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Donald P Tashkin,1 Ayca Ozol-Godfrey,2 Sanjay Sharma,2 Shahin Sanjar2 1Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine at UCLA Health Sciences, Los Angeles, CA, USA; 2Sunovion Pharmaceuticals Inc., Marlborough, MA, USACorrespondence: Donald P TashkinDivision of Pulmonary and Critical Care Medicine, David Geffen School of Medicine at UCLA Health Sciences, Los Angeles, CA, 90095, USATel +1 310-825-3163Email dtashkin@mednet.ucla.eduBackground: Chronic bronchitis (CB) is one of the conditions that contribute to chronic obstructive pulmonary disease (COPD). Despite its widespread prevalence among patients with COPD and overall negative impact on treatment outcomes, the effect of CB on the efficacy of bronchodilator therapy has not been evaluated. The objective of this post hoc analysis is to assess the effect of nebulized glycopyrrolate (GLY) on lung function and health-related quality of life outcomes in patients with St George’s Respiratory Questionnaire (SGRQ)-defined CB at baseline.Methods: Pooled data from the replicate, 12-week GOLDEN 3 and 4 studies (N=861) were grouped by CB status at baseline. The endpoints reported are changes from baseline in trough forced expiratory volume in 1 second (FEV1), SGRQ and EXAcerbations of Chronic Pulmonary Disease Tool-Respiratory Symptoms (EXACT-RS) scores. Safety of GLY was evaluated by monitoring the incidence of adverse events (AEs).Results: Following 12 weeks of treatment, GLY 25 μg twice-daily (BID) resulted in placebo-adjusted improvements from baseline in FEV1 of 77.1 mL and 124.4 mL in the CB and non-CB groups, respectively (p< 0.0001 vs placebo in both groups). Significant improvements in SGRQ total scores were observed with GLY 25 μg BID compared with placebo, regardless of baseline CB status. Although EXACT-RS improvements were noted in both CB and non-CB groups, significant improvements were observed only in the CB group. GLY 25 μg BID was generally well tolerated through 12 weeks of treatment, with a low incidence of AEs.Conclusion: Treatment with nebulized GLY 25 μg BID for 12 weeks resulted in significant improvements in lung function and SGRQ total scores, compared with placebo. Significant improvements in EXACT-RS total scores were observed only in the CB group. Together, these results support the use of GLY 25 μg BID in patients with COPD, regardless of their CB status.Keywords: chronic bronchitis, COPD, LAMA, nebulized glycopyrrolate

Nirupama Putcha,1 Ayca Ozol-Godfrey,2 Shahin Sanjar,2 Sanjay Sharma2 1Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA; 2Sunovion Pharmaceuticals Inc., Marlborough, MA, USACorrespondence: Nirupama PutchaDivision of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, 5501 Hopkins Bayview Circle, JHAAC 4B.74, Baltimore, MD, 21224, USATel +1 410-550-0545Email nputcha1@jhmi.eduPurpose: Patients with COPD often have multiple coexisting comorbidities, affecting quality of life, morbidity and mortality. However, the prevalence and impact of comorbidities on the efficacy of bronchodilators in COPD is poorly understood.Patients and Methods: In this post hoc analysis, pooled data from the 12-week, placebo-controlled GOLDEN 3 and 4 studies of nebulized glycopyrrolate (GLY) in individuals with moderate-to-very-severe COPD were used to quantify comorbidities and assess their impact on treatment efficacy and safety.Results: Comorbidities that were most prevalent in the GOLDEN 3 and 4 study population were hypertension, high cholesterol and osteoarthritis. Participants were grouped based on their pre-specified comorbidity count into Group A (≤ 2 comorbidities; n=439) and Group B (> 2 comorbidities; n=854). Treatment with GLY resulted in significant improvements in forced expiratory volume in 1 second (FEV1) and St George’s Respiratory Questionnaire (SGRQ) total scores, independent of comorbidity prevalence. A higher prevalence of cardiovascular disease (CVD) comorbidities was observed among individuals in Group B, compared with Group A. In a sub-analysis based on prevalence of CVD, treatment with GLY resulted in significant FEV1 improvements independent of CVD prevalence, although values were numerically higher in the CVD group. GLY also led to higher improvements in SGRQ scores in the CVD group. GLY was well tolerated regardless of comorbidity or CVD prevalence, with a lower incidence of serious adverse events compared with placebo.Conclusion: A simple comorbidity count demonstrated that a majority of patients with COPD in the GOLDEN 3 and 4 studies had multiple comorbidities, with CVD being common in those with high comorbidity count. Results from this post hoc analysis demonstrate that GLY improved FEV1 and SGRQ scores in individuals with COPD, independent of their comorbidities or CVD status.Keywords: comorbidities, COPD, cardiovascular disease, LAMA, nebulized glycopyrrolate

