Breakthrough of DPP-1 Inhibitor in decreasing the exacerbation frequency of bronchiectasis (Lancet Respir Med)

【Backgrounds】

Bronchiectasis is one of the most common highly heterogeneous chronic inflammatory airway diseases in China. It has a long course, heavy symptom burden, and is prone to recurrent acute exacerbations, which severely affect patients' quality of life and impose a huge economic burden on individuals and society. Current treatments for bronchiectasis mainly focus on symptom relief or management of airway infections, but there is a lack of drugs specifically targeting bronchiectasis in the stable phase to significantly reduce the risk of acute exacerbations. The need for new treatments for bronchiectasis, especially in the stable phase, remains largely unmet.

The airway inflammation in bronchiectasis is primarily neutrophilic and closely related to persistent bacterial infections. Excessive neutrophilic inflammation has been associated with increased exacerbation frequency and rapid lung function decline due to the degradation of airway elastin. Once activated, neutrophils release neutrophil serine proteases (NSPs), including neutrophil elastase (NE), which are considered central to the pathophysiology of bronchiectasis. Elevated levels of NE, proteinase 3 (PR3), and cathepsin G (CatG) can overwhelm the natural inhibitors, altering the airway microenvironment and increasing the risk of infection.

Neutrophils play a central role in inflammation development, being the primed cells "recruited" to inflammatory sites. They destroy the pathogens through phagocytosis and by producing reactive oxygen species and antimicrobial proteins (such as NSPs). During the promyelocyte stage of neutrophil maturation within the bone marrow, the lysosomal cysteine protease dipeptidyl peptidase-1 (DPP-1, also known as cathepsin C [CatC]) activates three NSPs — NE, CatG, and PR3 — by removing the N-terminal dipeptides. The involvement of DPP-1 in NSP activation suggests that DPP-1 inhibition may provide clinical benefits for patients with bronchiectasis.

HSK31858, an oral, potent, and highly selective DPP-1 inhibitor developed by Haisco Pharmaceutical Group Co., Ltd., exerts its pharmacological effects by inhibiting DPP-1 and, in turn, downstream neutrophil serine proteases (NSPs) related to bronchiectasis inflammation. Preclinical data for HSK31858 are superior to those of brensocatib, the world's first DPP-1 inhibitor, and phase II clinical trial results are promising. According to the Haisco patents, HSK31858 has demonstrated greater DPP-1 inhibitory activity than brensocatib in vitro (though not in a head-to-head study) and exhibited better pharmacokinetic properties, bioavailability, and safety in vivo.

【Main findings】

This Phase II study primarily enrolled patients with bronchiectasis who had experienced ≥2 acute exacerbations in the past year. The annualized exacerbation rates were 1.00 per patient-year (SD 1.44) for the 20 mg HSK31858 group, 0.75 per patient-year (SD 1.37) for the 40 mg HSK31858 group, and 1.88 per patient-year (SD 1.97) for the placebo group. Compared with the placebo group, both the 20 mg HSK31858 group (48% reduction) and the 40 mg HSK31858 group (60% reduction) significantly reduced the frequency of acute exacerbations. The number of patients who did not experience exacerbations was significantly higher in both the 20 mg and 40 mg HSK31858 groups than in the placebo group. The mean time to first exacerbation was significantly longer in the 20 mg HSK31858 group [124.1 days (SE 5.8)] and the 40 mg HSK31858 group [147.2 days (SE 5.5)] compared with the placebo group [146.2 days (SE 6.2)].

Subgroup analyses further suggested that the above findings were generally consistent, indicating that HSK31858 effectively reduced the risk of bronchiectasis exacerbations and prolonged the time to first exacerbation.

Additionally, HSK31858 rapidly and sustainably reduced the 24-hour sputum volume in patients with bronchiectasis [compared with baseline, the sputum volume decreased by 7.46 g (SE 2.42) in the 20 mg HSK31858 group, 8.82 g (SE 2.45) in the 40 mg HSK31858 group, and increased by 0.30 g (SE 2.50) in the placebo group]. HSK31858 also reduced the sputum purulence score to some extent [compared with the placebo group, the sputum purulence score decreased by -1.00 (95% CI: -1.59 to -0.43; p = 0.0007) in the 20 mg HSK31858 group and by -0.50 (95% CI: -1.11 to 0.06; p = 0.078) in the 40 mg HSK31858 group]. Consistent with the phase II WILLOW clinical trial of brensocatib, no improvement in lung function or quality of life scores was observed with HSK31858 in this study.

In terms of safety, the incidence of treatment-emergent adverse events was comparable between the HSK31858 20 mg group (86.5% vs. 85.3%, P >0.05) and the HSK31858 40 mg group (88.0% vs. 85.3%, P >0.05) and the placebo group. The incidence of specific adverse events (including serious infections, hyperkeratosis, and periodontitis) did not significantly increase in the HSK31858 groups.  

【Clinical significance】

Few drugs have effectively reduced the risk of acute exacerbations in bronchiectasis. For patients with frequent acute exacerbations, macrolides (e.g., azithromycin) can reduce the risk by about 50%, but long-term use easily leads to drug resistance, and their effective treatment window is between 6 to 12 months. The first DPP-1 inhibitor, brensocatib, reduces the risk by about 38%. In this study, HSK31858 demonstrated a higher reduction in the risk of acute exacerbations, partly due to higher sputum protease activity at baseline.

This study not only clarified the potential of the DPP-1 inhibitor HSK31858 in treating bronchiectasis but also revealed its possible mechanism of action. Previous studies have shown that the drug reduces inflammation in patients with bronchiectasis by inhibiting specific signaling pathways, thereby alleviating symptoms such as cough and sputum production and reducing the risk of acute exacerbations. This finding not only provides a new treatment option for patients with bronchiectasis but also lays a solid foundation for the development of more targeted therapies in the future.

This study also highlighted the importance of multidisciplinary collaboration in respiratory medicine research. Academician Nan-shan Zhong and Professor Wei-jie Guan's team worked closely with multiple domestic and international medical institutions and research organizations to advance the treatment of bronchiectasis. This interdisciplinary and cross-field collaboration model has injected new vitality into respiratory medicine research and provided fresh bold ideas for addressing complex diseases.

【Translation】

According to the CDE website, HSK31858, a Class 1 new drug, was included in the breakthrough therapy designation in 2024 for non-cystic fibrosis bronchiectasis, becoming the first drug in China's airway chronic disease field to receive such designation.

In summary, the multicenter research findings published in The Lancet Respiratory Medicine offer new hope for the treatment of bronchiectasis. As research progresses and the drug is further developed, more effective treatment options will emerge, bringing better quality of life and health security to patients with bronchiectasis.