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Gema Requena,1 Alexandrosz Czira,1 Victoria Banks,2 Robert Wood,2 Theo Tritton,2 Catherine Castillo,2 Jie Yeap,2 Rosie Wild,2 Chris Compton,1 Kieran J Rothnie,1 Felix JF Herth,3 Jennifer K Quint,4 Afisi S Ismaila5,6 1GSK, R&D Global Medical, Brentford, Middlesex, UK; 2Real-World Evidence, Adelphi Real World, Bollington, Cheshire, UK; 3Department of Pneumology and Critical Care Medicine, Thoraxklinik, University of Heidelberg and Translational Lung Research Center Heidelberg, Heidelberg, Germany; 4National Heart and Lung Institute, Imperial College London, London, UK; 5Value Evidence and Outcomes, GSK, Collegeville, PA, USA; 6Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, ON, CanadaCorrespondence: Gema Requena, Epidemiology, Value Evidence and Outcomes, R&D Global Medical, GSK, Brentford, Middlesex, UK, Tel +44 20 80476893, Email gema.x.requena@gsk.comPurpose: Chronic obstructive pulmonary disease (COPD) exacerbations are associated with significant morbidity and mortality and increased economic healthcare burden for patients with COPD. Long-acting muscarinic antagonist (LAMA)/long-acting β2-agonist (LABA) dual therapy is recommended for patients receiving mono-bronchodilator therapy who experience exacerbations or ongoing breathlessness. This study compared two single-inhaler LAMA/LABA dual therapies, umeclidinium/vilanterol (UMEC/VI) and indacaterol/glycopyrronium (IND/GLY), on moderate-to-severe exacerbation rates in patients with COPD in England.Patients and Methods: This retrospective cohort study used linked primary care electronic health record data (Clinical Practice Research Datalink-Aurum) and secondary care data (Hospital Episode Statistics) to assess outcomes for patients with COPD who had a first prescription for single-inhaler UMEC/VI or IND/GLY (index date) between 1 January 2015 and 30 September 2019 (indexing period). Analyses compared UMEC/VI and IND/GLY on moderate-to-severe, moderate, and severe exacerbations, healthcare resource utilization (HCRU), and direct costs at 6, 12, 18, and 24 months, and time-to-first on-treatment exacerbation up to 24 months post-index date. Following inverse probability of treatment weighting (IPTW), non-inferiority and superiority of UMEC/VI versus IND/GLY were assessed.Results: In total, 12,031 patients were included, of whom 8753 (72.8%) were prescribed UMEC/VI and 3278 (27.2%) IND/GLY. After IPTW, for moderate-to-severe exacerbations, weighted rate ratios were < 1 at 6, 12, and 18 months and equal to 1 at 24 months for UMEC/VI; around the null value for moderate exacerbations and < 1 at all timepoints for severe exacerbations. UMEC/VI showed lower HCRU incidence rates than IND/GLY for all-cause Accident and Emergency visits and COPD-related inpatient stays and associated all-cause costs at 6 months post-indexing. Time-to-triple therapy was similar for both treatments.Conclusion: UMEC/VI demonstrated non-inferiority to IND/GLY in moderate-to-severe exacerbation reduction at 6, 12 and 18 months. These results support previous findings demonstrating similarity between UMEC/VI and IND/GLY on reduction of moderate-to-severe exacerbations.Plain Language Summary: Sudden exacerbations, or flare-ups, of chronic obstructive pulmonary disease (COPD) are linked with worsening health and increased risk of death, as well as increased healthcare costs for people with COPD. Long-acting muscarinic antagonist (LAMA)/long-acting β2-agonist (LABA) dual therapy is recommended for patients with COPD who take LAMA or LABA monotherapy but continue to experience flare-ups or ongoing breathlessness. This study compared two single-inhaler LAMA/LABA dual therapies, umeclidinium/vilanterol (UMEC/VI) and indacaterol/glycopyrronium (IND/GLY), in terms of flare-ups in patients with COPD in England.We used two linked databases of de-identified medical records from general practitioners and hospitals for patients with COPD who had a first prescription for UMEC/VI or IND/GLY between 1 January 2015 and 30 September 2019. We compared the two treatments on COPD flare-ups, healthcare resource utilization and related costs, and changes in medication over the 2 years following starting treatment.We found that the treatments were comparable for moderate-to-severe flare-ups. Patients taking UMEC/VI had less Accident and Emergency (A&E) visits in total and less inpatient stays related to their COPD, and had a lower overall cost of healthcare for A&E visits and inpatient stays than patients taking IND/GLY. Changes to treatment and time before their first flare-up were similar for all patients, regardless of their prescribed treatment.This study showed that UMEC/VI is as effective as IND/GLY at preventing moderate-to-severe flare-ups. These results support previous findings demonstrating similarity between UMEC/VI and IND/GLY in reducing the rate of moderate-to-severe exacerbations after starting treatment.Keywords: COPD dual therapy, LABA/LAMA new users, healthcare resource utilization, exacerbations, comparative effectiveness, single-inhaler dual therapy

