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Ataru Igarashi,1 Yoshinosuke Fukuchi,2 Kazuto Hirata,3 Masakazu Ichinose,4 Atsushi Nagai,5 Masaharu Nishimura,6 Hajime Yoshisue,7 Kenichi Ohara,8 Jean-Bernard Gruenberger9 1Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan; 2Department of Respiratory Medicine, Graduate School of Medicine, Juntendo University, Tokyo, Japan; 3Department of Respiratory Medicine, Graduate School of Medicine, Osaka City University, Osaka, Japan; 4Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan; 5Research Institute for Respiratory Diseases, Shin-Yurigaoka General Hospital, Kawasaki City, Japan; 6Department of Pulmonary Medicine, Faculty School of Medicine, Hokkaido University, Hokkaido, Japan; 7Medical Division, Novartis Pharma K.K., Tokyo, Japan; 8Market Access Division, Novartis Pharma K.K., Tokyo, Japan; 9Market Access Division, Novartis Pharma AG, Basel, Switzerland Background: COPD remains a major health problem in Japan. Patients with COPD experience a reduced quality of life (QoL) and have a higher chance of work impairment and productivity loss. However, there is a lack of data on the impact of COPD in terms of QoL and work activity impairment in Japan. This study assessed the socioeconomic burden of COPD in Japan and the impact it may have on the working age population. Patients and methods: This was a 2-year retrospective chart review in COPD patients aged ≥40 years, with at least one health care visit to clinic or hospital in the previous 12 months. Patients were required to have available medical charts for at least the previous 24 months. Symptoms were assessed using COPD assessment test score; EuroQoL Group 5 Dimension (EQ-5D-5L) and work productivity and activity impairment general health questionnaires were used to evaluate health-related QoL and work productivity, and health care resource utilization data were obtained from clinical charts. Results: In total, 71 patients aged

Background: While food allergy (FA) has been increasingly recognized as a growing public health burden worldwide, epidemiological studies on FA in Japan are limited., Methods: This was a noninterventional, observational study using the administrative claims data from 2010 to 2019 (10 years). Patients with physician-diagnosed FA in Japan (prevalent cohort) were divided into high-risk or low-risk cohorts using adrenaline prescription. The high-risk cohort was further divided into anaphylaxis or nonanaphylaxis cohort based on the occurrence of anaphylaxis or a serious allergic reaction (SAR) during 1 year after adrenaline prescription. The primary objective was to examine yearly prevalence of FA. The secondary objectives were to describe demographics/clinical characteristics and healthcare resource utilization (HCRU), to evaluate the number of occurrences of anaphylaxis/SAR in the high-risk cohort, and the impact of anaphylaxis/SAR on HCRU., Results: The overall standardized prevalence rate was 0.325% (95% confidence interval [CI], 0.311-0.339) in 2010 and 0.797% (95% CI, 0.790-0.804) in 2019 and predominant in patients age <6 years (preschool; 3.377% [95% CI, 3.229-3.525] in 2010 and 5.726% [95% CI, 5.663-5.789] in 2019). Majority of FA patients (>80%) were children/adolescent throughout the 10 years. While high-risk cohort was a relatively minor population (8.5% in the prevalent cohort in 2019), the occurrence of anaphylaxis/SAR in the high-risk cohort was 227,690/100,000 patient-years. Multivariate analysis showed a significant increase in HCRU variables in the anaphylaxis versus nonanaphylaxis cohort (e.g., 2.08 [95% CI, 2.05-2.11] times more FA-related outpatient visits)., Conclusions: Prevalence of FA increased in a statistically significant way from 2010 to 2019; 1.7-fold increase was observed in patients <6 years old. Patients in the high-risk cohort appear to have suffered from frequent anaphylaxis/SAR, highlighting an unmet medical need for FA patients at "high-risk," considering the unavailability of approved medications to prevent anaphylaxis/SAR., (© 2024 The Author(s). Pediatric Allergy and Immunology published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: The most common symptoms of pollen allergy are rhinitis and conjunctivitis. However, in real-world clinical practice, we sometimes encounter patients with pollen allergy suffering from severe extrarespiratory symptoms including skin, gastrointestinal, or flu-like symptoms in relation to exposure to sensitized pollen., Objective: To elucidate the extrarespiratory symptoms in patients with pollen allergy., Methods: We performed a non-drug-focused prospective study of patients with pollen allergy (n = 384). During the 1-year observational period, they were asked to complete a weekly electronic diary consisting of visual analog scale (VAS) scores to assess all symptoms experienced in various organs over the past week. An association between seasonal pollen levels and seasonal increase in VAS scores was evaluated using a mixed-effects model for repeated measures. A k-means cluster analysis was performed to identify a group of patients experiencing stronger extrarespiratory symptoms., Results: In patients sensitized to grass or birch pollen, higher seasonal levels of these pollen grains were associated with higher VAS scores for headache, gastrointestinal symptoms, skin symptoms, and fatigue. A cluster analysis identified a group of severe pollen-allergic patients with higher extrarespiratory symptoms (n = 42). This group was characterized by a higher frequency of comorbid food allergy/atopic dermatitis, higher rate of IgE sensitization to pollens, and higher impaired activity and work productivity., Conclusions: This 1-year survey identified a small but nonnegligible group of patients with pollen-related extrarespiratory symptoms. More attention should be paid to this patient group considering their impaired activity and work productivity., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Introduction: Evidence on the prevalence of uncontrolled asthma upon the standard of care in Japan is scarce and inconsistent. We report the prevalence of uncontrolled asthma using the Japanese Guidelines for Asthma (JGL) 2018 and Global Initiative for Asthma (GINA) 2019 classifications in patients who are currently receiving standard-of-care treatment in a real-life setting., Methods: In this prospective, 12-week, noninterventional study, patients with asthma aged 20-75 years and continuously treated with medium- or high-dose inhaled corticosteroid (ICS)/LABA, with or without other controller(s), were assessed for their asthma control status. The demographics, clinical characteristics, treatment patterns, health care resource utilization, patient-reported outcomes (PROs), and adherence to prescribed treatments were assessed for patients classified as either controlled or uncontrolled., Results: Of 454 patients, 53.7% and 36.3% of the patients reported their asthma as uncontrolled based on the JGL and GINA criteria, respectively. Uncontrolled asthma was even higher (JGL, 75.0%; GINA, 63.5%) within the subpopulation of 52 patients receiving long-acting muscarinic antagonists (LAMAs; i.e., ICS/LABA/LAMA subpopulation). Sensitivity analysis by propensity matching identified significant odds ratios of controlled versus uncontrolled asthma for several demographics and clinical characteristics: male; sensitization to animals, fungi, or birch; comorbidities including food allergy or diabetes; and history of exacerbation were associated with the risk of uncontrolled asthma. No significant changes in PROs were observed., Conclusion: The frequency of uncontrolled asthma in the study population was high, as per JGL and GINA guidelines, despite good adherence to ICS/LABA treatment and other prescribed treatments over 12 weeks., (© 2023 S. Karger AG, Basel.)

