Publications by authors named "Ubaldo J Martin"

47 Publications

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

J Allergy Clin Immunol 2021 Feb 17. Epub 2021 Feb 17.

AstraZeneca, Gaithersburg, Md.

Background: Adults and adolescents with severe asthma who completed the 48-week SIROCCO and 56-week CALIMA phase III benralizumab trials entered the safety extension study BORA (NCT02258542). The continued safety and efficacy of benralizumab in the first year of BORA (year 2 of treatment) have been reported.

Objective: We sought to report outcomes for adolescents during years 2 and 3 of treatment in BORA.

Methods: Patients on benralizumab 30 mg every 4 weeks (Q4W) or every 8 weeks (Q8W) in SIROCCO/CALIMA continued their regimens in BORA (Q4W/Q4W and Q8W/Q8W, respectively), whereas placebo patients were rerandomized 1:1 to benralizumab (placebo/Q4W and placebo/Q8W, respectively) for 108 weeks. The primary outcome was safety; secondary outcomes included reduction in annual asthma exacerbation rate and change from baseline in prebronchodilator FEV.

Results: Adolescents (N = 86) were treated with benralizumab Q8W (n = 61) or Q4W (n = 25); 69 completed treatment (Q8W: n = 51; Q4W: n = 18). For Q4W and Q8W regimens, rates of treatment-emergent adverse events were 68% (17 of 25) and 74% (45 of 61), respectively, rates of treatment-emergent adverse events (TEAEs) were 68% (17/25) and 74% (45/61), TEAEs leading to discontinuation were 4% (1/25) and 0%, serious AEs were 8% (2/25) and 7% (4/61), and no deaths occurred. In efficacy analyses, 69% (42 of 61) Q8W patients were exacerbation-free (placebo/Q8W: 62% [18 of 29], Q8W/Q8W: 75% [24 of 32]). Mean ± SD change in FEV at week 108 versus BORA baseline was 0.327 ± 0.452 L (placebo/Q8W) and 0.323 ± 0.558 L (Q8W/Q8W).

Conclusions: Safety and efficacy profiles in this 2-year extension study (up to 3 years of benralizumab treatment in adolescents) were consistent with previous findings.
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http://dx.doi.org/10.1016/j.jaci.2021.02.009DOI Listing
February 2021

Efficacy and safety of glycopyrrolate/formoterol fumarate metered dose inhaler delivered using co-suspension delivery technology in Japanese patients with moderate-to-very severe chronic obstructive pulmonary disease.

Respir Investig 2021 Jan 8;59(1):135-144. Epub 2020 Sep 8.

AstraZeneca, Morristown, NJ, USA; AstraZeneca, Gaithersburg, MD, USA.

Background: PINNACLE-4 evaluated the efficacy and safety of the long-acting muscarinic antagonist/long-acting β-agonist fixed-dose combination glycopyrrolate/formoterol fumarate metered dose inhaler (GFF MDI) in patients from Asia, Europe, and the USA with moderate-to-very severe chronic obstructive pulmonary disease (COPD). This pre-specified analysis included Japanese patients in PINNACLE-4.

Methods: In this double-blind randomized study (NCT02343458), patients received GFF MDI (18/9.6 μg), glycopyrrolate (GP) MDI (18 μg), formoterol fumarate (FF) MDI (9.6 μg), or placebo MDI twice daily for 24 weeks. The primary endpoint was change from baseline in morning pre-dose trough forced expiratory volume in 1 s (FEV) over Weeks 12-24. Secondary lung function endpoints, patient-reported outcomes, and safety were assessed. The Japanese subpopulation (n = 150) analyses were exploratory.

Results: GFF MDI improved change from baseline in morning pre-dose trough FEV over Weeks 12-24 versus GP MDI, FF MDI, and placebo MDI (least squares mean [LSM] differences [95% confidence interval]: 69 [8-131], 60 [-1 to 121], and 275 [180-370] mL, respectively). GFF MDI numerically improved Transition Dyspnea Index focal score and change from baseline in St George's Respiratory Questionnaire total score versus placebo MDI (LSM differences 0.19 and -3.78, respectively). Treatment-related adverse events occurred in ≤4.5% of patients in any treatment group.

Conclusions: GFF MDI improved lung function versus monocomponents and placebo MDI in the Japan subpopulation of PINNACLE-4. The efficacy and safety results were generally consistent with those of the global study population, supporting the use of GFF MDI in Japanese patients with moderate-to-very severe COPD.
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http://dx.doi.org/10.1016/j.resinv.2020.06.007DOI Listing
January 2021

Functional respiratory imaging assessment of glycopyrrolate and formoterol fumarate metered dose inhalers formulated using co-suspension delivery technology in patients with COPD.

Ther Adv Respir Dis 2020 Jan-Dec;14:1753466620916990

AstraZeneca, Morristown, NJ, USA.

Background: Functional respiratory imaging (FRI) is a quantitative postprocessing imaging technique used to assess changes in the respiratory system. Using FRI, we characterized the effects of the long-acting muscarinic antagonist (LAMA), glycopyrrolate metered dose inhaler (GP MDI), and the long-acting β-agonist (LABA), formoterol fumarate metered dose inhaler (FF MDI), on airway volume and resistance in patients with moderate-to-severe chronic obstructive pulmonary disease.

Methods: Patients in this phase IIIb, randomized, double-blind crossover study received twice-daily GP MDI (18 μg) and FF MDI (9.6 μg). Primary endpoints were specific (i.e. corrected for lobar volume) image-based airway volume (siVaw) and specific image-based airway resistance (siRaw), measured using FRI. Secondary and other endpoints included additional FRI, spirometry, and body plethysmography parameters. Postdose efficacy assessments were performed within 60-150 min of dosing on day 15.

Results: A total of 23 patients were randomized and 19 completed both treatment periods. GP MDI and FF MDI both achieved significant improvements from baseline to day 15 in siVaw [11% ( = 0.0187) and 23% ( < 0.0001) increases, respectively] and siRaw [25% ( = 0.0219) and 44% ( < 0.0001) reductions, respectively]. Although, on average, improvements were larger for FF MDI than GP MDI, some individuals displayed greater responses with each of the two treatments. These within-patient differences increased with airway generation number. Spirometry and body plethysmography endpoints showed significant improvements from baseline in inspiratory capacity for both treatments, and numeric improvements for other endpoints.

Conclusion: Both GP MDI and FF MDI significantly improved siRaw and siVaw at day 15 baseline. FRI endpoints demonstrated increased sensitivity relative to spirometry and body plethysmography in detecting differences between treatments in a small number of patients. Intra-patient differences in treatment response between the LAMA and the LABA provide further support for the benefit of dual bronchodilator therapies.

Clinicaltrials.gov Registration Number: NCT02937584
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http://dx.doi.org/10.1177/1753466620916990DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7225799PMC
May 2020

Blood eosinophil count group shifts and kinetics in severe eosinophilic asthma.

Ann Allergy Asthma Immunol 2020 08 22;125(2):171-176. Epub 2020 Apr 22.

AstraZeneca, Wilmington, Delaware.

Background: Blood eosinophil count (BEC) measurements are a noninvasive, relatively reliable surrogate marker for eosinophilic airway inflammation. Single measurements of peripheral BEC greater than or equal to 150 cells/μL predict the response to anti-eosinophil therapies for patients with characteristics of severe eosinophilic asthma.

Objective: To describe how BECs shift over time for patients with severe, uncontrolled asthma receiving placebo in 2 large, randomized, placebo-controlled clinical trials of benralizumab (SIROCCO and CALIMA).

Methods: Our analysis included all adult patients who were randomized to placebo in the SIROCCO and CALIMA phase III benralizumab studies. Patients were categorized into baseline BEC groups of less than 150 cells/μL, greater than or equal to 150 cells/μL but less than 300 cells/μL, and greater than or equal to 300 cells/μL. The timing of the initial shift from baseline to a different group was evaluated at weeks 4, 8, 24, and 40 and at the end of treatment. Baseline characteristics, including oral corticosteroid use, were described based on the presence or absence of a BEC group shift.

Results: Of the 734 evaluable patients, 65% (n = 474) shifted BEC groups during the study, and most patients (86% [n = 410]) shifted by week 24. Patients who started in the less than 150 cells/μL group tended to shift groups earlier, with 59% shifting by week 4 compared with 38% to 55% for other groups in the same time frame. Patients who shifted BEC groups vs those who did not tend to have lower BECs, more oral corticosteroid use, and less incidence of nasal polyps or past polypectomy.

