Bioequivalence of budesonide/glycopyrrolate/formoterol fumarate with a next-generation propellant versus hydrofluoroalkane-134a in healthy adults: phase I,randomized,double-blind,single-dose,partial-replicate,three-way cross-over lung exposure and total systemic exposure studies

Abstract

Background:

Hydrofluoroolefin-1234ze (HFO-1234ze) is a next-generation propellant with 99.9% lower global warming potential (GWP) than hydrofluoroalkane-134a (HFA-134a).

Objectives:

We report systemic and lung exposure bioequivalence for budesonide/glycopyrrolate/formoterol fumarate (BGF) components with HFO-1234ze versus HFA-134a.

Design:

These phase I, randomized, double-blind, single-dose, 3-way cross-over trials in healthy adults included three phases (screening; three single-dose treatment periods with 3- to 7-day washouts; follow-up).

Methods:

Participants were randomized to four BGF inhalations (160/9/4.8 µg/actuation) with test (HFO-1234ze) or reference (HFA-134a) treatments in one of three sequences, with HFA-134a administered during two of the three treatment periods. For lung exposure, oral activated charcoal was administered before and after treatment. Bioequivalence was considered established if the 90% confidence interval (CI) for the geometric mean ratio (GMR) was within 80%–125% (or expanded limits, if appropriate) for maximum plasma concentration (Cmax), area under the plasma concentration–curve from time zero to the last quantifiable concentration (AUClast) and AUC from time zero to infinity (AUCinf; US approach only).

Results:

Bioequivalence criteria were met across BGF components. The 90% CI for the GMR was within 80%–125% (or expanded limits) for HFO-1234ze versus HFA-134a, for systemic (GMR: Cmax, 85.41–99.29; AUClast, 95.74–102.48; AUCinf, 90.72–102.58) and lung (GMR: Cmax, 93.39–104.24, AUClast, 97.02–107.76; AUCinf, 101.45–112.22) exposure. No serious adverse events were reported.

Conclusion:

Total systemic and lung exposure to all BGF components met bioequivalence criteria for HFO-1234ze versus HFA-134a, with no new or unexpected safety findings. The near-zero GWP HFO-1234ze propellant is a viable replacement for HFA-134a.

Trial registration:

NCT05569421 (clinicaltrials.gov/study/NCT05569421) and NCT05477108 (clinicaltrials.gov/study/NCT05477108).

Keywords

bioequivalence COPD global warming potential hydrofluoroolefin-1234ze next-generation propellant

Introduction

Many people living with respiratory diseases, such as chronic obstructive pulmonary disease (COPD) or asthma, require the use of pressurized metered dose inhalers (pMDIs) for delivery of therapies,^1–3 particularly in those unable to use dry powder inhalers due to reduced inspiratory flow.^2,4 Additionally, some therapies, either alone or in combination, are only available for delivery by pMDIs.² In pMDIs, propellants are used to atomize respiratory medications, enabling their inhalation and delivery to the lungs.³ However, currently marketed pMDI propellants, such as hydrofluoralkane-134a (HFA-134a), are greenhouse gases with global warming potential (GWP),^5,6 and thus, contribute to global climate change. Consequently, their phase-down is included within the scope of the Kigali Amendment of the Montreal Protocol.⁷ As it has been estimated that pMDIs annually contribute to 0.03% of total global greenhouse gas emissions, it is important to address any climate concerns resulting from their use.⁸

Triple therapy with budesonide/glycopyrrolate/formoterol fumarate (BGF) is indicated as a maintenance treatment for patients with COPD in multiple countries and regions.^9,10 In the phase III studies, ETHOS (NCT02465567) and KRONOS (NCT02497001),^11,12 BGF significantly improved lung function (KRONOS only) and reduced the annual rate of COPD exacerbations when compared with corresponding dual therapies in participants with moderate-to-very severe COPD.^11–14 Furthermore, in the ETHOS study, BGF was associated with a reduction in all-cause mortality versus dual therapy with glycopyrrolate/formoterol fumarate,^11,15 as recognized by the 2025 Global Initiative for Chronic Obstructive Lung Disease report.¹³

Hydrofluoroolefin-1234ze (HFO-1234ze) is in development for use as a propellant in pMDIs and has a GWP 99.9% lower than HFA-134a.¹⁶ The GWP₁₀₀ (a measure of the amount of atmospheric warming caused by a gas over 100 years relative to carbon dioxide (CO₂)) is approximately 1530 for HFA-134a, indicating that its warming potential is 1530 times greater than that of CO₂, versus 1.37 for HFO-1234ze.¹⁷ The GWP potential of HFA-134a necessitates the adoption of next-generation, low GWP propellants to mitigate the climate impacts of pMDIs while ensuring continued patient access to vital medications.^5,18

In a prior study, systemic exposure to the components of BGF triple therapy was comparable for HFO-1234ze relative to HFA-134a,¹⁹ and as such, further studies were conducted. Here, we report on the evaluation of total systemic exposure and of lung exposure (using charcoal block) bioequivalence, in two separate studies, for each of the three constituent components of BGF (160/9/4.8 μg per actuation with four inhalations as a single dose) delivered with HFO-1234ze as the propellant versus HFA-134a as the propellant.