Introduction: Although the prevalence and burden of asthma are continuously increasing, there is a lack of evidence on the landscape of moderate-to-severe asthma in Japan. Here, we report the prevalence of moderate-to-severe asthma and describe patient's demographics and clinical characteristics from 2010 to 2019 using the JMDC claims database., Methods: Patients (≥12 years) from the JMDC database with ≥2 asthma diagnoses in 2 different months in each index year were stratified as moderate-to-severe asthma based on the definition of asthma prevention and management guideline (Japanese Guidelines for Asthma, JGL) or Global Initiative for Asthma (GINA)., Primary Objective: 10-year trend (2010-2019) in the prevalence of moderate-to-severe asthma., Secondary Objective: Demographics and clinical characteristics of patients from 2010 to 2019., Results: Of 7,493,027 patients from the JMDC database, 38,089 and 133,557 were included in JGL and GINA cohorts, respectively, by 2019. Both cohorts presented an increasing trend in the prevalence rate of moderate-to-severe asthma from 2010 to 2019, irrespective of age groups. Demographics and clinical characteristics were consistent across the cohorts in each calendar year. Majority of patients were in the age group of 18-60 years in both JGL (86.6%) and GINA (84.2%) cohorts. Allergic rhinitis was the most frequent comorbidity and anaphylaxis the least frequent comorbidity reported in both the cohorts., Conclusions: In Japan, the prevalence rate of patients with moderate-to-severe asthma, as per JGL or GINA in the JMDC database, increased from 2010 to 2019. The demographics and clinical characteristics were similar in both cohorts over the assessment duration., (© 2023 S. Karger AG, Basel.)

Objective To evaluate the long-term safety and efficacy of indacaterol/glycopyrronium (IND/GLY) in patients with chronic obstructive pulmorary disease (COPD) in a real-world setting in Japan. Methods This 52-week, multicentre, post-marketing surveillance conducted in Japan between December 2013 and August 2019 included patients using IND/GLY for the first time to relieve airway obstructive disorder-related symptoms. Safety outcomes included the incidence of adverse events (AEs), serious AEs (SAEs), adverse drug reactions (ADRs), and serious ADRs during the 52-week period. The incidence of priority variables, including cardiovascular/cerebrovascular (CCV) AEs, β-adrenergic-related or anticholinergic AEs and cough, was also assessed. Safety outcomes were also evaluated in elderly patients. Efficacy outcomes included a physician's global assessment, COPD assessment test (CAT) and lung function test. Results Of the 1,167 patients registered, 1,108 were included in the safety and efficacy analysis. In the safety analysis population, the incidence of AEs was 13.54%, that of SAEs was 4.69%, that of ADR was 3.61%, and that of serious ADRs was 0.36% over 52 weeks. CCV AEs, β-adrenergic-related and anticholinergic AEs and cough were reported as 2.62%, 1.99% and 0.63%, respectively. The physician's global assessment showed that the overall response rate at the last assessment was 74.19%. The mean (95% confidence interval) CAT scores decreased from the start of treatment to Week 52 with IND/GLY [-6.9 (-7.8 to -6.1)]. The lung function (FEV 1 and FVC) improved over time from the start of IND/GLY to Week 52. Conclusion IND/GLY demonstrated a good long-term safety profile in a real-world setting in Japanese patients with COPD, with beneficial effects in terms of the lung function and symptoms in clinical use.