Conclusion: A single BEC measurement, particularly when low, may be inadequate to help establish a phenotype of severe eosinophilic asthma.

Trial Registration: ClinicalTrials.gov Identifiers NCT01928771 (SIROCCO trial) and NCT01914757 (CALIMA trial).
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http://dx.doi.org/10.1016/j.anai.2020.04.011DOI Listing
August 2020

Safety of Eosinophil-Depleting Therapy for Severe, Eosinophilic Asthma: Focus on Benralizumab.

Drug Saf 2020 05;43(5):409-425

Global Medical Affairs, BioPharmaceuticals Medical, AstraZeneca, One MedImmune Way, Gaithersburg, MD, 20878, USA.

Eosinophils play a pivotal role in the inflammatory pathology of asthma and have been the target of new biologic treatments for patients with eosinophilic asthma. Given the central role of interleukin (IL)-5 in the eosinophil lifecycle, several therapies directed against the IL-5 pathway have been developed, including the anti-IL-5 antibodies mepolizumab and reslizumab and the IL-5 receptor α (IL-5Rα)-directed cytolytic antibody benralizumab. Eosinophil-depleting therapies represent a relatively new class of asthma treatment, and it is important to understand their long-term efficacy and safety. Eosinophils have been associated with host protection and tumor growth, raising potential concerns about the consequences of long-term therapies that deplete eosinophils. However, evidence for these associations in humans is conflicting and largely indirect or based on mouse models. Substantial prospective clinical trial and postmarketing data have accrued, providing insight into the potential risks associated with eosinophil depletion. In this review, we explore the current safety profile of eosinophil-reducing therapies, with particular attention to the potential risks of malignancies and severe infections and a focus on benralizumab. Benralizumab is an IL-5Rα-directed cytolytic monoclonal antibody that targets and efficiently depletes blood and tissue eosinophils through antibody-dependent cell-mediated cytotoxicity. Benralizumab is intended to treat patients with severe, uncontrolled asthma with eosinophilic inflammation. The integrated analyses of benralizumab safety data from the phase III SIROCCO and CALIMA trials and subsequent BORA extension trial for patients with asthma, and the phase III GALATHEA and TERRANOVA trials for patients with chronic obstructive pulmonary disease, form the principal basis for this review.
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http://dx.doi.org/10.1007/s40264-020-00926-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7165132PMC
May 2020

Onset of Effect, Changes in Airflow Obstruction and Lung Volume, and Health-Related Quality of Life Improvements with Benralizumab for Patients with Severe Eosinophilic Asthma: Phase IIIb Randomized, Controlled Trial (SOLANA).

J Asthma Allergy 2020 17;13:115-126. Epub 2020 Feb 17.

Research and Development, AstraZeneca, Gaithersburg, MD, USA.

Objective: In the SOLANA trial, we sought to physiologically characterize benralizumab's onset of effect and maintenance of that effect for patients with severe eosinophilic asthma.

Methods: SOLANA (NCT02869438) was a multicenter, randomized, double-blind, parallel-group, placebo-controlled, Phase IIIb study conducted at 49 centers in six countries (Chile, Germany, Hungary, the Philippines, South Korea, and the United States). Eligible patients with baseline blood eosinophil counts ≥300 cells/µL were randomized to subcutaneous benralizumab (30 mg) or placebo administered at Days 0, 28, and 56. The primary endpoint was the average change from baseline in prebronchodilator forced expiratory volume in 1 s (pre-BD FEV) during the Day 28‒Day 84 period for benralizumab vs placebo. Secondary endpoints included patient-reported outcomes (PROs). A subset of patients participated in a whole-body plethysmography substudy. Safety was also assessed.

Results: In total, 233 patients were randomized to benralizumab (n=118) or placebo (n=115). Improvement from baseline in pre-BD FEV with benralizumab 30 mg was not statistically significant compared with placebo (least-squares mean change difference [95% confidence interval] 57 mL [-22 to 135]; p=0.16). Compared with placebo, benralizumab demonstrated early (Day 7) nonstatistically significant improvements in whole-body plethysmography assessments of hyperinflation and clinically meaningful improvements in PRO measures (Asthma Control Questionnaire 6 at Day 14 and St. George's Respiratory Questionnaire at Day 28), which were maintained over the treatment period. Benralizumab's safety profile was commensurate with previously reported studies.

Conclusion: The observed early changes in lung volume despite relatively small improvements in airflow obstruction suggest that the anti-inflammatory effect of benralizumab may be manifested as deflation over time for patients with hyperinflation, who potentially have a greater degree of airway remodeling. This early effect could partially explain the rapid PRO improvements observed for certain patients.
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http://dx.doi.org/10.2147/JAA.S240044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7034961PMC
February 2020

Glycopyrrolate/Formoterol Fumarate Metered Dose Inhaler Improves Lung Function versus Monotherapies in GOLD Category A Patients with COPD: Pooled Data from the Phase III PINNACLE Studies.

Int J Chron Obstruct Pulmon Dis 2020 9;15:99-106. Epub 2020 Jan 9.

Research and Development, AstraZeneca, Gaithersburg, MD, USA.

Background: The Global Initiative for Chronic Obstructive Lung Disease (GOLD) recommends a short-acting bronchodilator or single long-acting bronchodilator as an initial pharmacological treatment for GOLD category A patients with COPD. We pooled data from the PINNACLE-1, -2, and -4 studies to evaluate the efficacy and safety of the dual bronchodilator fixed-dose combination glycopyrrolate/formoterol fumarate metered dose inhaler (GFF MDI), formulated using co-suspension delivery technology, in GOLD category A patients with moderate-to-very severe COPD.

Materials And Methods: PINNACLE-1, -2, and -4 were Phase III, randomized, double-blind, parallel-group, multicenter studies (NCT01854645, NCT01854658, and NCT02343458). Patients received 24 weeks' treatment with GFF MDI 18/9.6 µg, glycopyrrolate (GP) MDI 18 µg, formoterol fumarate (FF) MDI 9.6 µg, or placebo MDI twice daily. GOLD category A patients were identified based on a COPD Assessment Test score of <10 and exacerbation history in the previous year (none/one not requiring hospitalization). Endpoints evaluated were change from baseline in morning pre-dose trough forced expiratory volume in 1 second (FEV), peak change from baseline in FEV within 2 hrs post-dose, and adverse events (AEs).

Results: The pooled intent-to-treat population comprised 729 GOLD category A patients. GFF MDI significantly improved morning pre-dose trough FEV at Week 24 versus GP MDI, FF MDI, and placebo MDI (least squares mean [LSM] differences 54 mL, 62 mL, and 188 mL, respectively; all ≤0.0053), and peak FEV at Week 24 versus GP MDI, FF MDI, and placebo MDI (LSM differences 124 mL, 104 mL, and 307 mL, respectively; all <0.0001). Improvements over 24 weeks were comparable to at Week 24. The AE profile of GFF MDI in GOLD category A patients was similar to monocomponents and placebo MDI.

Conclusion: GFF MDI significantly improved lung function versus monocomponents and placebo MDI in GOLD category A patients with moderate-to-very severe COPD, with no unexpected safety findings.
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http://dx.doi.org/10.2147/COPD.S229794DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6957003PMC
February 2021

Efficacy And Safety Of Glycopyrrolate/Formoterol Fumarate Metered Dose Inhaler (GFF MDI) Formulated Using Co-Suspension Delivery Technology In Chinese Patients With COPD.

Int J Chron Obstruct Pulmon Dis 2020 8;15:43-56. Epub 2020 Jan 8.

AstraZeneca, Morristown, NJ, USA.

Background: Glycopyrrolate/formoterol fumarate metered dose inhaler (GFF MDI) is a long-acting muscarinic antagonist/long-acting β-agonist fixed-dose combination therapy delivered by MDI, formulated using innovative co-suspension delivery technology. The PINNACLE-4 study evaluated the efficacy and safety of GFF MDI in patients with moderate-to-very severe chronic obstructive pulmonary disease (COPD) from Asia, Europe, and the USA. This article presents the results from the China subpopulation of PINNACLE-4.

Methods: In this randomized, double-blind, placebo-controlled, parallel-group Phase III study (NCT02343458), patients received GFF MDI 18/9.6 µg, glycopyrrolate (GP) MDI 18 µg, formoterol fumarate (FF) MDI 9.6 µg, or placebo MDI (all twice daily) for 24 weeks. The primary endpoint was change from baseline in morning pre-dose trough forced expiratory volume in 1 second at Week 24. Secondary lung function endpoints and patient-reported outcome measures were also assessed. Safety was monitored throughout the study.

