{"id":18274,"date":"2022-12-05T22:22:54","date_gmt":"2022-12-05T22:22:54","guid":{"rendered":"https:\/\/touchrespiratory.com\/?p=18274"},"modified":"2022-12-15T16:46:16","modified_gmt":"2022-12-15T16:46:16","slug":"brensocatib-an-anti-neutrophil-elastase-drug-with-potential-in-the-management-of-bronchiectasis","status":"publish","type":"post","link":"https:\/\/touchrespiratory.com\/bronchiectasis\/journal-articles\/brensocatib-an-anti-neutrophil-elastase-drug-with-potential-in-the-management-of-bronchiectasis\/","title":{"rendered":"Brensocatib: An Anti-neutrophil Elastase Drug With Potential in the Management of Bronchiectasis"},"content":{"rendered":"

Judith Durham (of The Seekers fame) died in August this year from bronchiectasis \u2013 a timely reminder of the morbidity and mortality associated with this disease of chronic airway inflammation and damage and a tribute to Durham\u2019s personal and professional resilience.1<\/span>\u00a0The measles that initiated Durham\u2019s airway damage is mercifully now rare (although bronchiectasis can develop following other infections), but non-cystic fibrosis\u00a0<\/a>bronchiectasis (bronchiectasis) itself has proved surprisingly resistant to eradication, with diverse phenotypes perpetuating a heterogeneous and complex disease even in 2022.2<\/span>\u00a0Treatments targeting the underlying aetiology of bronchiectasis (e.g. immunodeficiency, allergic aspergillosis, non-tuberculous mycobacteria) are important but do not repair the airway damage.<\/p>\n

Current approaches<\/h1>\n

Options for treating bronchiectasis have advanced considerably in the last 20 years.3<\/span>\u00a0Parallels with cystic fibrosis have prompted research that has sometimes proven useful. Standard treatments that aim to improve sputum clearance and measures to increase sputum hydration with nebulized hypertonic saline are widely used, although the scientific evidence for their efficacy is scant.4<\/span>\u00a0Other therapies, such as inhaled DNase, have not seen the benefits shown in people with cystic fibrosis.3<\/span>\u00a0Currently, there is no pharmacological treatment licensed for bronchiectasis.<\/p>\n

The role of chronic colonization with bacteria such as\u00a0Haemophilus influenzae<\/span>\u00a0and\u00a0Pseudomonas<\/span>\u00a0in patients with bronchiectasis has prompted trials of long-term antibiotic use in people with frequent exacerbations. Potential therapies include macrolides5<\/span>\u00a0and nebulized delivery of antibiotics such as tobramycin or colistin,6<\/span>\u00a0but these have proven to be variably effective in multiple trials.2<\/span><\/p>\n

Persistent airway inflammation \u2013 often initiated and sometimes perpetuated by infection \u2013 can lead to a complex dysfunctional milieu with immune-mediated damage, loss of mucociliary function, structural lung damage and further susceptibility to exacerbations.7<\/span>\u00a0Over-exuberant neutrophil activity is a major driver of this cycle, and increased levels of neutrophil elastase (one of several neutrophil serine proteases) have been correlated with exacerbation risk,8<\/span>\u00a0particularly in patients with chronic\u00a0Pseudomonas<\/span>\u00a0colonization.9<\/span><\/p>\n

Neutrophil extracellular traps (NETs) are meshworks of extracellular fibres of chromatin DNA, histones and bactericidal proteins such as neutrophil proteinase 3 (PR3) and neutrophil elastase.10<\/span>\u00a0NETs are involved in extracellular bacterial killing but may also contribute to local inflammatory tissue damage. Sputum NETs have been associated with worse disease severity, increased exacerbation frequency and decreased quality of life in patients with bronchiectasis, while the administration of intravenous antibiotics has been associated with a reduction of sputum NETs.10<\/span>\u00a0Aside from using antibiotics (macrolides may reduce NETs10<\/span>\u00a0and exert an anti-inflammatory effect), how else may this counterproductive inflammatory response be lessened? Inhaled steroids are contraindicated in bronchiectasis unless there is a significant eosinophilic phenotype.11<\/span>\u00a0Pilot studies of direct elastase inhibitors have proven the safety of these agents with some apparent benefit.12,13<\/span>\u00a0However, other options are clearly needed.<\/p>\n

Brensocatib<\/h1>\n

Brensocatib is a small-molecule, reversible inhibitor of the lysosomal cysteine proteinase dipeptidyl peptidase 1 (DPP1, also known as cathepsin C). DPP1 activates neutrophil serine proteases, and its inhibition within the bone marrow reduces the levels of what may be excessive neutrophil and airway serine proteases, including neutrophil elastase.14<\/span>\u00a0Studies in human neutrophils have shown that brensocatib significantly inhibits the activation of neutrophil serine proteases, resulting in a decreased elastolytic ability of the cells\u00a0in vitro<\/span>. Furthermore, brensocatib has been shown to produce concentration-dependent reductions in both the percentage of neutrophils with membrane-bound PR3 and the overall surface expression of PR3\u00a0in vitro<\/span>.14<\/span><\/p>\n

