Evaluating the efficacy and safety of Stapokibart (CM310) in the treatment of uncontrolled seasonal allergic rhinitis based on real-world research

Abstract

Purpose

More than 60% of seasonal allergic rhinitis (SAR) patients still remain inadequately control even after receiving standard-of-care (SoC). Recently, Stapokibart (CM310), has demonstrated efficacy in randomized controlled trials, but real-world evidence for SoC-refractory SAR is still insufficient.

Methods

This prospective real-world study enrolled 127 patients with moderate-to-severe SAR. All participants received Stapokibart treatment (600 mg subcutaneous loading dose, followed by 300 mg at week 2). Efficacy outcomes included the reflective total nasal /ocular symptom score (rTNSS/rTOSS), visual analogue scale (VAS), and rhinoconjunctivitis quality of Life questionnaire (RQLQ) change at weeks 2 and 12. Statistical analyses used Wilcoxon signed-rank test (Bonferroni-corrected) and generalized estimating equations (GEE).

Results

All outcomes improved significantly at Weeks 2 and 12 vs. baseline (all P < .001). Median rTNSS decreased from 8.00 (IQR:7.00–10.00) to 4.00 (2.00–5.00) at Week 2 and remained stable; rTOSS fell to 0.00 (0.00–1.75) at Week 12. VAS and RQLQ showed progressive improvements. Only 8 (6.3%) patients reported mild, transient injection-site adverse events; no severe events occurred.

Conclusion

Stapokibart is clinically effective and well-tolerated in SoC-refractory SAR, with sustained benefits up to 12 weeks. It is a valuable treatment for heterogeneous patients, supporting its routine clinical use.

Supplementary Information

The online version contains supplementary material available at 10.1007/s00405-026-10184-1.

Introduction

Allergic rhinitis (AR) is a chronic, immune-mediated inflammatory disorder of the nasal mucosa, primarily triggered by immunoglobulin E (IgE)-mediated reactions to aeroallergens [1, 2]. Clinically, AR is categorized into seasonal allergic rhinitis (SAR) and perennial allergic rhinitis (PAR), with SAR characterized by symptom recurrence that coincides with seasonal allergen exposure (typically pollens from grasses, weeds, or trees); while PAR is associated with persistent exposure to indoor allergens such as dust mites or mold [3, 4]. The core clinical manifestations of SAR include paroxysmal sneezing, clear rhinorrhea, nasal itching, and nasal congestion, often accompanied by ocular symptoms such as eye itching, redness, and tearing. These symptoms not only cause physical discomfort but also significantly impair patients’ sleep quality, daytime work efficiency, and social activities, thereby reducing overall quality of life [5]. As a highly prevalent chronic disease, AR imposes a substantial socioeconomic burden globally, with direct costs related to medication and medical consultations, as well as indirect costs from missed work or school days [6, 7].

Epidemiological data indicate that the global prevalence of AR ranges from 10% to 40%, and this rate has shown a steady upward trend in recent decades, likely driven by factors such as climate change, urbanization, and changes in lifestyle [8–10]. In China, the overall prevalence of AR has reached approximately 17.60%, with significant regional variations attributed to differences in climate, allergen profiles, and population demographics [6, 11]. Notably, in Southwest China, where Chengdu (the study site) is located, the epidemiological characteristics of SAR exhibit unique features. This region has a subtropical humid climate, with prolonged pollen seasons for local weeds (e.g., Artemisia and Humulus) and high indoor dust mite concentrations due to high humidity, leading to a higher incidence of SAR compared to some northern regions [12, 13]. A cross-sectional study in Sichuan Province (a core area of Southwest China) reported that the prevalence of SAR in adults is approximately 34.3% [14]. Moreover, some studies have indicated that more than 60% of patients with SAR using standard-of-care (SoC) regularly reported partial or poor symptom control; highlighting an urgent need for more effective therapeutic strategies in this region [11, 15].

