Abstract
Introduction
In the ASPEN trial, brensocatib, a dipeptidyl peptidase 1 inhibitor, significantly reduced the burden of pulmonary exacerbations versus placebo in participants with bronchiectasis. A prespecified subgroup analysis evaluated the efficacy and safety of brensocatib in participants of Asian race with bronchiectasis from ASPEN.
Methods
Participants with confirmed bronchiectasis and a history of exacerbations in the 12 months before screening [adults (18–85 years), ≥ 2; adolescents (12– < 18 years), ≥ 1] received once-daily brensocatib (10 or 25 mg) or matching placebo for 52 weeks (adults, 1:1:1; adolescents, 2:2:1). Efficacy endpoints included annualized exacerbation rate, time to first exacerbation, and change at 52 weeks in post-bronchodilator (BD) forced expiratory volume (FEV) in 1 s (post-BD FEV1) and Quality of Life–Bronchiectasis Respiratory Symptom Score (QOL-B RSS). Safety was monitored from enrollment through the end of study.
Results
Overall, 191 participants were of Asian race (n = 63, brensocatib 10 mg; n = 64, brensocatib 25 mg; n = 64, placebo). Brensocatib 10 mg and brensocatib 25 mg significantly reduced the annualized exacerbation risk (both by ~ 60%; p = 0.0005 and p = 0.0012, respectively) and prolonged the time to first exacerbation (hazard reduced by ~ 55%; p = 0.0039 and 0.0082, respectively) versus placebo. Brensocatib 25 mg significantly reduced post-BD FEV1 decline [least squares mean difference (95% CI): 69 (24–114) mL, p = 0.0029] and improved QOL-B RSS score [7.49 (2.48–12.50) points, p = 0.0034] versus placebo. The frequency of treatment-emergent adverse events was similar across treatment groups and consistent with the overall ASPEN results.
Conclusions
In participants of Asian race, brensocatib 10 mg and 25 mg reduced the burden of pulmonary exacerbations, and the 25-mg dose reduced lung function decline and improved patient-reported symptoms versus placebo. The efficacy and safety of brensocatib in participants of Asian race were largely consistent with the overall ASPEN population, with select outcomes showing numerically greater benefit, although ASPEN was not powered to detect treatment differences in prespecified subgroup analyses.
ClinicalTrials.gov identifier
Supplementary Information
The online version contains supplementary material available at https://doi.org/10.1007/s41030-026-00375-w.
Keywords: Asian race, ASPEN trial, Brensocatib, Bronchiectasis, DPP1 inhibitor, Lung function, Patient-reported outcomes, Pulmonary exacerbations
Plain Language Summary
Bronchiectasis is a long-term inflammatory lung disease that usually worsens over time. Brensocatib is a new medicine developed to treat bronchiectasis. In a clinical trial called ASPEN, people with bronchiectasis took brensocatib at doses of 10 mg or 25 mg or a placebo, for 52 weeks. In ASPEN, brensocatib reduced the number of exacerbations versus placebo. In this study, researchers wanted to know the effect of brensocatib in people of Asian race with bronchiectasis who took part in ASPEN. A total of 191 people of Asian race were assessed: 63 took brensocatib 10 mg, 64 took brensocatib 25 mg, and 64 took a placebo. During the study, both doses of brensocatib reduced the risk of people having an exacerbation by about 60% versus placebo and prolonged the time to their first exacerbation, reducing the chance of exacerbating by about 55%. Compared with placebo, the 25-mg dose reduced the decline in lung function caused by bronchiectasis and improved bronchiectasis symptoms as reported by the people themselves. The occurrence of side effects was similar among the people who took brensocatib and those who took placebo and was similar to the overall ASPEN clinical trial. In summary, brensocatib reduced the burden of exacerbations and improved lung function and the symptoms of bronchiectasis in people of Asian race from ASPEN, although the number of people was small. Generally, the benefits of brensocatib in people of Asian race were similar to those in the overall ASPEN clinical trial, and some benefits were numerically larger.
Supplementary Information
The online version contains supplementary material available at https://doi.org/10.1007/s41030-026-00375-w.
Key Summary Points
| Why carry out this study? |
| In the phase 3 ASPEN trial, brensocatib 10 mg and 25 mg reduced the burden of pulmonary exacerbations in participants with bronchiectasis; the 25-mg dose reduced also lung function decline and improved patient-reported outcomes. |
| This prespecified analysis evaluated the efficacy and safety of brensocatib in participants of Asian race from the ASPEN trial. |
| What was learned from the study? |
| In participants of Asian race with bronchiectasis, both doses of brensocatib significantly reduced the annualized rate of pulmonary exacerbations, the time to first exacerbation, and the proportion of participants remaining exacerbation-free. |
| The 25-mg dose also significantly reduced decline in post-bronchodilator forced expiratory volume in 1 s, forced vital capacity, and forced expiratory flow between 25 and 75% of vital capacity, and improved Quality of Life–Bronchiectasis Respiratory Symptom Score and Bronchiectasis Exacerbation and Symptom Tool symptom diary scores. |
| The efficacy and safety of brensocatib in participants of Asian race were largely consistent with the overall ASPEN population, with select outcomes showing numerically greater benefit. |
Introduction
Non-cystic fibrosis bronchiectasis, hereafter bronchiectasis, is a chronic and progressive inflammatory lung disease characterized by cough, sputum production, and recurrent bronchial infections and exacerbations [1–4]. Individuals of Asian race with bronchiectasis have unique characteristics, and the impacts of treatments in this population are largely unknown [5–9]. A review of individuals of Asian race with bronchiectasis focusing on established registries in India, Korea, and China indicated people were more likely to be younger and male compared with other global regions [5]. In addition, individuals of Asian race seemed to experience more severe dyspnea but showed less severe disease, although this was not in agreement with the rate of hospitalization [5] and was not a universal finding [8]. Moreover, individuals of Asian race were more likely to have fewer options for guideline-recommended treatment [5]. Notably, the underlying etiology of individuals with bronchiectasis was also shown to be different between Asian countries and other global regions, with post-tuberculosis bronchiectasis currently the leading cause of bronchiectasis in Asian cohorts [5]. In general, there is considerable heterogeneity in disease characteristics among people of Asian race [5, 8]. There is also a close relationship between the microbiome and inflammation in bronchiectasis [10], and the microbiome varies geographically [11]. In individuals from Asia with bronchiectasis, the microbiome is markedly different compared with those from Europe [12]. As well as unique disease characteristics, it is likely that individuals of Asian race with bronchiectasis may also exhibit different treatment effects.