Objective: To evaluate the long-term safety and efficacy of glycopyrronium (GLY) in patients with COPD in a real-world setting in Japan., Methods: This 52-week, multicentre, post-marketing surveillance conducted in Japan, between February 2013 and August 2019, included patients using GLY for the first time for the relief of airway obstructive disorder-related symptoms. Safety outcomes included incidence of adverse events (AEs), serious AEs (SAEs), adverse drug reactions (ADRs), serious ADRs (SADRs) and priority variables included cardiovascular/cerebrovascular (CCV) AEs and anticholinergic AEs during the 52-week period. Safety outcomes were also assessed in elderly patients. Efficacy outcomes included physician's global assessment, COPD assessment test (CAT) and lung function test., Results and Discussion: Of the 1,331 patients registered for this surveillance, safety and efficacy outcomes were evaluated in 1,277 patients. In the safety analysis population, the incidence of AEs was 15.51%, SAEs 4.70%, ADRs 5.01% and SADRs 0.31%. The CCV AEs and anticholinergic AEs were reported by 0.70% and 2.58% patients, respectively. Physician's global assessment showed that the overall response rate at the last assessment was 70%. The mean (95% CI) CAT scores decreased from the start of treatment to Week 52 with GLY, (-6.2 [-7.0 to -5.4]). Lung function in terms of trough FEV 1 and FVC improved over time from the start of GLY to Week 52., Conclusion: GLY demonstrated an acceptable long-term safety profile with no new safety concerns in a real-life setting. It demonstrated improvement in lung function and symptom control in Japanese COPD patients., Competing Interests: Chihiro Kato, Dong Wang, Noriko Nakamura, Takayoshi Sasajima, and Hajime Yoshisue are the employees of Novartis Pharma K.K., Tokyo, Japan., (© 2022 Kato et al.)

Objectives: Omalizumab is a recommended add-on therapy for patients with severe allergic asthma who remain uncontrolled despite treatment with standard of care (SoC). This study evaluated the cost-effectiveness of omalizumab compared with SoC applying real-world clinical outcomes in adult patients with severe allergic asthma in Japan., Methods: A validated Markov model was adapted for Japan and compared the cost-effectiveness of omalizumab as an add-on therapy to SoC versus SoC alone using the most recently updated price of omalizumab. A Japanese real-world postmarketing surveillance and a pivotal randomized clinical trial were used as inputs for clinical effectiveness. Japanese life tables and literature were accessed for mortality data and unit costs were extracted from a Japanese insurance claims database. Quality of life data were retrieved from the clinical trial., Results: In the base case, the incremental cost-effectiveness ratio for omalizumab add-on therapy was ¥2.85 million per quality-adjusted life-year gained (approximately €21 000; 1€ = ¥133.26) compared with SoC alone. The model appeared to be most sensitive to changes in clinically significant severe exacerbation fatality, day-to-day asthma symptom utilities for SoC, discount rates for benefits, day-to-day asthma symptom utilities for omalizumab responders, time horizon, and the annual cost of omalizumab. The results of the probabilistic sensitivity analysis showed that the probability of omalizumab being cost-effective was 93% to 98% at a threshold of ¥5 to ¥6 million (willingness-to-pay for 1 quality-adjusted life-year)., Conclusions: Omalizumab add-on therapy is cost-effective compared with SoC alone in Japan in severe allergic asthma population who are uncontrolled with high-dose inhaled corticosteroid and other controllers., (Copyright © 2021 International Society for Pharmacoeconomics and Outcomes Research, Inc. Published by Elsevier Inc. Published by Elsevier Inc. All rights reserved.)

Introduction: Allergic rhinitis (AR) is associated with a substantial health care burden. In Japan, clinical patient profiles in real-life settings and evidence on economic burden of AR are limited. We studied clinical characteristics of patients with AR in Japan, and their impact on health care resource utilization (HCRU) and associated costs., Methods: This was a noninterventional study in patients aged ≥2 years with ≥2 physician-diagnosed AR, from a Japanese Claims Database, conducted from 2009 to 2018. The study comprised 6 cohorts; 1 primary, 3 secondary (cohorts 1, 2, 2-s), and 2 comparison cohorts 1 and 2-s (matched surgery and non-surgery). The primary objective was to describe demographic and clinical characteristics of patients in primary cohort. The secondary objectives were assessment of demographic and clinical characteristics in secondary cohorts and comparison of HCRU-related variables and allergic comorbidities between comparison cohorts., Results: Of 5,260,253 subjects data retrieved, 879,348 were included in primary cohort, with demographics and clinical characteristics being consistent across study period. Most frequent AR-related comorbidities were allergic conjunctivitis (41.7%) and asthma (38.6%). By 2018, 4,246 patients were included in secondary cohort 1, 866,453 in secondary cohort 2, 258,855 in secondary cohort 2-s, 3,496 in comparison cohort 1, and 13,984 in comparison cohort 2-s. Monthly HCRU-related variables between comparison cohort 1 and comparison 2-s indicated that AR-related surgeries and prescriptions peaked in prepollen and pollen seasons, respectively. HCRU and related costs were comparable but slightly higher in surgery than in non-surgery cohort., Conclusion: Real-world evidence of patients with AR highlights the need for cost-effective health care with opportunities for developing novel therapies., (© 2022 S. Karger AG, Basel.)

Objectives: Japan has one of the highest asthma prevalence rates in Asia; however, there is a lack of epidemiological studies on asthma among children in Japan. This study aimed to describe the severity of asthma and the prescription patterns for its treatment among pediatric patients, by using a large-scale claims database., Methods: The analysis datasets were extracted from the JMDC database for the period of April 1, 2009 to March 30, 2015; included records were restricted to patients between 2 and 15 years of age. The Japanese Pediatric Guidelines for the treatment and management of asthma (JPGL) steps were used as a proxy for asthma treatment and severity. We also described the characteristics of asthma in children by stratifying the prevalence and incidence cohorts by index years., Results: In the prevalence cohort (56% male), from 2010 to 2014, approximately 80-90% of the children received step 1 or 2 treatment, with the remainder receiving step 3 or 4 treatment, as defined by the JPGL. The majority (approximately 90%) of patients visited clinics for asthma treatment, while a minority visited hospitals., Conclusions: Our study showed the severity of asthma among Japanese pediatric patients, as well as their demographic characteristics, using a large-scale claims database. The majority of pediatric asthma patients received treatment for mild-to-moderate asthma, while less than 10% received treatment for severe asthma.