The pathogenesis of SAR is closely linked to dysregulated type 2 immune responses. Upon exposure to specific allergens, nasal epithelial cells release alarmins (such as interleukin-25 (IL-25), interleukin-33 (IL-33), and thymic stromal lymphopoietin (TSLP)); these cytokines could induce type 2 cytokine production in group 2 innate lymphoid cells (ILC2s) and Type helper 2 T (Th2) cells [1, 2]. Alarmins are released together with many chemokines, attract type 2 response-related cells and sometimes activate inflammasomes and interleukin-1β (IL-1β). Like alarmins, cytokines involved in the type 2 response, including interleukin-4 (IL-4), interleukin-5 (IL-5), interleukin-9 (IL-9), interleukin-13 (IL-13), and interleukin-31 (IL-31), are also relevant in orchestrating one another and involve cells and overall type 2 immunity [16, 17]. These cytokines contribute to vascular permeability, the infiltration of eosinophils and other inflammatory cells into the nasal mucosa, local IgE production, increased mucus production, vascular leakage and expansion, and activation and differentiation of different subsets of Th2 cells [5, 18]. This sequential cascade of innate and adaptive immune activation ultimately manifests as SAR’s characteristic nasal and ocular symptoms.

Currently, the SoC for SAR includes intranasal corticosteroids (INCS), and oral second-generation H1-antihistamines [19, 20]. While INCS can alleviate nasal inflammation, they may cause local side effects such as nasal dryness or bleeding [21, 22]; oral antihistamines are effective against nasal and ocular symptoms, such as itching, sneezing, and runny nose, with a rapid onset and a lasting effect, but their efficacy on nasal congestion or blockage is limited, which is the most distressing symptom for many patients [23, 24]. Evidence-based guidelines have improved the knowledge of AR, but many patients remain inadequately controlled. Among the patients who had received the SoC, only 32.7% felt that their symptoms were completely controlled, and alternative treatments such as allergen-specific immunotherapy are limited by long treatment durations (3–5 years) and low patient adherence, leaving a significant unmet medical need [18, 25].

Against this background, biologic therapies targeting key molecules in the Th2 inflammatory pathway have emerged as promising alternatives for refractory SAR [26]. Stapokibart (CM310), a humanized monoclonal antibody that specifically targets IL-4 receptor alpha (IL-4Rα), which has attracted significant attention due to its unique mechanism of action. By high-affinity binding to IL-4Rα, it simultaneously blocks the interaction of IL-4Rα with both IL-4 and IL-13, thereby inhibiting the entire Th2 inflammatory cascade at its upstream [27].

Preclinical studies have confirmed that Stapokibart can effectively reduce the production of Th2-related cytokines and the infiltration of inflammatory cells in nasal mucosa; and early clinical trials further validated its efficacy and safety. Following, the phase 2 MERAK trial (NCT05470647), which enrolled moderate-to-severe SAR patients with a documented history of inadequate response to the SoC; showed that Stapokibart effectively improve mean percentage change from baseline in daily reflective total nasal symptom score (rTNSS), a morning (AM) instantaneous TNSS (AM iTNSS), daily reflective total ocular symptom score (rTOSS) and AM iTOSS in 2 weeks in patients with SAR, particularly for those with baseline blood eosinophil count of ≥ 300 cells/µL, which also has been set as one of the inclusion criteria in the ongoing phase 3 studies [28].

Recently, the subsequent phase 3 PHECDA trial (NCT05908032), a multicenter, randomized, placebo-controlled study in China, further confirmed that Stapokibart (loading dose 600 mg in the first day, followed by 300 mg every 2 weeks for 4 weeks) significantly improved rTNSS at 2 weeks (least-squares mean difference: -1.3; 95% CI: -2.0 to -0.6; P = .0008) and 4 weeks (least-squares mean difference: -1.7; 95% CI: -2.5 to -0.8; P = .0002) compared to placebo. The results of this trial showed that stapokibart improved both nasal and ocular symptoms and quality of life in patients with moderate-to-severe SAR [29].

Despite the positive results from randomized controlled trial (RCT), several limitations of this study highlight the need for real-world research (RWR) [30]. First, RCT typically enroll highly selected populations; for example, the PHECDA trial excluded patients with severe liver/kidney dysfunction, recent use of biologics, or active nasal infections, which may not reflect the diversity of patients in routine clinical practice, especially those with comorbidities or complex histories of AR treatment. Second, RCT is conducted under strictly controlled conditions, which differ from real-world clinical settings where patients may have variable adherence to SoC or require adjustments to concomitant medications. Third, existing RCT of Stapokibart has not specifically focused on Southwest China, where the unique allergen profile and climate conditions may affect treatment response. Finally, real-world data can provide insights into long-term safety and effectiveness in broader populations, which is critical for guiding clinical decision-making and optimizing treatment strategies.