Results: Overall, 466 patients from China were included in the intent-to-treat population (mean age 63.6 years, 95.7% male). Treatment with GFF MDI improved the primary endpoint compared to GP MDI, FF MDI, and placebo MDI (least squares mean differences: 98, 104, and 173 mL, respectively; all 0.0001). GFF MDI also improved daily total symptom scores and time to first clinically important deterioration versus monocomponents and placebo MDI, and Transition Dyspnea Index focal score versus placebo MDI. Rates of treatment-emergent adverse events were similar across the active treatment groups and slightly higher in the placebo MDI group.

Conclusion: GFF MDI improved lung function and daily symptoms versus monocomponents and placebo MDI and improved dyspnea versus placebo MDI. All treatments were well tolerated with no unexpected safety findings. Efficacy and safety results were generally consistent with the global PINNACLE-4 population, supporting the use of GFF MDI in patients with COPD from China.
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http://dx.doi.org/10.2147/COPD.S223638DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6956867PMC
February 2021

Two-year integrated steroid-sparing analysis and safety of benralizumab for severe asthma.

J Asthma 2021 Apr 26;58(4):514-522. Epub 2019 Dec 26.

Research and Development, AstraZeneca, Gaithersburg, MD, USA.

Objective: Treatment with benralizumab significantly reduces exacerbations and improves lung function after 1 year and decreases oral corticosteroid (OCS) use after 28 weeks for patients with severe, uncontrolled eosinophilic asthma. We assessed whether these effects on OCS reduction are sustained for up to an additional year of treatment while maintaining an acceptable safety profile.

Methods: Data on OCS maintenance dosage were collected for adult patients with baseline blood eosinophil counts ≥150 cells/μL treated with add-on benralizumab 30 mg (every 4 [Q4W] or 8 weeks [Q8W; first three doses Q4W]) from the 28-week ZONDA study and were integrated with results from the predefined 56-week adult completion phase of the BORA extension study. Efficacy and safety were summarized descriptively.

Results: For patients receiving benralizumab Q8W, the median daily OCS dosage reduction of 75% from baseline to end of treatment achieved in ZONDA was sustained at the end of the BORA extension period (median 67% reduction from baseline). This was estimated to result in a median cumulative OCS dosage of 2.98 g over the 1.5-year period for patients receiving benralizumab Q8W compared with 5.74 g if these patients had remained on their baseline OCS dosages prior to benralizumab initiation. All adverse event rates were similar between the BORA extension and ZONDA periods, with no new or unexpected safety findings.

Conclusion: This benralizumab 1.5-year integrated analysis demonstrates that OCS reductions and safety were maintained with further follow up and supports long-term use of benralizumab for patients with severe, uncontrolled eosinophilic asthma.
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http://dx.doi.org/10.1080/02770903.2019.1705333DOI Listing
April 2021

Two-Year Integrated Efficacy And Safety Analysis Of Benralizumab In Severe Asthma.

J Asthma Allergy 2019 9;12:401-413. Epub 2019 Dec 9.

AstraZeneca, Gaithersburg, MD, United States.

Background: Benralizumab is an interleukin-5 receptor alpha-directed cytolytic monoclonal antibody. Treatment with benralizumab significantly reduces exacerbations and improves lung function after 1 year for patients with severe, uncontrolled eosinophilic asthma.

Objective: We explored whether benralizumab efficacy was sustained after an additional year of treatment while maintaining an acceptable safety profile.

Methods: Data from the pivotal 48-week SIROCCO and 56-week CALIMA studies were integrated with data from the predefined 56-week adult phase of the BORA extension study to provide a 2-year integrated efficacy and safety analysis of benralizumab. BORA enrolled patients who had completed SIROCCO or CALIMA. Patients receiving benralizumab 30 mg subcutaneously, either every 4 weeks (Q4W) or every 8 weeks (Q8W; first three doses Q4W), were assessed. Efficacy was evaluated based on baseline blood eosinophil counts from the pivotal studies (≥300 and <300 cells/μL).

Results: Mean treatment exposures were 24.3 (Q4W, n=518) and 24.6 (Q8W, n=512) months. Exacerbation frequency reductions observed in SIROCCO/CALIMA were maintained; 50% of the patients had no exacerbations during the 2-year study period (crude exacerbation rate, Q8W: 0.56 exacerbations/year for patients with blood eosinophil counts ≥300 cells/μL). Lung function improvements with benralizumab were maintained for 2 years, as represented by increases in mean prebronchodilator forced expiratory volume in 1 second from baseline of 0.343 L and 0.364 L with 1 and 2 years of benralizumab Q8W treatment, respectively, for patients with blood eosinophil counts ≥300 cells/μL. Health-related quality of life improvements with benralizumab observed in the pivotal studies were also sustained. Adverse events and serious adverse event rates were similar between the BORA extension and SIROCCO/CALIMA periods, with no new or unexpected occurrence of adverse events.

Conclusion: This benralizumab 2-year integrated analysis further supports long-term use of benralizumab for patients with severe, uncontrolled eosinophilic asthma.
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http://dx.doi.org/10.2147/JAA.S227170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6910092PMC
December 2019

Single-Use Autoinjector Functionality And Reliability For At-Home Administration Of Benralizumab For Patients With Severe Asthma: GRECO Trial Results.

J Asthma Allergy 2019 23;12:363-373. Epub 2019 Oct 23.

AstraZeneca, Gaithersburg, MD, USA.

Purpose: Accessorized prefilled syringes (APFS) have demonstrated functionality and reliability for subcutaneous (SC) delivery, including self-administration, of benralizumab 30 mg in the clinic or at home. The multicenter, open-label GRECO study (NCT02918071) assessed functionality and reliability of a single-use autoinjector (AI) for at-home benralizumab administration by patients or their caregivers.

Patients And Methods: Adults with severe asthma received benralizumab SC injections at the study site at Weeks 0, 4, and 8. The first dose was administered by health care providers. Patients/caregivers had the option of administering the second dose and were required to administer the third dose under supervision. At Weeks 12 and 16, patients/caregivers administered benralizumab via AI at home. After each administration, patients/caregivers completed questionnaires concerning administration and device functioning. All AI devices used were returned for evaluation.

Results: A total of 595 AIs were used for 121 patients (mean age 48.5 years; 64% female) in the clinic and at home. Of 116 participants, 113 (97.4%; 95% confidence interval [CI]: 92.63-99.46) and 112 (96.6%; 95% CI: 91.41-99.05) successfully administered benralizumab at home at Weeks 12 and 16, respectively; 108 (93.1%; 95% CI: 86.86-96.98) were successful on both occasions. Throughout the study, 10 (1.7%) AI administrations were unsuccessful: 8 (1.3%) because of user error, 1 (0.2%) with undetermined cause, and 1 (0.2%) because of a manufacturing defect. Benralizumab efficacy (assessed by Asthma Control Questionnaire 6 score) and pharmacokinetics for patients using the AI were comparable to published results for patients receiving benralizumab via syringe in a clinical setting. No new or unexpected safety findings were observed.

Conclusion: AIs were functional, reliable, and performed well in the clinic and at home. Nearly all patients and caregivers successfully administered SC benralizumab via AI. Benralizumab availability in AI and APFS could provide patients with choices for self-administration.
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http://dx.doi.org/10.2147/JAA.S224266DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6815754PMC
October 2019

Corticosteroid tapering with benralizumab treatment for eosinophilic asthma: PONENTE Trial.

ERJ Open Res 2019 Jul 25;5(3). Epub 2019 Sep 25.

AstraZeneca, Barcelona, Spain.

Benralizumab is an interleukin-5 receptor α-directed cytolytic monoclonal antibody approved in several countries for the add-on maintenance treatment of patients with severe eosinophilic asthma aged 12 years and older. In the 28-week Phase III ZONDA trial (ClinicalTrials.gov identifier: NCT02075255), benralizumab produced a median 75% reduction from baseline in oral corticosteroid (OCS) dosage ( 25% for placebo) while maintaining asthma control for patients with OCS-dependent severe asthma. This manuscript presents the detailed protocol for the Phase IIIb PONENTE (ClinicalTrials.gov identifier: NCT03557307), a study that will build on the findings from ZONDA. As the largest steroid-sparing study undertaken in severe asthma, PONENTE has a faster steroid tapering schedule for prednisone dosages ≥7.5 mg·day than previous studies, and it includes an evaluation of adrenal insufficiency and an algorithm to taper OCS dosage when prednisone dosage is ≤5 mg·day. It also has a longer maintenance phase to assess asthma control for up to 6 months after completion of OCS tapering. The two primary endpoints are whether patients achieve 100% reduction in daily OCS use and whether patients achieve 100% reduction in daily OCS or achieve OCS dosage ≤5 mg·day, if adrenal insufficiency prevented further reduction, both sustained over ≥4 weeks without worsening of asthma. Safety and change from baseline in health-related quality of life will also be assessed. PONENTE should provide valuable guidance for clinicians on tapering OCS dosage, including the management of adrenal insufficiency, following benralizumab initiation for the treatment of patients who are OCS-dependent with severe, uncontrolled eosinophilic asthma.
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http://dx.doi.org/10.1183/23120541.00009-2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6759576PMC
July 2019

Predicting response to benralizumab in chronic obstructive pulmonary disease: analyses of GALATHEA and TERRANOVA studies.