Brensocatib was found to be a safe and side-effect-free agent in animal studies and in short-term studies with healthy human volunteers.15<\/span>\u00a0As such, it was further investigated in the WILLOW trial, a multicentre, international, phase IIa study in people with bronchiectasis and at least two exacerbations in the previous year.16<\/span><\/p>\n

The WILLOW trial randomized 256 patients in a 1:1:1 ratio to receive
\n10 mg brensocatib, 25 mg brensocatib or placebo once daily for 24 weeks, with time to the first exacerbation as the primary outcome. Brensocatib resulted in a significantly prolonged time to exacerbation: the 25th percentile of the time to the first exacerbation was 67 days in the placebo group compared with 134 days in the 10 mg brensocatib group (p=0.03 versus placebo) and 96 days with 25 mg brensocatib group (p=0.04). However, the absolute rate of exacerbations was significantly reduced only for the 10 mg dose, and brensocatib had no effect on forced expiratory volume in 1 second. Brensocatib reduced sputum neutrophil elastase activity but did not improve quality of life.<\/p>\n

<\/a>Genetic conditions with absent DPP1 activity have been associated with periodontitis and cutaneous hyperkeratosis.17<\/span> Of note, there were no differences between the three groups in periodontal disease, and while five patients experienced hyperkeratosis (four in the brensocatib groups and one in the placebo group), none required treatment interruption, and all of the events had resolved or abated by the end of the study. In this preliminary study, therefore, brensocatib improved time to exacerbation without significant side effects or increasing infection.<\/p>\n

In the on-going phase III ASPEN study (ClinicalTrials.gov identifier: NCT05344508),18<\/span> brensocatib is being investigated in a similar but larger cohort of patients to that recruited for the WILLOW trial. A total of 1,620 patients with non-cystic fibrosis bronchiectasis from more than 400 sites will again be randomized 1:1:1 to receive placebo, 10 mg brensocatib or 25 mg brensocatib once daily, this time for 52 weeks. The study will compare the rates of pulmonary exacerbation (primary outcome) among the three arms and assess safety and tolerability; secondary outcomes will include quality of life and lung function. ASPEN will also include an exploratory analysis of brensocatib in 40 adolescent patients aged \u226512 to \u226418 years.<\/p>\n

If the benefits seen in the WILLOW trial are replicated in ASPEN, and if regulatory approval is then granted, brensocatib, as a simple, single, daily tablet with (as yet) few side effects, will be a major addition to the treatment options available for patients with bronchiectasis.<\/p>\n

To what extent other direct inhibitors of airway serine proteases and perhaps other modulators of inflammation will be important remains to be seen. Whatever happens, someone born today is unlikely to suffer the same complications that Judith Durham endured for more than 75 years.<\/p>\n","protected":false},"excerpt":{"rendered":"

Judith Durham (of The Seekers fame) died in August this year from bronchiectasis \u2013 a timely reminder of the morbidity and mortality associated with this disease of chronic airway inflammation and damage and a tribute to Durham\u2019s personal and professional resilience.1\u00a0The measles that initiated Durham\u2019s airway damage is mercifully now rare (although bronchiectasis can develop […]<\/p>\n","protected":false},"author":77788,"featured_media":18381,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_relevanssi_hide_post":"","_relevanssi_hide_content":"","_relevanssi_pin_for_all":"","_relevanssi_pin_keywords":"","_relevanssi_unpin_keywords":"","_relevanssi_related_keywords":"","_relevanssi_related_include_ids":"","_relevanssi_related_exclude_ids":"","_relevanssi_related_no_append":"","_relevanssi_related_not_related":"","_relevanssi_related_posts":"","_relevanssi_noindex_reason":"","rank_math_lock_modified_date":false,"footnotes":""},"categories":[1],"tags":[],"class_list":["post-18274","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-uncategorized","vocabulary_1-bronchiectasis"],"acf":[],"_links":{"self":[{"href":"https:\/\/touchrespiratory.com\/wp-json\/wp\/v2\/posts\/18274"}],"collection":[{"href":"https:\/\/touchrespiratory.com\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/touchrespiratory.com\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/touchrespiratory.com\/wp-json\/wp\/v2\/users\/77788"}],"replies":[{"embeddable":true,"href":"https:\/\/touchrespiratory.com\/wp-json\/wp\/v2\/comments?post=18274"}],"version-history":[{"count":9,"href":"https:\/\/touchrespiratory.com\/wp-json\/wp\/v2\/posts\/18274\/revisions"}],"predecessor-version":[{"id":18622,"href":"https:\/\/touchrespiratory.com\/wp-json\/wp\/v2\/posts\/18274\/revisions\/18622"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/touchrespiratory.com\/wp-json\/wp\/v2\/media\/18381"}],"wp:attachment":[{"href":"https:\/\/touchrespiratory.com\/wp-json\/wp\/v2\/media?parent=18274"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/touchrespiratory.com\/wp-json\/wp\/v2\/categories?post=18274"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/touchrespiratory.com\/wp-json\/wp\/v2\/tags?post=18274"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}