection using PEIs resulted in silencing equivalent to other methods but with less efficiency and increased cell toxicity at 24h polymer exposure. Decreasing PEI exposure time to 4 h resulted in similar silencing efficacy (21 ± 9% expression versus NC, n = 6) with an improved toxicity profile. CONCLUSIONS: Polymeric bioconjugates transfected HASMCs in a manner similar to chemical complexes, with comparable cell toxicity and silencing efficiency. PEI bioconjugates demonstrated silencing equivalent to PBAE bioconjugates, although less efficient in terms of required polymer concentrations. Given the cost-to-benefit difference between the assayed polymers, and PEI's ability to transfect HASMCs within a short duration of exposure with an improved toxicity profile, this study shows that PEI bioconjugates are a potential transfection agent for vascular tissue. Future studies will expand on this method of gene therapy to validate delivery of gene-specific inhibitors aimed at attenuating smooth muscle cell proliferation, adhesion, and migration. These studies will lay the framework for our future experimental plans to expand on this method of gene therapy for in vivo transfection in animal models of vascular disease.

Dolutegravir: a next-generation integrase inhibitor for treatment of HIV infection.

Dolutegravir (DTG), a next-generation integrase strand transfer inhibitor (INSTI), was recently approved for use in the treatment of human immunodeficiency virus infection. In treatment-naive trial participants, DTG given at 50 mg once daily without pharmacologic boosting combined with a standard nucleoside backbone was shown to be noninferior or superior to first-line regimens containing efavirenz, darunavir/ritonavir, or raltegravir regardless of pretreatment viral load. This drug also exhibited efficacy in antiretroviral therapy-experienced participants and has proven to retain activity when dosed twice daily in some participants harboring resistance to the other INSTIs, raltegravir and elvitegravir. DTG has few drug interactions and is taken without regard to meals. It causes benign elevations in serum creatinine based on its inhibition of tubular creatinine secretion without affecting the glomerular filtration rate. Overall, DTG is well tolerated, with headache and insomnia being the most frequently reported adverse events.

Measuring respiratory symptoms of COPD: performance of the EXACT- Respiratory Symptoms Tool (E-RS) in three clinical trials.

BACKGROUND: Symptomatic relief is an important treatment goal for patients with COPD. To date, no diary for evaluating respiratory symptoms in clinical trials has been developed and scientifically-validated according to FDA and EMA guidelines. The EXACT - Respiratory Symptoms (E-RS) scale is a patient-reported outcome (PRO) measure designed to address this need. The E-RS utilizes 11 respiratory symptom items from the existing and validated 14-item EXACT, which measures symptoms of exacerbation. The E-RS total score quantifies respiratory symptom severity, and 3 domains assess breathlessness, cough and sputum, and chest symptoms. METHODS: This study examined the performance of the E-RS in each of 3 controlled trials with common and unique validation variables: one 6-month (N = 235, US) and two 3-month (N = 749; N = 597; international). Subjects completed the E-RS as part of a daily eDiary. Tests of reliability, validity, and responsiveness were conducted in each dataset. RESULTS: In each study, RS-Total score was internally consistent (Cronbach α) (0.88, 0.92, 0.92) and reproducible (intra-class correlation) in stable patients (2 days apart: 0.91; 7 days apart: 0.71, 0.74). RS-Total scores correlated significantly with the following criterion variables (Spearman's rho; p < 0.01, all comparisons listed here): FEV1% predicted (-0.19, -0.14, -0.15); St. George's Respiratory Questionnaire (SGRQ) (0.65, 0.52, 0.51); Breathlessness, Cough, and Sputum Scale (BCSS) (0.89, 0.89); modified Medical Research Council dyspnoea scale (mMRC) (0.40); rescue medication use (0.43, 0.42); Functional Performance Inventory Short-Form (FPI-SF) (0.43); 6-minute walk distance (6-MWT) (-0.30, -0.14) and incremental shuttle walk (ISWT) (-0.18) tests. Correlations between these variables and RS-Breathlessness, RS-Cough and Sputum, RS-Chest Symptoms scores supported subscale validity. RS-Total, RS-Breathlessness, and RS-Chest Symptoms differentiated mMRC levels of breathlessness severity (p < 0.0001). RS-Total and domain scores differentiated subjects with no rescue medication use and 3 or more puffs (p < 0.0001). Sensitivity to changes in health status (SGRQ), symptoms (BCSS), and exercise capacity (6MWT, ISWT) were also shown and responder definitions using criterion- and distribution-based methods are proposed. CONCLUSIONS: Results suggest the E-RS is a reliable, valid, and responsive measure of respiratory symptoms of COPD suitable for use in natural history studies and clinical trials. TRIAL REGISTRATION: MPEX: NCT00739648 ; AZ1: NCT00949975 ; AZ 2: NCT01023516.