Dysregulated neutrophilic inflammation plays a key role in driving the pathogenesis of bronchiectasis [3, 13]. Elevated levels of neutrophil serine proteases (NSPs), such as neutrophil elastase, cathepsin G, and proteinase 3, have been associated with disease progression and poorer clinical outcomes [14, 15]. Brensocatib is an oral, competitive, and reversible inhibitor of dipeptidyl peptidase 1 (DPP1), an enzyme that plays a key role in the activation of pro-inflammatory NSPs [16–18]. Brensocatib is approved in the US by the Food & Drug Administration for the treatment of non-cystic fibrosis bronchiectasis in adult and pediatric patients aged ≥ 12 years [18] and more recently has been approved by the European Medicines Agency and in the UK for the treatment of non-cystic fibrosis bronchiectasis in patients aged ≥ 12 years with 2 or more exacerbations in the prior 12 months [19, 20]. In the phase 3, randomized, double-blind ASPEN trial (NCT04594369), the efficacy and safety of brensocatib was compared with placebo in adult and adolescent participants with bronchiectasis [21]. Over 52 weeks, brensocatib at doses of 10 mg and 25 mg significantly reduced the annualized rate of pulmonary exacerbations, prolonged the time to first exacerbation, and increased the likelihood of remaining exacerbation-free [21]. The 25-mg dose also significantly reduced lung function decline, as measured by forced expiratory volume in 1 s (FEV)1, and nominally significantly improved patient-reported symptoms, as measured by Quality of Life–Bronchiectasis Respiratory Symptom Score (QOL-B RSS) and Bronchiectasis Exacerbation and Symptom Tool (BEST) symptom diary score [22]. In total, 11.1% of the participants in the ASPEN trial were of Asian race, but the efficacy and safety of brensocatib in this specific racial group has not been reported. The aim of this prespecified analysis was to determine the efficacy and safety of brensocatib 10 mg and 25 mg in participants of Asian race from the ASPEN trial and to compare descriptively results with the overall ASPEN population.
Methods
ASPEN Trial Design and Participant Population
The ASPEN trial has been described in detail elsewhere [21]. Participants (aged 12–85 years) with bronchiectasis (chronic cough or sputum production or recurrent respiratory infections) confirmed by chest imaging using computed tomography had ≥ 2 (adults) or ≥ 1 (adolescents) exacerbation(s) in the 12 months prior to screening. Exacerbations were defined as the presence of ≥ 3 of the following symptoms for at least 48 h resulting in a physician’s decision to prescribe systemic antibiotics: increased cough, increased sputum production or change in sputum consistency, increased sputum purulence, increased breathlessness and/or decreased exercise tolerance, fatigue and/or malaise, or hemoptysis. Key exclusion criteria were a primary diagnosis of chronic obstructive pulmonary disease or asthma (secondary diagnoses were permitted), bronchiectasis due to cystic fibrosis, or known or suspected immunodeficiency disorder. Eligible participants were randomized 1:1:1 (2:2:1 for adolescents) to once-daily oral brensocatib 10 mg or 25 mg or matching placebo for 52 weeks through a central interactive Web-response system. Adults were stratified by geographic region (North America, Europe, Japan, or Rest of World), sputum Pseudomonas (P.) aeruginosa status at screening (positive or negative), and the number of exacerbations in the 12 months before screening (2 or ≥ 3). The trial was conducted in accordance with the principles of the Declaration of Helsinki, the Good Clinical Practice guidelines of the International Council for Harmonisation, and applicable regulatory requirements. An institutional review board or independent ethics committee approved the protocol at each participating site (details provided as supplementary material). All participants provided their written informed consent before starting the study. Adolescents provided their signed assent if required per local requirements, and a parent or legal guardian provided their signed informed consent. For this analysis, participants were included if they self-identified as being of Asian race.
Endpoints and Assessments
Efficacy endpoints included the annualized exacerbation rate, with all reported exacerbation events reviewed by a blinded, independent adjudication committee to determine if the events met the protocol definition and to determine the start and end dates. Severe exacerbations were defined as those requiring intravenous antibiotics and/or hospitalization. Additional efficacy endpoints were the time to first exacerbation, proportion of participants remaining exacerbation-free at week 52, annualized rate of severe exacerbations, changes from baseline to week 52 in post-bronchodilator (post-BD) FEV1, forced vital capacity (FVC), and forced expiratory flow between 25% and 75% of vital capacity [FEF(25–75%)], change from baseline to week 52 in QOL-B RSS score in adults, and change from baseline to week 52 in overall BEST symptom diary score in adults. Safety was monitored from enrollment through the end of study (week 56), with endpoints including clinical laboratory tests, vital signs, and adverse events (AEs). Safety monitoring included AEs of special interest, specifically hyperkeratosis, periodontitis/gingivitis, and severe or opportunistic infections. Hyperkeratosis and periodontitis/gingivitis were included based on evidence from individuals with Papillon–Lefèvre syndrome, a rare genetic condition caused by a near-complete lack of DPP1 [23]. An independent, external data monitoring committee reviewed all AEs.
Statistical Analysis
The statistical methods used for this prespecified subgroup analysis were similar to those for the overall ASPEN trial [21]. The annualized rate of pulmonary exacerbations was analyzed using a negative binomial model with treatment group and stratification factors as the fixed effects and the time at risk (log scale) as an offset variable. Analysis of efficacy endpoints was based on the intent-to-treat population, i.e., all randomized participants using the treatment to which they were randomized. Safety analyses were based on the safety population, i.e., all participants who received at least 1 dose of study treatment. AEs were categorized based on their description in the investigator’s report and coded using the Medical Dictionary for Regulatory Activities (MedRA) version 27.0. All statistical analyses were conducted using SAS version 9.4 (SAS Institute, Cary, NC, USA). All p values for statistical differences between brensocatib treatment groups and placebo in participants of Asian race should be considered nominal without multiplicity control. Significance was set at p ≤ 0.05. No statistical comparisons were made between participants of Asian race and the overall ASPEN population.