Lancet Respir Med 2020 02 28;8(2):158-170. Epub 2019 Sep 28.

AstraZeneca, Gaithersburg, MD, USA.

Background: Benralizumab did not significantly reduce exacerbations compared with placebo in the phase 3 GALATHEA and TERRANOVA trials of benralizumab for patients with chronic obstructive pulmonary disease (COPD). We aimed to identify clinical and physiological characteristics of patients with COPD that could help to identify people who are likely to have the greatest treatment effect with benralizumab.

Methods: We analysed individual study and pooled results from GALATHEA and TERRANOVA. At study enrolment, patients from GALATHEA and TERRANOVA were aged 40-85 years, had moderate to very severe airflow limitation, had elevated blood eosinophil counts, and at least two exacerbations or one severe exacerbation in the previous year despite dual inhaled therapy (inhaled corticosteroids plus long-acting β-agonists or long-acting β-agonists plus long-acting muscarinic antagonists) or triple inhaled therapy (inhaled corticosteroids plus long-acting β-agonists plus long-acting muscarinic antagonists). We analysed data for 3910 patients who received benralizumab (30 mg or 100 mg subcutaneously every 8 weeks; first three doses every 4 weeks) or placebo with dual or triple therapy to identify factors consistently associated with annual exacerbation rate reduction. We evaluated the annual exacerbation rate for benralizumab versus placebo as the primary endpoint. GALATHEA and TERRANOVA are registered with ClinicalTrials.gov, NCT02138916 and NCT02155660, respectively.

Findings: For 2665 patients with elevated blood eosinophil counts, treatment effect with benralizumab every 8 weeks at 100 mg, but not at 30 mg, occurred for patients with a history of more frequent exacerbations, poorer baseline lung function, or greater baseline lung function improvement with short-acting bronchodilators. Patients with baseline blood eosinophil counts of 220 cells per μL or greater with: three or more exacerbations in the previous year receiving benralizumab every 8 weeks versus placebo, had rate ratios (RRs) of 0·69 (95% CI 0·56-0·83) for 100 mg and 0·86 (0·71-1·04) for 30 mg; postbronchodilator FEV of less than 40% had RRs of 0·76 (0·64-0·91) for 100 mg and 0·90 (0·76-1·06) for 30 mg; and postbronchodilator response of at least 15% had RRs of 0·67 (0·54-0·83) for 100 mg and 0·87 (0·71-1·07) for 30 mg. When combined factors were examined, patients with elevated baseline blood eosinophil counts, with three or more exacerbations in the previous year, and who were receiving triple therapy were identified as likely to benefit from benralizumab 100 mg every 8 weeks versus placebo (RR 0·70 [95% CI 0·56-0·88]). Benralizumab 30 mg every 8 weeks did not benefit patients meeting these criteria compared with placebo (RR 0·99 [95% CI 0·79-1·23]).

Interpretation: Elevated blood eosinophil counts combined with clinical characteristics identified a subpopulation of patients with COPD who had reductions in exacerbations with benralizumab treatment. These hypothesis-generating analyses identified the potential efficacy of benralizumab 100 mg for this subpopulation. These findings require prospective evaluation in clinical trials.

Funding: AstraZeneca.
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http://dx.doi.org/10.1016/S2213-2600(19)30338-8DOI Listing
February 2020

Comparison of autoinjector with accessorized prefilled syringe for benralizumab pharmacokinetic exposure: AMES trial results.

J Asthma 2021 Jan 20;58(1):93-101. Epub 2019 Sep 20.

AstraZeneca, Gaithersburg, MD, USA.

Objective: We compared the pharmacokinetic exposure following a single subcutaneous dose of benralizumab 30 mg using either autoinjectors (AI) or accessorized prefilled syringes (APFS). APFS and AI functionality and reliability for at-home benralizumab delivery have been demonstrated in the GREGALE and GRECO studies, respectively.

Methods: In the open-label AMES study (NCT02968914), 180 healthy adult men and women were randomized to one of two device (AI or APFS) and three injection site (upper arm, abdomen, or thigh) combinations. Randomization was stratified by weight (<70 kg, 70-84.9 kg, and ≥85 kg). Blood eosinophil counts were measured on Days 1, 8, 29, and 57.

Results: Benralizumab pharmacokinetic exposure was similar between AI and APFS. Geometric mean ratios (AI/APFS) (90% CI) were 92.8% (87.4-98.6) and 94.5% (88.2-101.2) for two area under the concentration‒time curve measurements (AUC and AUC). Benralizumab exposure was approximately 15-30% greater for thigh vs. abdomen or upper arm administration. Exposure was slightly greater for APFS vs. AI regardless of injection site or weight class. These differences were unlikely to be clinically relevant, as eosinophil depletion was achieved consistently with both devices at all injection sites. No device malfunctions were reported. No new or unexpected safety findings were observed.

Conclusion: Benralizumab pharmacokinetic exposure was similar between AI and APFS, with consistent blood eosinophil count depletion observed with both devices. These results support benralizumab administration with either AI or APFS, providing patients and physicians increased choice, flexibility, and convenience for potential at-home delivery.
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http://dx.doi.org/10.1080/02770903.2019.1663428DOI Listing
January 2021

A Randomized, Double-Blind, Double-Dummy Study of Glycopyrrolate/Formoterol Fumarate Metered Dose Inhaler Relative to Umeclidinium/Vilanterol Dry Powder Inhaler in COPD.

Adv Ther 2019 09 2;36(9):2434-2449. Epub 2019 Jul 2.

AstraZeneca, Gaithersburg, MD, USA.

Introduction: Glycopyrrolate/formoterol fumarate metered dose inhaler (GFF MDI), formulated using co-suspension delivery technology, is the only approved fixed-dose combination long-acting muscarinic antagonist/long-acting β-agonist (LAMA/LABA) delivered via MDI. Direct comparisons of GFF MDI versus other LAMA/LABAs have not previously been performed. We assessed the efficacy and safety of GFF MDI relative to umeclidinium/vilanterol dry powder inhaler (UV DPI) in patients with moderate-to-very severe chronic obstructive pulmonary disease (COPD).

Methods: In this phase IIIb randomized, double-blind, double-dummy, multicenter, 24-week study, patients received GFF MDI 18/9.6 μg (equivalent to glycopyrronium/formoterol fumarate dihydrate 14.4/10 μg; two inhalations per dose, twice-daily; n = 559) or UV DPI 62.5/25 μg (one inhalation, once-daily; n = 560). Primary endpoints were change from baseline in morning pre-dose trough forced expiratory volume in 1 s (FEV) and peak change from baseline in FEV within 2 h post-dose, both over 24 weeks. Additional lung function, symptom and safety endpoints were also assessed.

Results: For the primary endpoints, GFF MDI was non-inferior to UV DPI (using a margin of - 50 mL) for peak FEV (least squares mean [LSM] difference - 3.4 mL, 97.5% confidence interval [CI] - 32.8, 25.9) but not for trough FEV (LSM difference - 87.2 mL; - 117.0, - 57.4). GFF MDI was nominally superior to UV DPI for onset of action (p < 0.0001) and was nominally non-inferior to UV DPI for all symptom endpoints (Transition Dyspnea Index focal score, Early Morning/Night-Time Symptoms COPD instrument scores, and COPD Assessment Test score). Exacerbation and safety findings were similar between groups.

Conclusions: Over 24 weeks of treatment, GFF MDI was non-inferior to UV DPI for peak FEV, but not for morning pre-dose trough FEV. GFF MDI had a faster onset of action versus UV DPI. There were no clinically meaningful differences between treatments in symptom endpoints. Both treatments were well tolerated with similar safety profiles.