The primary objective of the separate studies was to assess and compare total systemic exposure (total systemic exposure study) and lung exposure (lung exposure study) bioequivalence of budesonide, glycopyrrolate (measured from plasma as the glycopyrronium analyte), and formoterol following pMDI delivery of BGF with HFO-1234ze versus with HFA-134a. Secondary objectives included characterizing the pharmacokinetic (PK) profiles of budesonide, glycopyrronium, and formoterol and assessing safety and tolerability profiles following administration of BGF with HFO-1234ze versus with HFA-134a.

Methods

Study designs and treatment

Both the total systemic exposure study (NCT05569421) and lung exposure study (NCT05477108) were phase I, randomized, double-blind, single-dose, partial-replicate, three-way cross-over studies in healthy volunteers assessing the PK, safety, and tolerability of BGF (160/9/4.8 μg per actuation with four inhalations as a single dose) when formulated with the test propellant HFO-1234ze versus the reference propellant HFA-134a. The systemic exposure study was performed at the Parexel Early Phase Clinical Unit (Glendale, CA, USA) from October 2022 to April 2023. The lung exposure study was performed at the Parexel Early Phase Clinical Unit at the Harbour Hospital (Baltimore, MD, USA) from July 2022 to April 2023. Consolidated Standards of Reporting Trials (CONSORT) guidelines were consulted during preparation of this manuscript.²⁰

In both studies (Figure 1), following a screening period of up to 28 days, eligible participants were randomized 1:1:1 to one of three treatment sequences (ABB, BAB, BBA). Each participant received a single dose of BGF formulated with HFO-1234ze (Treatment A) or HFA-134a (Treatment B; referenced/marketed product, administered on two occasions) in each of the 3-day treatment periods; each period was separated by a washout of 3–7 days. Each dose was administered on day 1 of each treatment period as four actuations of BGF 160/9/4.8 μg, with each actuation taking place within 30 s of the previous actuation. The total dose administered after the four inhalations, was higher than the approved therapeutic dose^9,10 to allow for reliable calculation of the PK parameters and to ensure glycopyrronium levels were not below the level of quantification. A healthcare provider observed dosing to ensure the required number of actuations were administered and that the full dose was inhaled. In the lung exposure study, participants received 10 g of oral activated charcoal (approximately 48 mL) immediately before and after dosing, and at 1 and 2-h post-dosing to block gastrointestinal absorption and enable an estimate of lung deposition. The charcoal block method for eliminating the gastrointestinal absorption component of inhaled drugs has been widely used and accepted by regulatory authorities.^21,22 In particular, this and similar regimens of charcoal administration have been used with inhaled budesonide,^23,24 formoterol,^24,25 and glycopyrronium.²⁶

Figure 1.

Study design for the total systemic exposure and lung exposure studies.

At screening, on admission, and pre-dose on day 1 of each treatment period, participants were instructed on inhalation technique using an AIM Aerosol Inhalation Trainer Device (Model 4500; Vitalograph Inc, Lenexa, KS, USA), and placebo pMDIs were used to demonstrate that participants had adequate pMDI technique. Participants resided in the study facility from the morning of the day before the first dose of the first treatment period (day 1), through all treatment and washout periods, and were discharged on day 2 of treatment Period 3. Each treatment was administered following an overnight fast of ⩾8 h, with a meal given 4 h after dosing. Water consumption was allowed until 1 h before dosing and from 2 h after dosing. A final safety follow-up call occurred within 3–7 days following administration of the final dose of treatment Period 3.

Study populations

In accordance with the inclusion criteria, in both studies, the populations were healthy, nonsmoking male and female adults aged 18−60 years who had suitable veins for cannulation or venipuncture, agreed to adhere to the reproductive restrictions, had a body mass index (BMI) 18−35 kg/m², weighed ⩾50 kg to ⩽120 kg, had a forced expiratory volume in 1 s (FEV₁) of ⩾80% of the predicted normal value and an FEV₁/forced vital capacity (FVC) > 70%, based on height, age and ethnicity, and who demonstrated proper inhalation technique and were able to properly use the pMDI device after training.