Results
Participant Population and Baseline Characteristics
In total, 191 (11.1%) participants from the overall ASPEN population (n = 1721) were of Asian race (brensocatib 10 mg, n = 63; brensocatib 25 mg, n = 64; placebo, n = 64). The mean (SD) age of participants of Asian race was 64.0 (12.6) years, and 39 (20.4%) were aged ≥ 75 years, compared with 60.2 (15.7) years and 260 (15.1%) in the overall ASPEN population (Table 1). The majority of participants of Asian race were female (n = 113; 59.2%), which was slightly lower than in the overall ASPEN population (n = 1107; 64.3%). Moreover, the majority of participants of Asian race were from Asian countries (n = 175, 91.6%), with 13 (6.8%) participants from Western countries and 3 (1.6%) participants from Oceania. The most common underlying causes of bronchiectasis in participants of Asian race were idiopathic or other (77.0%), pneumonia/childhood infections (13.1%), and allergic bronchopulmonary aspergillosis (ABPA; 4.2%). A larger proportion of participants of Asian race had idiopathic etiology or ABPA as the underlying cause compared with the overall ASPEN population (58.5% and 0.8%, respectively), but fewer had pneumonia/childhood infection as an underlying cause (29.2% in the overall ASPEN population). Primary ciliary dyskinesia was the underlying cause in 2.1% of participants of Asian race versus 6.9% in the overall ASPEN population. In general, history of relevant bacterial infections, including nontuberculous mycobacteria infections, was similar across treatment groups in participants of Asian race but higher in participants of Asian race than in the overall ASPEN population.
Table 1.
Demographic and clinical characteristics of participants of Asian race and the overall ASPEN population at baseline
| Participants of Asian race | Overall ASPEN population (N = 1721) | ||||
|---|---|---|---|---|---|
| Brensocatib 10 mg (n = 63) | Brensocatib 25 mg (n = 64) | Placebo (n = 64) | Overall (n = 191) | ||
| Age, mean (SD), years | 63.1 (15.2) | 66.0 (10.9) | 62.8 (11.1) | 64.0 (12.6) | 60.2 (15.7) |
| ≥ 75 years, n (%) | 16 (25.4) | 14 (21.9) | 9 (14.1) | 39 (20.4) | 260 (15.1) |
| Female, n (%) | 35 (55.6) | 38 (59.4) | 40 (62.5) | 113 (59.2) | 1107 (64.3) |
| Male, n (%) | 28 (44.4) | 26 (40.6) | 24 (37.5) | 78 (40.8) | 614 (35.7) |
| Geographic region, n (%)a | |||||
| South America | 0 | 0 | 0 | 0 | 488 (28.4) |
| Eastern Europe | 0 | 0 | 0 | 0 | 215 (12.5) |
| Western countries | 6 (9.5) | 2 (3.1) | 5 (7.8) | 13 (6.8) | 622 (36.1) |
| Asian countries | 56 (88.9) | 60 (93.8) | 59 (92.2) | 175 (91.6) | 260 (15.1) |
| Oceania | 1 (1.6) | 2 (3.1) | 0 | 3 (1.6) | 136 (7.9) |
| BMI, mean (SD), kg/m2 | 22.3 (3.1) | 22.3 (3.2) | 21.9 (3.6) | 22.2 (3.3) | 25.3 (5.2) |
| Causes of bronchiectasis, n (%) | |||||
| Idiopathic or other | 47 (74.6) | 51 (79.7) | 49 (76.6) | 147 (77.0) | 1006 (58.5) |
| Injury: pneumonia or childhood infection | 9 (14.3) | 8 (12.5) | 8 (12.5) | 25 (13.1) | 503 (29.2) |
| Hypersensitivity: ABPA | 2 (3.2) | 4 (6.3) | 2 (3.1) | 8 (4.2) | 13 (0.8) |
| Cilia abnormalities: primary ciliary dyskinesia | 3 (4.8) | 0 | 1 (1.6) | 4 (2.1) | 118 (6.9) |
| Autoimmune disease: rheumatoid arthritis | 0 | 0 | 2 (3.1) | 2 (1.0) | 6 (0.3) |
| Injury: smoke inhalation | 0 | 1 (1.6) | 1 (1.6) | 2 (1.0) | 25 (1.5) |
| Autoimmune disease: Sjogren’s syndrome | 0 | 0 | 1 (1.6) | 1 (0.5) | 3 (0.2) |
| Connective tissue disease: tracheobronchomegaly (Mounier-Kuhn syndrome) | 1 (1.6) | 0 | 0 | 1 (0.5) | 2 (0.1) |
| Injury: aspiration | 1 (1.6) | 0 | 0 | 1 (0.5) | 17 (1.0) |
| Chronic use of antibiotics, n (%) | 30 (47.6) | 24 (37.5) | 29 (45.3) | 83 (43.5) | 433 (25.2) |
| Use of macrolides | 26 (41.3) | 24 (37.5) | 25 (39.1) | 75 (39.3) | 329 (19.1) |
| Use of inhaled steroids, n (%) | 18 (28.6) | 24 (37.5) | 30 (46.9) | 72 (37.7) | 1000 (58.1) |
| P. aeruginosa-positive, n (%)b | 32 (50.8) | 32 (50.0) | 30 (46.9) | 94 (49.2) | 607 (35.3) |
| History of relevant bacterial infection, n (%)c | |||||
| Mycobacterium avium complex | 8 (12.7) | 7 (10.9) | 5 (7.8) | 20 (10.5) | 68 (4.0)d |
| Atypical mycobacterial infection | 1 (1.6) | 2 (3.1) | 1 (1.6) | 4 (2.1) | 5 (0.3)d |
| Mycobacterium abscessus | 1 (1.6) | 0 | 1 (1.6) | 2 (1.0) | 7 (0.4)d |
| Mycobacterial infection | 1 (1.6) | 0 | 0 | 1 (0.5) | 2 (0.1)d |
| Mycobacterium fortuitum | 0 | 0 | 1 (1.6) | 1 (0.5) | 2 (0.1)d |
| Mycobacterium chelonae | 0 | 0 | 0 | 0 | 1 (0.1)d |
| Haemophilus influenzae | 1 (1.6) | 0 | 0 | 1 (0.5) | 10 (0.6)d |
| Aspergillus fumigatus | 1 (1.6) | 1 (1.6) | 1 (1.6) | 3 (1.6) | 5 (0.3)d |
| Exacerbations in previous 12 months, n (%)b | |||||
| 2e | 39 (61.9) | 43 (67.2) | 41 (64.1) | 123 (64.4) | 1219 (70.8) |
| ≥ 3 | 24 (38.1) | 21 (32.8) | 23 (35.9) | 68 (35.6) | 502 (29.2) |
| BSI score, mean (SD) | 7.5 (3.7) | 7.8 (3.7) | 8.0 (3.6) | 7.8 (3.7) | 7.1 (3.6)f |
| BE-CT score, mean (SD) | 10.6 (3.2) | 10.8 (2.8) | 11.2 (3.6) | 10.8 (3.2) | 9.3 (3.3) |
| Hospitalized in prior 24 months for exacerbation, n (%) | 14 (22.2) | 17 (26.6) | 20 (31.3) | 51 (26.7) | 421 (24.5) |