Trial Registration: NCT03162055 (Clinicaltrials.gov) FUNDING: AstraZeneca.
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http://dx.doi.org/10.1007/s12325-019-01015-3DOI Listing
September 2019

Benralizumab for the Prevention of COPD Exacerbations.

N Engl J Med 2019 09 20;381(11):1023-1034. Epub 2019 May 20.

From the Department of Thoracic Medicine and Surgery, Lewis Katz School of Medicine, Temple University, Philadelphia (G.J.C.); Pulmonary and Critical Care Division, Brigham and Women's Hospital, Harvard Medical School, Boston (B.R.C.); the Institute for Lung Health, Leicester National Institute for Health Research Biomedical Research Centre, Department of Respiratory Sciences, University of Leicester, Leicester (C.E.B.), the University of Manchester, Manchester University NHS Hospital Trust, Manchester (D.S.), and the Respiratory Medicine Unit, Nuffield Department of Medicine, University of Oxford, Oxford (M.B.) - all in the United Kingdom; Respiratory Institute, Hospital Clinic, University of Barcelona, Institut D'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red (CIBER) Enfermedades Respiratorias, Barcelona (A.A.); the Department of Medical Sciences, University of Ferrara, Ferrara, Italy (A.P.); the Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, BC, Canada (D.D.S.); the Department of Medicine, Pulmonary and Critical Care Medicine, University Medical Center Giessen and Marburg, Philipps-Universität Marburg, German Center for Lung Research (DZL), Marburg, Germany (C.F.V.); University of Pittsburgh School of Medicine, Pittsburgh (F.C.S.); the Department of Respiratory Medicine, Bispebjerg University Hospital, Copenhagen (V.B.); Kishiwada City Hospital, Osaka, Japan (M.K.); the Departamento de Investigación en Tabaquismo y EPOC, Instituto Nacional de Enfermedades Respiratorias, Ismael Cosio Villegas, Mexico City (A.R.-V.); the Division of Respiratory and Chest Medicine, E-Da Hospital and I-Shou University, Kaohsiung, Taiwan (Y.-F.W.); the Department of Respiratory Medicine and Allergology, Skane University Hospital, Lund University, Lund, Sweden (L.B.); and AstraZeneca, Gaithersburg, MD (V.H.S., M.J., S.O., N.M., P.N., M.G., U.J.M.).

Background: The efficacy and safety of benralizumab, an interleukin-5 receptor alpha-directed cytolytic monoclonal antibody, for the prevention of exacerbations in patients with moderate to very severe chronic obstructive pulmonary disease (COPD) are not known.

Methods: In the GALATHEA and TERRANOVA trials, we enrolled patients with COPD (at a ratio of approximately 2:1 on the basis of eosinophil count [≥220 per cubic millimeter vs. <220 per cubic millimeter]) who had frequent exacerbations despite receiving guideline-based inhaled treatment. Patients were randomly assigned to receive benralizumab (30 or 100 mg in GALATHEA; 10, 30, or 100 mg in TERRANOVA) every 8 weeks (every 4 weeks for the first three doses) or placebo. The primary end point was the treatment effect of benralizumab, measured as the annualized COPD exacerbation rate ratio (benralizumab vs. placebo) at week 56 in patients with baseline blood eosinophil counts of 220 per cubic millimeter or greater. Safety was also assessed.

Results: In GALATHEA, the estimates of the annualized exacerbation rate were 1.19 per year (95% confidence interval [CI], 1.04 to 1.36) in the 30-mg benralizumab group, 1.03 per year (95% CI, 0.90 to 1.19) in the 100-mg benralizumab group, and 1.24 per year (95% CI, 1.08 to 1.42) in the placebo group; the rate ratio as compared with placebo was 0.96 for 30 mg of benralizumab (P = 0.65) and 0.83 for 100 mg of benralizumab (P = 0.05). In TERRANOVA, the estimates of the annualized exacerbation rate for 10 mg, 30 mg, and 100 mg of benralizumab and for placebo were 0.99 per year (95% CI, 0.87 to 1.13), 1.21 per year (95% CI, 1.08 to 1.37), 1.09 per year (95% CI, 0.96 to 1.23), and 1.17 per year (95% CI, 1.04 to 1.32), respectively; the corresponding rate ratios were 0.85 (P = 0.06), 1.04 (P = 0.66), and 0.93 (P = 0.40). At 56 weeks, none of the annualized COPD exacerbation rate ratios for any dose of benralizumab as compared with placebo reached significance in either trial. Types and frequencies of adverse events were similar with benralizumab and placebo.

Conclusions: Add-on benralizumab was not associated with a lower annualized rate of COPD exacerbations than placebo among patients with moderate to very severe COPD, a history of frequent moderate or severe exacerbations, and blood eosinophil counts of 220 per cubic millimeter or greater (Funded by AstraZeneca [GALATHEA and TERRANOVA] and Kyowa Hakko Kirin [GALATHEA]; GALATHEA and TERRANOVA ClinicalTrials.gov numbers, NCT02138916 and NCT02155660.).
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http://dx.doi.org/10.1056/NEJMoa1905248DOI Listing
September 2019

Long-term safety and efficacy of benralizumab in patients with severe, uncontrolled asthma: 1-year results from the BORA phase 3 extension trial.

Lancet Respir Med 2019 01 8;7(1):46-59. Epub 2018 Nov 8.

AstraZeneca, Gaithersburg, MD, USA.

Background: Benralizumab is an interleukin-5 receptor α-directed cytolytic monoclonal antibody that has been shown to safely reduce exacerbations and improve lung function for patients with asthma. We assessed the long-term safety and efficacy of benralizumab for patients with severe, uncontrolled eosinophilic asthma.

Methods: We conducted a randomised, double-blind, parallel-group, phase 3 extension study at 447 sites in 24 countries. Eligible patients had to have completed the SIROCCO or CALIMA trials and remained on subcutaneous benralizumab 30 mg every 4 weeks (Q4W) or every 8 weeks (Q8W). Patients who had received placebo in those trials were re-randomised in a 1:1 ratio, using an interactive web-based system, to benralizumab 30 mg either Q4W or Q8W (first three doses 4 weeks apart). Treatment lasted for 56 weeks for adult patients (age ≥18 years) and 108 weeks for adolescent patients (age 12-17 years). The primary endpoint was the safety and tolerability of the two dosing regimens of benralizumab up to 68 weeks for adult patients (including the follow-up visit post-treatment) and up to 56 weeks for adolescent patients. This endpoint was assessed in the full analysis set, which included all patients from the SIROCCO and CALIMA predecessor studies who received at least one dose of study treatment in BORA and did not continue into another trial. This study is registered with ClinicalTrials.gov (NCT02258542).

Findings: Between Nov 19, 2014, and July 6, 2016, we enrolled 1926 patients, of whom 633 had received benralizumab Q4W and 639 had received benralizumab Q8W in SIROCCO or CALIMA. The remaining 654 patients had received placebo in those trials and were randomly re-assigned in this trial to receive benralizumab Q4W (n=320) or Q8W (n=334). 1576 patients, including 783 who received benralizumab Q4W (265 newly assigned) and 793 who received benralizumab Q8W (281 newly assigned), were included in the full analysis set. The most common adverse events in all groups were viral upper respiratory tract infection (14-16%) and worsening asthma (7-10%). The most common serious adverse events were worsening asthma (3-4%), pneumonia (<1% to 1%), and pneumonia caused by bacterial infection (0-1%). The percentages of patients who had any on-treatment adverse event, any serious adverse event, or any adverse event leading to treatment discontinuation during BORA were similar between patients originally assigned benralizumab and those originally assigned placebo and between benralizumab treatment regimens. The percentage of patients who had any adverse event was similar between SIROCCO or CALIMA (71-75%; benralizumab group only) and BORA (65-71%), as was the percentage of patients who had an adverse event that led to treatment discontinuation (2% in SIROCCO and CALIMA vs 2-3% in BORA).

Interpretation: The 2 years of safety results validate that observations observed in the first year of benralizumab continued through a second year of treatment. No new consequences of long-term eosinophil depletion occurred, and the incidence of other adverse events, including opportunistic infections, were similar during the second year.

Funding: AstraZeneca and Kyowa Hakko Kirin.
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http://dx.doi.org/10.1016/S2213-2600(18)30406-5DOI Listing
January 2019

Improved lung function and patient-reported outcomes with co-suspension delivery technology glycopyrrolate/formoterol fumarate metered dose inhaler in COPD: a randomized Phase III study conducted in Asia, Europe, and the USA.

Int J Chron Obstruct Pulmon Dis 2018;13:2969-2984. Epub 2018 Sep 26.

AstraZeneca, Gaithersburg, MD, USA.

