Highlights
– A 100‑patient CT substudy of the phase 3 ASPEN trial found that oral brensocatib (25 mg) reduced bronchiectasis subscores for mucus plugging and increased percent healthy parenchyma at 52 weeks versus placebo (nominal P values .0084 and .0154).
– On quantitative AI‑assisted airway measures (LungQ‑BA), 25 mg was associated with fewer bronchus‑artery pairs (P = .0499); the 10‑mg dose showed significantly smaller bronchus outer diameters versus placebo.
– Findings are hypothesis generating: small sample size, multiple comparisons, and semi‑quantitative scoring limit definitive claims that brensocatib is disease modifying, but the imaging signals complement clinical benefits observed in the parent ASPEN trial.
Background and Unmet Need
Noncystic fibrosis bronchiectasis (NCFB) is a chronic airway disease characterized by persistent neutrophilic inflammation, recurrent infective exacerbations, airway dilation, mucus retention, and progressive lung damage. Exacerbations drive morbidity, accelerate lung function decline, and increase healthcare utilization. Therapeutic options to reduce exacerbation frequency are limited, and true disease‑modifying treatments that slow structural progression are lacking.
Brensocatib (Brinsupri), an oral inhibitor of dipeptidyl peptidase‑1 (DPP‑1), targets upstream activation of neutrophil serine proteases (including neutrophil elastase, proteinase 3, and cathepsin G) and was developed to blunt neutrophil‑mediated airway injury. In April 2025 the phase 3 ASPEN trial reported that once‑daily brensocatib reduced exacerbation risk, prolonged time to first exacerbation, and increased the odds of remaining exacerbation‑free over one year. In August 2025 the FDA approved brensocatib (10‑mg and 25‑mg oral doses) for adults and adolescents 12 years and older with NCFB who meet criteria based on the label.
Study Design: CT Substudy of the ASPEN Trial
Investigators performed an imaging substudy within the larger ASPEN phase 3 program to assess whether brensocatib affects structural lung disease over 52 weeks. The substudy analyzed paired computed tomography (CT) scans from 100 trial participants randomized in ASPEN: 37 received brensocatib 10 mg daily, 24 received 25 mg daily, and 39 received placebo.
CTs were scored at baseline and at 52 weeks using two complementary approaches: the Bronchiectasis Scoring Technique for CT (BEST‑CT), a semi‑quantitative visual scoring tool developed and validated in bronchiectasis registries, and LungQ‑BA, an artificial intelligence–assisted quantitative platform that extracts airway metrics (for example, bronchus–artery pairs and airway diameters). Primary analyses compared within‑group change at 52 weeks and between‑group differences versus placebo. The substudy was presented at the CHEST 2025 Annual Meeting by James D. Chalmers et al.
Key Findings
Overall, analyses demonstrated modest but statistically significant imaging differences favoring brensocatib—most consistently with the 25‑mg dose—across mucus‑related and some airway metrics at 52 weeks.
Mucus Plugging and Parenchymal Change (BEST‑CT)
– The 25‑mg arm showed significant reductions in BEST‑CT subscores for bronchiectasis with mucus plugging and for mucus plugging overall compared with placebo (P = .0084 and P = .0154, respectively).
– Patients receiving 25 mg also had a greater increase in the percentage of “healthy” lung parenchyma at 52 weeks compared with placebo.
Airway Metrics (LungQ‑BA)
– On LungQ‑BA, patients randomized to 25 mg had significantly fewer bronchus–artery pairs at 52 weeks versus placebo (P = .0499). Fewer bronchus–artery pairs can reflect reductions in bronchial wall thickening or other airway remodeling features captured by the platform.
– The 10‑mg group demonstrated significantly smaller bronchus outer diameter measures than placebo at 52 weeks, suggesting a dose‑independent signal for some airway caliber changes.
Clinical Correlation
These imaging results align with the clinical outcomes reported in the parent ASPEN program: fewer exacerbations, delayed time to first exacerbation, and slower lung function decline with brensocatib—particularly noted for the 25‑mg dose. The investigators and independent commentators interpreted the imaging signals as consistent with a biologically plausible downstream effect of DPP‑1 inhibition on mucus clearance and airway inflammation.
Safety and Dosing Considerations
The ASPEN program established the overall safety profile that supported FDA approval of brensocatib 10 mg and 25 mg. In the imaging substudy, no new safety signals were reported in relation to CT findings. Based on the combined clinical and imaging data, some investigators favor the 25‑mg dose as first‑line for patients at higher risk of progression or those with marked mucus plugging, while acknowledging the label allows either dose.
