Phase 2 testing of DPP-1 inhibitors brenokatib in bronchiectasis


abstract

The background

Patients with bronchiectasis often have exhaustions known to be related to neutrophilic inflammation. The activity and amount of neutrophil serine products, including neutrophil elastis, increase the mucus of patients with bronchiectasis at baseline and further increase during excision. Brenocatib (INS1007) is an oral reversible inhibitor of dipeptidyl peptidase 1 (DPP-1), an enzyme responsible for the activation of neutrophil serine proteases.

Ways

In a Phase 2, randomized, double-blind, placebo-controlled trial, we randomly assigned, in a 1: 1: 1 ratio, patients with bronchiectasis who received at least two exacerbations in the previous year to receive placebo Were, 10 mg Brenocatib once daily for 24 weeks, or 25 mg Brenocatib. The first exacerbation (primary end point), rate of exacerbations (secondary end point), sputum neutrophil elastase activity and safety time were assessed.

result

Of the 256 patients, 87 were assigned to receive a placebo, 82 to receive 10 mg of brinsocatib, and 87 to receiving 25 mg of brinsocatib. The 25th percentile of first extinguishing time was 67 days in the placebo group, 134 days in the 10-mg brenoacetib group, and 96 days in the 25-mg brenocotib group. Brenocatib treatment increased the time for the first expression compared to placebo (10-mg brenocatib vs placebo for p = .03; 25-mg brenoacetib vs. placebo for p = .04). The adjusted hazard ratio for exacerbation was 0.58 (95% Confidence Interval) compared to Brencotib with Placebo [CI], In the 25-mg group (P = 0.046), in the 10-mg group (P = 0.03) and 0.62 (95% CI, 0.38 to 0.99). The incidence-rate ratio was 0.64 (95% CI, 0.42 to 0.98) in the 10-mg group, compared with placebo (P = 0.04) in the 25-mg group, and 0.75 (95% CI, 0.50 to 1.13). , As compared with placebo (P = 0.17). With both brancocatib doses, sputum neutrophil elastase activity was reduced from baseline over the 24-week treatment period. The incidence of dental and skin adverse events of particular interest was higher with placebo compared to placebo with 10-mg and 25-mg brinsocatib doses, respectively.

The conclusion

In this 24-week trial, a decrease in neutrophil serine protease activity in patients with bronchiectasis with bronchocutib was associated with an improvement in bronchiectasis clinical outcomes. (Written by Insmed; WILLOW ClinicalTrials.gov number, NCT03218917)