Nicola A Hanania,1 Abebaw M Yohannes,2 Ayca Ozol-Godfrey,3 Michael Tocco,3 Thomas Goodin,3 Sanjay Sharma,3 Shahin Sanjar3 1Section of Pulmonary, Critical Care and Sleep Medicine, Baylor College of Medicine, Houston, TX, 77030, USA; 2Department of Physical Therapy, Azusa Pacific University, Azusa, CA, USA; 3Sunovion Pharmaceuticals Inc., Marlborough, MA, USACorrespondence: Nicola A HananiaSection of Pulmonary, Critical Care and Sleep Medicine, Baylor College of Medicine, Houston, TX, USATel +1 713-873-3454Email hanania@bcm.eduBackground: Anxiety and depression (A/D) are common in patients with chronic obstructive pulmonary disease (COPD) and are often associated with lower adherence to treatment and worse patient-related outcomes. However, studies on the impact of comorbid A/D on responses to bronchodilators are limited.Methods: This post hoc analysis of pooled data (N=861) from the GOLDEN 3 and 4 studies compared the efficacy and safety of nebulized glycopyrrolate (GLY) 25 μg in patients with moderate-to-very-severe COPD, grouped by self-reported A/D. Changes in forced expiratory volume in 1 second (FEV1) and health-related quality of life determined by St George’s Respiratory Questionnaire (SGRQ) scores in patients with or without comorbid A/D (A/D [+] or A/D [–]) were examined following 12 weeks of GLY 25 μg twice-daily (BID) or placebo treatment.Results: A/D (+) patients were predominantly female, younger, included a higher proportion of current smokers, and had higher baseline SGRQ scores compared with the A/D (–) group. At 12 weeks, GLY resulted in placebo-adjusted improvements from baseline in FEV1 of 46.9 mL (p=0.19; not significant) and 106.7 mL (p< 0.0001), in the A/D (+) and A/D (–) groups, respectively. Improvements were observed with GLY compared to placebo in SGRQ scores, regardless of baseline A/D status; the placebo-adjusted least squares mean change from baseline in SGRQ total scores was – 3.16 (p> 0.05) and – 3.34 (p< 0.001), for the A/D (+) and A/D (–) groups, respectively. Despite numerical improvements in SGRQ scores with GLY in the A/D (+) group, a higher response to placebo was observed. GLY was generally well tolerated throughout 12 weeks of treatment; incidence of adverse events was higher in the A/D (+) group compared with the A/D (–) group in both treatment arms.Conclusion: GLY 25 μg BID resulted in numerical improvements in FEV1, SGRQ total scores and SGRQ responder rates in patients with moderate-to-very-severe COPD, regardless of A/D status at baseline; significant improvements were noted only in the A/D (+) group. The results emphasize the importance of considering underlying comorbidities including A/D when evaluating the efficacy of COPD treatments.Keywords: anxiety, COPD, depression, LAMA, nebulized glycopyrrolate