Background: COPD is a major global cause of mortality and morbidity. PINNACLE-4 evaluated the efficacy and safety of GFF MDI (glycopyrrolate/formoterol fumarate metered dose inhaler) in patients from Asia, Europe, and the USA with moderate-to-very severe COPD.

Methods: In this double-blind, placebo-controlled, Phase III study, patients were randomized to treatment with GFF MDI 18/9.6 μg, glycopyrrolate (GP) MDI 18 μg, formoterol fumarate (FF) MDI 9.6 μg, or placebo MDI (all twice daily) for 24 weeks. Lung function, patient-reported outcomes (symptoms and health-related quality of life), and safety were assessed.

Results: Of the 1,756 patients randomized, 1,740 patients were included in the intent-to-treat population (mean age 64.2 years, 74.1% male, and 40.2% Asian). GFF MDI significantly improved morning predose trough FEV at Week 24 (primary endpoint) vs placebo MDI, GP MDI, and FF MDI (least squares mean differences: 165, 59, and 72 mL, respectively; all <0.0001). GFF MDI also significantly improved other lung function endpoints vs placebo MDI, GP MDI, and FF MDI and patient-reported outcomes vs placebo MDI and GP MDI. A larger proportion of patients treated with GFF MDI achieved the minimum clinically important difference in Transition Dyspnea Index score vs GP MDI and placebo MDI and in St George's Respiratory Questionnaire score vs placebo MDI. Adverse event rates were similar across treatment groups.

Conclusion: These results demonstrated the efficacy of GFF MDI in patients with moderate-to-very severe COPD. GFF MDI was well tolerated, with a safety profile commensurate with long-acting bronchodilators.
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http://dx.doi.org/10.2147/COPD.S171835DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6167125PMC
March 2019

Pharmacokinetics and safety of a single dose of the novel LAMA/LABA fixed-dose combination of glycopyrronium/formoterol fumarate dihydrate metered dose inhaler, formulated using co-suspension delivery technology, in Japanese healthy subjects.

Pulm Pharmacol Ther 2018 12 13;53:33-38. Epub 2018 Sep 13.

AstraZeneca, One MedImmune Way, Gaithersburg, MD, 20878, USA. Electronic address:

Background: Chronic obstructive pulmonary disease (COPD) causes significant mortality in Japan. GFF MDI is a long-acting muscarinic antagonist/long-acting β-agonist fixed-dose combination of glycopyrronium (GP) and formoterol fumarate dihydrate (FF), delivered by a metered dose inhaler (MDI) using co-suspension delivery technology, for the long-term maintenance treatment of COPD.

Methods: This randomized, Phase I, single-dose, four-treatment, four-period, crossover study (NCT02196714) examined the pharmacokinetic (PK) and safety profile of two doses of GFF MDI (28.8 μg/10 μg and 14.4 μg/10 μg) and two doses of GP MDI (28.8 μg and 14.4 μg), both formulated using co-suspension delivery technology, in healthy Japanese subjects (18-45 years of age). PK parameters included area under the curve (AUC) from 0 to 12 h (AUC), AUC from 0 to the time of the last measurable plasma concentration, maximum observed plasma concentration (C), and time to C. Safety was monitored throughout the study.

Results: Plasma GP profiles were comparable between GFF MDI and GP MDI formulations containing the same GP dose. Increases in GP AUC and C were generally dose proportional from 14.4 to 28.8 μg after administration of either formulation.

Conclusions: The addition of FF 10 μg to GP MDI 28.8 μg or 14.4 μg in a fixed-dose combination did not appreciably alter the PK of GP, nor did an increase in GP dose from 14.4 μg to 28.8 μg in a fixed-dose combination with FF 10 μg appreciably alter the PK of formoterol. Both formulations of GFF MDI and GP MDI were well tolerated in healthy Japanese subjects. Data from this study support further evaluation of GFF MDI in Japanese patients with COPD.
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http://dx.doi.org/10.1016/j.pupt.2018.09.005DOI Listing
December 2018

A randomized study using functional respiratory imaging to characterize bronchodilator effects of glycopyrrolate/formoterol fumarate delivered by a metered dose inhaler using co-suspension delivery technology in patients with COPD.

Int J Chron Obstruct Pulmon Dis 2018 30;13:2673-2684. Epub 2018 Aug 30.

AstraZeneca, Gaithersburg, MD, USA.

Background: Functional respiratory imaging (FRI) uses high-resolution computed tomography (HRCT) scans to assess changes in airway volume and resistance.

Patients And Methods: In this randomized, double-blind, 2-week, crossover, Phase IIIB study, patients with moderate-to-severe COPD received twice-daily glycopyrrolate/formoterol fumarate delivered by a metered dose inhaler (GFF MDI, 18/9.6 μg) and placebo MDI, formulated using innovative co-suspension delivery technology. Co-primary endpoints included the following: specific image-based airway volume (siVaw) and specific image-based airway resistance (siRaw) at Day 15, measured using FRI. Secondary and other endpoints included the following: change from baseline in post-dose forced expiratory volume in 1 second (FEV) and inspiratory capacity (IC; spirometry) and ratio to baseline in post-dose functional residual capacity (FRC) and residual volume (RV; body plethysmography).

Results: Twenty patients (46-78 years of age) were randomized and treated; of whom 19 completed the study. GFF MDI treatment increased siVaw by 75% and reduced siRaw by 71% vs placebo MDI (both <0.0001). Image-based airway volume (iVaw) and image-based airway resistance (iRaw), without adjusting for lobe volume, demonstrated corresponding findings to the co-primary endpoint, as lobe volumes did not change with either treatment. Approximately 48% of the delivered dose of glycopyrronium and formoterol fumarate was estimated to be deposited in the lungs. Compared with placebo, GFF MDI treatment improved post-dose FEV and IC (443 mL and 454 mL, respectively; both <0.001) and reduced FRC and RV (13% and 22%, respectively; both <0.0001). There were no significant safety findings.

Conclusion: GFF MDI demonstrated significant, clinically meaningful benefits on FRI-based airway volume and resistance in patients with moderate-to-severe COPD. Benefits were associated with improvements in FEV, IC, and hyperinflation.

Clinical Trial Registration: ClinicalTrials.gov: NCT02643082.
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http://dx.doi.org/10.2147/COPD.S171707DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6124470PMC
January 2019

Inhaler usability of a pressurized metered dose inhaler and a soft mist inhaler in patients with COPD: A simulated-use study.

Chron Respir Dis 2019 Jan-Dec;16:1479972318787914. Epub 2018 Jul 17.

2 AstraZeneca, Gaithersburg, MD, USA.

The objective of this study was to evaluate task performance and handling errors with soft mist inhalers (SMIs) or pressurized metered-dose inhalers (pMDIs) among patients with chronic obstructive pulmonary disease (COPD) experienced with, but not recently trained in, using these devices. This exploratory, noninterventional, simulated-use study (D5970R00004) assessed handling/usability of SMIs and pMDIs in inhaler-experienced patients with COPD (40-78 years; diagnosis ≥6 months). Patients received a device and instruction-for-use leaflet but no training and were recorded while performing tasks required for checking the device, priming, and dosing. Errors that could substantially affect the lung-delivered dose were considered critical. Sixteen of 61 patients (52% male) had used SMIs and 55 had used pMDIs. Thirty-one patients received an SMI and 30 a pMDI. Overall, 79% made ≥5 performance errors (SMI 94%; pMDI 63%) and 49% made ≥5 critical errors (SMI 68%; pMDI 30%). All patients made ≥1 error; three (all pMDI) made no critical errors. Regardless of the device used and previous inhaler experience, patient-centered training, education, and continuous retraining on correct inhaler use should be key aspects of routine patient care in COPD.
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http://dx.doi.org/10.1177/1479972318787914DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6302969PMC
June 2020

Randomized study of the effects of Aerochamber Plus Flow-Vu on the efficacy, pharmacokinetics and safety of glycopyrronium/formoterol fumarate dihydrate metered dose inhaler in patients with chronic obstructive pulmonary disease.

Respir Med 2018 05 30;138:74-80. Epub 2018 Mar 30.

AstraZeneca, Gaithersburg, MD, USA.

Objectives: This study compared the efficacy, pharmacokinetics (PK), and safety of GFF MDI (Bevespi Aerosphere), a fixed-dose combination of glycopyrronium and formoterol fumarate dihydrate (14.4/10 μg) delivered by a metered dose inhaler (MDI) formulated using innovative co-suspension delivery technology, in patients with moderate-to-very severe chronic obstructive pulmonary disease (COPD) with and without the Aerochamber Plus Flow-Vu valved holding chamber (VHC).