To address these gaps, we conducted a prospective RWR at the Chengdu Second People’s Hospital (affiliated with Sichuan University) to evaluate the efficacy and safety of Stapokibart in adult patients with moderate-to-severe SAR who had inadequate response to SoC. This study aimed to validate the efficacy of Stapokibart in a real-world setting, explore its performance in patients with comorbidities or specific allergen sensitization patterns, and provide evidence to support its rational use in routine clinical practice for refractory SAR.

Methods

Study design

This present study was a single-center, real-world, prospective, single-arm, open-label, interventional study, which conducted at the department of otorhinolaryngology head and neck surgery, in the Sichuan University affiliated Chengdu Second People’s Hospital from January 2025 to June 2025. The primary aim of this study was to evaluate the efficacy and safety of the stapokibart in adults with moderate-to-severe SAR and inadequately controlled by SoC, which based on a real-word environment. The study adhered to the Declaration of Helsinki and Good Clinical Practice guidelines, with data collected in natural clinical workflows and documented via standardized case report forms (CRFs) to ensure integrity. This trial received approval from the independent medical ethics committee at Sichuan University affiliated Chengdu Second People’s Hospital (Approval number: No. [KY] PJ2025415), and all participants provided written informed consent before enrollment. The study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline (shown in Table 1 of supplemental materials).

Table 1.

Demographic and clinical characteristics of the patients with uncontrolled SAR

Variables	Overall (N = 127, 100%)
Age, years	37.65 ± 8.93
Sex
Male	70 (55.12%)
Female	57 (44.88%)
Duration of SAR, years	7.72 ± 5.56
Allergen
Non-dust mite	95 (74.80%)
Dust mite	32 (25.20%)
Comorbidity of asthma	11 (8.66%)
Comorbidity of conjunctivitis	30 (23.62%)

SAR seasonal allergic rhinitis

Study population and recruitment

Eligible participants were consecutive outpatients aged ≥ 18 years, clinically diagnosed with moderate-to-severe SAR per the Chinese Guidelines for Diagnosis and Treatment of Allergic Rhinitis (2022 Revision) [31, 32], with symptoms (nasal itching, sneezing, rhinorrhea, nasal congestion) linked to seasonal allergens (e.g., Artemisia, Weed-pollen, Humulus, dust mite). Inclusion required inadequate response to SoC (rTNSS ≥ 6 points (0–12 scale), or nasal congestion subscore ≥ 2 points and one of the three symptoms of runny nose, nasal itching, and sneezing ≥ 2 points after 2 weeks treatment of INCS or oral second-generation H1-antihistamines). Exclusions included severe hepatic or renal dysfunction, uncontrolled hypertension or asthma, use of biologics, systemic corticosteroids, or immunosuppressants in the past three months, pregnancy or lactation, suffering from active infection, tumors, autoimmune diseases, or other nasal diseases. The recruitment process included a one-week eligibility screening period during which the participants’ medical history and various baseline symptom scores are collected, and the detailed process of patient recruitment and inclusion/exclusion is shown in Fig. 1.

Fig. 1.

The study’s flow chart for the inclusion/exclusion criteria and treatment procedure of aimed moderate-to-severe SAR patients

Intervention procedure

According to the instructions on the product label, all patients received subcutaneous injections of Stapokibart as per the standard procedure, with a 600 mg loading dose (split into two 300 mg injections at different sites, interval ≤ 1 h) was given on day 1; followed by a 300 mg maintenance dose at 2 week later [27, 28]. Subcutaneous injection was performed at one site (2 sites for the first administration, each site up to 2 mL) based on the abdominal quartiles (right lower, right upper, left lower, and left upper quadrants). If a subject’s abdomen is not suitable for a subcutaneous injection, alternative sites such as the upper arm or thigh may be chosen. Subjects were observed at the study site for 0.5 to 1 h after each subcutaneous injection of the investigational product to monitor for signs or symptoms of any allergic reactions or injection site reactions. Stable-dose SoC medications were allowed, while prohibited medications (e.g., other biologics, leukotriene modifiers) were restricted, and all concomitant medications were documented [27, 29].