Gema Requena,1 Alexandrosz Czira,1 Victoria Banks,2 Robert Wood,2 Theo Tritton,2 Catherine M Castillo,2 Jie Yeap,2 Rosie Wild,2 Chris Compton,1 Kieran J Rothnie,1 Felix Herth,3,4 Jennifer K Quint,5 Afisi S Ismaila6,7 1GSK, R&D Global Medical, Brentford, Middlesex, UK; 2Real-World Evidence, Adelphi Real World, Bollington, Cheshire, UK; 3Department of Pulmonology and Respiratory Care Medicine, Thoraxklinik at the University of Heidelberg, Heidelberg, Germany; 4Translational Lung Research Center Heidelberg, Member of the German Center for Lung Research DZL, Heidelberg, Germany; 5National Heart and Lung Institute, Imperial College London, London, UK; 6Value Evidence and Outcomes, GSK, Collegeville, PA, USA; 7Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, ON, CanadaCorrespondence: Gema Requena, GSK, R&D Global Medical, Brentford, Middlesex, UK, Tel +44 20 80476893, Email gema.x.requena@gsk.comPurpose: Routinely collected healthcare data on the comparative effectiveness of the long-acting muscarinic antagonist/long-acting β2-agonist combination umeclidinium/vilanterol (UMEC/VI) versus tiotropium bromide/olodaterol (TIO/OLO) for chronic obstructive pulmonary disease (COPD) is limited. This study compared rescue medication prescriptions in patients with COPD in England receiving UMEC/VI versus TIO/OLO.Patients and Methods: This retrospective cohort study used primary care data from the Clinical Practice Research Datalink Aurum database linked with secondary care administrative data from Hospital Episode Statistics. Patients with a COPD diagnosis at age ≥ 35 years were included (indexed) following initiation of single-inhaler UMEC/VI or TIO/OLO between July 1, 2015, and September 30, 2019. Outcomes included the number of rescue medication prescriptions at 12-months (primary), and at 6-, 18- and 24-months (secondary), adherence at 6-, 12-, 18- and 24-months post-index, defined as proportion of days covered ≥ 80% (secondary), and time-to-initiation of triple therapy (exploratory). Inverse probability of treatment weighting (IPTW) was used to balance potential confounding baseline characteristics. Superiority of UMEC/VI versus TIO/OLO for the primary outcome of rescue medication prescriptions was assessed using an intention-to-treat analysis with a p-value < 0.05.Results: In total, 8603 patients were eligible (UMEC/VI: n = 6536; TIO/OLO: n = 2067). Following IPTW, covariates were well balanced across groups. Patients initiating UMEC/VI had statistically significantly fewer (mean [standard deviation]; p-value) rescue medication prescriptions versus TIO/OLO in both the unweighted (4.84 [4.78] vs 5.68 [5.00]; p < 0.001) and weighted comparison (4.91 [4.81] vs 5.48 [5.02]; p = 0.0032) at 12 months; consistent results were seen at all timepoints. Adherence was numerically higher for TIO/OLO versus UMEC/VI at all timepoints. Time-to-triple therapy was similar between treatment groups.Conclusion: UMEC/VI was superior to TIO/OLO in reducing rescue medication prescriptions at 12 months after treatment initiation in a primary care cohort in England, potentially suggesting improvements in symptom control with UMEC/VI compared with TIO/OLO.Keywords: COPD treatment, LABA/LAMA, primary care setting, rescue medication, treatment escalation

Alexandrosz Czira,1 Gema Requena,1 Victoria Banks,2 Robert Wood,2 Theo Tritton,2 Catherine M Castillo,2 Jie Yeap,2 Rosie Wild,2 Chris Compton,1 Kieran J Rothnie,1 Felix Herth,3,4 Jennifer K Quint,5 Afisi S Ismaila6,7 1R&D Global Medical, GSK, Brentford, Middlesex, UK; 2Real-World Evidence, Adelphi Real World, Bollington, Cheshire, UK; 3Department of Pulmonology and Respiratory Care Medicine, Thoraxklinik at the University of Heidelberg, Heidelberg, Germany; 4Translational Lung Research Center Heidelberg, Member of the German Center for Lung Research DZL, Heidelberg, Germany; 5National Heart and Lung Institute, Imperial College London, London, UK; 6Value Evidence and Outcomes, GSK, Collegeville, PA, USA; 7Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, ON, CanadaCorrespondence: Alexandrosz Czira, Value Evidence and Outcomes, R&D Global Medical, GSK, Brentford, Middlesex, UK, Tel +44 7788 351610, Email alexandrosz.x.czira@gsk.comPurpose: To compare adherence to once-daily umeclidinium/vilanterol (UMEC/VI), a long-acting muscarinic antagonist/long-acting β2-agonist (LAMA/LABA), and twice-daily inhaled corticosteroids (ICS)/LABA single-inhaler dual therapy in patients with chronic obstructive pulmonary disease (COPD) in a primary care cohort in England.Patients and Methods: Active comparator, new-user, retrospective cohort study using CPRD-Aurum primary care data and linked Hospital Episode Statistics secondary care administrative data. Patients without exacerbations in the previous year were indexed on first/earliest prescription date of once-daily UMEC/VI or twice-daily ICS/LABA as initial maintenance therapy between July 2014-September 2019. Primary outcome: medication adherence at 12 months post-index, defined as proportion of days covered (PDC) ≥ 80%. PDC represented proportion of time over the treatment duration that the patient was theoretically in possession of the medication. Secondary outcomes: adherence at 6, 18, and 24 months post-index, time-to-triple therapy, time-to-first on-treatment COPD exacerbation, COPD-related and all-cause healthcare resource utilization (HCRU), and direct health-care costs. A propensity score was generated and inverse probability of treatment weighting (IPTW) was used to balance potential confounders. Superiority was defined as > 0% difference between treatment groups.Results: In total, 6815 eligible patients were included (UMEC/VI:1623; ICS/LABA:5192). At 12 months post-index, weighted odds of a patient being adherent were significantly greater with UMEC/VI versus ICS/LABA (odds ratio [95% CI]: 1.71 [1.09, 2.66]; p=0.0185), demonstrating superiority of UMEC/VI. Patients taking UMEC/VI were statistically significantly more adherent than those taking ICS/LABA at 6, 18, and 24 months post-index (p< 0.05). Differences in time-to-triple therapy, time-to-moderate COPD exacerbations, HCRU, and direct medical costs were not statistically significant between treatments after IPTW was applied.Conclusion: At 12 months post-treatment initiation, once-daily UMEC/VI was superior to twice-daily ICS/LABA in medication adherence among patients with COPD without exacerbations in the previous year, newly initiating dual maintenance therapy in England. The finding was consistent at 6, 18, and 24 months.Keywords: adherence, comparative effectiveness, chronic obstructive pulmonary disease (COPD) treatment, inhaled corticosteroid/long-actingβ2-agonist (ICS/LABA) dual therapy, long-acting muscarinic antagonist (LAMA)/LABA dual therapy

Gema Requena,1 Victoria Banks,2,&ast; Alexandrosz Czira,1 Robert Wood,2 Theo Tritton,2 Rosie Wild,2 Chris Compton,1 Afisi S Ismaila3,4 1Value Evidence and Outcomes, GSK, R&D Global Medical, Brentford, Middlesex, UK; 2Real-World Evidence, Adelphi Real World, Bollington, Cheshire, UK; 3Value Evidence and Outcomes, GSK, Collegeville, PA, USA; 4Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, ON, Canada&ast;At the time of the studyCorrespondence: Gema Requena, Epidemiology, Value Evidence and Outcomes, R&D Global Medical, GSK, Middlesex, UK, Tel +44 20 80476893, Email gema.x.requena@gsk.comPurpose: Selection of treatments for patients with chronic obstructive pulmonary disease (COPD) may impact clinical outcomes, healthcare resource use (HCRU) and direct healthcare costs. We aimed to characterize these outcomes along with treatment patterns, for patients with COPD following initiation of single-inhaler long-acting muscarinic antagonist/long-acting β2-agonist (LAMA/LABA) dual therapy in the primary care setting in England.Patients and Methods: This retrospective cohort study used linked primary care electronic medical record data (Clinical Practice Research Datalink-Aurum) and secondary care administrative data (Hospital Episode Statistics) in England to assess outcomes for patients with COPD who had a prescription for one of four single-inhaler LAMA/LABA dual therapies between 1st June 2015– 31st December 2018 (indexing period). Outcomes were assessed during a 12-month follow-up period from the index date (date of earliest prescription of a single-inhaler LAMA/LABA within the indexing period). Incident users were those without previous LAMA/LABA dual therapy prescriptions prior to index; this manuscript focuses on a subset of