{
  "abstract": "Background Neutrophilic inflammation plays a key role in the pathophysiology of non-cystic fibrosis bronchiectasis (hereafter bronchiectasis). Neutrophil serine proteases (NSPs), such as neutrophil elastase (NE), cathepsin G (CatG), and proteinase 3 (PR3), are associated with disease progression and poorer clinical outcomes. Brensocatib, an oral, selective, competitive, and reversible inhibitor of dipeptidyl peptidase 1, prevents activation of NSPs. In the phase 3 ASPEN trial ( NCT04594369), brensocatib 10 mg and 25 mg significantly reduced pulmonary exacerbation (PEx) burden vs placebo (annualized rate, time to first, increased odds of remaining PEx-free); Brensocatib 25 mg significantly reduced lung function decline and nominally significantly improved patient-reported symptoms. We report pharmacodynamic substudy data on the effect of brensocatib vs placebo on sputum NSP concentrations over treatment and follow-up periods in adults from ASPEN.Methods In ASPEN, adults with ≥2 PEx in the 12 months before screening and were randomised 1:1:1 to once-daily brensocatib (10 mg or 25 mg) or placebo for 52 weeks. Sputum samples were collected at screening and pre-dosing at baseline and weeks 4, 16, 28, 40, 52, and 56 (4 weeks post-treatment). The pharmacodynamic analysis set includes adults who consented to the substudy, received ≥1 dose of study drug, and ≥1 pre-dose and post-dose biomarker measurement.Results ASPEN enrolled 1680 adults. The pharmacodynamic analysis set included brensocatib 10 mg n=105; brensocatib 25 mg n=108; placebo n=115. Baseline characteristics were consistent across treatment groups and with the overall population. All treatment groups displayed high inter-patient variability in baseline levels of active sputum NE, CatG, and PR3. Percent of baseline activity in NE, CatG, and PR3 decreased by week 4 in brensocatib 10 mg and 25 mg, with no appreciable change in placebo. These trends were maintained throughout treatment for all NSPs ( table 1), with values returning toward baseline by 4 weeks post-treatment.Abstract S38 Table 1Percent change from baseline in sputum concentrations of active neutrophil serine proteases in adult patients at week 52 (end of treatment)Conclusions Sputum pharmacodynamic analyses showed that, consistent with the phase 2 WILLOW trial, brensocatib treatment resulted in a dose-dependent reduction of NSP activity within 4 weeks. NSP activity was stably suppressed throughout the treatment period and increased toward baseline after 4 weeks off-treatment. Furthermore, brensocatib 25 mg showed a more pronounced reduction of sputum NSP activity than the 10 mg dose.",
  "authors": [
    {
      "affiliations": [
        "University of Connecticut School of Medicine, Farmington, CT, USA"
      ],
      "name": "ML Metersky"
    },
    {
      "affiliations": [
        "Population and Health Sciences Institute, NIHR Biomedical Research Centre for Aging, Newcastle University and Department of Respiratory Medicine, Newcastle upon Tyne NHS Foundation Trust, Newcastle upon Tyne, UK"
      ],
      "name": "A De Soyza"
    },
    {
      "affiliations": [
        "Hôpital Cochin and Cystic Fibrosis National Reference Center, Service de Pneumologie, AP-HP and Université Paris Cité, Inserm U1016-Institut Cochin, Paris, France"
      ],
      "name": "P-R Burgel"
    },
    {
      "affiliations": [
        "National Jewish Health and University of Colorado, Denver, CO, USA"
      ],
      "name": "CL Daley"
    },
    {
      "affiliations": [
        "Pennsylvania State University, Hershey, PA, USA"
      ],
      "name": "D Mauger"
    },
    {
      "affiliations": [
        "Royal Papworth Hospital NHS Foundation Trust and University of Cambridge, Cambridge, UK"
      ],
      "name": "CS Haworth"
    },
    {
      "affiliations": [
        "Insmed Incorporated, Bridgewater, NJ, USA"
      ],
      "name": "A Teper"
    },
    {
      "affiliations": [
        "Insmed Incorporated, Bridgewater, NJ, USA"
      ],
      "name": "C Fernandez"
    },
    {
      "affiliations": [
        "Insmed Incorporated, Bridgewater, NJ, USA"
      ],
      "name": "K Mange"
    },
    {
      "affiliations": [
        "Insmed Incorporated, Bridgewater, NJ, USA"
      ],
      "name": "C Fan"
    },
    {
      "affiliations": [
        "Insmed Incorporated, Bridgewater, NJ, USA"
      ],
      "name": "X Zhang"
    },
    {
      "affiliations": [
        "Division of Respiratory Medicine and Gastroenterology, University of Dundee, Dundee, UK"
      ],
      "name": "JD Chalmers"
    }
  ],
  "title": "S38 Effects of brensocatib on neutrophil serine protease levels in patients with non-cystic fibrosis bronchiectasis: a pharmacodynamic analysis of the ASPEN trial",
  "uid": "d145ed58-2d7e-5960-8299-caa8edb75375"
}