Outcome measures

Data were collected at baseline, at the completion of the Stapokibart treatment cycle (two weeks), and at the follow-up period (12 weeks) after the Stapokibart treatment.

The efficacy outcomes included the daily rTNSS, daily rTOSS, Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) scores, and visual analogue scale (VAS) scores for overall nasal/comorbid symptoms (including cough, asthma, skin lesions or pruritus), all of which were assessed at week 2 (end of treatment) and week 12 (follow-up period) after the first day of treatment, with each outcome compared against its respective baseline value. Specifically, rTNSS quantifies four nasal symptoms (nasal congestion, runny nose, nasal itching, and sneezing) on a 0–3 scale per symptom, yielding a total score ranging from 0 to 12, and is calculated as the average of morning and evening assessments over a 12-hour period; rTOSS evaluates three ocular symptoms (ocular itching and burning, eye redness, and tearing/watery eyes), with each symptom scored 0–3 points and a total score ranging from 0 to 9; the RQLQ comprises 28 items scored individually from 0 to 6, with an overall score ranging from 0 to 168; and the VAS measures the severity of target symptoms on a 0–10 scale. Safety assessments involved treatment-emergent adverse events (TEAEs), vital signs, and physical examination; and adverse events (AEs) or severe AEs (SAEs).

Statistical analyses

This study planned to enroll 120 eligible patients with moderate-to-severe SAR. The sample size was determined based on the statistical inference needs of the core efficacy endpoint and the integrity of real-world data. Referring to similar studies and the PHECDA clinical trial, the rTNSS was used as the primary efficacy endpoint. Assuming a reduction of approximately 4 points in rTNSS from baseline to 2 weeks post-treatment, with an expected standard deviation of 3.2 points, a two-sided α of 0.05, and a statistical power of 80%, the calculation indicated that a single group required at least 100 patients to meet parametric test power. Considering a potential dropout or data missing rate of ≤ 20% in real-world studies, the sample size was adjusted to 120 patients to ensure the final number of valid cases for analysis was ≥ 100, providing sufficient data support for efficacy and safety analyses.

All statistical analyses were performed using R language version 4.5.1, with a two-sided P value < 0.05 considered statistically significant. The analysis dataset included all participants who received the complete treatment of stapokibart and the full efficacy or safety assessments at 2 weeks and 12 weeks after treatment. Categorical variables (e.g., sex, allergen types) were summarized as frequencies and percentages; continuous variables (e.g., age, baseline rTNSS) were presented as mean ± standard deviation if normally distributed, or median (interquartile range, IQR) if non-normally distributed. Normality of continuous efficacy variables were tested prior to subsequent statistical comparisons.

For pairwise comparisons of efficacy indicators between post-treatment time points and baseline, given the large number of efficacy indicators analyzed, multiple testing correction was performed using the Bonferroni method for all indices to control type I error. Specifically, the statistical comparisons of all indices at 2 weeks and 12 weeks after treatment versus baseline were conducted via Wilcoxon signed-rank test, with the corresponding P values adjusted using the Bonferroni method, and the significance level was adjusted to 0.0045 accordingly.

To identify factors associated with post-treatment efficacy, multivariable generalized linear regression models were constructed separately for two different sets of outcome variables, including the efficacy indicator scores at 2 weeks after treatment, and those at 12 weeks after treatment. For each model, the covariates included baseline demographic characteristics (age, sex), clinical features (allergen type, comorbidities, duration of SAR), as well as the baseline score of the corresponding efficacy indicator. Adjusted mean differences and 95% confidence intervals were reported for each covariate to quantify their associations with post-treatment outcomes. Furthermore, generalized estimating equations (GEE) were employed to explore the temporal changes in efficacy indicators over the entire observation period.

For safety analyses, TEAEs were summarized by counts and percentages, with no formal statistical testing performed. Regarding missing data, baseline missing values were addressed through telephone follow-up for data completion where possible. For missing data during follow-up or in patients who withdrew from treatment, the corresponding observations were excluded from the analysis to avoid bias introduced by imputation in incomplete follow-up scenarios.

