An anti-TSLP monoclonal antibody for uncontrolled CRSwNP: the DUBHE randomized clinical trial

Abstract

To explore the therapeutic potential of blocking thymic stromal lymphopoietin (TSLP) in patients with chronic rhinosinusitis with nasal polyps (CRSwNP), we conducted a phase 1b/2a, randomized, double-blind, placebo-controlled trial to assess the safety and efficacy of CM326, a monoclonal antibody against TSLP. We enrolled 84 eligible patients with uncontrolled CRSwNP and stratified them based on baseline tissue eosinophil count. Patients are assigned to receive CM326 220 mg (n = 40) or placebo (n = 20) every 2 weeks (Q2W) and CM326 220 mg (n = 20) or placebo (n = 4) every 4 weeks (Q4W) for 16 weeks. Subsequently, all patients continue on CM326 220 mg Q2W or Q4W for an additional 36 weeks, followed by a 12-week follow up. Primary endpoints are safety of CM326 and change from baseline in NPS at week 16 in patients with eosinophilic CRSwNP (ECRSwNP). Main secondary endpoints include the change from baseline in NPS at week 16 in non-eosinophilic CRSwNP (nonECRwNP) and pharmacodynamic markers. Throughout the 64-week study, all treatment-emergent adverse events (TEAEs) are mild or moderate. CM326 Q2W improves NPS in patients with ECRSwNP compared with placebo at week 16 (mean difference [95% CI], -1.2 [-2.3 to -0.1], P = 0.04), with sustained benefits during the open-label and follow-up periods. Notably, peripheral blood and tissue eosinophil counts and concentrations of plasma IL-13 and IL-5 are reduced by week 16 with the treatment of CM326 Q2W versus placebo. A post-hoc analysis demonstrates that all participants with baseline TSLP > 330 fg/mL achieve a substantial reduction in NPS by week 16 with the treatment of CM326 Q2W (mean difference vs. placebo: -1.75 [95%CI, -3.06 to -0.44], P = 0.01). Overall, CM326 is well tolerated and effective in patients with uncontrolled ECRSwNP. A baseline plasma TSLP level of 330 fg/mL may serve as a predictive marker for treatment efficacy of CM326. ClinicalTrials.gov Identifier: NCT05324137.

Fig. 1. Patient flow in the DUBHE randomized clinical trial.

* Four enrolled patients in the open-label cohort were not included in further analysis of this study. The cohort of every two weeks was stratified by tissue eosinophil count ( < 55/HPF, ≥55/HPF) and NPS ( < 5, ≥5). The cohort of every four weeks only included patients with NPS ≥ 5 and was stratified by tissue eosinophil count ( < 55/HPF, ≥55/HPF). HPF high-power field; NPS nasal polyp score; Q2W every two weeks; Q4W every four weeks; FAS full analysis set; SS safety set; PDS pharmacodynamic set; IMGS immunogenicity set; mFAS modified full analysis set.

Fig. 2. Change from baseline over time in NPS in patients with ECRSwNP or nonECRSwNP.

a, b Change from baseline over time in NPS in patients with eosinophilic chronic rhinosinusitis with nasal polyps (ECRSwNP) in the Q2W (a) and Q4W cohort (b); c, d Change from baseline over time in NPS in patients with non-eosinophilic chronic rhinosinusitis with nasal polyps (nonECRSwNP) in the Q2W (c) and Q4W cohort (d). Error bars denote standard error. Baseline values are presented as mean (standard deviation). NPS nasal polyp score; Q2W every 2 weeks; Q4W every 4 weeks. Group differences within 16 weeks were tested using t-test. P values were two sided and nominal, without adjustments for multiplicity. No between comparison was performed during the open-label and follow-up periods as all patients received CM326 during the open-label period.

Fig. 3. Change from baseline in pharmacodynamic biomarkers in the Q2W cohort.

a Peripheral blood eosinophil count; b Tissue eosinophil count; c Hematoxylin and eosin stain of biopsied nasal polyp tissue at baseline and week 16 from a patient (magnification: ×400); d Plasma interleukin-5 (IL-5); e Plasma interleukin-13 (IL-13); f Total serum immunoglobulin E (IgE); g Serum thymus and activation-regulated chemokine (TARC); h Serum periostin; i Plasma thymic stromal lymphopoietin (TSLP). HPF high-power field; Q2W every 2 weeks. Error bars denote standard error. Baseline values are presented as mean (standard deviation). Biomarkers were analyzed under pharmacodynamic set using Wilcoxon rank-sum test. P values were two sided and nominal, without adjustments for multiplicity. No between comparison was performed during the open-label and follow-up periods as all patients received CM326 during the open-label period.