Key exclusion criteria included previous receipt of BGF formulated with HFO-1234ze and histories of any significant respiratory disorders (including SARS-CoV-2 infection, COPD, asthma, idiopathic pulmonary fibrosis or a severe course of COVID-19). Additional exclusion criteria included a history or presence of gastrointestinal, hepatic, or renal diseases that may interfere with drug absorption, metabolism, distribution, excretion, or any clinically significant disease or disorder that, in the opinion of the investigator, may either put the participant at risk or influence the study results.

Endpoints

The primary PK endpoints were the maximum plasma concentration (Cmax (both studies)), the area under the plasma concentration–time curve (AUC) from time zero to infinity (AUCinf, (US approach only)), and the AUC from time zero to the last quantifiable concentration (AUClast (both studies)). Secondary PK endpoints included time to Cmax, the terminal rate constant estimated by log-linear least squares regression of the terminal part of the concentration–time curve, the half-life associated with terminal slope of a semi-logarithmic concentration–time curve, and the mean residence time of the unchanged drug in the systemic circulation from time zero to infinity.

Safety and tolerability endpoints included adverse events (AEs) and serious adverse events (SAEs), vital signs (including systolic and diastolic blood pressure, pulse rate, body temperature, and respiratory rate), resting 12-lead electrocardiogram (ECG), physical examination, and laboratory assessments (including hematology, clinical chemistry, and urinalysis). AEs were reported by preferred term and system organ class using Medical Dictionary for Regulatory Activities (MedDRA: version 26.0 for the systemic exposure study and version 25.1 for the lung exposure study, Herndon, VA) and were summarized according to severity and relatedness to treatment, as determined by the investigator. AEs leading to the discontinuation of study treatment were also documented.

Assessments

To assess PK endpoints, blood samples were collected pre-dose, at 2, 5, 10, 20, 30, and 45 min post-dose, and at 1, 2, 4, 8, 12, and 24 h post-dose on day 1 of each treatment period. Plasma extracted from whole blood samples was used for the assessment of budesonide, glycopyrronium, and formoterol. Analyses were conducted by LabCorp Early Development Laboratories Limited (Harrogate, UK) using validated high-performance liquid chromatography tandem mass spectrometry assays, on behalf of the study sponsor similar to as previously reported.²⁷

The bioanalytical methods were validated according to regulatory guidance, with a lower limit of quantification (LLOQ) in plasma of 5.0 pg/mL for budesonide and 1.0 pg/mL for glycopyrronium and formoterol, intra- and inter-assay precision (reported as coefficient of variation (CV)), well below ⩽15% (⩽20% at LLOQ), and accuracy within the accepted ±15% (±20% at LLOQ) of the nominal concentration at all levels for all analytes. To support the accuracy and precision of measurements established with spiked quality control samples in plasma, and to verify the reliability of the reported plasma concentrations in study samples, incurred sample reanalysis was also performed for this clinical study. It was observed that 91.5% (236 of 258 for budesonide), 89.9% (241 of 268 for glycopyrronium), and 91.2% (238 of 261 for formoterol), of the repeated and original results, were within 20% of the mean of the two values, which was acceptable and within the acceptance criteria of the current regulatory guidance. All study samples were analyzed within the known stability period.

To assess safety and tolerability, AEs and SAEs were recorded from screening through follow-up (3−7 days after the final dose). Vital signs were recorded at screening, on day 1 of all treatment periods, and at 3−7 days after the early termination visit, if applicable. Twelve-lead ECGs, as well as clinical laboratory evaluations, urinalysis, and body weight measurements were recorded at screening, on day 2, treatment Period 3, and at the early termination visit, if applicable. Physical examinations were performed at screening, admission, and at discharge or the early termination visit.

Statistical analysis

Each study included three populations: the randomized set included all participants randomized to treatment; the safety analysis set included all participants who received ⩾1 inhalation of any treatment. In both studies, the PK analysis set included all participants in the safety analysis set who had ⩾1 primary PK parameter that was quantifiable and without any impactful protocol deviations. In the lung exposure study, the randomized set was identical to the safety analysis set.