| Post-BD FEV1, mean (SD), % predicted | 84.6 (21.7) | 86.2 (27.4) | 74.2 (23.7) | 81.6 (24.8) | 73.5 (23.4)f |
| Post-BD FVC, mean (SD), % predicted | 91.1 (19.7) | 87.9 (22.3) | 81.8 (19.7) | 86.9 (20.8) | 81.9 (19.4)f |
| Post-BD FEF(25–75%), mean (SD), L/s | 1.31 (0.90) | 1.37 (0.77) | 1.10 (0.75) | 1.26 (0.81) | 1.39 (0.99)f |
| Blood eosinophil count ≥ 300 cells/μL, n (%) | 15 (23.8) | 11 (17.2) | 9 (14.1) | 35 (18.3) | 332 (19.3) |
| Blood neutrophil count > 5000 cells/μL, n (%) | 22 (34.9) | 17 (26.6) | 26 (40.6) | 65 (34.0) | 540 (31.4)d |
| History of COPD, n (%) | 16 (25.4) | 7 (10.9) | 15 (23.4) | 38 (19.9) | 262 (15.2) |
| History of asthma, n (%) | 9 (14.3) | 14 (21.9) | 9 (14.1) | 32 (16.8) | 321 (18.7) |
| History of smoking, n (%)g | 15 (23.8) | 14 (21.9) | 22 (34.4) | 51 (26.7) | 510 (29.6) |
| QOL-B RSS, mean (SD)h | |||||
| n | 60 | 60 | 60 | 180 | 1472 |
| Mean (SD) | 60.4 (18.7) | 62.6 (16.4) | 61.8 (16.5) | 61.6 (17.1) | 60.6 (17.0) |
ABPA allergic bronchopulmonary aspergillosis, BE-CT Bronchiectasis–Computed Tomography, BMI body mass index, BSI Bronchiectasis Severity Index, COPD chronic obstructive pulmonary disease, FEF(25–75%) forced expiratory flow between 25 and 75% of vital capacity, FEV1 forced expiratory volume in 1 s, FVC forced vital capacity P. aeruginosa Pseudomonas aeruginosa, post-BD post-bronchodilator QOL-B RSS Quality of Life–Bronchiectasis Respiratory Symptom Score
aCountries in each geographic region are as follows: South America—Argentina, Brazil, Chile, Colombia, Mexico, Peru; Eastern Europe—Bulgaria, Greece, Hungary, Latvia, Poland, Serbia, Slovakia, Turkey, Ukraine; Western countries—Austria, Belgium, Canada, Denmark, France, Germany, Ireland, Italy, Netherlands, Portugal, Spain, United Kingdom, United States of America; Asian countries—Israel, Japan, Korea (Republic of), Malaysia, Taiwan, Thailand; Oceania—Australia, New Zealand
bStratification criteria for adults
cParticipants may have had more than one relevant infection
dn = 1719
eAdolescents were permitted to have ≥ 1 exacerbation in the prior 12 months. Adolescents with 1 exacerbation are included in the 2-exacerbations category
fn = 1713
gCurrent smokers were excluded from the study
hQOL-B RSS score was measured in only adult participants and is scored from 0 to 100. Higher scores reflect fewer symptoms
At baseline, some of the participant characteristics suggested that participants of Asian race had greater disease severity than those in the overall ASPEN population (Table 1). For instance, a larger proportion of participants of Asian race had ≥ 3 exacerbations in the prior 12 months compared with the overall ASPEN population, were P. aeruginosa positive, had higher mean (SD) Bronchiectasis Severity Index (BSI) and Bronchiectasis–Computed Tomography (BE-CT) scores, and higher antibiotic use including macrolides. However, a similar proportion of participants of Asian race were hospitalized in the prior 24 months compared with the overall ASPEN population, both populations had similar mean QOL-B RSS scores, and participants of Asian race had lower inhaled steroid use. Moreover, participants of Asian race had higher mean post-BD % predicted FEV1 and FVC compared with the overall ASPEN population. Mean post-BD FEF(25–75%) was lower in participants of Asian race compared with the overall ASPEN population, suggesting marginally worse small airway function and more localized airway disease in participants of Asian race.
Annualized Exacerbation Rate
In participants of Asian race, both doses of brensocatib significantly reduced the annualized exacerbation rate versus placebo (Fig. 1A). The annualized exacerbation rates (95% CI) were 0.48 (0.31–0.73) and 0.49 (0.31–0.78) for brensocatib 10 mg and 25 mg, respectively, and 1.21 (0.88–1.65) for placebo. Rate ratios (95% CI) versus placebo were 0.40 (0.23–0.67) (p = 0.0005) and 0.41 (0.24–0.70) (p = 0.0012) for brensocatib 10 mg and 25 mg, respectively, corresponding to an approximate 60% risk reduction in both brensocatib groups. The reduction in annualized exacerbation rate (95% CI) with brensocatib treatment was numerically larger in participants of Asian race than in the overall ASPEN population [brensocatib 10 mg, 1.02 (0.91–1.13); brensocatib 25 mg, 1.04 (0.93–1.16); placebo, 1.29 (1.16–1.43)], giving rate ratios (95% CI) versus placebo of 0.79 (0.68–0.92) for brensocatib 10 mg and 0.81 (0.69–0.94) for brensocatib 25 mg [21].
Fig. 1.
Annualized exacerbation rate over 52 weeks in participants of Asian race. Exacerbations were adjudicated events. The annualized exacerbation rate was estimated using a negative binomial model with treatment group and stratification factors as the fixed effects and the time at risk (log scale) as an offset variable
The annualized rates of severe exacerbations in participants of Asian race were not estimable by negative binomial model for any treatment group. In total, 3 (4.8%) participants in the brensocatib 10-mg group, 5 (7.8%) participants in the brensocatib 25-mg group, and 11 (17.2%) participants in the placebo group had a severe exacerbation.