Edward M Kerwin,1 Lindsey Murray,2 Xiaoli Niu,3 Carole Dembek3 1Clinical Research Institute of Southern Oregon, Medford, OR, USA; 2Evidera, Bethesda, MD, USA; 3Sunovion Pharmaceuticals Inc., Marlborough, MA, USACorrespondence: Xiaoli NiuSunovion Pharmaceuticals Inc., 84 Waterford Dr, Marlborough, MA 01752, USATel +1 508 357 7863Email xiaoli.niu@sunovion.comPurpose: Using a composite endpoint, pooled data from two 12-week Phase III placebo-controlled trials (GOLDEN 3, NCT02347761; GOLDEN 4, NCT02347774) were analyzed to determine whether glycopyrrolate inhalation solution (25 mcg and 50 mcg) administered twice daily (BID) via the eFlow® Closed System nebulizer (GLY) reduced the risk of clinically important deterioration (CID) in patients with moderate-to-very-severe COPD.Methods: CID was defined as ≥ 100-mL decrease from baseline in post-bronchodilator trough forced expiratory volume in one second (FEV1), or ≥ 4-unit increase in baseline St. George’s Respiratory Questionnaire (SGRQ) total score, or moderate/severe exacerbation. The relative treatment effect of GLY versus placebo on the odds of CID (any and by component endpoints) was expressed as the odds ratio (OR) and 95% confidence interval (CI). Subgroups categorized by age (< 65/≥ 65 years), sex, smoking status (current/former), long-acting beta agonist (LABA) use, FEV1 (< 50%/≥ 50%), and peak inspiratory flow rate (PIFR) (< 60 L/min/≥ 60 L/min) were analyzed.Results: Compared to placebo, GLY 25 mcg and 50 mcg BID over 12 weeks significantly reduced the risk of CID by 50% (OR: 0.50 [0.37– 0.68]) and 40% (OR: 0.60 [0.44– 0.80]), respectively. Subjects treated with GLY 25 mcg BID were 59% less likely to experience CID in FEV1 (OR: 0.41 [0.27– 0.62]) and 48% less likely to perceive CID in health status (OR: 0.52 [0.37– 0.73]). Statistically significant reductions were also observed at the higher dose. The incidence of moderate/severe exacerbations was low and comparable among the cohorts. GLY 25 mcg BID was significantly more effective than placebo (p< 0.05) in preventing CID irrespective of age, smoking status, LABA use, COPD severity, or PIFR. Subjects < 65 years (OR 0.45 [0.29– 0.68]) and those with PIFR < 60 L/min (OR 0.36 [0.20– 0.67]) exhibited the largest benefit.Conclusion: Nebulized GLY over 12 weeks significantly reduced the risk of CID and provided greater short-term stability in patients with moderate-to-very-severe COPD.Keywords: nebulized glycopyrrolate, clinically important deterioration, composite measure

Introduction: Lung hyperinflation in chronic obstructive pulmonary disease (COPD) is associated with activity limitation, impaired cardiac output, and mortality. Several studies have demonstrated that long-acting muscarinic antagonists (LAMAs) delivered by dry powder inhalers can promote lung deflation; however, the potential of nebulized LAMAs on improving hyperinflation in COPD is currently unknown. Methods: This single-center, randomized, double-blind, two-way crossover study (NCT04155047) evaluated the efficacy of a single dose of nebulized LAMA [glycopyrrolate (GLY) 25 µg] versus placebo in patients with COPD and lung hyperinflation. Patients with moderate-to-severe COPD and a residual volume (RV) ≥ 130% of predicted normal were included. The primary endpoint was changed from baseline in RV at 6 h post-treatment. Other endpoints included changes from baseline in spirometric and plethysmographic measures up to 6 h post-treatment. Results: A total of 22 patients (mean pre-bronchodilator RV, 153.7% of predicted normal) were included. The primary objective of the study was not met; the placebo-adjusted least squares (LS) mean [95% confidence interval (CI) change from baseline in RV with GLY at 6 h post-treatment was − 0.323 l (− 0.711 to 0.066); p = 0.0987]. A post hoc evaluation of the primary analysis was conducted after excluding a single statistical outlier; substantial improvements in RV with GLY compared with placebo was observed after exclusion of this outlier [placebo-adjusted LS mean change from baseline (95% CI) in RV was − 0.446 l (− 0.741 to − 0.150)]. Improvements from baseline were also observed with GLY compared with placebo in spirometric and plethysmographic measures up to 6 h post-treatment. GLY was generally safe, and no new safety signals were detected. Conclusions: This is the first study to evaluate the effect of nebulized GLY on lung deflation. Nebulized GLY resulted in marked improvements in RV up to 6 h post-treatment, compared with placebo. Improvements were also observed with GLY in spirometric and plethysmographic parameters of lung function. Trial Registration: ClinicalTrials.gov identifier, NCT04155047. [ABSTRACT FROM AUTHOR]