Methods: In this multicenter, open-label, crossover, Phase III study (NCT02454959), patients were randomized to receive GFF MDI 14.4/10 μg (equivalent to glycopyrrolate/formoterol fumarate 18/9.6 μg) twice daily for 7 days with and without the VHC. The primary endpoint was forced expiratory volume in 1 s area under the curve from 0 to 12 h (FEV AUC) on Day 8. Steady state PK parameters for glycopyrronium and formoterol (AUC, peak concentration [C] and time to peak concentration [t]) were estimated from 12-h plasma concentration time data on Day 8. Safety and tolerability were also assessed throughout.

Results: Eighty patients were randomized. On Day 8, the ratio (90% confidence interval [CI]) of least squares mean (LSM) FEV AUC for GFF MDI with VHC (LSM = 1538 mL; n = 67) versus without VHC (LSM = 1516 mL; n = 68) was 101.4% (100.1, 102.7). PK parameters were comparable overall with a slightly higher exposure to glycopyrronium with the VHC. The AUC geometric LSM ratio (90% CI) for GFF MDI with versus without VHC was 115.99% (99.74, 134.89) for glycopyrronium and 96.66% (86.69, 107.78) for formoterol. GFF MDI with and without VHC were well tolerated with a similar adverse event profile.

Conclusions: The magnitude of bronchodilatory effect was similar with and without a VHC following GFF MDI treatment. This, together with the PK and safety profiles, supports the use of the VHC with GFF MDI for the maintenance treatment of COPD, which could be particularly useful for patients who have difficulty with the coordination of an MDI.
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http://dx.doi.org/10.1016/j.rmed.2018.03.033DOI Listing
May 2018

Pharmacokinetics of glycopyrronium/formoterol fumarate dihydrate delivered via metered dose inhaler using co-suspension delivery technology in patients with moderate-to-very severe COPD.

Int J Chron Obstruct Pulmon Dis 2018 21;13:945-953. Epub 2018 Mar 21.

AstraZeneca, Gaithersburg, MD, USA.

Purpose: The efficacy and tolerability of GFF MDI (Bevespi Aerosphere), a fixed-dose combination of glycopyrronium (GP)/formoterol fumarate dihydrate (FF) 14.4/10 μg (equivalent to glycopyrrolate/formoterol fumarate 18/9.6 μg) delivered by metered dose inhaler (MDI) using innovative co-suspension delivery technology, has been investigated in a Phase III clinical trial program (NCT01854645, NCT01854658, NCT01970878) in patients with COPD. Here, we present findings from a pharmacokinetic (PK) sub-study of NCT01854645 (PINNACLE-1).

Methods: PINNACLE-1 was a multicenter, randomized, double-blind, parallel-group, 24 wk chronic-dosing, placebo- and active-controlled study. The PK sub-study assessed the systemic accumulation of glycopyrronium and formoterol following administration of GFF MDI 14.4/10 μg, GP MDI 14.4 μg, or FF MDI 10 μg (all BID) for 12 wks. Plasma for PK analysis was collected for up to 12 h after dosing, on Day 1 and Week 12.

Results: Of 2,103 patients randomized in PINNACLE-1, 292 participated in the PK sub-study. The plasma concentration-time profiles of glycopyrronium were similar following treatment with GFF MDI or GP MDI, both after single dosing and at Week 12. Accumulation at Week 12 relative to Day 1 was up to 2.30-fold for glycopyrronium. The plasma concentration-time profiles of formoterol were similar following treatment with GFF MDI or FF MDI, both after single dosing and at Week 12. Accumulation at Week 12 relative to Day 1 was up to 1.62-fold for formoterol.

Conclusion: Overall, the results have characterized the accumulation of glycopyrronium and formoterol associated with GFF MDI, GP MDI, and FF MDI, and indicated that there were no meaningful PK interactions, whether drug-drug or due to formulation, between glycopyrronium and formoterol following treatment with GFF MDI formulated using co-suspension delivery technology.
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http://dx.doi.org/10.2147/COPD.S154988DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5868634PMC
October 2018

Cardiovascular safety profile of a fixed-dose combination of glycopyrrolate and formoterol fumarate delivered via metered dose inhaler using co-suspension delivery technology.

Pulm Pharmacol Ther 2018 04 4;49:67-74. Epub 2018 Feb 4.

AstraZeneca, One MedImmune Way, Gaithersburg, MD 20878, USA. Electronic address:

Background: Glycopyrrolate/formoterol fumarate (GFF) metered dose inhaler (MDI) is a fixed-dose combination of the long-acting muscarinic antagonist (LAMA), glycopyrrolate (GP), and the long-acting β-agonist (LABA), formoterol fumarate (FF), delivered via metered dose inhaler using innovative co-suspension delivery technology. Here we report the results of two studies that examined the cardiovascular safety of GFF MDI.

Methods: The thorough QT (TQT) study was a Phase I, randomized, double-blind, single-dose, crossover study to assess GFF MDI 18/9.6 (Bevespi Aerosphere), GFF MDI 144/38.4 and GP MDI 144 μg, compared with placebo MDI and open-label moxifloxacin 400 mg (active control) in healthy volunteers (PT003009). The cardiovascular safety study in patients with chronic obstructive pulmonary disease (COPD) was a Phase IIb, randomized, multicenter, double-blind, 14-day dosing, parallel-group study to evaluate GFF MDI 36/9.6, GP MDI 36 and FF MDI 9.6 μg compared with open-label FF dry powder inhaler (DPI; Foradil Aerolizer) 12 μg, in patients with moderate-to-severe COPD (PT003003 [NCT01349803]).

Results: Seventy healthy volunteers were randomized in the TQT study. GFF MDI 144/38.4, GFF MDI 18/9.6 and GP MDI 144 μg all met the confidence interval-based criteria for negative QT prolongation potential. In the study in patients with COPD, 237 subjects were randomized and treated. GFF MDI 36/9.6, GP MDI 36, and FF MDI 9.6 μg did not result in clinically meaningful changes from baseline in 24-h mean heart rate at Day 14 (primary endpoint) or in any of the other Holter monitoring endpoints at Day 14, compared with FF DPI 12 μg.

Conclusions: No clinically significant effects on cardiovascular safety occurred at therapeutic or supratherapeutic doses of GFF MDI, apart from a small and transient increase in heart rate following supratherapeutic dose of GFF MDI 144/38.4 μg. Furthermore, there were no unexpected safety findings reported in either healthy volunteers or patients with COPD.
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http://dx.doi.org/10.1016/j.pupt.2018.01.007DOI Listing
April 2018

Gamma scintigraphic pulmonary deposition study of glycopyrronium/formoterol metered dose inhaler formulated using co-suspension delivery technology.

Eur J Pharm Sci 2018 Jan 18;111:450-457. Epub 2017 Oct 18.

National Heart and Lung Institute (NHLI), Imperial College London, Royal Brompton Hospital, London, UK.

This gamma scintigraphy imaging study was the first to assess pulmonary and extrathoracic deposition and regional lung deposition patterns of a radiolabelled long-acting muscarinic antagonist/long-acting β-agonist fixed-dose combination glycopyrronium/formoterol fumarate dihydrate (GFF) 14.4/10μg (equivalent to glycopyrrolate/formoterol fumarate 18/9.6μg), delivered by pressurized metered dose inhaler (pMDI) using novel co-suspension delivery technology. In this Phase I, randomized, single-centre, single-blind, single-dose, two-treatment, crossover, placebo-controlled study (PT003020), 10 healthy male adults received two actuations of GFF pMDI (7.2/5.0μg per actuation) and placebo pMDI (containing phospholipid-based porous particles without active pharmaceutical ingredient), both radiolabelled with Tc, up to 5MBq per actuation. Gamma scintigraphy images of lungs, stomach, head and neck were recorded. In addition, images of the actuators after use, collected mouth washings and exhalation filters were acquired. On average, 38.4% of the emitted dose of radiolabelled GFF pMDI, and 32.8% of radiolabelled placebo pMDI, was deposited in the lungs. The percentage emitted dose detected in the oropharyngeal and stomach regions was 61.4% and 66.9% for radiolabelled GFF pMDI and placebo pMDI, respectively. For both treatments, ≤0.25% of the emitted dose was detected in the exhalation filter. The normalized outer/inner ratio was 0.57 and 0.59 for radiolabelled GFF pMDI and placebo pMDI, respectively, and the standardized central/peripheral ratio was 1.85 and 1.94 respectively, indicating delivery of both co-suspension delivery technology formulations throughout the airways. There were no new or unexpected safety findings. In conclusion, both formulations were efficiently and uniformly deposited in the lungs with similar regional deposition patterns, oropharyngeal and stomach deposition, exhalation fraction and actuator-recovered dose.
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http://dx.doi.org/10.1016/j.ejps.2017.10.026DOI Listing
January 2018

Baseline Symptom Score Impact on Benefits of Glycopyrrolate/Formoterol Metered Dose Inhaler in COPD.