Time to First Exacerbation
Brensocatib 10 mg and 25 mg significantly prolonged the time to first exacerbation versus placebo in participants of Asian race (Fig. 2A). The median time (95% CI) to first exacerbation was not estimable for either dose of brensocatib and was 39.86 weeks (28.57, not estimable) for the placebo group. Hazard ratios (95% CI) versus placebo were 0.45 (0.26–0.77) (p = 0.0039) and 0.47 (0.27–0.82) (p = 0.0082) for brensocatib 10 mg and 25 mg, respectively, corresponding to a hazard reduction of approximately 55% for both brensocatib doses. The reduction in hazard in participants of Asian race was numerically greater than in the overall ASPEN population where the median time (95% CI) to first exacerbation was 49.00 weeks (40.00–not estimable) for brensocatib 10 mg, 50.71 weeks (37.57, not estimable) for brensocatib 25 mg, and 36.71 (31.14–41.43) for placebo [21]. Hazard ratios (95% CI) were 0.81 (0.70–0.95) for the 10-mg dose and 0.83 (0.70–0.97) for the 25-mg dose versus placebo [21].
Fig. 2.
a Time to first exacerbation in participants of Asian race and b proportion of participants of Asian race remaining exacerbation-free at week 52. In a, week 1 refers to the baseline assessment. In b, data for those participants who withdrew from the trial early were imputed because they might have had an exacerbation had they remained in the trial. Analysis in b is based on 100 logistic regression models including treatment group and stratification factors as effects. NE not estimable
Proportion of Participants Exacerbation-Free at Week 52
A significantly greater proportion of participants of Asian race in both brensocatib groups were exacerbation-free versus placebo (Fig. 2B). In the brensocatib 10-mg and 25-mg groups, 66.1% and 69.0% of participants, respectively, were exacerbation-free versus 42.9% in the placebo group. Odds ratios (95% CI) versus placebo were 3.29 (1.46–7.40) (p = 0.0041) and 3.19 (1.43–7.13) (p = 0.0046) for brensocatib 10 mg and 25 mg, respectively. The odds of remaining exacerbation-free with brensocatib treatment were numerically larger in participants of Asian race than in the overall ASPEN population where the proportion of participants remaining exacerbation-free in the brensocatib 10-mg and 25-mg groups and the placebo group were 48.5%, 48.5%, and 40.3% respectively [21]. Odds ratios (95% CI) versus placebo in the overall ASPEN population were 1.41 (1.11–1.81) for brensocatib 10 mg and 1.40 (1.10–1.79) for brensocatib 25 mg.
Post-BD FEV1 at Week 52
Compared with placebo, participants of Asian race who received brensocatib 10 mg or 25 mg had less decline in post-BD FEV1 (Fig. 3A), significantly so for the 25-mg dose. The least squares (LS) mean (SE) change from baseline in post-BD FEV1 was −62 (14.8) mL for brensocatib 10 mg, −11 (15.6) mL for brensocatib 25 mg, and −80 (16.6) mL for placebo, a difference (95% CI) versus placebo of 18 (−27 to 63) mL (p = 0.4368) for brensocatib 10 mg and 69 (24–114) mL (p = 0.0029) for brensocatib 25 mg. The reductions in post-BD FEV1 decline versus placebo in participants of Asian race were numerically larger than in the overall ASPEN population [21]. In the overall ASPEN population, the LS mean (SE) change from baseline in post-BD FEV1 was −50 (9.3) mL for brensocatib 10 mg, −24 (9.9) mL for brensocatib 25 mg, and −62 (9.4) mL for placebo, a difference (95% CI) versus placebo of 11 (−14 to 37) mL for brensocatib 10 mg and 38 (11–65) mL for brensocatib 25 mg.
Fig. 3.
Change from baseline in post-BD FEV1 over 52 weeks in participants of Asian race. an is the number of participants used in the analysis. Change from baseline was analyzed using a linear repeated measures model including treatment group, visit, treatment-by-visit interaction, and stratification factors as fixed effects, and baseline FEV1 value as covariate. The variance–covariance structure is compound symmetric with the robust sandwich variance estimator. Baseline was defined as the most recent nonmissing assessment determined as best effort prior to the first dose of treatment. FEV1 forced expiratory volume in 1 s, LS least squares, post-BD post-bronchodilator
Post-BD FVC at Week 52
Participants of Asian race who received brensocatib 10 mg and 25 mg had significantly less decline in post-BD FVC compared with placebo (Fig. 4A). The LS mean (SE) change from baseline in post-BD FVC was −36.0 (27.2) mL for brensocatib 10 mg, −10.3 (26.0) mL for brensocatib 25 mg, and −133.1 (27.4) mL for placebo, a difference (95% CI) versus placebo of 97 (20–174) mL (p = 0.0134) for brensocatib 10 mg and 123 (50–196) mL (p = 0.0010) for brensocatib 25 mg. The reductions in post-BD FVC decline with brensocatib treatment in participants of Asian race were numerically larger than those observed in the overall ASPEN population [21]. The LS mean (SE) change from baseline in post-BD FVC was −51 (12) mL for brensocatib 10 mg, −12 (13) mL for brensocatib 25 mg, and −87 (12) mL for placebo, a difference (95% CI) versus placebo of 36 (3–69) mL for brensocatib 10 mg and 75 (40–110) mL for brensocatib 25 mg.
Fig. 4.
Change from baseline in post-BD FVC over 52 weeks in participants of Asian race. an is the number of participants used in the analysis. Change from baseline was analyzed using a linear repeated measures model including treatment group, visit, treatment-by-visit interaction, and stratification factors as fixed effects and baseline FVC value as covariate. The variance–covariance structure is compound symmetric with the robust sandwich variance estimator. Baseline was defined as the most recent nonmissing assessment determined as best effort prior to the first dose of treatment. FVC forced vital capacity, LS least squares, post-BD post-bronchodilator
Post-BD FEF(25–75%) at Week 52
In participants of Asian race, the decline in FEF(25–75%) was numerically larger for brensocatib 10 mg compared with placebo [LS mean change (SE) from baseline, −89 (30.6) mL/s for brensocatib 10 mg and −38 (41.3) mL/s for placebo] (Fig. 5A). By comparison, brensocatib 25 mg numerically increased FEF(25–75%) [LS mean change (SE) from baseline, 40 (47.3) mL/s)]. The LS mean difference (95% CI) versus placebo was −51 (−152 to 50) mL/s (p = 0.3241) for brensocatib 10 mg and 78 (−47 to 203) mL/s (p = 0.2194) for brensocatib 25 mg. The increase in FEF(25–75%) with the brensocatib 25-mg dose in participants of Asian race was not observed in the overall ASPEN population, where there were no notable changes across any treatment group (Fig. 5B). In the overall ASPEN population, the LS mean (SE) change from baseline was −58 (15.8) mL/s for brensocatib 10 mg, −43 (16.9) mL/s for brensocatib 25 mg, and −36 (16.2) mL/s for placebo, giving LS mean differences (95% CI) versus placebo of −22 (−66 to 22) mL/s for brensocatib 10 mg and −8 (−54 to 38) mL/s for brensocatib 25 mg.