Objective Evidence concerning the safety and efficacy of indacaterol maleate in a real-life setting is limited. The objective of this post-marketing surveillance was to evaluate the real-life safety and efficacy of indacaterol maleate in Japanese patients with chronic obstructive pulmonary disease (COPD). Methods This was a 52-week post-marketing surveillance conducted between April 2012 and December 2018. The safety endpoints included the incidence of adverse events (AEs), serious adverse events (SAEs), and adverse drug reactions (ADRs). The efficacy endpoints included the physician-reported global evaluation of treatment effectiveness (GETE), change from baseline in the COPD assessment test (CAT) results, forced vital capacity (FVC), forced expiratory volume in 1 second (FEV 1 ), and %FEV 1 following 4, 12, 26, and 52 weeks of indacaterol administration. Results Of the 1,846 enrolled patients, 1,726 were included in the safety and efficacy analyses. The mean age of the patients was 72.5 years old. Cough, pneumonia and COPD worsening were the most common AEs reported, while pneumonia (1.04%) was the most common SAE, and cough (1.68%) was the most common ADR. GETE showed that 69.70% of patients achieved an excellent/good/moderate response following indacaterol treatment. The CAT score decreased, and lung function parameters (FVC, FEV 1 and %FEV 1 ) improved across all the COPD stages following treatment with indacaterol. Conclusion Indacaterol showed a favorable safety and tolerability profile in Japanese patients with COPD without new safety signals observed in real-life settings. These findings demonstrated that indacaterol is an effective maintenance treatment in real-life practice for Japanese patients with COPD.

Background: Omalizumab is approved as add-on therapy for pediatric asthma since 2013 in Japan, however, its data in clinical practice is limited. This post-marketing surveillance aimed to evaluate long-term safety and effectiveness of omalizumab in Japanese pediatric patients with severe allergic asthma in real-life setting., Methods: This 104-week, multicenter surveillance was conducted from September 2013 to May 2019 by central registration method. Patients with severe allergic asthma aged ≥6 and < 15 years at initiation of treatment who were first-time omalizumab users were included. The primary endpoints included incidence of adverse drug reactions and physician's Global Evaluation of Treatment Effectiveness (GETE). The secondary endpoints included incidence of serious adverse events, adverse events and adverse drug reactions of special interest and asthma exacerbation-related events., Results: Of the 128 patients enrolled, 127 completed the surveillance and were included for safety and effectiveness analysis. Thirteen patients experienced 20 adverse drug reactions with an incidence rate of 10.2%. The most frequent adverse drug reactions were pyrexia (2.4%) and urticaria (1.6%). In total, adverse events and serious adverse events occurred in 60 (47.2%) and 30 patients (23.6%) respectively. Two patients experienced anaphylactic reaction and 1 patient experienced type 1 hypersensitivity. 77.2% had an effective response to omalizumab according to GETE at final assessment, and frequency of all asthma exacerbation-related events decreased in post-treatment versus pre-treatment., Conclusions: Long-term omalizumab treatment showed no new safety signals in pediatric patients with severe allergic asthma. The observed safety and effectiveness profile was consistent with previous studies., (Copyright © 2021 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

Many asthma patients remain uncontrolled despite guideline-based therapies. We examined real-life asthma control in Japanese patients prescribed with inhaled corticosteroid/long-acting β 2 -agonist (ICS/LABA). Patients (≥12 years) with ≥2 asthma diagnoses, newly initiated on medium-/high-dose ICS/LABA (Japanese asthma guidelines), from 01 April 2009 to 31 March 2015 were included, using Japan Medical Data Center Claims Database. Primary objective: proportion of patients with uncontrolled asthma in the year following ICS/LABA initiation. Secondary objectives: predictors of uncontrolled asthma and healthcare resource utilization. In medium-dose (N = 24,937) and high-dose (N = 8661) ICS/LABA cohorts, 23% and 21% patients, respectively, were uncontrolled. Treatment step up and exacerbation were most common indicators of uncontrolled asthma. Predictors of uncontrolled asthma, analyzed by multivariable Cox model, included systemic corticosteroid use, exacerbation history, comorbidities, and being female. In both cohorts, healthcare resource utilization was higher in patients with uncontrolled asthma. Over 20% patients with persistent asthma who initiated medium- or high-dose ICS/LABA were uncontrolled, highlighting unmet need for novel therapies in these patients.