Mechanistic Rationale
DPP‑1 inhibition reduces maturation of neutrophil serine proteases in the bone marrow, thereby lowering the burden of activated proteases delivered to the airway during neutrophilic inflammation. Neutrophil elastase and related enzymes contribute to mucus hypersecretion, impaired mucociliary clearance, airway wall damage, and progressive dilation. The observed reductions in mucus plugging provide a mechanistic bridge: attenuated neutrophil protease activity may decrease mucus production/tenacity and airway wall inflammation, enabling improvements detectable on CT over 12 months.
Expert Commentary and Interpretation
Independent experts at CHEST and in subsequent interviews highlighted that structural change on CT over a single year is uncommon in bronchiectasis because the disease often progresses slowly. That the substudy detected reductions in mucus plugging and small airway changes is therefore notable, but several cautionary points apply:
- The substudy enrolled 100 patients, a small fraction of the ASPEN cohort (>1,700 overall), limiting power and generalizability.
- Multiple endpoints and comparisons were tested, and reported P values were nominal (not adjusted for multiplicity), increasing the risk of type I error.
- BES T‑CT is semi‑quantitative and reader‑dependent; although validated in registry work, visual scoring introduces variability. The addition of LungQ‑BA (AI‑based metrics) mitigates but does not eliminate measurement uncertainty.
Consequently, experts describe the findings as hypothesis generating rather than definitive proof of disease modification. They nonetheless consider the results clinically meaningful in the context of symptomatic and exacerbation benefits observed in ASPEN, and assert that the strongest expected benefits will be in patients with neutrophil‑predominant disease and frequent exacerbations despite standard airway clearance and antibiotic strategies.
Limitations
Key limitations include: the modest substudy sample size relative to the parent trial; nominal P values without correction for multiple comparisons; potential reader variability in semi‑quantitative scoring; and the 52‑week follow‑up interval, which may be short to detect structural change in many patients. Funding and contribution by the manufacturer, Insmed, were disclosed and some investigators reported consulting or grant relationships with Insmed, which should be considered in interpretation.
Clinical Implications and Practical Guidance
For clinicians managing NCFB, the totality of ASPEN data plus this CT substudy supports considering brensocatib (particularly 25 mg) for adults and adolescents with frequent exacerbations or progressive lung function decline despite guideline‑recommended airway clearance and antibiotic strategies. Patients with prominent mucus plugging on CT or high risk for progression may be prioritized. Real‑world considerations including cost, payer coverage, and long‑term adherence will influence uptake. Shared decision‑making should weigh individual exacerbation history, phenotype (neutrophilic inflammation), comorbidities, and patient preferences.
Research and Policy Directions
To confirm and quantify structural benefits, the field needs larger, prospectively planned imaging cohorts or inclusion of imaging endpoints across the whole trial population with prespecified endpoints and multiplicity control. Longer follow‑up (>1 year), phenotype‑based subgroup analyses, and real‑world registries assessing safety, adherence, cost‑effectiveness, and longer‑term structural outcomes will be important. Standardization of CT acquisition and scoring—or wider use of validated AI‑driven analytic platforms—would improve reproducibility across studies.
Conclusion
The CT substudy from the ASPEN program offers the first imaging evidence that brensocatib may reduce mucus plugging and produce modest improvements in airway metrics and healthy parenchyma over 52 weeks, with the 25‑mg dose showing the most consistent signal. These data complement clinical reductions in exacerbations and slower lung function decline reported in the parent trial and provide biologically plausible support that DPP‑1 inhibition could influence disease biology in NCFB. Given the study’s exploratory nature and limitations, imaging results should be considered hypothesis generating. Larger, prespecified imaging studies and longer follow‑up are needed to determine whether brensocatib is truly disease modifying and to define which patient subgroups gain the greatest structural benefit.
Funding and clinicaltrials.gov
The substudy and parent ASPEN trial were supported by Insmed. Investigators disclosed consulting and grant relationships with Insmed where relevant. The phase 3 ASPEN trial is referenced in the primary publication: Chalmers JD et al., N Engl J Med. 2025;392(16):1569–1581 (DOI: 10.1056/NEJMoa2411664).
References
1. Chalmers JD, Burgel PR, Daley CL, De Soyza A, Haworth CS, Mauger D, Loebinger MR, McShane PJ, Ringshausen FC, Blasi F, Shteinberg M, Mange K, Teper A, Fernandez C, Zambrano M, Fan C, Zhang X, Metersky ML; ASPEN Investigators. Phase 3 Trial of the DPP‑1 Inhibitor Brensocatib in Bronchiectasis. N Engl J Med. 2025 Apr 24;392(16):1569‑1581. doi: 10.1056/NEJMoa2411664. PMID: 40267423.
2. Manufacturer press release: Insmed announces FDA approval of brensocatib (Brinsupri) for non‑cystic fibrosis bronchiectasis, August 2025.
3. Presentation: Chalmers JD. Brensocatib’s effects on lung structure: CT substudy of ASPEN. American College of Chest Physicians (CHEST) 2025 Annual Meeting.