Aims: This study compared medication use, healthcare resource utilization (HRU), and exacerbations among individuals with chronic obstructive pulmonary disease (COPD) who initiated glycopyrrolate/eFlow Closed System nebulizer 25 mcg/mL glycopyrrolate (hereafter GLY) in a real-world setting before and after treatment initiation. Materials and methods: Retrospective claims and hospital charge master data were used to identify individuals ≥ 40 years of age diagnosed with COPD who initiated GLY between 1 April 2018 and 28 February 2019 (first prescription claim-index date). Patients were excluded if they had ≥1 asthma diagnosis in the 6-month pre-index period. The proportion of patients with COPD-related medications, other outpatient HRU, hospitalizations, and exacerbations were compared between the 6-month preindex and 6-month follow-up periods. Among patients utilizing the service, per-person utilization rates were compared between the two periods. Results: Among patients initiating GLY (n=767), the mean age was 71.4 years, 56.1% were female, and the mean Charlson Comorbidity Index score was 2.0. The mean number of GLY claims per person was 3.8 during the follow-up period. Compared to the pre-index period, a lower proportion of patients had claims for COPD medications including oral corticosteroids (62.1% vs. 69.1%, p=.0001) and fixeddose SAMA/SABA (26.1% vs. 33.0%, p<.0001) and a higher proportion of patients had claims for LABA (29.7% vs. 22.6%, p<.0001) during the follow-up period. Fewer patients had ≥1 COPD-related physician office visit (42.4% vs. 49.8%, p<.0001), radiology test (40.7% vs. 46.5%, p=.005), or moderate exacerbation (48.0% vs. 53.2%, p=.01) after initiating GLY. Among patients with linkage to inpatient data (n=316), fewer were hospitalized (7.9% vs. 13.0%, p=.037) and hospital length of stay was shorter (1.9 vs. 3.6 days, p=.017) after initiating GLY/eFlow. Conclusions: Among patients initiating GLY in a real-world setting, COPD medications, hospitalizations, other HRU, and exacerbations decreased after treatment initiation compared with the 6-month pre-index period. [ABSTRACT FROM AUTHOR]

Jill A Ohar,1 Alyssa Bowling,2 Thomas Goodin,2 Barry Price,2 Ayca Ozol-Godfrey,2 Sanjay Sharma,2 Shahin Sanjar2 1Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA; 2Sunovion Pharmaceuticals Inc, Marlborough, MA, USA Purpose: Bronchodilator reversibility has been reported in patients with COPD, although correlations between reversibility and treatment response are unclear. The effect of reversibility on lung function, health status, and dyspnea was assessed in patients with moderate-to-severe COPD receiving glycopyrrolate (GLY) 15.6 µg twice daily vs placebo in the Glycopyrrolate Effect on syMptoms and lung function 1 and 2 (GEM1 and GEM2) replicate, 12-week, placebo-controlled studies. Patients and methods: Reversibility was defined as a post-bronchodilator increase of ≥12% and ≥0.200 L in FEV1. FEV1 area under the curve from 0 to 12 hours (AUC0–12 h), trough FEV1, St George’s Respiratory Questionnaire (SGRQ) total score, COPD Assessment Test (CAT™) score, Transition Dyspnea Index (TDI) focal score, daily symptom scores, and rescue medication use were assessed by reversibility status. Incidences of adverse events and serious adverse events were also assessed. Results: Data from 846 patients enrolled in GEM1 and GEM2 with known reversibility status were pooled for post hoc analysis. GLY significantly improved FEV1 AUC0–12 h, trough FEV1, SGRQ and CAT total scores, and rescue medication use compared with placebo in reversible and nonreversible patients. Significant improvements in TDI focal score and daily symptom scores with GLY over placebo were observed only among reversible patients. Improvements in FEV1 AUC0-12 h (0.165 vs 0.078 L; P