Background and Objective: The 52-week IRIDIUM study demonstrated the efficacy of indacaterol acetate/glycopyrronium bromide/mometasone furoate (IND/GLY/MF) versus IND/MF and salmeterol xinafoate/fluticasone propionate (SAL/FLU) in patients with symptomatic asthma, despite long-acting β 2 -agonist/inhaled corticosteroids (LABA/ICS) medium-dose or high-dose, predicted forced expiratory volume in 1 s (FEV 1 ) <80% and at least one exacerbation in the previous year. Here, we present data from a post hoc analysis of the IRIDIUM study in the Asian subpopulation., Methods: This post hoc analysis evaluated improvements in lung function, asthma control and reduction in asthma exacerbations with IND/GLY/MF medium- (150/50/80 µg) and high-dose (150/50/160 µg) versus IND/MF medium- (150/160 µg) and high-dose (150/320 µg), all one time per day and SAL/FLU high-dose (50/500 µg) two times per day, in Asian patients from the IRIDIUM study., Results: In total, 258 patients (IND/GLY/MF medium-dose, 52; IND/GLY/MF high-dose, 52; IND/MF medium-dose, 51; IND/MF high-dose, 51; SAL/FLU high-dose, 52) were included. IND/GLY/MF medium- and high-dose showed greater improvement in trough FEV 1 at week 26 versus respective doses of IND/MF (Δ, 100 mL and 101 mL; both p<0.05, respectively), and SAL/FLU high-dose (Δ, 125 mL; p=0.0189, and 136 mL; p=0.0118, respectively), which were maintained over 52 weeks. Both doses of IND/GLY/MF showed greater improvement in morning and evening peak expiratory flow versus respective doses of IND/MF and SAL/FLU high-dose at week 52. The changes in Asthma Control Questionnaire-7 scores from baseline were comparable in all treatment groups. IND/GLY/MF medium- and high-dose showed greater reductions in severe (34%, 69%), moderate or severe (18%, 54%) and all exacerbations (21%, 34%) compared with SAL/FLU high-dose over 52 weeks., Conclusion: One time per day, single-inhaler IND/GLY/MF improved lung function, reduced asthma exacerbations and provided comparable asthma control versus IND/MF and SAL/FLU in Asian patients with inadequately controlled asthma despite LABA/ICS. The results of this analysis were consistent with the overall population in the IRIDIUM study., Competing Interests: Competing interests: Authors received no compensation related to development of the manuscript. HS received lecture fees from Astellas Pharma, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Kyorin Pharma and Novartis Pharma. YG reports receiving personal fees from Novartis, GlaxoSmithKline, AstraZeneca, and Boehringer Ingelheim, outside the submitted work. NB, TI, HY, IN and MH are employees of Novartis., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Omalizumab is an anti-immunoglobulin E monoclonal antibody approved for patients with severe allergic asthma in Japan. With regard to omalizumab dosage in Japanese adults with severe allergic asthma in clinical practice settings, this post-marketing surveillance evaluated safety and efficacy of the dosing table revision (DTR) based on a dosing regimen of omalizumab administration every 4 weeks dosing regimen and dosing table expansion (DTE) for patients with baseline IgE levels >700 IU/mL., Methods: This 52-week, multicenter study, conducted from September 2013 to November 2018, evaluated omalizumab safety outcomes including adverse events (AEs), serious AEs (SAEs), adverse drug reactions (ADRs), efficacy outcomes including Global Evaluation of Treatment Effectiveness (GETE), change in oral corticosteroid dose, and asthma exacerbation-related events such as hospitalization, emergency room visits, and worsening of symptoms., Results: Of the 405 patients registered in the study, safety was evaluated in 392 and efficacy in 390. The mean age of patients was 58.5 years and 58.7% were women. In total, 41.3% of the patients were subjected to DTE and 58.7% to DTR. In the safety dataset, 6.6% experienced an ADR, 32.9% experienced an AE, and 16.1% experienced an SAE. In the efficacy dataset, 63.3% of patients at Week 16 and 63.5% at Week 52 had an 'effective' or 'good' GETE score. Omalizumab was associated with a reduction in worsening of asthma symptoms requiring systemic corticosteroids and frequency of hospitalization. All outcomes were comparable among the DTE and DTR subgroups., Conclusion: The findings from this study support the safety and efficacy of omalizumab administered based on the revised and expanded dosing table in Japanese patients with severe allergic asthma., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background and Objective: Indacaterol/glycopyrronium (IND/GLY) 110/50 μg once daily (q.d.) has demonstrated greater improvements in lung function, patient-reported outcomes and lower exacerbation rates versus mono long-acting muscarinic antagonists (LAMA) in chronic obstructive pulmonary disease (COPD) patients. However, data are limited on initial treatment with IND/GLY 110/50 μg q.d. versus mono LAMA in COPD patients, not previously on maintenance treatment with long-acting bronchodilators (LABD)., Methods: A pooled analysis of ARISE, SHINE and SPARK trials was conducted to evaluate the efficacy of IND/GLY 110/50 μg q.d. versus open-label (OL) tiotropium (TIO) 18 μg q.d. and GLY 50 μg q.d. in COPD patients, not on maintenance treatment with LABD at study entry (LABD-naïve). Efficacy was assessed after 24/26 weeks of treatment., Results: In total, 998 LABD-naïve patients were included (IND/GLY: 353; OL TIO: 328; GLY: 317). Patients treated with IND/GLY 110/50 μg q.d. experienced greater improvements in trough forced expiratory volume in 1 s (FEV 1 ) versus OL TIO 18 μg q.d. (least squares mean treatment difference (Δ): 0.086 L) and GLY 50 μg q.d. (Δ: 0.080 L) after 24/26 weeks. Improvements in electronic diary (eDiary) symptom scores, transition dyspnoea index (TDI) focal score, St George's Respiratory Questionnaire (SGRQ) total score and rescue medication use were also greater with IND/GLY versus OL TIO and GLY. Greater proportion of patients achieved minimal clinically important difference in trough FEV 1 , TDI and SGRQ with IND/GLY versus OL TIO and GLY., Conclusion: LABD-naïve patients treated with IND/GLY 110/50 μg q.d. achieved improvements in lung function, daily symptoms, dyspnoea, health-related quality of life and rescue medication use versus those who received single LAMA., (© 2019 The Authors. Respirology published by John Wiley & Sons Australia, Ltd on behalf of Asian Pacific Society of Respirology.)

