Stapokibart for moderate-to-severe seasonal allergic rhinitis: a randomized phase 3 trial

Abstract

Seasonal allergic rhinitis (SAR) places a significant socioeconomic burden, particularly on individuals with poorly managed recurrent and severe symptoms despite standard-of-care treatment. Stapokibart, a humanized monoclonal antibody that targets the interleukin (IL)-4 receptor subunit alpha, inhibits its interaction with both IL-4 and IL-13 in type 2 inflammation. Here we aim to assess the efficacy and safety of stapokibart as an add-on therapy in adults with moderate-to-severe SAR. The study was a phase 3 multicenter, randomized, double-blind, placebo-controlled clinical trial with 108 patients diagnosed with moderate-to-severe SAR and having baseline blood eosinophil counts ≥300 cells μl^-1. Participants were randomized (1:1) to receive 600 mg (loading dose) to 300 mg stapokibart subcutaneously or a placebo every 2 weeks for 4 weeks. The primary endpoint was mean change from baseline in daily reflective total nasal symptom score (rTNSS) over the first 2 weeks. Multiplicity-tested secondary endpoints included changes in rTNSS over 4 weeks, reflective total ocular symptom score and Rhinoconjunctivitis Quality of Life Questionnaire score over 2 weeks and 4 weeks. Compared with the placebo, stapokibart led to a significant improvement in the mean change from baseline in daily rTNSS during the 2-week (least-squares mean difference, -1.3; 95% confidence interval, -2.0 to -0.6; P = 0.0008) and 4-week (least-squares mean difference, -1.7; 95% confidence interval, -2.5 to -0.8; P = 0.0002) treatments. Stapokibart significantly improved the multiplicity-tested secondary endpoints. Treatment-emergent adverse events were comparable between the groups. Pharmacodynamics and exploratory analyses indicated that the observed improvements in outcomes during pollen season may be attributed to the reduction of type 2 inflammation in response to stapokibart treatment. The results of this trial show that pollen seasonal administration of stapokibart improved both nasal and ocular symptoms and quality of life in patients with moderate-to-severe SAR. ClinicalTrials.gov registration: NCT05908032 .

Fig. 1. Consort diagram in the trial of stapokibart for moderate-to-severe seasonal AR.

The flow chart depicts the process of patient screening, randomization and final analysis in the study. ^aThree patients had multiple reasons for not meeting the eligibility criteria, which resulted in nonadditive data. ^bPatients were excluded based on the following objective circumstances: had insufficient assessments until enrollment completion (n = 29), poor compliance (n = 9), unable to tolerate background treatment during screening (n = 1) and had anemia and abnormal renal function leading to safety concerns (n = 1). Source data

Fig. 2. Change from baseline over time in daily rTNSS during the 4-week treatment period.

Onset of action for stapokibart was observed on day 4 (orange triangle), and the maximum effect was observed on day 14 and day 18 (gray vertical dotted lines) over the 2- and 4-week treatment periods, respectively. The changes from baseline in daily rTNSS up to week 4 were analyzed through a mixed-effect model for repeated measures, with the baseline daily rTNSS as the covariate and the treatment group, study site, visit and treatment-by-visit interaction as fixed effects. LS mean changes are shown for 50 patients in the stapokibart group and 58 in the placebo group. The error bars indicate standard errors. Differences in LS means and the corresponding 95% CIs were calculated. P values were two sided and nominal, without adjustments for multiple comparisons. The rTNSS is used to assess the overall severity of nasal symptoms over the past 12 h on a scale from 0 to 12. Lower scores indicate less severe nasal symptoms. Source data

Fig. 3. RNA-seq analysis of nasal brushing in study participants receiving stapokibart (n = 53) versus placebo (n = 47) at baseline and weeks 2 and 4.

a, Heatmap illustrating the overlapping differentially expressed genes (absolute value log₂(fold change) > 2 and q-value < 0.05) comparing post-stapokibart time points to baseline, as well as intergroup comparisons at each posttreatment time point. b, Normalized enrichment scores (NES) for the top 20 pathways that showed significant downregulation in posttreatment comparisons (weeks 2 and 4) between stapokibart and placebo. c, NES for the top 20 pathways that showed significant downregulation in a post-stapokibart comparison (at weeks 2 and 4) relative to baseline. Source data

Extended Data Fig. 1. Subgroup analysis of mean change from baseline in daily rTNSS over 2-week treatment.

