英国邓迪宁威尔医院James D. Chalmers团队研究了DPP-1抑制剂Brensocatib治疗支气管扩张患者的疗效。2020年9月7日，该研究发表在《新英格兰医学杂志》上。
研究组进行了一项临床2期、随机、双盲、安慰剂对照试验，招募了256名前一年至少有两次恶化的支气管扩张患者，按1：1：1随机分组，其中87名接受安慰剂治疗，82名接受10mg Brensocatib治疗，87名接受25mg Brensocatib治疗，每日一次，持续24周。对首次恶化的时间、恶化率、痰中性粒细胞弹性蛋白酶活性和安全性进行评估。
安慰剂组首次恶化时间的第25百分位数为67天，Brensocatib 10mg组为134天，Brensocatib 25mg组为96天。与安慰剂相比，Brensocatib治疗显著延长了患者首次恶化的时间，Brensocatib 10mg组的恶化校正风险比为0.58，Brensocatib 25mg组为0.62，差异具有统计学意义。
与安慰剂组相比，Brensocatib 10mg组的恶化率比率为0.64，差异显著，Brensocatib 25mg组为0.75，差异不显著。
Title: Phase 2 Trial of the DPP-1 Inhibitor Brensocatib in Bronchiectasis
Author: James D. Chalmers, M.B., Ch.B., Ph.D.,, Charles S. Haworth, M.B., Ch.B., M.D.,, Mark L. Metersky, M.D.,, Michael R. Loebinger, B.M., B.Ch., Ph.D.,, Francesco Blasi, M.D., Ph.D.,, Oriol Sibila, M.D., Ph.D.,, Anne E. O’Donnell, M.D.,, Eugene J. Sullivan, M.D.,, Kevin C. Mange, M.D., M.S.C.E.,, Carlos Fernandez, M.D., M.P.H.,, Jun Zou, Ph.D.,, and Charles L. Daley, M.D.
Patients with bronchiectasis have frequent exacerbations that are thought to be related to neutrophilic inflammation. The activity and quantity of neutrophil serine proteases, including neutrophil elastase, are increased in the sputum of patients with bronchiectasis at baseline and increase further during exacerbations. Brensocatib (INS1007) is an oral reversible inhibitor of dipeptidyl peptidase 1 (DPP-1), an enzyme responsible for the activation of neutrophil serine proteases.
In a phase 2, randomized, double-blind, placebo-controlled trial, we randomly assigned, in a 1:1:1 ratio, patients with bronchiectasis who had had at least two exacerbations in the previous year to receive placebo, 10 mg of brensocatib, or 25 mg of brensocatib once daily for 24 weeks. The time to the first exacerbation (primary end point), the rate of exacerbations (secondary end point), sputum neutrophil elastase activity, and safety were assessed.
Of 256 patients, 87 were assigned to receive placebo, 82 to receive 10 mg of brensocatib, and 87 to receive 25 mg of brensocatib. The 25th percentile of the time to the first exacerbation was 67 days in the placebo group, 134 days in the 10-mg brensocatib group, and 96 days in the 25-mg brensocatib group. Brensocatib treatment prolonged the time to the first exacerbation as compared with placebo (P=0.03 for 10-mg brensocatib vs. placebo; P=0.04 for 25-mg brensocatib vs. placebo). The adjusted hazard ratio for exacerbation in the comparison of brensocatib with placebo was 0.58 (95% confidence interval [CI], 0.35 to 0.95) in the 10-mg group (P=0.03) and 0.62 (95% CI, 0.38 to 0.99) in the 25-mg group (P=0.046). The incidence-rate ratio was 0.64 (95% CI, 0.42 to 0.98) in the 10-mg group, as compared with placebo (P=0.04), and 0.75 (95% CI, 0.50 to 1.13) in the 25-mg group, as compared with placebo (P=0.17). With both brensocatib doses, sputum neutrophil elastase activity was reduced from baseline over the 24-week treatment period. The incidence of dental and skin adverse events of special interest was higher with the 10-mg and 25-mg brensocatib doses, respectively, than with placebo.
In this 24-week trial, reduction of neutrophil serine protease activity with brensocatib in patients with bronchiectasis was associated with improvements in bronchiectasis clinical outcomes.