2026/03/28 by James D Chalmers, Charles L Daley · 1 voice
Biochemistry, Genetics and Molecular Biology · Medicine · #Cystic Fibrosis Research Advances #Gastroesophageal reflux and treatments #Genomics and Rare Diseases
paper · doi:10.1093/ajrccm/aamag096
openalex publication_date 2026/03/28 · openalex created_date 2026/04/02 · openalex updated_date 2026/06/18
The oral dipeptidyl peptidase-1(DPP1) inhibitor brensocatib became the first US Food and Drug Administration (FDA) approved therapy for non-cystic fibrosis bronchiectasis (NCFB) on August 12, 2025, and the first therapy for NCFB approved by the European Medicines Agency (EMA) on November 18, 2025. These approvals were based on data from the phase-2 WILLOW trial1 and the phase-3 ASPEN trial.2 ASPEN enrolled 1680 adult and 41 adolescent NCFB patients to either 25 mg or 10 mg brensocatib or placebo. The primary outcome was exacerbation frequency over 52 weeks, which was reduced by approximately 20% at both doses.2 The regulatory approvals in the United States and Europe are markedly different. While in both regions, brensocatib is approved for patients with NCFB who are 12 years or over, the FDA approved both doses. In contrast, the EMA only approved the 25 mg dose, and specifically for patients with 2 or more exacerbations in the previous year. This opens the likelihood of different patterns of brensocatib usage in the United States and Europe and raises the question of how clinicians should use these medications. This is particularly relevant in the United States, where there is currently no guidance on appropriate dosing. Here, we review the evidence for brensocatib dosing that formed the basis of these regulatory decisions and give a clinical perspective on the efficacy and safety of each dose, touching on important topics beyond exacerbation reduction, such as disease progression and symptoms.3 In WILLOW and ASPEN, there was no difference in any exacerbation endpoints comparing the 10 mg and 25 mg doses with placebo.1,2 This is consistent with observations from trials of other DPP1 inhibitors, where higher doses were not associated with greater exacerbation benefits.4 This is central to the FDA decision to approve both doses. Nevertheless, the secondary endpoints of the ASPEN trial provide differentiation between the 2 doses. A statistically significant benefit on FEV1 decline was observed for the 25 mg dose but not for 10 mg. The placebo group declined by 62 mL/year, which was reduced to –24 mL in the brensocatib 25 mg group (difference 38 ml 95%CI, 11-65 mL, P = .04). No significant benefit was seen with 10 mg (–50 mL, between-group difference 11 mL, P = .4)2 The minimum clinically important difference (MCID) of FEV1 in bronchiectasis is not known. The widely reported threshold of 100 mL is based on symptomatic benefit with bronchodilators, not preventing progressive lung damage over time. The magnitude of the exploratory endpoint of forced vital capacity (FVC) provides important context. This showed a between-group difference of 75 mL (95% CI, 40-110 mL, nominal P < .0001) for the 25 mg dose and 36 mL (95% CI, 3-69 mL, nominal P = .03) for the 10 mg dose.2 The recent FDA approval of nerandomilast for idiopathic pulmonary fibrosis (IPF)and progressive pulmonary fibrosis (PFF) was based on the absolute change from baseline in FVC vs placebo over 52 weeks for nerandomilast of 68.8 mL 95% CI, 30.3-107.4 for the 18 mg dose, 44.9 mL 95% CI, 6.4-83.3 mL for 9 mg in IPF and 67.2 mL 95% CI, 31.9-102.5 and 81.1 mL (95% CI, 46-116.3) in PFF.5,6 These are similar to the FVC benefit observed with brensocatib in NCFB. While the mechanisms of fibrosis and airway remodelling in NCFB are different, these data indicate that regulators regard these levels of lung function preservation as clinically relevant. The other key differentiator is symptoms. In ASPEN, symptoms were measured with the quality-of-life bronchiectasis (QOL-B) questionnaire and the Bronchiectasis Exacerbation and Symptom Tool (BEST), a validated daily diary. The QOL-B improved by an average of 8.575 points in patients receiving brensocatib 25 mg (vs 6.841 points for 10 mg and 4.809 points for placebo) over 52-weeks, exceeding the 8-point MCID for the QOL-B.7 The between-group difference, 3.8 (95% CI, 1.7-5.9), is not considered statistically significant because of statistical hierarchy despite an unadjusted nominal P-value of .0004. 