Chest 2017 12 16;152(6):1169-1178. Epub 2017 Jul 16.

Clinical Development and Medical Affairs, Pearl Therapeutics, Inc, Morristown, NJ; and Respiratory Global Medicines, AstraZeneca, Gaithersburg, MD.

Background: The clinical severity of COPD is currently categorized by symptom burden and exacerbation risk. Previous 24-week phase III trials (NCT01854645 and NCT01854658) that demonstrated better improvement of lung function with glycopyrrolate/formoterol fumarate (GFF) metered dose inhaler (MDI) (an MDI fixed-dose of GFF 18/9.6 μg) over individual monocomponent MDIs included a cross-section of patients with moderate to very severe airflow limitation and a broad range of COPD symptoms.

Methods: These post hoc analyses of pooled data investigated whether baseline symptom burden, assessed using the COPD Assessment Test (CAT) score, impacted GFF MDI-associated improvements in lung function, health status, rescue medication use, and exacerbation risk.

Results: In 3,699 patients, improvement in FEV at week 24 between the GFF MDI and monocomponent MDIs and a placebo MDI was similar in magnitude regardless of baseline CAT score. In contrast, the magnitude of mean difference in the St. George's Respiratory Questionnaire total score for GFF MDI vs monocomponent MDIs and the placebo MDI increased with increasing baseline CAT scores. Likewise, reduced rescue medication use and lower exacerbation risk were more pronounced in GFF MDI groups with a higher baseline symptom burden.

Conclusions: Beneficial effects of GFF MDI on health status, rescue medication use, and exacerbation risk in symptomatic patients with COPD increased as a function of baseline symptom burden, whereas lung function benefits were independent. These data suggest a greater clinical benefit from dual bronchodilators in symptomatic patients than in patients without symptoms.

Trial Registry: ClinicalTrials.gov; No.: NCT01854645 and NCT01854658; URL: www.clinicaltrials.gov.
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http://dx.doi.org/10.1016/j.chest.2017.07.007DOI Listing
December 2017

Serious Asthma Events with Budesonide plus Formoterol vs. Budesonide Alone.

N Engl J Med 2016 Sep;375(9):850-60

From Wake Forest School of Medicine, Winston-Salem, NC (S.P.P., E.R.B.); University of Genoa, Genoa, Italy (G.W.C.); Hallym University, Seoul, South Korea (Y.B.P.); Centro de Investigacion y Atencion Integral, Durango, Mexico (R.R.); AstraZeneca, Macclesfield, United Kingdom (S.H.); AstraZeneca Research and Development, Gothenburg, Sweden (H.F., C.J.); and AstraZeneca, Gaithersburg, MD (U.J.M.).

Background: Concerns remain about the safety of adding long-acting β2-agonists to inhaled glucocorticoids for the treatment of asthma. In a postmarketing safety study mandated by the Food and Drug Administration, we evaluated whether the addition of formoterol to budesonide maintenance therapy increased the risk of serious asthma-related events in patients with asthma.

Methods: In this multicenter, double-blind, 26-week study, we randomly assigned patients, 12 years of age or older, who had persistent asthma, were receiving daily asthma medication, and had had one to four asthma exacerbations in the previous year to receive budesonide-formoterol or budesonide alone. Patients with a history of life-threatening asthma were excluded. The primary end point was the first serious asthma-related event (a composite of adjudicated death, intubation, and hospitalization), as assessed in a time-to-event analysis. The noninferiority of budesonide-formoterol to budesonide was defined as an upper limit of the 95% confidence interval for the risk of the primary safety end point of less than 2.0. The primary efficacy end point was the first asthma exacerbation, as assessed in a time-to-event analysis.

Results: A total of 11,693 patients underwent randomization, of whom 5846 were assigned to receive budesonide-formoterol and 5847 to receive budesonide. A serious asthma-related event occurred in 43 patients who were receiving budesonide-formoterol and in 40 patients who were receiving budesonide (hazard ratio, 1.07; 95% confidence interval [CI], 0.70 to 1.65]); budesonide-formoterol was shown to be noninferior to budesonide alone. There were two asthma-related deaths, both in the budesonide-formoterol group; one of these patients had undergone an asthma-related intubation. The risk of an asthma exacerbation was 16.5% lower with budesonide-formoterol than with budesonide (hazard ratio, 0.84; 95% CI, 0.74 to 0.94; P=0.002).

Conclusions: Among adolescents and adults with predominantly moderate-to-severe asthma, treatment with budesonide-formoterol was associated with a lower risk of asthma exacerbations than budesonide and a similar risk of serious asthma-related events. (Funded by AstraZeneca; ClinicalTrials.gov number, NCT01444430 .).
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http://dx.doi.org/10.1056/NEJMoa1511190DOI Listing
September 2016

Plasma Fibrinogen Qualification as a Drug Development Tool in Chronic Obstructive Pulmonary Disease. Perspective of the Chronic Obstructive Pulmonary Disease Biomarker Qualification Consortium.

Am J Respir Crit Care Med 2016 Mar;193(6):607-13

11 Department of Preventive Medicine and Environmental Health, University of Kentucky, College of Public Health, Lexington, Kentucky.

The COPD Foundation Biomarker Qualification Consortium (CBQC) is a unique public-private partnership established in 2010 between the COPD Foundation, the pharmaceutical industry, and academic chronic obstructive pulmonary disease (COPD) experts with advisors from the U.S. NHLBI and the Food and Drug Administration (FDA). This was a direct response to the 2009 publication of a guidance on qualification of drug development tools by the FDA. Although data were believed to be available from publicly funded and industry-funded studies that could support qualification of several tools, the necessary data resided in disparate databases. The initial intent of the CBQC was to integrate these data and submit a dossier for the qualification. This led to the FDA qualification of plasma fibrinogen as a prognostic or enrichment biomarker for all-cause mortality and COPD exacerbations in July 2015. It is the first biomarker drug development tool qualified for use in COPD under the FDA's drug development tool qualification program. This perspective summarizes the FDA's qualification process, the formation of the CBQC, and the effort that led to a successful outcome for plasma fibrinogen and discusses implications for future biomarker qualification efforts.
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http://dx.doi.org/10.1164/rccm.201509-1722PPDOI Listing
March 2016

Plasma Fibrinogen as a Biomarker for Mortality and Hospitalized Exacerbations in People with COPD.

Chronic Obstr Pulm Dis 2015;2(1):23-34

Respiratory Therapy Area Unit, GlaxoSmithKline, Philadelphia, Pennsylvania.

Background: In 2010 the COPD Foundation established the COPD Biomarkers Qualification Consortium (CBQC) as a partnership between the Foundation, the Food and Drug Administration (FDA), and the pharmaceutical industry to pool publicly-funded and industry data to develop innovative tools to facilitate the development and approval of new therapies for COPD. We present data from the initial project seeking regulatory qualification of fibrinogen as a biomarker for the stratification of COPD patients into clinical trials.

Methods: This analysis pooled data from 4 publicly-funded studies and 1 industry study into a common database resulting in 6376 individuals with spirometric evidence of COPD. We used a threshold of 350 mg/dL to determine vs. fibrinogen, and determined the subsequent risk of hospitalizations from exacerbations and death using Cox proportional hazards models.

Results: High fibrinogen levels at baseline were present in 2853 (44.7%) of individuals with COPD. High fibrinogen was associated with an increased risk of hospitalized COPD exacerbations within 12 months (hazard ratio [HR]: 1.64; 95% confidence interval [CI]: 1.39-1.93) among participants in the Atherosclerosis Risk in Communities Study (ARIC), the Cardiovascular Health Study (CHS), and the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study. High fibrinogen was associated with an increased risk of death within 36 months (HR: 1.94; 95% CI: 1.62-2.31) among all participants.

Conclusions: Fibrinogen levels ≥ 350 mg/dL identify COPD individuals at an increased risk of exacerbations and death and could be a useful biomarker for enriching clinical trials in the COPD population.
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http://dx.doi.org/10.15326/jcopdf.2.1.2014.0138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4326107PMC
January 2015