Bronchiectasis refers to abnormal dilations of the bronchi in the lungs. Thick mucus accumulates in these enlarged airways and is often difficult to clear by coughing. This mucus stasis is associated with chronic airway inflammation and provides an ideal breeding ground for bacteria and other pathogens, which in turn exacerbate the disease. The result is a chronic, progressive lung disease. Most patients suffer from persistent coughing and sputum production, shortness of breath, fatigue, weight loss, and frequent infections requiring antibiotic treatment. The dilations are irreversible, and there is currently no cure for the disease. To date, no standardized treatment approach exists for bronchiectasis. While national and international guidelines recommend physiotherapy-based airway clearance techniques, mucolytics, and antibiotics to treat infections, these approaches do not adequately address the chronic inflammation and the progression of the disease. If lung function becomes severely impaired over time, lung transplantation remains the only therapeutic option.
Hope now comes from the ASPEN study, the largest global clinical trial to date on bronchiectasis, involving more than 1,700 patients. The study investigated the anti-inflammatory effects of the investigational drug Brensocatib. The ASPEN study showed that Brensocatib, administered orally at doses of 10 and 25 milligrams, reduced the risk of exacerbations requiring antibiotic treatment by approximately 20 percent. In addition, treatment with 25 milligrams of Brensocatib significantly slowed the decline in lung function and thus improved patients’ quality of life. The results of the ASPEN study have been published in the prestigious New England Journal of Medicine.
The first author of the study is Professor James Chalmers, Head of the Division of Respiratory Medicine and Gastroenterology at the University of Dundee and a member of the Scientific Advisory Board of the German Center for Lung Research (DZL). Prof. Dr. Felix Ringshausen, Senior Physician at the Department of Pulmonology and Infectious Diseases at Hannover Medical School (MHH), Head of the Bronchiectasis Outpatient Clinic, and Principal Investigator (PI) at the DZL site BREATH, was the only German scientist involved in the publication of the study results. Prof. Ringshausen has been conducting bronchiectasis research at BREATH for many years. His conclusion: “Brensocatib is the first agent to treat the disease at its root and is likely to become the first medication approved for the treatment of bronchiectasis.” The drug is expected to be launched in the U.S. this summer, with approval in Europe anticipated by the end of this year or early next year.
Excessive Immune Response
Bronchiectasis can be caused by congenital lung diseases such as cystic fibrosis or primary ciliary dyskinesia (PCD). However, they more commonly develop after severe infections such as pneumonia or tuberculosis, uncontrolled asthma, or as a result of chronic obstructive pulmonary disease (COPD). Typically, inflammatory processes damage the walls of the bronchi and destroy the lung’s elastic connective tissue. This impairs the lung’s natural self-cleaning mechanism—known as mucociliary clearance.
This vicious cycle of inflammation, impaired clearance, structural airway damage, and recurrent infections is further exacerbated by neutrophil granulocytes. These white blood cells are part of the immune system and combat bacterial infections. Their weapons include enzymes called serine proteases. During their maturation in the bone marrow, these serine proteases are activated—a process regulated by the protein dipeptidyl peptidase 1 (DPP-1). “In chronic airway inflammation, such as in bronchiectasis, the highly effective 'bacterial police' of neutrophils overshoots its target, releasing too many serine proteases into the airways,” explains Prof. Ringshausen. These enzymes then not only attack pathogens but also damage bronchial walls and surrounding lung tissue. As a result, lung clearance worsens, creating a relentless cycle of inflammation, airway damage, and recurrent infections that drive disease progression.
Few Side Effects
Brensocatib disrupts this cycle by inhibiting the DPP-1 protein and thereby mitigating the activation of serine proteases. The benefit: the drug is a reversible inhibitor and does not permanently suppress enzyme production. “Once Brensocatib is discontinued, DPP-1 is no longer blocked and can fully reactivate the enzymes to support bacterial defense,” says Prof. Ringshausen.
In the ASPEN study, patients receiving Brensocatib in addition to standard therapy remained symptom-free longer than those in the placebo group. Side effects were generally mild. Despite the reduced activity of neutrophils, patients treated with Brensocatib did not suffer more bacterial infections than the placebo group. Only cases of dry skin increased slightly. A positive outcome, emphasizes the bronchiectasis expert: “Brensocatib reduced the risk of symptom exacerbation, slowed the decline in lung function, and convincingly improved the quality of life for patients.”
Text: MHH/ Kirsten Pötzke, edited
Original publication: 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.
