Abstract Background Bronchiectasis is a chronic respiratory disease characterized by recurrent exacerbations. Dipeptidyl peptidase 1(DPP-1) inhibitors, such as brensocatib and HSK31858, represent a novel therapeutic class targeting neutrophil-mediated inflammation. This study aimed to evaluate the comparative efficacy of these agents against each other and a common placebo anchor. Methods We conducted a systematic network meta-analysis (NMA). A frequentist NMA was performed using R packages meta and netmeta to synthesize aggregate data. Treatment effects were expressed as Risk Ratios (RR) for annualized exacerbation rates and Mean Differences (MD) for change in FEV1, with 95% Confidence Intervals (CIs). Treatments were ranked using P-scores. To enhance the time-to-event analysis for exacerbations, we also performed a pooled analysis of individual participant data (IPD) extracted from study Kaplan-Meier curves, reconstructing IPD for a pooled time-to-first-exacerbation analysis. Results The NMA included five randomized controlled trials including 2552 patients with seven treatments across two DPP-1 inhibitors and a comparator . For reducing exacerbation risk, a clear dose-response relationship was observed. The most effective treatment was HSK31858 40 mg (RR 0.42, 95% CI 0.30-0.59, p 0.0001),and HSK31858 20 mg (RR 0.54, 95% CI 0.41-0.72, p 0.0001). Brensocatib 10 mg also significantly reduced exacerbations compared to placebo (RR 0.67, 95% CI 0.49-0.91, p = 0.0096). This finding was robustly supported by the pooled Kaplan-Meier analysis for freedom from exacerbations. The survival curves demonstrated a highly significant separation favoring all active treatments over placebo (log-rank p = 0.00015). In contrast, none of the treatments demonstrated a statistically significant improvement in FEV1 over placebo (p value 0.05). Conclusion DPP-1 inhibitors significantly reduce exacerbation frequency in patients with bronchiectasis, showing a clear dose-dependent effect. HSK31858 40 mg and HSK31858 20 mg ranked highest in efficacy, followed by brensocatib 10 mg. While improvements in lung function were not observed, the consistent reduction in exacerbations supports DPP-1 inhibition as a promising therapeutic strategy targeting neutrophilic inflammation. Future direct head-to-head studies are needed to confirm comparative efficacy, optimal dosing, and long-term safety among these emerging agents This abstract is funded by: None
Naeem et al. (Fri,) studied this question.