The "Brake Pads" of Respiratory Inflammation: The Domestically Produced New Drug HSK31858 Brings New Hope for the Treatment of Bronchiectasis
Introduction
For many patients suffering from chronic cough, sputum production, and recurrent lung infections due to bronchiectasis, existing treatment methods often only treat the symptoms but not the root cause, making it difficult to stop the gradual deterioration of the condition. Recently, a study published in the "British Journal of Clinical Pharmacology" brought us the latest news about a domestically developed innovative drug, HSK31858. This Phase I clinical trial conducted in healthy Chinese volunteers initially confirmed the drug's safety and potential, lighting a new beacon of hope for conquering this challenging respiratory disease.
Background: What is the Tricky Bronchiectasis?
Bronchiectasis is a chronic respiratory disease characterized by permanent, irreversible dilation and thickening of the bronchial walls (air passages) in our lungs due to recurrent infections and inflammation. You can imagine it as an old, rusty water pipe that has lost its original elasticity and smoothness, becoming rough, deformed, and prone to accumulating "dirt" – which is sputum.
In the lungs of bronchiectasis patients, this "accumulation of dirt" manifests as impaired mucus clearance, with a large amount of thick sputum accumulating, becoming a "breeding ground" for bacteria, thereby triggering frequent acute exacerbations (lung infections), forming a vicious cycle of "infection → inflammation → airway damage → re-infection." Patients often have to endure chronic cough, sputum production, difficulty breathing, and even hemoptysis, severely affecting their quality of life.
Currently, treatment primarily focuses on anti-infection, expectoration, and airway clearance, but there is a lack of targeted drugs that can fundamentally block the inflammatory cascade and slow down disease progression. Scientists have found that in this vicious cycle, an immune cell called "neutrophil" plays a key "destroyer" role.
Drawing the Fire from Under the Cauldron: How Do DPP-1 Inhibitors "Disarm" Destructive Enzymes?
Neutrophils are the body's "front-line soldiers," rapidly reaching the site of infection to clear pathogens. But sometimes, these soldiers "overdo it," releasing a powerful weapon called "neutrophil elastase" (NE). In the lungs of bronchiectasis patients, NE is overactive, not only killing bacteria but also "friendly fire," damaging the elastic fibers and tissue structure of the airways, exacerbating inflammation and damage.
Drugs that directly inhibit NE have repeatedly failed in past clinical trials. So, scientists changed their approach, deciding to start from an upstream link. They found that NE is not fully mature when "manufactured" and needs to be "activated" and "armed" by an enzyme called "dipeptidyl peptidase-1" (DPP-1). DPP-1 is like the general manager of an arsenal, responsible for installing "ammunition" on NE and other proteases, giving them killing power.
Therefore, if DPP-1 activity can be inhibited, it is equivalent to cutting off the "arming" process of NE at the source, preventing it from being activated. This is the mechanism of action of DPP-1 inhibitors – by "drawing the fire from under the cauldron," they reduce the amount of active NE, thereby reducing its damage to lung tissue and breaking the vicious cycle of inflammation. The first-in-class drug Brensocatib has been shown in a large Phase III clinical study (ASPEN study) to significantly reduce the frequency of acute exacerbations in patients, validating the great potential of this target.
Key Findings: Phase I Exploration of Domestically Produced New Drug HSK31858
The protagonist of this study, HSK31858, is an oral, reversible DPP-1 inhibitor independently developed in China. This Phase I study aims to evaluate its safety, tolerability, pharmacokinetics (the process of drug absorption, distribution, metabolism, and excretion in the body), and pharmacodynamics (the effect of the drug on the body) in healthy adult volunteers.
The study was divided into two parts:
- Single-dose study: Volunteers received a single dose of HSK31858 (15mg to 80mg) or placebo.
- Multiple-dose study: Volunteers received different doses of HSK31858 (10mg, 20mg, 40mg) or placebo daily for 28 consecutive days.
Core research results show:
- Good Safety: HSK31858 showed good safety and tolerability throughout the study. No serious adverse events or study discontinuations due to adverse events occurred. This is crucial for the early development of a new drug and is its "pass" to the next stage of research.
- Predictable Pharmacokinetics: The drug was rapidly absorbed after oral administration, reaching peak blood concentration in about 0.75-1 hour. Its half-life was relatively long (about 16.5-21.0 hours), suggesting its potential for once-daily dosing, which is convenient for patients. At the same time, food had no significant effect on the total absorption of the drug, with few restrictions on administration.
- Significant Pharmacodynamics: The study clearly confirmed that HSK31858 dose-dependently inhibited NE activity in the blood. After 28 days of once-daily administration, the 40mg dose group showed a maximum reduction of 76.4% in NE activity compared to baseline, demonstrating a powerful target inhibition effect.
Limitations and Application Prospects
It needs to be emphasized that this is only a Phase I clinical trial conducted in healthy individuals. Its main purpose is to evaluate the drug's "safety" and "how it works," not to verify its "efficacy" in real patients. Whether HSK31858 can, like its counterpart Brensocatib, effectively reduce the risk of acute exacerbations in bronchiectasis patients and improve their quality of life, still requires larger-scale Phase II and Phase III clinical trials for confirmation.
Nevertheless, the positive results of this study are undoubtedly an exciting start. It indicates that HSK31858 has ideal drug-forming properties and powerful biological effects, paving the way for its further clinical development, and recommending 20mg or 40mg once daily as potential effective doses for subsequent research.
Summary
The Phase I clinical study of HSK31858 successfully validated its safety and effective target inhibition capability in healthy Chinese volunteers. As an innovative drug that is expected to control the core pathology of bronchiectasis – neutrophilic inflammation – at its source, it represents an important new direction in this field of treatment. We have reason to expect that with the advancement of subsequent clinical research, this domestically produced new drug will soon bring more effective and safer treatment options to a wide range of bronchiectasis patients, helping them break free from the disease and regain smooth breathing.