Demographics and clinical characteristics are reported in the randomized set and summarized by treatment sequence. All PK analyses used the PK analysis set and are reported by treatment. Plasma PK parameters were estimated for budesonide, glycopyrronium, and formoterol for both treatments by non-compartmental analysis using Phoenix^®, Phoenix WinNonlin: Radnor, PA; WinNonlin^® Version 8.2 (or higher) and/or SAS^® Version 9.4, SAS: Cary, NC (or higher)and are presented using appropriate descriptive statistics by treatment. Safety analyses were conducted in the safety analysis set and are summarized by treatment. As different MedDRA versions were used to classify AEs, specific AEs from the lung exposure study were re-assessed according to MedDRA version 26.0 and the data presented are merged across studies.

Bioequivalence was assessed between the test and reference treatments based on the PK analysis set using average bioequivalence (ABE), average bioequivalence with expanded limits (ABEL), or reference-scaled average bioequivalence (RSABE) depending on US or EU regulatory requirements. For both regulatory approaches, bioequivalence was considered established if the 90% confidence interval (CI) for the geometric mean ratio (GMR) of each PK parameter was within 80%–125% (or the expanded equivalence limits, where appropriate). Further, the acceptance criteria for GMR, and the acceptance criteria for 90% CIs of GMR had to be satisfied for each PK parameter and each analyte.

For the US regulatory approach, the GMR and its 90% CIs were estimated for Cmax, AUClast and AUCinf for budesonide, glycopyrronium, and formoterol using ABE or RSABE methods depending on the within-participant standard deviation (swr) of the reference treatment. The ABE is a linear mixed effects model, with the log-transformed PK parameter as a dependent variable, sequence and period as fixed effects and participant and treatment nested within-participant as random effects. If the swr of the reference treatment was <0.294 (i.e., CV < 30%), the ABE method was used, and the acceptance criteria for the 90% CIs of GMR were the fixed limits of 80%–125%. Conversely, if swr was ⩾ 0.294 (i.e., CV ⩾ 30%), the RSABE method was used,²⁸ and bioequivalence was demonstrated if the criteria bound was ⩽ 0 and the point estimate of GMR fell between 80% and 125%. Criteria bound was defined as the 95% upper CI for ${({\bar{Y}}_{T} - {\bar{Y}}_{R})}^{2} - θ S_{W R}^{2};$ where ${\bar{Y}}_{T}$ and ${\bar{Y}}_{R}$ are the means of the ln-transformed PK parameter for test treatment and reference treatment; $θ \equiv {(\frac{l n (1.25)}{0.25})}^{2}$ is the scaled ABE limit.

For the EU regulatory approach, GMRs and their 90% CIs were estimated for Cmax and AUClast for budesonide, glycopyrronium, and formoterol using an analysis of variance model, with the log-transformed PK parameter as a dependent variable and sequence, period, treatment, and participant within sequence as fixed effects. As with the US approach, if the swr of the reference treatment was <0.294, the ABE method was used for Cmax, and the acceptance limits for the 90% CIs of GMR were 80%–125%. If swr was ⩾0.294, the ABEL method was used for Cmax, and the acceptance limits for the 90% CIs of the GMR were expanded to where the upper (U) and lower (L) limits were defined as: (U, L) = e ± k·swr, where the regulatory constant k = 0.760. If within-participant CV exceeded 50%, then the acceptance limits were capped at 69.84% and 143.19%. For AUClast, expanded limits were not allowed, even when the CV exceeded 30%, and the ABE method was used, and the acceptance limits of the 90% CIs of the GMR were 80% to 125%. The ABE or ABEL approaches were performed via an analysis of variance model, with log-transformed PK parameter as dependent variable, sequence, period, treatment, and participant within sequence as fixed effects.²⁹

Study sample sizes were determined for a partial replicate, three-way cross-over study based on the precision in estimating AUCinf, AUClast, and Cmax of BGF formulated with HFA-134a from previous studies.^27,30–33 The partial replicate design was utilized to allow for expanded limits if CV exceeded 30%. In studies with higher intra-participant variability, larger absolute differences between the logarithmic means have been observed.³⁴ As such, the studies were powered for a true GMR of 0.9.³⁴ It was planned to randomize 108 participants in each study to achieve a minimum of 96 evaluable participants, assuming a 10% dropout rate, which was determined to provide a 90% probability of obtaining a 90% CI within the pre-specified limits of 69.84% to 143.19% for Cmax, as well as the fixed limits of 80%–125% for AUCinf and AUClast, and a GMR estimate within the bounds of 80%–125%.

Results

Participant disposition

In the systemic exposure study, a total of 279 participants were screened, 108 were randomized and 107 (99.1%) participants completed the study (Supplemental Figure 1 for CONSORT diagram). In the lung exposure study, 223 participants were screened, 108 randomized; 103 (98.1%) participants completed the study (Supplemental Figure 1 for CONSORT diagram).

