Understanding Brensocatib's Mechanism and Safety in Bronchiectasis

In this segment of the HCPLive RX Review Special Report, Albert Rizzo, MD, and James Chalmers, MBChB, PhD, address safety considerations for brensocatib, marketed as Brinsupri, following its FDA approval in August 2025. Chalmers explains that both the phase 2 WILLOW trial and the large phase 3 ASPEN trial demonstrated a reassuring safety profile, with adverse events and serious events occurring at rates comparable to placebo. Importantly, despite targeting neutrophil activity, there was no observed increase in pneumonia or other infections—a critical finding given neutrophils’ role in host defense.

The most notable side effect seen in ASPEN was mild hyperkeratosis, occurring in roughly 3% of patients on the higher dose. Chalmers explains that this skin thickening resembles findings in the rare Papillon-Lefevre syndrome, where the DPP1 enzyme is absent, but emphasizes that in the trial cases were largely reversible, self-limiting, and only led to one discontinuation. He advises clinicians to counsel patients on this potential effect, noting that it may occur at variable times during therapy, even after several months of treatment.

Chalmers also outlines brensocatib’s novel mechanism of action as a first-in-class DPP1 inhibitor. By blocking DPP1 in the bone marrow, brensocatib prevents proteolytic enzymes like neutrophil elastase and cathepsin G from being activated and packaged into neutrophils. As a result, neutrophils migrate to the lung but are less capable of driving tissue injury, dampening inflammation without broadly impairing infection defense. This upstream, targeted approach, Chalmers notes, helps explain both its efficacy in reducing exacerbations and its favorable safety profile.

Our Panelists:

Albert Rizzo, MD, is a pulmonologist at ChristianaCare Pulmonary Associates at the ChristianaCare in Newark, Delaware, and clinical assistant professor of medicine at Thomas Jefferson University Medical School, Philadelphia. Triple board certified in internal medicine, pulmonary, critical care and sleep medicine, he also served as the former Chief Medical Officer of the American Lung Association.

James Chalmers, MBChB, PhD, is a Clinical Professor (Teaching and Research) of Respiratory Research, Respiratory Medicine and Gastroenterology, at University of Dundee, United Kingdom, where he also serves as Asthma and Lung UK Chair of Respiratory Research. He was a primary investigator on Insmed's ASPEN trial of brensocatib.

Editor's note: Rizzo's disclosures include Pfizer, AstraZeneca, and Genentech. Chalmer's disclosures include AstraZeneca, Boehringer Ingelheim, Genentech, Gilead, Grifols Biologicals, Insmed, Novartis, and Zambon.

Reference

Johnson V. FDA Approves First Bronchiectasis Therapy, Brensocatib, for Ages 12 and Up. HCPLive. Article. August 12, 2025. https://www.hcplive.com/view/fda-approves-first-bronchiectasis-therapy-brensocatib-12-up