10 mg vs placebo was not significant even without adjustment. For the exploratory endpoint of BEST, no difference was seen comparing 10 mg vs placebo, but a nominally significant difference was observed for the 25 mg dose (–0.57, nominal P < .0001).2 Greater benefit on symptoms correlates with greater effects of the 25 mg dose on airway mucins.8 This suggests that a substantial proportion of patients will experience clinically meaningful improvements in daily symptoms when prescribed the 25 mg dose but not with the 10 mg dose. The other discriminating factor when considering dose selection is safety. The overall rate of adverse events was not different between brensocatib and placebo. Adverse events of special interest were hyperkeratosis and dental issues.1,2 In the ASPEN trial, hyperkeratosis was reported in 3% of the 25 mg dose group, 1.4% of the 10 mg group, and 0.7% of the placebo group. Only 1 patient withdrew as a result of hyperkeratosis, suggesting this is generally a mild and manageable side effect. Periodonitis or gingivitis was reported in 2.1% of the 25 mg dose group, 1.4% for the 10 mg group and 2.7% in the placebo group.2 A concern that the additional lung function and symptom benefit did not outweigh an increased risk of hyperkeratosis and dental side effects appears to have informed the FDA decision to approve both doses. This may seem surprising since the highest frequency of dental AEs was in the placebo group, but the FDA review included data from the phase-2 trial that reported dental adverse events to be highest in the 10 mg group. A subsequent detailed analysis of systematic dental examinations performed during the trial found no evidence of progressive periodontitis.9 In summary, both the 25 mg and 10 mg doses are associated with a 20% reduction in the risk of exacerbations in the ASPEN trial, while the 25 mg dose also has a meaningful effect on disease progression as measured by FEV1 and FVC, and is associated with a greater improvement in symptoms compared to the 10 mg dose. The rate of overall adverse events is similar, but the 25 mg dose carries a higher risk of hyperkeratosis, which is generally mild. We propose that the available data support initiating patients on the 25 mg dose, and that it is currently hard to identify a clinical scenario where it would be appropriate to initiate the 10 mg dose. This aligns with the decision by EMA to only approve a single dose. There is no evidence to suggest that starting at a lower dose and titrating up would be appropriate, as the therapy works in the bone marrow and takes approximately 4 weeks to gradually have its pharmacodynamic effect.1 In the United States, where the 10 mg dose is available, it is reasonable to decrease the dose from 25 mg to 10 mg in those who have significant skin side effects. There are many unanswered questions related to the clinical application of DPP1 in bronchiectasis that are summarized in Table 1.10 Selected unanswered questions in the clinical use of DPP1 inhibitors in clinical practice. Long-term real-life studies on efficacy and safety in subgroups Biomarker and multiomic studies to identify predictors of response not evident clinically Long-term follow-up (registry or postmarketing surveillance study) of brensocatib Phase 3 trial of verducatib extends to 76 weeks Registry data Postmarketing surveillance studies Phase 3 trial data from other DPP1i Post hoc analyses of the ASPEN trial data Postmarketing surveillance study of brensocatib incorporating CT imaging Phase 3 trials of other DPP1i incorporating CT imaging Further analysis of the ASPEN trial Postmarketing surveillance studies of brensocatib, particularly in the United States, where both doses are available, and patients without an exacerbation history are eligible for treatment Postmarketing surveillance Reporting is often higher in trials than in real life, but equally more frail or susceptible patients may be excluded from trials Postmarketing surveillance Additional analyses of the ASPEN trial data Phase 3 trials of other DPP1i Clinical guidelines Real-life registry studies with comparative effectiveness/development of pathways Cost-effectiveness analysis James D. Chalmers and Charles L. Daley jointly wrote the article and revised it. James D. Chalmers is the guarantor. Supplementary material is available at American Journal of Respiratory and Critical Care Medicine online. James D. Chalmers reports grants or contracts from AstraZeneca, Chiesi, Genentech, Gilead Sciences, GlaxoSmithKline, Insmed, Grifols, Trudell, Verona and Boehringer Ingelheim, and consulting fees from AstraZeneca, Biomx, Chiesi, CSL Behring, Expedition, GlaxoSmithKline, Insmed, Grifols, Boehringer Ingelheim, Pfizer, Sanofi/Regeneron and Zambon. Charles Daley reports grants or contracts from AN2, Astrazeneca, GlaxoSmithKline, Insmed, Mannkind, Paratek, Renovion, Spero, Trudell and Verona and consulting fees from AN2, Astrazeneca, COPD Foundation, Galapagos, Gates Foundation, GlaxoSmithKline, Grifols, Hyfe, Insmed, MicuRx, Monaghan Medical, Nob Hill, Otsuka, Paratek, Pfizer, and Spero. Please see the ICMJE disclosure forms, which have been provided as supplementary material.