Demographics

Baseline participant demographics were generally well-balanced across treatment groups within each study (Table 1). In the systemic exposure study, most participants were male (54.6%), the mean (standard deviation (SD)) age was 37.1 (10.3) years, and the mean (SD) BMI was 27.25 (3.85) kg/m². In the lung exposure study, most participants were male (57.4%), the mean (SD) age was 38.1 (11.0) years, and the mean (SD) BMI was 26.94 (3.63) kg/m². The distribution of participant race differed between studies, with the majority of participants in the systemic exposure study being White (55.6%) and the majority in the lung exposure study being Black (59.3%).

Table 1.

Participant demographics by treatment sequence for the systemic exposure and lung exposure studies.

Study	Systemic exposure study				Lung exposure study
Treatment sequence	ABB(n = 36)	BAB(n = 36)	BBA(n = 36)	Total(N = 108)	ABB(n = 36)	BAB(n = 36)	BBA(n = 36)	Total(N = 108)
Age, mean (SD), years	36.0 (10.0)	35.8 (9.6)	39.5 (11.2)	37.1 (10.3)	37.9 (10.5)	37.8 (11.7)	38.6 (11.1)	38.1 (11.0)
Sex, n (%)
Male	22 (61.1)	17 (47.2)	20 (55.6)	59 (54.6)	22 (61.1)	21 (58.3)	19 (52.8)	62 (57.4)
Female	14 (38.9)	19 (52.8)	16 (44.4)	49 (45.4)	14 (38.9)	15 (41.7)	17 (47.2)	46 (42.6)
Race, n (%)
White	21 (58.3)	19 (52.8)	20 (55.6)	60 (55.6)	12 (33.3)	10 (27.8)	13 (36.1)	35 (32.4)
Black/African American	8 (22.2)	8 (22.2)	10 (27.8)	26 (24.1)	21 (58.3)	24 (66.7)	19 (52.8)	64 (59.3)
Asian	4 (11.1)	3 (8.3)	2 (5.6)	9 (8.3)	2 (5.6)	1 (2.8)	2 (5.6)	5 (4.6)
Native Hawaiian/Other Pacific Islander	0	1 (2.8)	0	1 (0.9)	0	0	0	0
American Indian/Alaska Native	1 (2.8)	0	0	1 (0.9)	0	1 (2.8)	1 (2.8)	2 (1.9)
Other	2 (5.6)	5 (13.9)	4 (11.1)	11 (10.2)	1 (2.8)	0	1 (2.8)	2 (1.9)
Body mass index, kg/m²
Mean (SD)	26.66 (3.84)	27.72 (3.99)	27.36 (3.75)	27.25 (3.85)	27.09 (3.42)	25.46 (3.19)	28.26 (3.77)	26.94 (3.63)
Median (range)	26.90 (19.3–33.8)	28.35 (19.4–34.7)	27.65 (20.1–34.5)	27.65 (19.3–34.7)	27.00 (20.2–34.0)	25.55 (19.1–32.5)	27.80 (19.4–34.8)	26.85 (19.1–34.8)

Treatment A: BGF HFO-1234ze 160/9/4.8 µg per actuation, four inhalations as a single dose (test formulation). Treatment B: BGF HFA-134a 160/9/4.8 µg per actuation, four inhalations as a single dose (reference formulation). In the lung exposure study, Treatments A and B were administered with oral activated charcoal to block gastrointestinal absorption.

BGF, budesonide/glycopyrrolate/formoterol fumarate; HFA-134a, hydrofluoroalkane-134a; HFO-1234ze, hydrofluoroolefin-1234ze; SD, standard deviation.

Pharmacokinetics

Following administration, the geometric mean plasma concentration–time profiles of budesonide, glycopyrronium, and formoterol were similar across all treatments for both studies (Figure 2), as were the individual PK measures (Supplemental Tables 1 and 2).

Figure 2.

Geometric mean (geometric SD) plasma concentration versus nominal sampling time for each BGF component (linear scale) in the systemic (a) and lung exposure (b) studies.

Bioequivalence

Total systemic exposure and lung exposure for each BGF analyte met bioequivalence criteria for HFO-1234ze relative to HFA-134a using both the US and EU regulatory approaches (Figure 3), with GMRs for all BGF analytes consistent across approaches. For budesonide, RSABE was used per the US regulatory approach for Cmax in both studies as the CV was >30% and RSABE was used for AUC parameters in the lung exposure study as the CV was >30%, whereas ABE was used for the AUC parameters in the systemic exposure study as the CV was <30%; the GMR for all measures was within 80%–125% and the criteria bound was <0. ABE was used per the EU regulatory approach for AUClast, and ABEL was used for Cmax in both studies as the CV exceeded 30%, resulting in AUClast acceptable limits within 80%–125% for both studies and Cmax acceptance limit expansion of 76.64%–130.48% for the systemic exposure study and 73.29%–136.44% for the lung exposure study.