incident users: non-triple therapy users (patients without concomitant inhaled corticosteroid use at index).Results: Of 10,991 incident users included, 9888 (90.0%) were non-triple therapy users, indexed on umeclidinium/vilanterol (n=4805), aclidinium/formoterol (n=2109), indacaterol/glycopyrronium (n=1785) and tiotropium/olodaterol (n=1189). At 3 months post-index, 63.3% of non-triple therapy users remained on a single-inhaler LAMA/LABA, and 22.1% had discontinued inhaled therapy. Most patients (86.9%) required general practitioner consultations in the first 3 months post-index. Inpatient stays were the biggest contributor to healthcare costs. Acute exacerbations of COPD (AECOPDs), adherence, time-to-triple therapy, time-to-first on-treatment moderate-to-severe AECOPD, time-to-index treatment discontinuation, HCRU and healthcare costs were similar across indexed therapies.Conclusion: Patients initiating treatment with single-inhaler LAMA/LABA in primary care in England were unlikely to switch treatments in the first three months following initiation, but some may discontinue respiratory medication. Outcomes were similar across indexed treatments.Keywords: COPD, single-inhaler LAMA/LABA dual therapy, primary care setting, treatment patterns, clinical outcomes

David MG Halpin,1 Kieran J Rothnie,2 Victoria Banks,3 Alexandrosz Czira,2 Chris Compton,4 Robert Wood,3 Theo Tritton,3 Olivia Massey,3 Rosie Wild,3 Neil Snowise,5 Kirill Nikitin,2 Raj Sharma,4 Afisi S Ismaila,6,7 Claus F Vogelmeier8 1University of Exeter Medical School, College of Medicine and Health, University of Exeter, Exeter, UK; 2Value Evidence and Outcomes, R&D Global Medical, GSK, Brentford, UK; 3Real-World Evidence, Adelphi Real World, Bollington, UK; 4Global Medical, GSK, London, UK; 5Institute of Pharmaceutical Science, Faculty of Life Sciences and Medicine, King’s College, London, UK; 6Value Evidence and Outcomes, GSK, Collegeville, PA, USA; 7Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, ON, Canada; 8Department of Medicine, Pulmonary and Critical Care Medicine, University of Marburg, Member of the German Center for Lung Research (DZL), Marburg, GermanyCorrespondence: David MG Halpin, University of Exeter Medical School, College of Medicine and Health, University of Exeter, Exeter, EX1 2LU, UK, Tel +44 (0)1392 201178, Email d.halpin@nhs.netPurpose: Triple therapy comprising a long-acting muscarinic antagonist, long-acting β2-agonist and inhaled corticosteroid is recommended for patients with chronic obstructive pulmonary disease (COPD) who continue to experience frequent exacerbations or symptoms whilst receiving dual therapy. Adherence and persistence to multiple-inhaler triple therapy (MITT) is known to be poor. This study assessed comparative adherence to single-inhaler triple therapy (SITT) versus MITT in a real-world setting in England.Patients and Methods: This was a retrospective cohort study using linked primary care (Clinical Practice Research Datalink Aurum) and secondary care (Hospital Episode Statistics [HES] Admitted Patient Care) data to identify patients with COPD who were newly initiated on SITT or MITT between November 2017 and June 2019. Eligible patients were aged ≥ 35 years and had a forced expiratory volume in 1 second/forced vital capacity < 0.7, linkage to HES and continuous registration with a general practitioner for 12 months pre- and 6 months post-initiation. Inverse probability of treatment weighting was used to balance baseline characteristics between cohorts. Adherence was measured using the proportion of days covered by days’ supply of SITT or MITT prescriptions. Persistence was measured with a gap of > 30 days between the end of a prescription and the following refill used to determine non-persistence.Results: Overall, 4080 SITT and 6579 MITT users comprised the study cohort. After weighting, the baseline characteristics between the cohorts were comparable (absolute standardized mean difference < 10%). SITT users had significantly higher adherence than MITT users at 6, 12, and 18 months post-initiation (p< 0.001 for all comparisons). Median persistence was higher among SITT users than MITT users (5.09 months vs 0.99 months).Conclusion: Patients with COPD in England initiating SITT had significantly better adherence and persistence compared with MITT initiators. These improvements continued at least 18 months following treatment initiation.Keywords: COPD, Clinical Practice Research Datalink, Hospital Episode Statistics, MITT, proportion of days covered, SITT

