Zhang Dandan, Zhang Wenwen, Hu Ping, Zhang Wei
Department of Pharmacy, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.
Front Pharmacol. 2025 Aug 22;16:1656316. doi: 10.3389/fphar.2025.1656316. eCollection 2025.
Dipeptidyl peptidase 1 (DPP1) inhibitors constitute a major advance in respiratory disease therapeutics. Through selective blockade of neutrophil serine protease (NSP) activation, these agents establish novel treatment paradigms for inflammatory respiratory conditions characterized by neutrophil-driven pathology. This comprehensive review examines the development status, clinical efficacy, and safety profile of DPP1 inhibitors in neutrophil-driven diseases, particularly non-cystic fibrosis bronchiectasis (NCFBE) and chronic obstructive pulmonary disease (COPD). Leading compounds including brensocatib, BI 1291583, and HSK31858 have demonstrated substantial clinical efficacy. In the pivotal WILLOW Phase II trial, brensocatib significantly extended time to first exacerbation (hazard ratio 0.58-0.62, p < 0.05) in bronchiectasis patients. The subsequent ASPEN Phase III trial confirmed these findings, with brensocatib reducing annualized exacerbation rates by 21% (10 mg) and 19% (25 mg) compared to placebo (adjusted p = 0.004 and p = 0.005, respectively). Similarly, HSK31858 demonstrated comparable efficacy in Chinese patients, reducing exacerbation risk by 48%-59% in the SAVE-BE trial. While the clinical phenotype observed in Papillon-Lefèvre syndrome (PLS) necessitates careful monitoring of skin and periodontal health during DPP1 inhibition therapy, clinical trials have shown these adverse events occur at low frequencies (1%-4%) and are predominantly mild to moderate in severity. Future research priorities include establishing standardized monitoring protocols for dermatological and periodontal health, developing biomarkers for patient stratification, validating long-term safety profiles, and optimizing combination treatment strategies. With brensocatib potentially becoming the first approved mechanism-specific therapy for bronchiectasis by mid-2025, DPP1 inhibitors represent a paradigm shift in managing neutrophil-mediated respiratory diseases.
二肽基肽酶1（DPP1）抑制剂是呼吸系统疾病治疗领域的一项重大进展。通过选择性阻断中性粒细胞丝氨酸蛋白酶（NSP）的激活，这些药物为以中性粒细胞驱动的病理为特征的炎症性呼吸系统疾病建立了新的治疗模式。这篇综述全面考察了DPP1抑制剂在中性粒细胞驱动疾病，特别是非囊性纤维化支气管扩张症（NCFBE）和慢性阻塞性肺疾病（COPD）中的研发状况、临床疗效和安全性。包括布瑞索替（brenocatib）、BI 1291583和HSK31858在内的领先化合物已显示出显著的临床疗效。在关键的WILLOW II期试验中，布瑞索替显著延长了支气管扩张症患者首次病情加重的时间（风险比0.58 - 0.62，p < 0.05）。随后的ASPEN III期试验证实了这些结果，与安慰剂相比，布瑞索替使年化病情加重率分别降低了21%（10毫克）和19%（25毫克）（校正p值分别为0.004和0.005）。同样，HSK31858在中国患者中显示出相当的疗效，在SAVE - BE试验中使病情加重风险降低了48% - 59%。虽然在帕皮隆 - 勒费弗尔综合征（PLS）中观察到的临床表型需要在DPP1抑制治疗期间仔细监测皮肤和牙周健康，但临床试验表明这些不良事件发生频率较低（1% - 4%），且严重程度主要为轻度至中度。未来的研究重点包括建立皮肤病学和牙周健康的标准化监测方案、开发用于患者分层的生物标志物、验证长期安全性以及优化联合治疗策略。随着布瑞索替可能在2025年年中成为首个获批的针对支气管扩张症的机制特异性疗法，DPP1抑制剂代表了中性粒细胞介导的呼吸系统疾病管理模式的转变。