Results

A total of 142 adult patients with moderate-to-severe SAR were initially screened and recruited; among them, 15 patients were excluded from the final analysis due to failure to receive subsequent treatment or complete the full treatment course (attributed to personal work or other non-medical reasons) after baseline screening, as details shown in Fig. 1. Ultimately, 127 patients who fully completed the entire treatment process were retained and included in the final analysis, with their demographic and clinical characteristics summarized in Table 1; furthermore, 94 patients (74.02%) completed the follow-up survey conducted at the 12th week after the treatment. The mean age of participants was 37.65 ± 8.93 years, and the sex distribution was slightly skewed toward males, with 70 male patients (55.12%), and 57 (44.88%) female patients. The mean duration of SAR was 7.72 ± 5.56 years. Regarding allergen sensitization, the majority of patients (95 cases, 74.80%) were sensitized to non-dust mite allergens, and 32 patients (25.20%) were sensitized to dust mites. In addition, 30 patients (23.62%) had comorbid conjunctivitis, and 11 patients (8.66%) had comorbid asthma.

Table 2; Fig. 2 present the changes in allergic rhinitis symptoms (assessed via rTNSS and rTOSS), overall symptom severity (VAS), and quality of life (RQLQ) at 2 weeks and 12 weeks compared with baseline. All efficacy outcomes demonstrated statistically significant improvements at both post-treatment time points relative to baseline (all P < .001), with statistical comparisons performed using the Wilcoxon signed-rank test and P values adjusted via the Bonferroni method for multiple testing (significance level set to 0.0045; detailed in Table 2 notes).

Table 2.

Effect of stapokibart on allergic rhinitis symptoms at 2 weeks and 12 weeks

Variables	Before treatment (N = 127, 100%)	2 weeks after treatment#		12 weeks after treatment#
		N = 127, 100%	P values	N = 94, 74.02%	P values
rTNSS	8.00 (7.00, 10.00)	4.00 (2.00, 5.00)	< 0.001	4.00 (2.00, 5.00)	< 0.001
Independent nasal symptom of rTNSS
Nasal itching	2.00 (1.00, 2.00)	1.00 (0.00, 1.00)	< 0.001	1.00 (0.00, 1.00)	< 0.001
Runny nose	2.00 (2.00, 3.00)	1.00 (1.00, 2.00)	< 0.001	1.00 (0.00, 2.00)	< 0.001
Sneezing	2.00 (2.00, 3.00)	1.00 (1.00, 2.00)	< 0.001	1.00 (0.00, 2.00)	< 0.001
Nasal congestion	2.00 (2.00, 3.00)	1.00 (0.50, 2.00)	< 0.001	1.00 (0.00, 2.00)	< 0.001
rTOSS	5.00 (2.00, 7.00)	2.00 (0.00, 3.00)	< 0.001	0.00 (0.00, 1.75)	< 0.001
Independent ocular symptom of rTOSS
Ocular itching	2.00 (1.00, 3.00)	1.00 (0.00, 1.00)	< 0.001	0.00 (0.00, 1.00)	< 0.001
Watery eyes	1.00 (0.00, 2.00)	0.00 (0.00, 1.00)	< 0.001	0.00 (0.00, 0.00)	< 0.001
Eye redness	2.00 (1.00, 3.00)	1.00 (0.00, 1.00)	< 0.001	0.00 (0.00, 0.00)	< 0.001
VAS	8.00 (7.00, 9.00)	4.00 (2.00, 5.00)	< 0.001	3.00 (2.00, 5.00)	< 0.001
Total RQLQ score	87.00 (64.00, 112.50)	37.00 (18.50, 45.00)	< 0.001	14.50 (3.00, 33.75)	< 0.001

^# The statistical comparisons of all indices were performed using the Wilcoxon signed-rank test, with P values of various indices after 2 weeks and 12 weeks adjusted using the Bonferroni method for multiple tests (the significance level was adjusted to 0.0045). rTNSS reflective total nasal symptom score, rTOSS reflective total ocular symptom score, VAS visual analogue scale, RQLQ Rhinoconjunctivitis Quality of Life Questionnaire, QOL quality of life

rTNSS was calculated by summing up the individual scores for nasal congestion, runny nose, nasal itching and sneezing; the individual nasal symptom score ranges from 0 (no symptom) to 3 points (severe); total score ranges from 0 to 12, with lower score indicating less severe nasal symptoms. rTOSS was calculated by summing up the individual scores for itching and burning eyes, eye redness and tearing and watering eyes; the individual nasal symptom score ranges from 0 (no symptom) to 3 points (severe); total score ranges from 0 to 9, with lower score indicating less severe nasal symptoms. VAS was calculated by summing up the individual pain scores; total score ranges from 0 to 10, with lower score indicating less pain symptoms. RQLQ is a 28-item instrument specifically designed to assess the QOL status in adult patients with rhinoconjunctivitis; each item score ranges from 0 to 6, and total score ranges from 0 to 168, with lower score indicating a higher QOL

Fig. 2.

