This study evaluates CM326, a monoclonal antibody targeting TSLP, for safety and efficacy in patients with refractory chronic rhinosinusitis with nasal polyps (CRSwNP). Results demonstrate that CM326 significantly improves Nasal Polyp Score (NPS) after 16 weeks of treatment, particularly in patients with baseline TSLP levels exceeding 330 fg/mL. Additionally, TSL6P levels may serve as a potential efficacy-predicting biomarker, offering new insights for personalized treatment strategies.
Literature Overview
This article, 'An anti-TSLP monoclonal antibody for uncontrolled CRSwNP: the DUBHE randomized clinical trial', published in
Background Knowledge
Chronic rhinosinusitis with nasal polyps (CRSwNP) is a chronic inflammatory disease affecting 2%-4% of the global population, characterized by nasal congestion, rhinorrhea, headache, and olfactory dysfunction that severely impair quality of life. Despite widespread use of current treatments (e.g., topical/systemic corticosteroids, surgery), a subset of patients remains refractory. Research reveals CRSwNP's heterogeneous inflammatory phenotypes, including eosinophilic inflammation (ECRSwNP) associated with elevated IL-4/IL-5 and tissue eosinophil infiltration, and neutrophilic subtypes. This heterogeneity drives the development of precision therapies targeting specific inflammatory phenotypes.
Thymic stromal lymphopoietin (TSLP), a cytokine secreted by epithelial cells under inflammatory stimuli, activates dendritic cells, type 2 innate lymphoid cells (ILC2), and Th2 cells to promote secretion of type 2 cytokines (IL-4, IL-5, IL-9, IL-13) and amplify type 2 immune responses. Preclinical studies demonstrate that anti-TSLP monoclonal antibody tezepelumab effectively reduces asthma exacerbations through Th2-independent mechanisms, suggesting broader therapeutic potential for TSLP inhibition.
CM326, a humanized anti-TSLP monoclonal antibody, demonstrated favorable safety profiles, linear pharmacokinetics, and low immunogenicity in phase 1 trials, supporting progression to phase 2 studies. The DUBHE trial presented here aims to comprehensively evaluate CM326's safety and efficacy in CRSwNP patients while exploring TSLP as a predictive biomarker for response, thereby expanding therapeutic applications for TSLP-targeted interventions.
Research Methods and Experiments
This multicenter, randomized, double-blind, placebo-controlled phase 1b/2a clinical trial enrolled 84 patients with refractory CRSwNP, stratified by baseline tissue eosinophil levels. Participants were randomized into two cohorts: every two weeks (Q2W) receiving CM326 220mg or placebo (40 vs 20 cases), and every four weeks (Q4W) receiving CM326 220mg or placebo (20 vs 4 cases). The 16-week treatment period was followed by a 36-week open-label extension and 12-week follow-up. Primary endpoints included safety and NPS score changes in ECRSwNP patients at week 16, with secondary endpoints assessing NPS changes in nonECRSwNP patients and pharmacodynamic biomarker modulation.
Key Conclusions and Perspectives
Research Significance and Prospects
This study represents the first investigation of TSLP as a predictive biomarker in CRSwNP and validates CM326's therapeutic potential in ECRSwNP. Future studies should expand sample sizes to confirm efficacy and long-term safety across diverse populations. Additionally, further research is needed to establish TSLP as a reliable inflammatory subtype biomarker and explore its utility in different treatment regimens. As a next-generation anti-TSLP monoclonal antibody with preliminary validation in asthma and allergic inflammation, CM326's application could extend to other type 2 inflammation-related diseases including allergic asthma and atopic dermatitis.
Conclusion
Through the DUBHE clinical trial, this study systematically evaluated CM326's safety and efficacy in treating refractory CRSwNP. CM326 demonstrated significant NPS improvement under the Q2W regimen while reducing type 2 inflammation biomarkers (IL-5, IL-13, eosinophils). Notably, plasma TSLP levels >330 fg/mL emerged as a novel predictive biomarker for therapeutic response. The drug showed robust efficacy in ECRSwNP but limited effects in nonECRSwNP, suggesting preferential targeting of specific inflammatory phenotypes. With favorable tolerability and sustained effects, CM326 requires larger phase 3 trials to validate its therapeutic potential across broader CRSwNP populations. This research establishes TSLP-targeted therapy in CRSwNP management and provides new perspectives for antibody treatments in other type 2 inflammatory diseases.