This study compared medication use, healthcare resource utilization (HRU), and exacerbations among individuals with chronic obstructive pulmonary disease (COPD) who initiated glycopyrrolate/eFlow Closed System nebulizer 25 mcg/mL glycopyrrolate (hereafter GLY) in a real-world setting before and after treatment initiation. Retrospective claims and hospital charge master data were used to identify individuals ≥ 40 years of age diagnosed with COPD who initiated GLY between 1 April 2018 and 28 February 2019 (first prescription claim = index date). Patients were excluded if they had ≥1 asthma diagnosis in the 6-month pre-index period. The proportion of patients with COPD-related medications, other outpatient HRU, hospitalizations, and exacerbations were compared between the 6-month pre-index and 6-month follow-up periods. Among patients utilizing the service, per-person utilization rates were compared between the two periods. Among patients initiating GLY (n = 767), the mean age was 71.4 years, 56.1% were female, and the mean Charlson Comorbidity Index score was 2.0. The mean number of GLY claims per person was 3.8 during the follow-up period. Compared to the pre-index period, a lower proportion of patients had claims for COPD medications including oral corticosteroids (62.1% vs. 69.1%, p =.0001) and fixed-dose SAMA/SABA (26.1% vs. 33.0%, p <.0001) and a higher proportion of patients had claims for LABA (29.7% vs. 22.6%, p <.0001) during the follow-up period. Fewer patients had ≥1 COPD-related physician office visit (42.4% vs. 49.8%, p <.0001), radiology test (40.7% vs. 46.5%, p =.005), or moderate exacerbation (48.0% vs. 53.2%, p =.01) after initiating GLY. Among patients with linkage to inpatient data (n = 316), fewer were hospitalized (7.9% vs. 13.0%, p =.037) and hospital length of stay was shorter (1.9 vs. 3.6 days, p =.017) after initiating GLY/eFlow. Among patients initiating GLY in a real-world setting, COPD medications, hospitalizations, other HRU, and exacerbations decreased after treatment initiation compared with the 6-month pre-index period. [ABSTRACT FROM AUTHOR]

Jill Ohar,1 Robert Tosiello,2 Thomas Goodin,2 Shahin Sanjar2 1Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA; 2Sunovion Pharmaceuticals Inc., Marlborough, MA, USA Background: The efficacy and safety of nebulized glycopyrrolate inhalation solution (GLY), administered twice daily (BID) via the innovative eFlow® Closed System nebulizer (PARI Pharma GmbH, Starnberg, Germany), were demonstrated in two replicate, placebo-controlled, 12-week Phase III studies (GOLDEN 3 and GOLDEN 4). This report evaluates the efficacy and safety of GLY by baseline disease severity and age in the pooled GOLDEN 3 and GOLDEN 4 patient population (N=1,294). Methods: Patients were grouped by baseline predicted post-bronchodilator FEV1 (

Edward M Kerwin,1 Robert Tosiello,2 Barry Price,2 Shahin Sanjar,2 Thomas Goodin2 1Clinical Research Institute of Southern Oregon, Inc., Medford, OR, USA; 2Sunovion Pharmaceuticals Inc., Marlborough, MA, USA Background: Phase III studies demonstrated efficacy and safety of nebulized glycopyrrolate inhalation solution (GLY) in subjects with COPD. Secondary analyses were performed to examine the effect of background long-acting beta2-agonist (LABA) use on the efficacy and safety of nebulized GLY. Methods: In two 12-week placebo-controlled studies (GOLDEN 3 and GOLDEN 4) and one 48-week, open-label active-controlled study (GOLDEN 5), a total of 2,379 subjects were stratified by background LABA use (LABA-yes: n=861; LABA-no: n=1,518) and randomized to placebo vs GLY 25 or 50 µg twice daily, or GLY 50 µg twice daily vs tiotropium (TIO) 18 µg once daily. Lung function, patient-reported outcomes, exacerbations, and safety were assessed. Results: Compared with placebo, pooled data from the 12-week studies showed significant improvements from baseline with GLY 25 and 50 µg across LABA subgroups in trough FEV1 (LABA-yes: 0.101 and 0.110 L; LABA-no: 0.092 and 0.101 L, respectively; P