Safety, immunogenicity, and surrogate markers of clinical efficacy for modified vaccinia Ankara as a smallpox vaccine in HIV-infected subjects.

BACKGROUND: Human immunodeficiency virus (HIV)-infected persons are at higher risk for serious complications associated with traditional smallpox vaccines. Alternative smallpox vaccines with an improved safety profile would address this unmet medical need. METHODS: The safety and immunogenicity of modified vaccinia Ankara (MVA) was assessed in 91 HIV-infected adult subjects (CD4(+) T-cell counts, ≥350 cells/mm(3)) and 60 uninfected volunteers. The primary objectives were to evaluate the safety of MVA and immunogenicity in HIV-infected and uninfected subjects. As a measure of the potential efficacy of MVA, the ability to boost the memory response in people previously vaccinated against smallpox was evaluated by the inclusion of vaccinia-experienced HIV-infected and HIV-uninfected subjects. RESULTS: MVA was well tolerated and immunogenic in all subjects. Antibody responses were comparable between uninfected and HIV-infected populations, with only 1 significantly lower total antibody titer at 2 weeks after the second vaccination, while no significant differences were observed for neutralizing antibodies. MVA rapidly boosted the antibody responses in vaccinia-experienced subjects, supporting the efficacy of MVA against variola. CONCLUSIONS: MVA is a promising candidate as a safer smallpox vaccine, even for immunocompromised individuals, a group for whom current smallpox vaccines have an unacceptable safety profile.

Long-term safety and efficacy of cipaglucosidase alfa plus miglustat in individuals living with Pompe disease: an open-label phase I/II study (ATB200-02).

Cipaglucosidase alfa plus miglustat (cipa + mig) is a novel, two-component therapy for Pompe disease. We report data from the Phase I/II ATB200-02 study for up to 48 months of treatment. Four adult cohorts, including one non-ambulatory ERT-experienced (n = 6) and three ambulatory cohorts, (two enzyme replacement therapy [ERT]-experienced cohorts [2-6 years (n = 11) and ≥ 7 years (n = 6)]), one ERT-naïve cohort (n = 6), received 20 mg/kg intravenous-infused cipa plus 260 mg oral mig biweekly. Change from baseline (CFBL) for multiple efficacy endpoints at 12, 24, 36, and 48 months, pharmacodynamics, pharmacokinetics, safety, and immunogenicity data were assessed. Six-minute walking distance (% predicted) improved at 12, 24, 36, and 48 months: pooled ambulatory ERT-experienced cohorts, mean(± standard deviation [SD]) CFBL: 6.1(± 7.84), n = 16; 5.4(± 10.56), n = 13; 3.4(± 14.66), n = 12; 5.9(± 17.36), n = 9, respectively; ERT-naïve cohort: 10.7(± 3.93), n = 6; 11.0(± 5.06), n = 6; 9.0(± 7.98), n = 5; 11.7(± 7.69), n = 4, respectively. Percent predicted forced vital capacity was generally stable in ERT-experienced cohorts, mean(± SD) CFBL - 1.2(± 5.95), n = 16; 1.0(± 7.96), n = 13; - 0.3(± 6.68), n = 10; 1.0(± 6.42), n = 6, respectively, and improved in the ERT-naïve cohort: 3.2(± 8.42), n = 6; 4.7(± 5.09), n = 6; 6.2(± 3.35), n = 5; 8.3(± 4.50), n = 4, respectively. Over 48 months, CK and Hex4 biomarkers improved in ambulatory cohorts. Overall, cipa + mig was well tolerated with a safety profile like alglucosidase alfa. ATB200-02 results show the potential benefits of cipa + mig as a long-term treatment option for Pompe disease. Trial registration number: NCT02675465 January 26, 2016.