Effects of the DPP-1 inhibitor HSK31858 in adults with bronchiectasis in China (SAVE-BE): a phase 2, multicentre, double-blind, randomised, placebo-controlled trial

Abstract

Background: Airway neutrophil inflammation with excessive neutrophil serine proteases is implicated in frequent exacerbations of bronchiectasis. HSK31858 is a novel reversible inhibitor of DPP-1. We aimed to assess the efficacy and safety of HSK31858 in decreasing the frequency of bronchiectasis exacerbations among adults with bronchiectasis.

Methods: SAVE-BE was a phase 2, double-blind, randomised, placebo-controlled trial in 25 tertiary centres in China. Participants were aged 18 years or older with a physician diagnosis of bronchiectasis, according to chest high-resolution CT showing bronchial dilatation and compatible respiratory symptoms, and at least two exacerbations within 12 months before screening. Participants were randomly assigned (1:1:1) via a central interactive web-response system to receive 20 mg HSK31858, 40 mg HSK31858, or placebo, orally, once daily for 24 weeks. Randomisation was stratified by exacerbation frequency in the previous year (less than three vs three or more annually) and study investigators and participants were masked to group assignment for analysis of study outcomes. The primary endpoint was the annualised exacerbation frequency over 24 weeks, assessed in the full analysis set. Safety was monitored throughout the study. This trial is registered with ClinicalTrials.gov, NCT05601778.

Findings: Between Dec 6, 2022, and March 31, 2024, 292 patients were screened, 226 of whom were enrolled and randomly assigned (75 to the 20 mg HSK31858 group, 76 to the 40 mg HSK31858 group, and 75 to the placebo group. 74 patients received 20 mg HSK31858, 75 received 40 mg HSK31858, and 75 received placebo and were included in the full analysis set. In the full analysis set, 136 (61%) participants were female and 88 (39%) were male. The mean annualised frequency of exacerbations was 1·00 per person-year (SD 1·44) in the 20 mg HSK31858 group, 0·75 per person-year (1·37) in the 40 mg HSK31858 group, and 1·88 per person-year (1·97) in the placebo group. The least-squares mean frequency of exacerbations was 1·05 per person-year (95% CI 0·73-1·51) in the 20 mg HSK31858 group, 0·83 per person-year (0·55-1·25) in the 40 mg HSK31858 group, and 2·01 per person-year (1·53-2·63) in the placebo group. The incidence rate ratio compared with placebo was 0·52 (95% CI 0·34-0·80; p=0·0031) for the 20 mg HSK31858 group and 0·41 (0·26-0·66; p=0·0002) for the 40 mg HSK31858 group. The incidence of adverse events was similar across the three groups. Neither HSK31858 dose was associated with an increased incidence of adverse events of special interest (eg, hyperkeratosis, gingivitis, or life-threatening infections).

Interpretation: Both HSK31858 doses improved clinical outcomes in adults with bronchiectasis, significantly reducing the exacerbation frequency compared with placebo. The development of new drugs targeted at amelioration of neutrophilic inflammation (eg, via suppression of DPP-1 activity) might lead to new options for hindering the progression of bronchiectasis.

Funding: Haisco.