Maintenance bronchodilator therapy with long-acting β-agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) is the cornerstone treatment for patients with stable chronic obstructive pulmonary disease (COPD). Fixed-dose combinations (FDCs) of LABA/LAMA are recommended for the majority of symptomatic COPD patients by global guidelines; regional guidelines such as the Japanese and Korean guidelines also provide similar recommendations for the use of LABA/LAMA FDCs. This review comprehensively describes the latest clinical evidence from key studies on the efficacy and safety of four approved LABA/LAMA fixed-dose combinations: indacaterol/glycopyrronium, vilanterol/umeclidinium, formoterol/aclidinium, and olodaterol/tiotropium. Additionally, in this review we describe the rationale behind the use of LABA/LAMA FDC therapy, key findings from the preclinical and clinical trial evaluation of respective LABA and LAMA monocomponents, and the efficacy and safety of LABA/LAMA FDCs. Special emphasis is placed on the clinical evidence for the monocomponents and LABA/LAMA FDCs from the Asian population. This detailed overview of the efficacy and safety of LABA/LAMA FDCs in global and Asian COPD patients is envisaged to provide a better understanding of the benefits of these therapies and to inform healthcare providers and patients on their appropriate use.Funding: Novartis Pharma K.K.

Background: Omalizumab (anti-IgE monoclonal antibody) is an approved add-on therapy for Japanese patients with severe allergic asthma. As directed by the Ministry of Health, Labor and Welfare Japan, a post-marketing surveillance (PMS) study on omalizumab was conducted between 2009 and 2017., Methods: The PMS observed safety and efficacy of omalizumab in patients treated with open-label omalizumab for 52 weeks (with optional 2-year extension period). Primary safety outcomes included incidence and severity of adverse events (AEs) and adverse drug reactions (ADRs). Primary efficacy outcomes included physician-assessed global evaluation of treatment effectiveness (GETE). Asthma-exacerbation-related events including requirement for additional systemic steroid therapy, hospitalization, emergency room visits, unscheduled doctor visits, and absenteeism were also evaluated., Results: Of 3893 patients registered, 3620 (age [mean ± SD] 59.3 ± 16.11 years) were evaluated for 52 weeks; 44.12% were aged ≥65 years and 64.45% were women. Overall, 32.24% reported AEs and 15.30% reported serious AEs. ADRs were seen in 292 (8.07%) patients. GETE results showed that the majority of patients experienced clinical improvements (58.29% at 16 weeks and 62.40% at 52 weeks). Nearly half of all patients (47.96%) were free from asthma exacerbations after therapy. Omalizumab also reduced all events related to asthma exacerbations. No specific ADRs were observed in the elderly population., Conclusions: This post-marketing study confirmed the clinically meaningful benefits of omalizumab in a majority of patients from Japan, and showed safety and efficacy in a real-life clinical setting to be consistent with previous reports., (Copyright © 2018. Published by Elsevier Ltd.)

Protein kinases are known for their highly conserved adenosine triphosphate (ATP)-binding site, rendering the discovery of selective inhibitors a major challenge. In theory, allosteric inhibitors can achieve high selectivity by targeting less conserved regions of the kinases, often with an added benefit of retaining efficacy under high physiological ATP concentration. Although often overlooked in favor of ATP-site directed approaches, performing a screen at high ATP concentration or stringent hit triaging with high ATP concentration offers conceptually simple methods of identifying inhibitors that bind outside the ATP pocket. Here, we applied the latter approach to the With-No-Lysine (K) (WNK) kinases to discover lead molecules for a next-generation antihypertensive that requires a stringent safety profile. This strategy yielded several ATP noncompetitive WNK1-4 kinase inhibitors, the optimization of which enabled cocrystallization with WNK1, revealing an allosteric binding mode consistent with the observed exquisite specificity for WNK1-4 kinases. The optimized compound inhibited rubidium uptake by sodium chloride cotransporter 1 (NKCC1) in HT29 cells, consistent with the reported physiology of WNK kinases in renal electrolyte handling.

Background: A disintegrin and metalloprotease (ADAM)-33 is a susceptibility gene for asthma and chronic obstructive pulmonary disease whose function remains unknown., Objective: Because asthmatic bronchoalveolar lavage fluid contains high levels of soluble ADAM33 (sADAM33), which includes the catalytic domain, we postulated that its release from cell membranes might play functional roles in airway remodeling by promoting angiogenesis., Methods: The proangiogenic activity of the highly purified catalytic domain of ADAM33 or a catalytically inactive mutant was studied in vitro (Matrigel assay), ex vivo (human embryonic/fetal lung explants) and in vivo (chorioallantoic membrane assay). The regulation of sADAM33 release from cells overexpressing full-length ADAM33 and its biological activity were characterized., Results: We show that the purified catalytic domain of ADAM33, but not its inactive mutant, causes rapid induction of endothelial cell differentiation in vitro, and neovascularization ex vivo and in vivo. We also show that TGF-beta(2) enhances sADAM33 release from cells overexpressing full-length ADAM33 and that this truncated form is biologically active., Conclusion: The discovery that sADAM33 promotes angiogenesis defines it as a tissue remodeling gene with potential to affect airflow obstruction and lung function independently of inflammation. As TGF-beta(2) enhances sADAM33 release, environmental factors that cause epithelial damage may synergize with ADAM33 in asthma pathogenesis, resulting in a disease-related gain of function. This highlights the potential for interplay between genetic and environmental factors in this complex disease.