Gema Requena,1 Victoria Banks,2 Alexandrosz Czira,1 Robert Wood,2 Theo Tritton,2 Rosie Wild,2 Chris Compton,1 Maria Duarte,1 Afisi S Ismaila3,4 1Value Evidence and Outcomes, Epidemiology, GSK, R&D Global Medical, Brentford, Middlesex, UK; 2Real-world Evidence, Adelphi Real World, Bollington, Cheshire, UK; 3Value Evidence and Outcomes, GSK, Collegeville, PA, USA; 4Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, ON, CanadaCorrespondence: Gema Requena, Epidemiology, Value Evidence and Outcomes, R&D Global Medical, GSK, Brentford, Middlesex, UK, Tel +44 20 80476893, Email gema.x.requena@gsk.comPurpose: Treatment pathways of patients with chronic obstructive pulmonary disease (COPD) receiving single-inhaler dual therapies remain unclear. We aimed to describe characteristics, prescribed treatments, healthcare resource use (HCRU) and costs of patients with COPD who initiated single-inhaler long-acting muscarinic antagonist/long-acting β2-agonist (LAMA/LABA) dual therapy in primary care in England.Patients and Methods: Retrospective study using linked data from Clinical Practice Research Datalink Aurum and Hospital Episode Statistics datasets. Patients with COPD with ≥ 1 single-inhaler LAMA/LABA prescription between June 2015 and December 2018 (index) were included. Demographic and clinical characteristics, prescribed treatments, HCRU and costs were evaluated in the 12 months pre-index. Data are presented for patients not receiving concomitant inhaled corticosteroids at index (non-triple users).Results: Of 10,991 patients initiating LAMA/LABA, 9888 were non-triple users, of whom 21.3% (n=2109) received aclidinium bromide/formoterol, 18.1% (n=1785) received indacaterol/glycopyrronium, 12.0% (n=1189) received tiotropium bromide/olodaterol and 48.6% (n=4805) received umeclidinium/vilanterol. Demographic and clinical characteristics were similar across indexed therapies. LAMA monotherapy was the most frequently prescribed respiratory therapy at 12 (18.4– 25.8% of patients) and 3 months (23.9– 33.7% of patients) pre-index across indexed therapies; 42.5– 59.0% of patients were prescribed no respiratory therapy at these time points. COPD-related HCRU during the 12 months pre-index was similar across indexed therapies (general practitioner consultations: 62.0– 68.6% patients; inpatient stays: 19.3– 26.1% patients). Pre-index COPD-related costs were similar across indexed therapies, with inpatient stays representing the highest contribution. Mean total direct annual COPD-related costs ranged from £ 805–£ 1187.Conclusion: Characteristics of patients newly initiating single-inhaler LAMA/LABA dual therapy were highly consistent across indexed therapies. As half of non-triple users were not receiving respiratory therapy one year prior to LAMA/LABA initiation, there may be an opportunity for early optimization of treatment to relieve clinical burden versus current prescribing patterns in primary care in England.Keywords: COPD, initial maintenance therapy, primary care setting, patient characteristics, single-inhaler LAMA/LABA dual therapy, treatment patterns

The equilibrium-binding affinities of six adriamycin analogues and four daunomycin derivatives for negatively charged dimyristoyl phosphatidylcholine/dimyristoyl phosphatidic acid (DMPC/DMPA) small unilamellar vesicles are compared with values for electroneutral DMPC liposomes. Binding of the daunomycin series to negatively charged dimyristoyl phosphatidyl glycerol (DMPG) vesicles was also examined. Under physiological conditions of pH and ionic strength, substitution of the amino group of adriamycin or daunomycin resulted in a reduced affinity for negatively charged bilayers, even if the substituent enhanced the degree of ionization of the amine. Decreasing the ionic strength increases the binding affinity for acidic membranes but decreases the drug affinity for neutral membranes. We propose that the electrostatic bond of the phosphate-amino group that has been shown to exist between anthracyclines and phosphatidic acid is sterically destabilized by substitution of the amino group. The results are consistent with a mode of anthracycline binding to negatively charged membranes which is driven by hydrophobic and electrostatic considerations but is destabilized by steric bulk at the amino group. The data also provide insight into the design of new anthracyclines with high membrane affinities and reduced uptake; such directed interaction with plasma membranes may enhance antineoplastic potential while reducing cardiac toxicity. [ABSTRACT FROM AUTHOR]