Fig. 5.
a Change from baseline in post-BD FEF(25–75%) over 52 weeks in participants of Asian race and b the overall ASPEN population. an is the number of participants used in the analysis. Change from baseline was analyzed using a linear repeated measures model including treatment group, visit, treatment-by-visit interaction, and stratification factors as fixed effects and baseline FEF(25–75%) value as covariate. The variance–covariance structure is compound symmetric with the robust sandwich variance estimator. Baseline was defined as the most recent nonmissing assessment determined as best effort prior to the first dose of treatment. FEF(25–75%) forced expiratory flow between 25 and 75% of vital capacity, LS least squares, post-BD post-bronchodilator
QOL-B RSS at Week 52
Both brensocatib doses significantly increased QOL-B RSS in participants of Asian race compared with placebo (Fig. 6). The LS mean (SE) change from baseline was 2.53 (1.66) points for brensocatib 10 mg, 4.28 (1.63) points for brensocatib 25 mg, and − 3.21 (1.96) points for placebo, giving a LS mean difference (95% CI) versus placebo of 5.74 (0.66–10.82) points (p = 0.0267) for brensocatib 10 mg and 7.49 (2.48–12.50) points (p = 0.0034) for brensocatib 25 mg. These findings were consistent with the overall ASPEN population, where the LS mean (95% CI) change from baseline was 6.84 (0.77) points for brensocatib 10 mg, 8.58 (0.76) points for brensocatib 25 mg, and 4.81 (0.75) points for placebo [21]. The LS mean difference (95% CI) versus placebo was 2.03 (− 0.08 to 4.14) points for brensocatib 10 mg and 3.77 (1.68–5.85) points for brensocatib 25 mg. Changes versus placebo were therefore numerically larger for both doses of brensocatib in the participants of Asian race compared with the overall ASPEN population.
Fig. 6.
Change from baseline in QOL-B RSS over 52 weeks in adult participants of Asian race. an is the number of participants with observations used in the analysis. QOL-B RSS measures respiratory symptoms and was assessed in adults only. Higher scores (range 0–100) reflect fewer symptoms. Change from baseline was analyzed using a linear repeated measures model including treatment group, visit, treatment-by-visit interaction, and stratification factors as fixed effects and baseline QOL-B RSS value as covariate. The variance–covariance structure is compound symmetric with the robust sandwich variance estimator. Baseline was defined as the most recent nonmissing value prior to the first dose of treatment. LS least squares, QOL-B RSS Quality of Life–Bronchiectasis Respiratory Symptom Score
BEST Symptom Diary Score at Week 52
In participants of Asian race, both doses of brensocatib reduced BEST symptom diary scores compared with placebo (Fig. 7), significantly so for the 25-mg dose. The LS mean (SE) change from baseline was − 0.111 (0.197) points for brensocatib 10 mg, − 0.352 (0.182) points for brensocatib 25 mg, and 0.282 (0.167) for placebo, giving a LS mean difference (95% CI) versus placebo of − 0.392 (− 0.908 to 0.123) points (p = 0.1347) for brensocatib 10 mg and − 0.634 (− 1.124 to − 0.144) points (p = 0.0115) for brensocatib 25 mg. These findings were consistent with those in the overall ASPEN population where the LS mean (SE) change from baseline was − 0.594 (0.081) points for brensocatib 10 mg, − 0.999 (0.092) points for brensocatib 25 mg, and − 0.426 (0.091) points for placebo [21]. The LS mean difference (95% CI) versus placebo was − 0.168 (− 0.407 to 0.072) points for brensocatib 10 mg and − 0.572 (− 0.828 to − 0.316) points for brensocatib 25 mg. Changes versus placebo were therefore numerically larger for both doses of brensocatib in the participants of Asian race compared with the overall ASPEN population.
Fig. 7.
Change from baseline in BEST symptom diary score over 52 weeks in participants of Asian race. an is the number of participants with observations used in the analysis. BEST scores range 0–26; lower scores indicate fewer symptoms. Change from baseline was analyzed using a linear repeated measures model including treatment group, visit, treatment-by-visit interaction, and stratification factors as fixed effects and baseline BEST value as covariate. The variance–covariance structure is compound symmetric with the robust sandwich variance estimator. Baseline score was defined as the average from screening to baseline (inclusive). BEST Bronchiectasis Exacerbation and Symptom Tool, LS least squares
Safety in Participants of Asian Race
The frequency of treatment-emergent AEs, serious AEs, and treatment-related AEs were similar across treatment groups in participants of Asian race (Table 2). Few treatment-emergent AEs led to treatment discontinuation or study discontinuation in each treatment group. The most commonly reported treatment-emergent AEs occurring in ≥ 5% of participants in any treatment group and with a higher incidence in either brensocatib group than in the placebo group were hemoptysis, eczema, nasopharyngitis, pain in extremity, arthralgia, upper respiratory tract infection, and rash (Table 2). For the AEs of special interest (Table 2), hyperkeratosis was reported in 1 (1.6%) participant in the brensocatib 10-mg group, 5 (7.8%) participants in the brensocatib 25-mg group, and no participants in the placebo group. One (1.6%) participant in the brensocatib 10-mg group reported periodontitis/gingivitis as did 4 (6.3%) participants in the brensocatib 25-mg group and 3 (4.7%) participants in the placebo group. No participants in any treatment group reported severe infection. Pneumonia was reported in 2 (3.2%), 2 (3.1%), and 4 (6.3%) participants in the brensocatib 10-mg, brensocatib 25-mg, and placebo groups, respectively. The safety profile of both doses of brensocatib was consistent with the overall ASPEN population as described previously [21].
Table 2.