Figure 3.

Geometric mean ratios (90% CI) for total systemic exposure (a) and lung exposure (b) parameters for each BGF component for HFO-1234ze relative to HFA-134a. The grey area represents the bioequivalence boundary for the GMR and 90% CIs of GMR at the fixed limits of 80%–125%. ^aUS approach results based on ABE method for Cmax, AUClast, and AUCinf if intra-subject CV < 30%, or RSABE method if intra-subject CV ⩾ 30%. When the RSABE method was used, bioequivalence was demonstrated if the criteria bound was ⩽0 together with a GMR within 80%–125%. The GMR and its 90% CIs were estimated for Cmax, AUClast, and AUCinf for budesonide, glycopyrronium, and formoterol using a linear mixed effects model, with the log-transformed PK parameter as a dependent variable, sequence and period as fixed effects, and participant and treatment nested within-participant as random effects. ^bEU approach results based on ABE method for Cmax if intra-subject CV < 30%, or ABEL method for Cmax if intra-subject CV ⩾ 30%, and the ABE method for AUClast. GMRs and their 90% CIs were estimated for Cmax and AUClast for budesonide, glycopyrronium, and formoterol using an analysis of variance model, with the log-transformed PK parameter as a dependent variable, and sequence, period, treatment, and subject within sequence as fixed effects.

For glycopyrronium, RSABE was used per the US regulatory approach for Cmax and AUC parameters in both studies as the CV was >30%; the GMR for all measures was within 80%–125%, and the criteria bound was <0. ABEL was used per the EU regulatory approach for Cmax in both studies as the CV exceeded 30%, resulting in Cmax acceptance limit expansion of 75.47%–132.50% for the systemic exposure study and 74.24%–134.70% for the lung exposure study. ABE was used per the EU regulatory approach for AUClast, with acceptable limits within 80% to 125% for both studies.

For formoterol, RSABE was used per the US regulatory approach for Cmax and AUC parameters in the lung exposure study as the CV was >30%, whereas RSABE was only used for Cmax in the systemic exposure study as the CV was <30% for AUCinf and AUClast; the GMR for all measures was within 80%–125% and the criteria bound was <0. In both studies, ABE was used per the EU regulatory approach for AUClast, whereas ABEL was used for Cmax as the CV exceeded 30%. AUClast acceptable limits were within 80%–125% for both studies, and Cmax acceptance limit expansion was 79.52%–125.75% for the systemic exposure study and 74.21%–134.75% for the lung exposure study.

Safety and tolerability

In the systemic exposure study, 14.8% of participants experienced any AEs with BGF HFO-1234ze compared with 19.6% and 8.4%, respectively, for each replicate of BGF HFA-134a (Table 2). Similar results were observed in the lung exposure study, in which 11.7% of participants experienced any AE with BGF HFO-1234ze compared with 18.1% and 3.8%, respectively, for each replicate of BGF HFA-134a (Table 2).

Table 2.

Overall summary of AEs for the systemic exposure study and lung exposure study.

	Systemic exposure			Lung exposure
AE category, n (%)	BGF HFO-1234ze^a N = 108	BGF HFA-134a(Replicate 1)^b N = 107	BGF HFA-134a(Replicate 2)^b N = 107	BGF HFO-1234ze^a N = 103	BGF HFA-134a(Replicate 1)^b N = 105	BGF HFA-134a(Replicate 2)^b N = 104
Any AE	16 (14.8)	21 (19.6)	9 (8.4)	12 (11.7)	19 (18.1)	4 (3.8)
SAE	0	0	0	0	0	0
AE leading to discontinuation of study intervention	0	0	0	0	0	0
Treatment-related AE^c	10 (9.3)	12 (11.2)	4 (3.7)	4 (3.9)	6 (5.7)	2 (1.9)
Treatment-related SAE^c	0	0	0	0	0	0

BGF HFO-1234ze 160/9/4.8 µg per actuation, four inhalations as a single dose, administered during one treatment period (test formulation; Treatment A).

BGF HFA-134a 160/9/4.8 µg per actuation, four inhalations as a single dose, administered during one treatment period (reference formulation; Treatment B).

Any AE/SAE determined by the investigator to have a possible causal link to the study intervention/investigational product.