Background: Phase III studies demonstrated efficacy and safety of nebulized glycopyrrolate inhalation solution (GLY) in subjects with COPD. Secondary analyses were performed to examine the effect of background long-acting beta 2 -agonist (LABA) use on the efficacy and safety of nebulized GLY., Methods: In two 12-week placebo-controlled studies (GOLDEN 3 and GOLDEN 4) and one 48-week, open-label active-controlled study (GOLDEN 5), a total of 2,379 subjects were stratified by background LABA use (LABA-yes: n=861; LABA-no: n=1,518) and randomized to placebo vs GLY 25 or 50 µg twice daily, or GLY 50 µg twice daily vs tiotropium (TIO) 18 µg once daily. Lung function, patient-reported outcomes, exacerbations, and safety were assessed., Results: Compared with placebo, pooled data from the 12-week studies showed significant improvements from baseline with GLY 25 and 50 µg across LABA subgroups in trough FEV 1 (LABA-yes: 0.101 and 0.110 L; LABA-no: 0.092 and 0.101 L, respectively; P <0.001) and St George's Respiratory Questionnaire total score (SGRQ; LABA-yes: -2.957 and -3.888; LABA-no: -3.301 and -2.073, respectively; P <0.05). Incidence of treatment-emergent adverse events (TEAEs) was similar in LABA subgroups, and lower in GLY 25 µg vs placebo. In the 48-week active-controlled study, GLY and TIO both showed improvement from baseline across LABA subgroups in FEV 1 (LABA-yes: 0.106 and 0.092 L; LABA-no: 0.096 and 0.096 L, respectively) and in SGRQ total score (LABA-yes: -5.190 and -3.094; LABA-no: -4.368 and -4.821, respectively). Incidence of TEAEs was similar between GLY and TIO, and across LABA subgroups. Exacerbation rates were similar across treatments and LABA subgroups, and cardiovascular events of special interest were more frequent in the LABA-no subgroup. Nebulized GLY, combined with LABA, did not generate any additional safety signals., Conclusion: Nebulized GLY demonstrated efficacy and was well tolerated up to 48 weeks in subjects with COPD with/without background LABA., Competing Interests: Disclosure EMK has participated in consulting, advisory boards, speaker panels, or received travel reimbursement for Amphastar, AstraZeneca, Forest, Mylan, Novartis, Oriel, Pearl, Sunovion, Teva, and Theravance. He has conducted multicenter clinical research trials for ~40 pharmaceutical companies. RT, BP, SS, and TG are employees of Sunovion Pharmaceuticals Inc. The authors report no other conflicts of interest in this work.

Introduction: COPD is highly prevalent in the US and globally, requiring new treatment strategies due to the high disease burden and increase in the aging population. Here, we profile the newly FDA-approved LONHALA MAGNAIR (glycopyrrolate [GLY]/eFlow® Closed System [CS]; 25 mcg twice daily), a nebulized long-acting muscarinic antagonist (LAMA) for the long-term maintenance treatment of COPD, including chronic bronchitis and/or emphysema. Areas covered: An overview of COPD and treatment landscape, focusing on GLY/eFlow CS, reviewing the published literature pertinent to the drug/device combination is reported. Expert commentary: GLY/eFlow CS consists of glycopyrrolate delivered via a novel electronic nebulizer and is the first nebulized LAMA to be approved by the FDA. GLY/eFlow CS has been studied in an extensive clinical development program, including phase II dose-ranging studies, two 12-week phase III studies demonstrating statistically significant and clinically important improvements in pulmonary function and patient-reported outcomes with a well-tolerated safety profile, and a 48-week phase III study highlighting the long-term safety of GLY/eFlow CS, along with long-term improvements in lung function and patient-reported outcomes. Additional studies are required to assess the impact of GLY/eFlow CS on COPD exacerbations, identify alternative uses of the eFlow CS nebulizer, and direct comparisons to other LAMAs.