The distribution of different allergic rhinitis symptom scores at the baseline, two weeks, and 12 weeks

The median rTNSS decreased from 8.00 (IQR, 7.00–10.00) at baseline to 4.00 (IQR, 2.00–5.00) at 2 weeks and remained stable at 4.00 (IQR, 2.00–5.00) at 12 weeks, with all individual nasal symptoms (nasal itching, runny nose, sneezing, nasal congestion) showing consistent and significant reductions. For ocular symptoms, the median rTOSS declined from 5.00 (IQR, 2.00–7.00) at baseline to 2.00 (IQR, 0.00–3.00) at 2 weeks and further to 0.00 (IQR, 0.00–1.75) at 12 weeks, with marked improvements in all individual ocular symptoms (ocular itching, watery eyes, eye redness). The median VAS score for overall symptom severity decreased from 8.00 (IQR, 7.00–9.00) at baseline to 4.00 (IQR, 2.00–5.00) at 2 weeks and 3.00 (IQR, 2.00–5.00) at 12 weeks, reflecting a sustained reduction in subjective symptom burden. Additionally, the median total RQLQ score showed a substantial and persistent improvement, falling from 87.00 (IQR, 64.00–112.50) at baseline to 37.00 (IQR, 18.50–45.00) at 2 weeks and 14.50 (IQR, 3.00–33.75) at 12 weeks, indicating clinically meaningful alleviation of disease-related impairment in daily functioning.

Table 3 presents the results of multivariable generalized linear regression models exploring factors associated with rTNSS, rTOSS, VAS, and RQLQ scores at 2 weeks and 12 weeks after treatment, adjusted for baseline demographic and clinical characteristics as well as baseline scores of the respective outcome measures. While most models showed only a small number of statistically significant associations; for example, baseline rTOSS was significantly associated with post-treatment rTNSS at both time points, duration of SAR and comorbidity of conjunctivitis were among the few significant factors in rTOSS models at 2 weeks, and baseline VAS correlated with post-treatment VAS; the RQLQ models had multiple significant correlates at both 2 weeks and 12 weeks, including sex, age, duration of SAR, comorbidities of asthma or conjunctivitis, and baseline scores of several efficacy indicators, indicating that quality of life outcomes were more strongly influenced by baseline characteristics compared to models of symptom severity scores.

Table 3.

Generalized linear model analyses of symptom differences before and after stapokibart treatment