Treatment-emergent adverse events in participants of Asian race by treatment group
| Brensocatib 10 mg (n = 63) | Brensocatib 25 mg (n = 64) | Placebo (n = 64) | |
|---|---|---|---|
| Any AE, n (%) | 55 (87.3) | 48 (75.0) | 54 (84.4) |
| Serious AE | 11 (17.5) | 8 (12.5) | 16 (25.0) |
| Related AE | 9 (14.3) | 10 (15.6) | 11 (17.2) |
| Serious related AE | 0 | 0 | 0 |
| AE leading to treatment discontinuation | 3 (4.8) | 5 (7.8) | 4 (6.3) |
| AE leading to study discontinuation | 3 (4.8) | 1 (1.6) | 4 (6.3) |
| AE, n (%)a | |||
| Hemoptysis | 6 (9.5) | 3 (4.7) | 5 (7.8) |
| Eczema | 4 (6.3) | 1 (1.6) | 2 (3.1) |
| Nasopharyngitis | 4 (6.3) | 7 (10.9) | 4 (6.3) |
| Pain in extremity | 4 (6.3) | 2 (3.1) | 0 |
| Arthralgia | 3 (4.8) | 4 (6.3) | 1 (1.6) |
| Upper respiratory tract infection | 3 (4.8) | 4 (6.3) | 0 |
| Rash | 1 (1.6) | 7 (10.9) | 3 (4.7) |
| Any AE of special interest, n (%)b | 4 (6.3) | 8 (12.5) | 7 (10.9) |
| Hyperkeratosis | 1 (1.6) | 5 (7.8) | 0 |
| Periodontitis/gingivitis | 1 (1.6) | 4 (6.3) | 3 (4.7) |
| Severe infection | 0 | 0 | 0 |
| Pneumonia | 2 (3.2) | 2 (3.1) | 4 (6.3) |
Treatment-emergent AEs were defined as occurring up to 28 days after last dose of study treatment. Safety analysis sets included all participants who were randomized and received ≥ 1 dose of brensocatib or placebo
AE adverse event, DPP1 dipeptidyl peptidase 1
aTreatment-emergent adverse events occurring in ≥ 5% of participants of Asian race in any treatment group and with a higher incidence in either of the brensocatib groups compared with the placebo group. AEs are arranged based on descending frequency in the brensocatib 10-mg group
bCertain AEs (hyperkeratosis and periodontitis/gingivitis) were of special interest with brensocatib treatment due to their presence in Papillon–Lefèvre syndrome, which is characterized by mutations of the DPP1 gene and near-complete loss of DPP1 function [23]
Discussion
This study demonstrates the benefits of brensocatib 10 mg and 25 mg versus placebo on exacerbation burden, lung function, and patient-reported symptoms in participants of Asian race with bronchiectasis. Although findings were generally consistent with the results of the overall ASPEN study [21], the benefits of brensocatib versus placebo were generally numerically larger in participants of Asian race. Thus, we observed a numerically larger risk reduction in the rate of exacerbations, a prolonged time to first exacerbation, and increased odds of remaining exacerbation-free for both doses of brensocatib in the participants of Asian race compared with the overall ASPEN population. Similarly, the reductions in lung function decline, as measured by post-BD FEV1 and FVC, and improvements in patient-reported symptoms were numerically greater for the 25-mg dose versus placebo in the participants of Asian race compared with the overall ASPEN population. Moreover, as has previously been reported in the overall ASPEN population and other subgroups, the 25-mg dose demonstrated greater numerical improvement, particularly in lung function and patient-reported symptoms endpoints, compared with the 10-mg dose in participants of Asian race [21, 24].
At baseline, some of the participant characteristics indicated that participants of Asian race generally had greater disease severity compared with the overall ASPEN population. For instance, a larger proportion had ≥ 3 exacerbations in the prior 12 months or were P. aeruginosa-positive, and BSI and BE-CT scores were higher. In contrast, participants of Asian race at baseline had higher post-BD % predicted FEV1 compared with the overall ASPEN population, indicating large airway function was relatively less compromised in participants of Asian race. However, proximal and distal bronchioles are known to contribute to the pathogenesis of bronchiectasis [25], and individuals of Asian race, particularly those in East Asia, are susceptible to diffuse panbronchiolitis, which is predominantly characterized by inflammation in small airways [26, 27]. Part of this analysis, therefore, evaluated baseline FEF(25–75%), a measure of small airway function, and the effect of brensocatib on FEF(25–75%). At baseline, participants of Asian race had numerically lower FEF(25–75%) compared with the overall ASPEN population, indicating more compromised small airway function. In the overall ASPEN population, the effects of both doses of brensocatib on FEF(25–75%) were minimal with changes at 52 weeks similar to those in the placebo group. For the brensocatib 10-mg dose in the participants of Asian race, there was greater decline in FEF(25–75%) at 52 weeks versus placebo. However, in the brensocatib 25-mg group there was a numerical increase in FEF(25–75%) compared with placebo, indicating a potentially beneficial effect of brensocatib on small airway function at this dose. These results highlight that brensocatib at 25 mg may selectively have positive effects on bronchiectatic small airways in participants of Asian race, although further studies would need to confirm this finding.
The results reported here were similar to those recently described in a prespecified analysis of Japanese participants (n = 87) from the ASPEN trial [24]. In Japanese participants, the efficacy of brensocatib at 10 mg and 25 mg versus placebo were generally consistent with the overall ASPEN population. In agreement with the data in participants of Asian race shown here, the effects of brensocatib versus placebo in Japanese participants for some endpoints numerically exceeded those in the overall ASPEN population. It should be acknowledged that Japanese participants comprised part of the cohort of participants of Asian race, albeit there were more than twice as many participants of Asian race as Japanese participants in ASPEN. Nonetheless, the two datasets provide supportive evidence that the beneficial effects of brensocatib may be numerically greater in participants of Asian origin than in non-Asian participants.
Brensocatib is the first-in-class DPP1 inhibitor to receive regulatory approval for the treatment of bronchiectasis in the US, Europe, and the UK [18]. Other DPP1 inhibitors are currently in development for the treatment of bronchiectasis and have been examined, at least in part, in specific Asian populations. In the phase 2 SAVE-BE, randomized, placebo-controlled trial conducted specifically in Chinese adults, the DPP1 inhibitor HSK31858 at doses of 20 mg and 40 mg significantly reduced exacerbation frequency, increased the likelihood of remaining exacerbation-free, and increased the time to first exacerbation versus placebo at 24 weeks [28]. However, neither dose improved lung function as measured by % predicted FEV1 [28]. The DPP1 inhibitor BI 1291583 has been evaluated in the phase 2 trial AIRLEAF [29]. In a prespecified subgroup analysis of AIRLEAF in individuals from Asia, doses of 1, 2.5, and 5 mg showed a greater benefit versus placebo in time to first exacerbation. A randomized phase 1 study of BI 1291583 in healthy Japanese subjects evaluated safety and pharmacokinetics and did not identify any safety or exposure concerns [30]. No clinically significant differences in the pharmacokinetics of brensocatib have been observed based on race, including in participants of Asian race [18] and specifically in Japanese participants [31]. These results, together with our findings, indicate that DPP1 inhibitors are associated with enhanced benefits in participants of Asian race. The mechanisms of this are unclear and do not appear related to pharmacokinetics or disease severity but may be due to differences in exposure/environment, genetics, and/or cultural-related factors. Further research is required to understand the mechanism of the enhanced response.
