HSK-31858 Advanced Drug Monograph

HSK-31858 Medication Report

Name: HSK-31858 Name (English): HSK-31858

Mechanism of Action: HSK-31858 is a novel, oral, potent, and highly selective small molecule inhibitor of dipeptidyl peptidase 1 (DPP1). DPP1 is an enzyme responsible for activating neutrophil serine proteases (NSPs), including neutrophil elastase (NE), proteinase 3, and cathepsin G, during neutrophil maturation in the bone marrow. By inhibiting DPP1, HSK-31858 reduces the activation of these NSPs, which are implicated in the damaging inflammation and progression of neutrophil-mediated inflammatory diseases.

Uses: HSK-31858 is being investigated for the treatment of respiratory diseases characterized by neutrophilic inflammation. Clinical trials are ongoing for the following indications:

• Bronchiectasis: Phase 2 trials have shown that HSK-31858 significantly reduces the frequency of exacerbations and prolongs the time to the first exacerbation in adults with bronchiectasis. A Phase 3 trial is currently recruiting participants with non-cystic fibrosis bronchiectasis.
• Cystic Fibrosis: A Phase 3 trial is recruiting participants with cystic fibrosis and bronchiectasis.
• Asthma: A Phase 2 trial is enrolling participants with asthma.
• Chronic Obstructive Pulmonary Disease (COPD): A Phase 2 trial is enrolling participants with COPD and bronchiectasis.
• Airway Mucus Hypersecretion in Chronic Airway Inflammatory Diseases: A Phase 2 trial is enrolling participants.

Side Effects: In a Phase 2 trial in adults with bronchiectasis, the incidence of adverse events was similar across the HSK-31858 and placebo groups. No increased incidence of adverse events of special interest (e.g., hyperkeratosis, gingivitis, or life-threatening infections) was associated with either dose of HSK-31858 (20 mg or 40 mg). The most frequently occurring treatment-emergent adverse events included upper respiratory tract infections, increased cough, hemoptysis, and increased body weight, with similar proportions across treatment and placebo groups. A Phase 1 study in healthy volunteers also indicated that HSK-31858 was safe and well-tolerated, with no serious adverse events or discontinuations due to adverse events reported.

Pharmacokinetics: HSK-31858 is rapidly absorbed after oral administration, reaching peak plasma concentrations ($T_{max}$) within 0.75 to 1.0 hour. The terminal half-life ($t_{1/2}$) ranges from 16.5 to 21.0 hours in the fasted state with single doses. Both the maximum concentration ($C_{max}$) and the area under the concentration-time curve (AUC) exhibit a dose-dependent increase. Food does not significantly affect the AUC. Multiple once-daily doses result in approximately a 2-fold accumulation in AUC.

Clinical Trials: HSK-31858 has undergone and is currently in several phases of clinical development:

• Phase 1: Completed in healthy volunteers, assessing safety, tolerability, pharmacokinetics, and pharmacodynamics.
• Phase 2: Completed in adults with bronchiectasis in China, demonstrating efficacy in reducing exacerbation frequency. Ongoing trials in asthma and COPD with bronchiectasis.
• Phase 3: Currently recruiting participants with non-cystic fibrosis bronchiectasis and cystic fibrosis with bronchiectasis.

Regulatory Status: HSK-31858 is currently investigational and not approved for marketing in any region. A licensing agreement exists between Haisco Pharmaceutical Group and Chiesi Group for the development, manufacture, and commercialization of HSK-31858 outside of greater China.