Background: Interleukin (IL) 13 is a key cytokine in asthma, regulating fibrosis, airway remodeling, induction of immunoglobulin E synthesis by B cells, bronchial hyperresponsiveness, and mucus production. IL-13 signals through the type II IL-4 receptor (IL-4R), which is composed of the IL-4Ralpha and the IL-13Ralpha1 chains. Another IL-13 binding chain, IL-13Ralpha2, binds IL-13 with high affinity but has no known signaling capability and is thought to serve as a decoy receptor providing tight regulation of IL-13 responses., Methods: In this study, we investigated the cellular localization of IL-13Ralpha2 in human primary bronchial epithelial cells and fibroblasts using flow cytometry and confocal microscopy, as well as the in vivo expression of IL-13Ralpha2 in the human bronchial mucosa by means of immunohistochemistry., Results: IL-13Ralpha2 is predominantly an intracellular rather than a membrane-bound molecule in both human primary bronchial epithelial cells and fibroblasts and displays a diffuse granular cytoplasmic distribution in both cell types. IL-13Ralpha2 protein is expressed in vivo in the human bronchial mucosa with its expression being higher in bronchial epithelial cells than bronchial fibroblasts both in vivo and in vitro., Conclusions: IL-13Ralpha2 is expressed by both human primary bronchial epithelial cells and fibroblasts as an intracellular protein with a diffuse cytoplasmic distribution. In vivo, IL-13Ralpha2 is expressed in the human airway mucosa mainly by bronchial epithelial cells.

Background: Cysteinyl leukotrienes (cys-LTs) are potent asthma-related mediators that function through their G protein-coupled receptors, cys-LT receptor type 1 (CysLT1R) and cys-LT receptor type 2 (CysLT2R)., Objective: Because many G protein-coupled receptors transactivate the epidermal growth factor receptor (EGFR) through metalloprotease-mediated ligand shedding, we investigated the effects of cys-LTs on signal transduction and proliferation of bronchial fibroblasts., Methods: Human bronchial fibroblasts were grown from biopsy specimens of healthy subjects. Mitogenesis was assessed on the basis of tritiated methylthymidine incorporation., Results: Leukotriene (LT) D(4) alone did not increase mitogenesis but dose-dependently increased thymidine incorporation and cell proliferation in the presence of epidermal growth factor (EGF). The enhancement was not prevented by CysLT1R antagonists (MK-571 and montelukast) or by a dual antagonist (BAY u9773), which is consistent with the lack of detectable mRNA for CysLT1R and CysLT2R in bronchial fibroblasts. LTD(4) did not cause EGFR transphosphorylation nor was the synergism blocked by the metalloprotease inhibitor GM6001. The EGFR-selective kinase inhibitor AG1478 suppressed the synergy between LTD(4) and EGF but had no effect on synergistic interactions of LTD(4) with other receptor tyrosine kinase growth factors. The effect of LTD(4) involved a pertussis toxin-sensitive and protein kinase C-mediated intracellular pathway, leading to sustained growth factor-dependent phosphorylation of extracellular signal-regulated kinase 1/2 and protein kinase B (PKB/Akt)., Conclusion: Cys-LTs do not transactivate EGFR but have a broader capability to synergize with receptor tyrosine kinase pathways., Clinical Implications: This study implies a critical role of cys-LTs in airway fibrosis in asthma and other chronic airway diseases, which might not be blocked by therapy with current LT receptor antagonists.

The ability to identify novel disease genes by positional cloning led to the identification of a disintegrin and metalloprotease (ADAM)33 gene on chromosome 20p13 as a susceptibility gene for asthma. Case-control and family-based association studies have mostly confirmed a link between ADAM33 and asthma. Its restricted expression to mesenchymal cells as well as its association with bronchial hyperresponsiveness and accelerated decline in lung function over time point strongly to its involvement in the structural airway components of asthma, such as remodeling. Extensive alternative splicing, expression during branching morphogensis in the developing fetus, impaired lung function in childhood, the production of a soluble form linked to chronic asthma, and tight epigenetic regulation indicate a level of complexity in the way ADAM33 influences disease phenotype. Its recent association with chronic obstructive pulmonary disease as well as with asthma and lung development points to functions relating to airway wall modeling and remodeling as a general morphogenetic repair gene rather than being restricted to asthma.

Lung epithelial structure is altered in asthma; however, the precise mechanisms underlying epithelial repair, including differentiation from basal to columnar epithelial cells, are not well defined. In the course of random sequencing of a cDNA library from human lung biopsies, we have identified a novel gene, ciliated bronchial epithelium 1 (CBE1). Expression of CBE1 was induced during in vitro differentiation of bronchial epithelial cells. Synchronous expression with tektin and hepatocyte nuclear factor 3/forkhead homologue 4, down-regulation by interleukin-13, and its tissue distribution strongly suggested that CBE1 is associated with ciliated cells. Two isoforms of the 0.7-kb full-length cDNA were identified, resulting in open reading frames with different carboxyl termini, with no homology to known proteins. Expression of CBE1 in ciliated epithelial cells was confirmed by immunohistochemistry. Quantitative reverse transcription-polymerase chain reaction analysis using bronchial biopsies showed no difference of expression of CBE1 between normal subjects and subjects with asthma. Expression studies showed that CBE1 is nuclear- or perinuclear-localized, depending on cell type. Regulated expression during differentiation and the subcellular localization of CBE1 suggest that it may play an important role in the differentiation and/or function of ciliated cells in human airways.

While epidermal growth factor receptor (EGFR) plays a pivotal role in the repair process of epithelial cells, it is also involved in the overproduction of mucus and goblet cell hyperplasia (GCH), which occurs in chronic airway diseases such as asthma. Among the EGFR ligands, transforming growth factor (TGF)-alpha is thought to be the most important in the synthesis of mucus. Pro-TGF-alpha is cleaved to give an active form by members of the matrix metalloproteinases (MMP)/a disintegrin and metalloproteinases (ADAM) family. Thus MMP/ADAM inhibitors might prevent GCH by inhibiting transactivation of EGFR. Upon stimulation of differentiating normal human bronchial epithelial (NHBE) cells by IL-13, GCH was induced. The mucin genes MUC5AC, MUC5B, and MUC2 were upregulated whereas the expression of ciliated cell markers was greatly repressed. GM6001, a broad-spectrum inhibitor for MMP/ADAM, inhibited IL-13-induced mucin gene expression and mucus production as measured by periodic acid-Schiff staining. This was accompanied by an inhibition of TGF-alpha release. These results suggest that MMP/ADAMs play a pivotal role in the development of GCH in lung epithelial cells.

