Gamma scintigraphy allows assessment of the total lung deposition, regional distribution, and extrathoracic (oropharyngeal and stomach) deposition of inhaled treatment. Chronic obstructive pulmonary disease (COPD) is a disease of the small airways, and targeting inhaled therapeutics to the distal lungs is important. This Phase I, single-dose, gamma scintigraphy study (NCT03906045) assessed the pulmonary deposition of a fixed-dose combination of budesonide, glycopyrrolate, and formoterol fumarate administered by metered dose inhaler (BGF MDI) following a maximal breath-hold of #10 seconds in patients with moderate-to-severe/very severe COPD. METHODS: BGF MDI was radiolabeled with 99m Tc, administered as two actuations of 160/9/4.8 mg, (320/18/9.6 mg total dose), j5 MBq per actuation, and delivered via an Aerosphere inhaler. The primary objective was to assess the pulmonary deposition of radiolabeled BGF MDI. Secondary objectives assessed radiolabeled BGF MDI for regional airway deposition patterns in the lungs, deposited dose in the oropharyngeal and stomach regions, and deposited dose detected on the actuator and exhalation filter. Adverse events (AEs) were monitored. RESULTS: Patients with moderate COPD (n=10, mean post-bronchodilator forced expiratory volume in 1 second [FEV 1 ] % predicted, 61.1 [SD, 8.7]) and severe/very severe COPD (n=8, mean post-bronchodilator FEV 1 % predicted, 38.6 [SD, 7.4]) were enrolled (mean age, 62.0; 55.6% males). All patients were included in the safety analysis, with deposition data analyzed in the perprotocol population (n=17). The mean percentage of the emitted dose deposited in the lungs was 32.1% (SD, 15.6). The mean percentage of the emitted dose deposited in the oropharyngeal and stomach regions was 67.2% (SD, 15.1). A low percentage (0.7%, SD 0.9) of the emitted dose was detected in the exhalation filter, and the mean percentage of the metered dose detected in the actuator after inhalation was 11.2% (SD, 1.7). The mean outer/inner (O/I) regional airway deposition ratio was 1.0, while the mean normalized O/I regional airway deposition ratio was 0.6. The mean central/peripheral (C/P) regional airway deposition ratio was 0.9, and the mean standardized C/P was 2.2. There was no meaningful difference in the percentage of the emitted dose deposited in the lungs between moderate and severe/very severe COPD (least squares mean,-5.8 [95% CI,-24.1, 12.6]). No AEs were observed. CONCLUSIONS: These results indicate that doses of BGF 320/18/9.6 mg were deposited homogeneously throughout the entire lung of patients with moderate-to-very severe COPD, across disease severities, generally comparable to BGF deposition in prior studies with healthy volunteers. CLINICAL IMPLICATIONS: BGF MDI was efficiently deposited in both the central and peripheral regions of the lungs of patients with moderate-to-very severe COPD.

Background Triple therapy with inhaled corticosteroids/long-acting muscarinic antagonists/long-acting β2-agonists (ICS/LAMA/LABA) is recommended for patients with chronic obstructive pulmonary disease (COPD) with continued symptoms or exacerbations, despite treatment with LAMA/LABA or ICS/LABA. The pulmonary, extrathoracic, and regional lung deposition patterns of a radiolabeled ICS/LAMA/LABA triple fixed-dose combination budesonide/glycopyrrolate/formoterol fumarate (BGF 320/18/9.6 μg), delivered via a single Aerosphere metered dose inhaler (MDI) were previously assessed in healthy volunteers and showed good deposition to the central and peripheral airways (whole lung deposition: 37.7%). Here, we report the findings assessing BGF in patients with moderate-to-very severe COPD. Methods This phase I, single-dose, open-label gamma scintigraphy imaging study (NCT03906045) was conducted in patients with moderate-to-very severe COPD. Patients received two actuations of BGF MDI (160/9/4.8 μg per actuation) radiolabeled with technetium‑99‑pertechnetate, not exceeding 5 MBq per actuation. Immediately following each inhalation, patients performed a breath-hold of up to 10 s, then exhaled into an exhalation filter. Gamma scintigraphy imaging of the anterior and posterior views of the lungs and stomach, and a lateral head and neck view, were performed immediately after exhalation. The primary objective of the study was to assess the pulmonary deposition of BGF. Secondary objectives assessed the deposited dose of radiolabeled BGF in the oropharyngeal and stomach regions, on the actuator, and on the exhalation filter in addition to regional airway deposition patterns in the lungs. Results The mean BGF emitted dose deposited in the lungs was 32.1% (standard deviation [SD] 15.6) in patients with moderate-to-very severe COPD, 35.2% (SD 12.8) in patients with moderate COPD, and 28.7% (SD 18.4) in patients with severe/very severe COPD. Overall, the mean normalized outer/inner ratio was 0.55 (SD 0.19), while the standardized central/peripheral ratio was 2.21 (SD 1.64). Conclusions Radiolabeled BGF 320/18/9.6 μg was efficiently delivered and deposited throughout the entire lung, including large and small airways, in patients with moderate-to-very severe COPD, with similar deposition in patients with moderate COPD and patients with severe/very severe COPD. Trial registration: ClinicalTrials.gov, NCT03906045. Registered 8 April 2019, https://clinicaltrials.gov/ct2/show/NCT03906045