AE, adverse event; BGF, budesonide/glycopyrrolate/formoterol fumarate; HFA-134a, hydrofluoroalkane-134a; HFO-1234ze, hydrofluoroolefin-1234ze; SAE, serious adverse event.

No AEs led to treatment discontinuation (Table 2), and no SAEs or deaths were reported during either study. Combined across studies, headache was the most common AE (Table 3), which was reported in 2.8% of participants with HFO-1234ze and in 5.2% (replicate 1) and 0.9% (replicate 2) of participants with HFA-134a.

Table 3.

Most frequently reported AEs (reported by ⩾ 2 participants in any treatment group) combined across both the systemic exposure study and the lung exposure study.

Preferred term, n (%)	BGF HFO-1234ze^a N = 211	BGF HFA-134a(Replicate 1)^b N = 212	BGF HFA-134a(Replicate 2)^b N = 211
Headache	6 (2.8)	11 (5.2)	2 (0.9)
Catheter site bruise	2 (0.9)	2 (0.9)	1 (0.5)
Cough	1 (0.5)	4 (1.9)	0
Dizziness	2 (0.9)	2 (0.9)	1 (0.5)
Nausea	3 (1.4)	2 (0.9)	0
Throat irritation	2 (0.9)	3 (1.4)	0
Constipation	1 (0.5)	3 (1.4)	0
Feces discolored	2 (0.9)	2 (0.9)	0
Vessel puncture site bruise	2 (0.9)	2 (0.9)	0
Back pain	1 (0.5)	2 (0.9)	0
Catheter site pain	0	1 (0.5)	2 (0.9)
Catheter site swelling	0	0	3 (1.4)
Dry throat	0	2 (0.9)	1 (0.5)
Abdominal pain	2 (0.9)	0	0

BGF HFO-1234ze 160/9/4.8 µg per actuation, four inhalations as a single dose (test formulation; Treatment A).

BGF HFA-134a 160/9/4.8 µg per actuation, four inhalations as a single dose (reference formulation; Treatment B).

AE, adverse event; BGF, budesonide/glycopyrrolate/formoterol fumarate; HFA-134a, hydrofluoroalkane-134a; HFO-1234ze, hydrofluoroolefin-1234ze.

Discussion

The development of pMDI propellants with near-zero GWP, such as HFO-1234ze, aims to reduce the environmental impact of respiratory disease care while ensuring access to essential medicines for patients.^5,18 HFO-1234ze has a near-zero 100-year global warming potential (GWP₁₀₀ = 1.37) compared with approximately 1530 for HFA-134a (a reduction exceeding 99.9%),^17,35,36 which translates to a substantial decrease in carbon dioxide equivalent emissions per device and overall, because pMDIs are used by the majority of patients.⁴ The current findings demonstrate that total systemic and lung exposure in healthy adults is bioequivalent, and that safety and tolerability profiles are comparable, when BGF is administered using near-zero GWP HFO-1234ze propellant versus HFA-134a. Taken together, the current findings demonstrate that BGF pMDI HFO-1234z represents a viable alternative propellant to HFA-134a.

PK parameters were similar for the BGF HFO-1234ze and BGF HFA-134a formulations. Analysis of total systemic and lung exposure demonstrated bioequivalence for all three BGF components (budesonide, glycopyrronium, and formoterol) with HFO-1234ze versus HFA-134a, using both US and EU regulatory approaches. Data from the systemic exposure study are consistent with a prior study, which also showed similar systemic exposure with HFO-1234ze and HFA-134a.¹⁹ However, as the previous study was not designed to specifically establish bioequivalence, the current data extend previous findings to directly verify bioequivalence not only for systemic exposure but also lung exposure. The overall PK variables observed for each component were as expected and generally comparable with previous findings of BGF in healthy adults.^{19,27,30–33} Both BGF HFO-1234ze and BGF HFA-134a were also well-tolerated, with similar safety profiles observed with each propellant in both the systemic and lung exposure studies. No new or unexpected safety findings were observed following single dosing of healthy participants with either propellant.

Collectively, based on these findings, it is expected that BGF HFO-1234ze will have similar clinical characteristics to BGF HFA-134a from both efficacy and safety perspectives. In phase III studies, BGF pMDI HFA-134a has been shown to improve lung function and reduce the rate of COPD exacerbations in people with moderate-to-very severe COPD.^11–13,37 These lung bioequivalence findings support the likelihood that the BGF HFO-1234ze formulation will have comparable efficacy to the approved BGF HFA-134a formulation in patients with COPD. Further, the systemic bioequivalence data suggest the safety profile of the HFO-1234ze formulation in clinical practice will be similar to the current HFA-134a formulation. Additional studies aim to further evaluate and confirm clinical and safety outcomes.