This subgroup analysis had several limitations. First, the comparisons between treatment groups in participants of Asian race should be considered hypothesis generating only, because the study was not powered to detect treatment differences in subgroups, and no treatment by subgroup interaction was performed. All reported p values are nominal. Second, the sample size of participants of Asian race was relatively small, and larger statistically powered trials are required to confirm the benefits of brensocatib in this population, particularly for secondary and exploratory endpoints. Third, participants self-identified as being of Asian race rather than identification being based on geography or genetics; therefore, the population should not be interpreted as biologically homogenous.
Conclusions
In participants of Asian race enrolled in the ASPEN trial, brensocatib 10 mg and 25 mg reduced the burden of pulmonary exacerbations, improved lung function, and improved patient-reported symptoms compared with placebo. Generally, the improvements observed in participants of Asian race were consistent with those in the overall ASPEN population, although some endpoints demonstrated numerically greater benefit. This finding of potentially greater benefits in participants of Asian race expands upon similar findings from Japanese participants enrolled in ASPEN [24]. Safety in participants of Asian race was generally comparable across treatment groups and consistent with previously reported safety for the overall ASPEN cohort, although the incidence of hyperkeratosis was higher in the brensocatib 25-mg group. Despite some differences in baseline characteristics from the overall ASPEN population, these results demonstrate the positive impact of brensocatib in participants of Asian race with bronchiectasis.
Supplementary Information
Below is the link to the electronic supplementary material.
Acknowledgements
The authors thank the participants of the study.
Medical Writing, Editorial, and Other Assistance
Medical writing support was provided by David Cope, PhD, of Envision Spark, an Envision Medical Communications agency, and funded by Insmed Incorporated.
Author Contributions
Study design: Xiangmin Zhang, Chunpeng Fan, Melanie Lauterio, Sebastian Fucile, Dianne Griffis, Ariel Teper; Data collection: Doreen Addrizzo-Harris, James D. Chalmers, Stefano Aliberti, Pierre-Régis Burgel, Brian M. Morrissey; Data interpretation: all authors; Statistical analysis: Xiangmin Zhang, Chunpeng Fan; Manuscript review and revisions: all authors; Approved final version for submission: all authors. All authors made substantial contributions to the conception or design of the work, or the acquisition, analysis, or interpretation of data, or the creation of new software used in the work; drafted the work or revised it critically for important intellectual content; approved the version to be published; and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Funding
This study and the journal’s Rapid Service Fee was funded by Insmed Incorporated.
Data Availability
All data generated or analyzed during this study are included in this published article.
Declarations
Conflict of Interest
Doreen Addrizzo-Harris: clinical trial support to the institution from AN2 Therapeutics, Armata Pharmaceuticals, Chiesi, Boehringer Ingelheim, Hillrom, Insmed Incorporated, Novartis, Sanofi, Verona, and Zambon; consulting fees from AstraZeneca, Boehringer Ingelheim, Clarametyx, MannKind, Paratex, and Sanofi; and member of the data and safety monitoring board for MannKind. James D. Chalmers: grants and personal fees from AstraZeneca, Boehringer Ingelheim, GSK, Insmed Incorporated, and Zambon; a grant from Gilead; and personal fees from Chiesi and Novartis. Stefano Aliberti: grant support from GSK; consulting fees from AN2 Therapeutics, AstraZeneca, Boehringer Ingelheim, BRAHMS GmbH, Chiesi Farmaceutica SpA, CSL Behring GmbH, Fondazione Internazionale Menarini, GlaxoSmithKline SpA, Insmed Incorporated, Menarini, Moderna, MSD Italia Srl, Pfizer, PhysioAssist SAS, Verona Pharma PLC, Vertex Pharmaceuticals, and Zambon SpA; speaking fees from Boehringer Ingelheim, Fondazione Internazionale Menarini, GlaxoSmithKline SpA, Insmed Incorporated, Vertex Pharmaceuticals, and Zambon; data monitoring committee work with AstraZeneca, Insmed Incorporated, MSD Italia Srl, and Verona Pharma PLC. Pierre-Régis Burgel: grants from GSK and Vertex, outside the submitted work; clinical trials advisory activity for AstraZeneca, Chiesi, GSK, Insmed Incorporated, MSD, Vertex, Viatris, and Zambon; substantial financial contributions to the budget of his institution from Association Vaincre la Mucoviscidose, Filière MUCO-CFTR, GSK, Société Française de la Mucoviscidose, and Vertex. Pierre-Régis Burgel is an editorial board member of Pulmonary Therapy. Pierre-Régis Burgel was not involved in the selection of peer reviewers for the manuscript nor any of the subsequent editorial decisions. Brian M. Morrissey: grants from the Cystic Fibrosis Foundation and clinical trial support to the institution from Boehringer Ingelheim, CSL Behring, Insmed Incorporated, US National Institutes of Health, and Vertex Pharmaceuticals. Xiangmin Zhang, Chunpeng Fan, Melanie Lauterio, Sebastian Fucile, Dianne Griffis, and Ariel Teper: employees and shareholders of Insmed Incorporated.
Ethical Approval
The trial was conducted in accordance with the principles of the Declaration of Helsinki, the Good Clinical Practice guidelines of the International Council for Harmonisation, and applicable regulatory requirements. An institutional review board or independent ethics committee approved the protocol at each participating site (details provided as supplementary material). All participants provided their written informed consent before starting the study. Adolescents provided their signed assent if required per local requirements, and a parent or legal guardian provided their signed informed consent.
Footnotes
Prior Presentation: Previously presented at the American College of Chest Physicians (CHEST) annual meeting, October 19–22, 2025; Chicago, IL, USA © 2026.
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Data Availability Statement
All data generated or analyzed during this study are included in this published article.