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Thank you so much for the introduction! I'm excited to chat tonight about the Phase 2 Trial of the DPP-1 Inhibitor Brensocatib in Bronchiectasis, nejm.org/doi/full/10.10…. #NTMTwitterJC

First, I will touch on the high points of the article and then will pose some discussion questions about clinical implications of the article #NTMTwitterJC

Patients with bronchiectasis have frequent exacerbations associated with neutrophilic inflammation. Neutrophil serine proteases (NSPs), including neutrophil elastase, are increased in the sputum of patients with bronchiectasis. #NTMTwitterJC

Neutrophil elastase has been associated with disease severity, bacterial load, frequency of exacerbations and shorter time to exacerbation. Not good! #NTMTwitterJC

NSP’s are activated during neutrophil maturation in the bone marrow by an enzyme, dipeptidyl peptidase 1 (DDP-1). Brensocatib is a potent inhibitor of DPP-1 that prevents activation of nonserine proteases like neutrophil elastase. May be good! #NTMTwitterJC

Let’s discuss the results of the Phase 2 clinical trial of the DPP-1 inhibitor brensocatib in the treatment of patients with non-CF bronchiectasis. #NTMTwitterJC

The Willow Study was a Phase 2 randomized, placebo-controlled trial of brensocatib in adult patients with non-CF bronchiectasis who had a history of at least two exacerbations in the previous 12 months. Primary outcome-time to first exacerbation. #NTMTwitterJC

Patients were randomized in a 1:1:1 fashion to receive 10 mg brensocatib, 25 mg brensocatib or placebo given daily. Patients were stratified by Pseudomonas aeruginosa in sputum and use of macrolides. #NTMTwitterJC

416 patients were screened (256 were eligible for randomization). The study population had a median age of around 65 years, over 60% were female, 80% white, most had moderately severe bronchiectasis with 30-40% experiencing ≥ 3 exacerbations in prior 12 months. #NTMTwitterJC

It worked! Brensocatib reduced the time to first exacerbation compared with placebo (primary) and decreased the frequency of exacerbations including severe exacerbations (secondary). #NTMTwitterJC

Neutrophil elastase levels were lower with both brensocatib doses compared with placebo and returned to normal within 4 weeks of stopping the drug. #NTMTwitterJC

It was also safe. SAEs were more common in the placebo group. Headache and dyspnea were more common with brensocatib affecting 4-10% of patients. #NTMTwitterJC

Skin and dental issues that were adverse events of special interest were also more common in the brensocatib groups but discontinuation was unusual, occurring in only 7% in the brensotatib arms vs 11% in the placebo. #NTMTwitterJC

If the results are confirmed in the ongoing Phase 3 ASPEN study, we may have our first drug for treatment of bronchiectasis! #NTMTwitterJC