These studies are limited by factors generally associated with phase I studies, including their limited dosing duration, which can influence safety and tolerability evaluations, and the restriction of the study population to healthy participants without diagnosed respiratory diseases. However, inclusion of healthy participants is consistent with the conduct of other bioequivalence studies, as it minimizes daily fluctuation in lung function that can occur in participants with respiratory diseases that could potentially confound the PK comparisons between treatment.^19,27,30,38 While healthy volunteers are commonly included in phase I studies, differences in inhalation technique and lung pathology in patients with COPD may affect drug deposition and pharmacokinetics, and should be considered when interpreting these findings.^39,40

Conclusion

For people living with COPD who may be unable to produce the adequate inspiratory flow required to use dry powder inhalers, pMDIs are essential, as the propellants in pMDIs facilitate the inhalation and delivery of medications to the lungs. However, currently marketed pMDI propellants, such as HFA-134a, are greenhouse gases with GWP that contribute to global climate change. The current findings indicate total systemic and lung exposure to BGF components was bioequivalent when formulated with the near-zero GWP HFO-1234ze propellant compared with the currently marketed HFA-134a propellant, with no new or unexpected safety findings. These findings suggest HFO-1234ze is a viable replacement for HFA-134a for use in BGF, ensuring access to essential medicines and supporting the recently completed clinical program for the transition of BGF to the next-generation HFO-1234ze propellant. It is anticipated that initial availability of the BGF pMDI utilizing HFO-1234ze will occur in 2025.

Supplemental Material

sj-doc-2-tar-10.1177_17534666261417149 – Supplemental material for Bioequivalence of budesonide/glycopyrrolate/formoterol fumarate with a next-generation propellant versus hydrofluoroalkane-134a in healthy adults: phase I, randomized, double-blind, single-dose, partial-replicate, three-way cross-over lung exposure and total systemic exposure studies

Supplemental material, sj-doc-2-tar-10.1177_17534666261417149 for Bioequivalence of budesonide/glycopyrrolate/formoterol fumarate with a next-generation propellant versus hydrofluoroalkane-134a in healthy adults: phase I, randomized, double-blind, single-dose, partial-replicate, three-way cross-over lung exposure and total systemic exposure studies by Artur Bednarczyk, Magnus Aurivillius, Mandeep Jassal, Mihir Shah, Ibrahim Raphiou, David Petullo, John Xu, Maria Heijer, Klementyna Sychowicz, Kathryn Collison, Carlos Silva, Jitendar Reddy, David Han, Ronald Goldwater, Michael Gillen and Mehul Patel in Therapeutic Advances in Respiratory Disease

Supplemental Material

sj-docx-1-tar-10.1177_17534666261417149 – Supplemental material for Bioequivalence of budesonide/glycopyrrolate/formoterol fumarate with a next-generation propellant versus hydrofluoroalkane-134a in healthy adults: phase I, randomized, double-blind, single-dose, partial-replicate, three-way cross-over lung exposure and total systemic exposure studies

Supplemental material, sj-docx-1-tar-10.1177_17534666261417149 for Bioequivalence of budesonide/glycopyrrolate/formoterol fumarate with a next-generation propellant versus hydrofluoroalkane-134a in healthy adults: phase I, randomized, double-blind, single-dose, partial-replicate, three-way cross-over lung exposure and total systemic exposure studies by Artur Bednarczyk, Magnus Aurivillius, Mandeep Jassal, Mihir Shah, Ibrahim Raphiou, David Petullo, John Xu, Maria Heijer, Klementyna Sychowicz, Kathryn Collison, Carlos Silva, Jitendar Reddy, David Han, Ronald Goldwater, Michael Gillen and Mehul Patel in Therapeutic Advances in Respiratory Disease

Footnotes

Acknowledgements

AstraZeneca would like to thank the study participants and investigational site staff for their participation in these clinical studies. Medical writing and submission support, under the direction of the authors, was provided by Mark Bloom, PhD, and Rebecca Douglas, PhD, CMC Connect, a division of IPG Health Medical Communications, funded by AstraZeneca, in accordance with Good Publication Practice (GPP 2022) guidelines. Artificial Intelligence was not used in the development of this manuscript.

Declarations

ORCID iD

Magnus Aurivillius

Supplemental material

Supplemental material for this article is available online.

Prior publication

Portions of the data being reported have been presented at the 2024 annual meeting of the American Thoracic Society (17–22 May 2024) and the associated abstracts published.^41,42

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