Mean change from baseline in daily rTNSS over 2-week treatment in each subgroup was analyzed using the Analysis of Covariance (ANCOVA) model, with the baseline daily rTNSS, study site, and treatment group as covariates. Difference in LS means and the corresponding 95% CI were calculated. Baseline specific IgE: grade <4 refers to a concentration <17.5 kUA l⁻¹; grade ≥4 refers to a concentration ≥17.5 kUA l⁻¹. The ADA-positive subgroup includes all subjects with post-treatment present ADA or post-treatment enhanced ADA, and the ADA-negative subgroup included all subjects with either negative ADA or pre-existing ADA. The Nab-positive subgroup included all subjects with post-treatment Nab positivity, and the Nab-negative subgroup included all subjects with post-treatment Nab negativity. ADA, anti-drug antibody; CI, confidence interval; IgE, immunoglobulin E; LS, least- squares; Nab, neutralizing antibody; rTNSS, reflective total nasal symptom score. Source data

Extended Data Fig. 2. Evaluation of mild or no symptoms.

a, Median duration of mild or no nasal, ocular symptoms, and nasal and ocular symptoms over 2-week and 4-week treatment. The number of days with mild or no symptoms over 2 or 4 weeks of treatment was summarized for 50 patients in the stapokibart group and 58 in the placebo group, and the difference between groups was analyzed by Hodges-Lehmann method, together with its 95% CI. b, Proportion of patients with mild or no nasal symptoms at days 1, 7, 14, 21, and 28 (post-hoc analysis). Mild or no nasal symptoms were defined as all individual symptom scores of ≤ 1 point. The P values were two-sided and nominal, without adjustments for multiple comparisons. Source data

Extended Data Fig. 3. Change from baseline in total RQLQ score and individual domains scores at 2-week (a) and 4-week treatment (b).

Least-squares mean changes are shown for 50 patients in the stapokibart group and 58 in the placebo group; error bars indicate standard errors. Data are shown as differences in median value (95% confidence interval). Scatter points indicate change from baseline value for individual patient. The total RQLQ is used to assess the quality of life status in adult patients with rhinoconjunctivitis; total scores range from 0 to 6, with lower scores indicating a higher quality of life. The individual domain ranges from 0 (no trouble) to 6 points (extreme trouble). Data was analyzed using the Analysis of Covariance (ANCOVA) model, with the baseline RQLQ score, study site, and treatment group as covariates. Missing data for RQLQ was imputed by last observation carried forward method. Changes from baseline in total RQLQ score at week 2 and week 4 were multiplicity-tested efficacy outcomes with type I error controlled by step-down test procedures. P values for individual domains scores were two-sided and nominal, without adjustments for multiple comparisons. RQLQ, Rhinoconjunctivitis Quality of Life Questionnaire. Source data

Extended Data Fig. 4. Mean serum concentration of stapokibart over the course of the study period.

Error bars denote standard errors. Source data

Extended Data Fig. 5. Median change and percentage change from baseline over time in pharmacodynamic markers.

a, b, Serum thymus and activation-regulated chemokine (TARC). c, d, Serum total immunoglobulin E (IgE). e, f, Plasma eotaxin-3. g, h, Blood eosinophil count. i, j, Blood eosinophil percentage. Comparisons between groups were analyzed using two-sided Wilcoxon rank-sum test, and P values were nominal without adjustments for multiple comparisons. Error bars denote interquartile ranges. Source data

Extended Data Fig. 6. Median change and percentage change from baseline over time in exploratory biomarkers in serum and nasal secretion.

Changes of four grass pollen-specific immunoglobulin E (sIgE) in serum (a, c) and nasal secretion (b, d) were analyzed in patients with positive baseline sIgE ( ≥ 0.1 kU [kUA] l⁻¹). e, f, Charcot-Leyden Crystal Protein (CLC) in serum and nasal secretion; cystatin SN (CST-1) in nasal secretion. Comparisons between groups were analyzed using two-sided Wilcoxon rank-sum test, and P values were nominal without adjustments for multiple comparisons. Error bars denote interquartile ranges. Source data