DPP1 Inhibition in Bronchiectasis: Mechanism and Pivotal Trial Data

In "DPP1 Inhibition in Bronchiectasis: Mechanism and Pivotal Trial Data," our experts turn to the mechanism and pivotal trial data behind the newest anti-inflammatory therapy for bronchiectasis, brensocatib.

Dr. Basavaraj asks Dr. ElMaraachli to explain the mechanism of action behind DPP1 inhibition in bronchiectasis. Dr. ElMaraachli describes dipeptidyl peptidase 1, or DPP1, as the enzyme responsible for activating neutrophil serine proteases during neutrophil maturation. Extensive prior research demonstrated that excess neutrophilic inflammation, reflected in elevated neutrophil elastase and other serine proteases, correlates with worse bronchiectasis outcomes, including more frequent exacerbations and faster lung function decline. This evidence provided the scientific rationale for hypothesizing that inhibiting DPP1 could interrupt the dysregulated inflammatory cascade that perpetuates disease once an initial trigger sets it in motion.

Dr. Khabbaza then reviews results from the phase 3 ASPEN trial, the largest bronchiectasis study conducted to date, enrolling more than 1,700 patients randomized to placebo or one of two brensocatib doses. All participants had experienced at least two exacerbations in the prior year, and the primary endpoint tracked exacerbation frequency over 52 weeks. Both treatment doses produced significantly fewer annualized exacerbations than placebo, along with longer time to first exacerbation. Notably, the higher dose also slowed the rate of lung function decline compared with placebo, a finding Dr. Khabbaza calls especially promising for long-term disease modification.

Asked how he selects patients for brensocatib, Dr. Khabbaza identifies two main groups: those with two or more annual exacerbations mirroring the ASPEN population, and patients with a non-exacerbating but symptomatic phenotype whose daily symptoms appear driven by neutrophilic inflammation. He monitors patients clinically rather than with bloodwork, noting that the most common side effect is mild skin change, which rarely requires discontinuation. He describes the drug's safety profile as reassuring across several hundred treated patients, with most showing meaningful improvement in daily symptoms.

The next episode in this series, "Sequencing Therapies for Bronchiectasis: A Practical Approach," features Dr. Metersky and Dr. ElMaraachli mapping out how to sequence today's bronchiectasis therapies.