To investigate the molecular mechanisms responsible for the regional selectivity of early atherogenesis, we have applied a non-uniform shear stress to cultured human umbilical vein endothelial cells (HUVEC). We used a microcarrier culture system and a combination of subtraction and reverse-subtraction methods to isolate a number of genes upregulated by shear stress. The resultant subtracted library includes several known genes (e.g. MCP-1, TM) whose responsiveness to shear stress has been previously reported, indicating that the library is enriched for genes upregulated by shear stress. Also included are atherosclerosis-related genes (e.g. CTGF, IL-8) whose responsiveness to shear stress had not been demonstrated, other known genes whose relationship to atherosclerosis had not been reported, and novel genes. Some responsive to centrifugal force and shear stress (RECS) genes are also upregulated following stimulation by steady laminar shear stress in a parallel plate chamber. Interestingly, the library includes ET-1 and PAI, which are well known atherogenic factors that are downregulated by laminar shear stress. This implies that turbulent shear stress has effects on HUVEC that are different from those elicited by laminar shear stress. Importantly, analysis of specimens taken from human aorta showed that several RECS genes are transcriptionally upregulated in atherosclerotic lesions, suggesting that the subtracted library includes novel therapeutic targets for the treatment of atherosclerosis.

IL-4 has been shown to be involved in the accumulation of leukocytes, especially eosinophils, at sites of inflammation by acting on vascular endothelial cells. To identify novel molecules involved in the IL-4-dependent eosinophil extravasation, cDNA prepared from HUVEC stimulated with IL-4 was subjected to differential display analysis, which revealed a novel CC chemokine designated as eotaxin-3. The human eotaxin-3 gene has been localized to chromosome 7q11.2, unlike most other CC chemokine genes. The predicted mature protein of 71 aa showed 27-42% identity to other human CC chemokines. The recombinant protein induced a transient increase in the cytosolic Ca2+ concentration and in vitro chemotaxis on eosinophils. Furthermore, in cynomolgus monkeys, the accumulation of eosinophils was observed at the sites where the protein was injected. Eotaxin-3 inhibited the binding of 125I-eotaxin, but not 125I-macrophage inflammatory protein-1alpha, to eosinophils and acted on cell lines transfected with CCR-3, suggesting that eotaxin-3 recognized CCR-3. IL-13 as well as IL-4 up-regulated eotaxin-3 mRNA in HUVEC, whereas neither TNF-alpha, IL-1beta, IFN-gamma, nor TNF-alpha plus IFN-gamma did. The expression profile of eotaxin-3 is different from those of eotaxin, RANTES, and monocyte chemoattractant protein-4, which are potent eosinophil-selective chemoattractants and are induced by either TNF-alpha or TNF-alpha plus IFN-gamma. These results suggest that eotaxin-3 may contribute to the eosinophil accumulation in atopic diseases.

To investigate the mechanism of transcriptional regulation of cryIVA and cryIVB, encoding 130-kDa dipteran-active crystal proteins, in Bacillus thuringiensis subsp. israelensis, we introduced each gene into several sporulation mutants of Bacillus subtilis. A spoIIG mutation, the wild-type gene of which encodes sigma E precursor, completely blocked the cryIVB transcription. In contrast, low but detectable transcription of cryIVA was observed in the spoIIG mutant. In the wild-type B. subtilis, no transcription of cryIVB was detected before T2 (2 h after the onset of stationary phase), while the cryIVA transcription started at the late exponential phase at low levels. Furthermore, in a wild-type strain of B. thuringiensis subsp. israelensis, transcription of cryIVA began earlier than that of genes encoding other crystal components, cryIVB and cytA. A consensus sequence recognized by an RNA polymerase containing sigma H of B. subtilis was found upstream of the transcription start point of cryIVA, which overlapped with that recognized by sigma E.

There are five amino acid sequences highly conserved among Bacillus thuringiensis delta-endotoxins. We have changed the amino acid residues in block 5, one of the conserved sequences, of CryIVA. When the amino acid residues with charged side chains were replaced by others, the amount of production of the altered CryIVA protein was markedly decreased. It is suggested that the decrease is caused by the unstable conformation of the altered CryIVA protein molecule, as judged by digestion with trypsin and thermolysin. On the other hand, the substitution of amino acid residues in block 5 did not affect the insecticidal activity of CryIVA. These results strongly suggest that block 5 of CryIVA is one of the stability-determining elements of the protoxin molecule.

A 20-kDa protein of Bacillus thuringiensis var. israelensis (Bti) has been shown to be necessary for the efficient expression of the 27-kDa mosquitocidal protein gene in Escherichia coli. We have investigated the effects of this 20-kDa protein on the expression of two 130-kDa mosquitocidal protein genes (cryIVA, cryIVB) in E. coli by supplying the 20-kDa protein gene in trans. When a recombinant plasmid, pLH4BX, which was constructed to express cryIVA under the E. coli lac promoter on pUC19, coexisted with the 20-kDa protein gene, a striking increase in production of the fused CryIVA was detected. This was not accompanied by an increase in the amount of intracellular mRNA, suggesting that 20-kDa protein exerts a posttranscriptional effect. We conclude that the 20-kDa protein also stimulates the production of 130-kDa protein in E. coli.