Variables	2 weeks after treatment (N = 127, 100%)				12 weeks after treatment (N = 94, 74.02%)
	Coefficients	95%CI of coefficients		P values	Coefficients	95%CI of coefficients		P values
lower		upper	lower			upper	lower
rTNSS model
Sex (Ref = male)	0.021	-0.157	0.197	0.818	0.079	-0.142	0.299	0.481
Age	0.002	-0.008	0.012	0.643	0.007	-0.005	0.018	0.268
Duration of SAR	0.006	-0.012	0.024	0.505	0.003	-0.020	0.026	0.768
Allergen (Ref = non-dust mite)	0.069	-0.160	0.292	0.549	-0.138	-0.416	0.130	0.321
Asthma	-0.073	-0.415	0.249	0.664	-0.663	-1.245	-0.157	0.016
Conjunctivitis	0.123	-0.104	0.345	0.282	-0.194	-0.510	0.111	0.219
Baseline rTNSS	0.047	-0.003	0.097	0.066	0.058	-0.006	0.124	0.078
Baseline rTOSS	-0.037	-0.073	-0.002	0.037	-0.052	-0.095	-0.008	0.021
Baseline VAS	-0.023	-0.087	0.042	0.479	0.081	-0.006	0.171	0.074
Baseline RQLQ	0.003	0.000	0.006	0.070	0.001	-0.003	0.005	0.726
rTOSS model
Sex (Ref = male)	-0.127	-0.375	0.119	0.313	0.725	0.283	1.178	0.001
Age	-0.008	-0.021	0.006	0.269	0.014	-0.009	0.036	0.242
Duration of SAR	0.028	0.003	0.052	0.024	0.016	-0.026	0.058	0.450
Allergen (Ref = non-dust mite)	-0.317	-0.658	0.012	0.064	0.410	-0.125	0.931	0.127
Asthma	-0.016	-0.452	0.393	0.942	-0.127	-1.048	0.643	0.765
Conjunctivitis	0.292	0.000	0.578	0.048	-0.192	-0.814	0.405	0.536
Baseline rTNSS	0.022	-0.046	0.091	0.521	0.045	-0.095	0.188	0.530
Baseline rTOSS	0.073	0.022	0.124	0.005	0.078	-0.014	0.174	0.100
Baseline VAS	-0.091	-0.182	0.003	0.052	0.139	-0.074	0.357	0.207
Baseline RQLQ	0.004	0.000	0.009	0.045	0.008	0.001	0.016	0.032
VAS model
Sex (Ref = male)	-0.097	-0.286	0.090	0.312	-0.006	-0.235	0.219	0.956
Age	-0.001	-0.012	0.009	0.810	0.006	-0.006	0.018	0.286
Duration of SAR	0.008	-0.011	0.027	0.395	0.006	-0.017	0.029	0.601
Allergen (Ref = non-dust mite)	0.077	-0.164	0.311	0.527	-0.009	-0.287	0.259	0.946
Asthma	0.005	-0.349	0.338	0.979	-0.591	-1.175	-0.083	0.033
Conjunctivitis	0.095	-0.149	0.332	0.441	-0.184	-0.506	0.127	0.254
Baseline rTNSS	-0.010	-0.062	0.042	0.701	-0.010	-0.074	0.055	0.765
Baseline rTOSS	-0.033	-0.070	0.004	0.077	-0.035	-0.080	0.010	0.124
Baseline VAS	0.075	0.004	0.148	0.040	0.113	0.024	0.206	0.015
Baseline RQLQ	0.002	-0.001	0.006	0.156	-0.002	-0.006	0.003	0.456
RQLQ model
Sex (Ref = male)	-0.135	-0.194	-0.076	< 0.001	0.165	0.077	0.254	< 0.001
Age	0.001	-0.002	0.004	0.541	0.010	0.005	0.014	< 0.001
Duration of SAR	0.017	0.011	0.023	< 0.001	0.031	0.022	0.039	< 0.001
Allergen (Ref = non-dust mite)	-0.149	-0.227	-0.071	< 0.001	-0.092	-0.202	0.016	0.098
Asthma	-0.057	-0.164	0.048	0.290	-0.721	-0.943	-0.510	< 0.001
Conjunctivitis	0.209	0.135	0.282	< 0.001	-0.213	-0.344	-0.082	0.001
Baseline rTNSS	0.012	-0.005	0.028	0.158	0.029	0.003	0.056	0.032
Baseline rTOSS	-0.031	-0.043	-0.020	< 0.001	-0.060	-0.078	-0.042	< 0.001
Baseline VAS	-0.020	-0.042	0.001	0.065	0.055	0.017	0.094	0.005
Baseline RQLQ	0.007	0.006	0.008	< 0.001	0.010	0.008	0.012	< 0.001

SAR seasonal allergic rhinitis, rTNSS reflective total nasal symptom score, rTOSS reflective total ocular symptom score, VAS visual analogue scale, RQLQ Rhinoconjunctivitis Quality of Life Questionnaire, QOL quality of life

rTNSS was calculated by summing up the individual scores for nasal congestion, runny nose, nasal itching and sneezing; the individual nasal symptom score ranges from 0 (no symptom) to 3 points (severe); total score ranges from 0 to 12, with lower score indicating less severe nasal symptoms. rTOSS was calculated by summing up the individual scores for itching and burning eyes, eye redness and tearing and watering eyes; the individual nasal symptom score ranges from 0 (no symptom) to 3 points (severe); total score ranges from 0 to 9, with lower score indicating less severe nasal symptoms. VAS was calculated by summing up the individual pain scores; total score ranges from 0 to 10, with lower score indicating less pain symptoms. RQLQ is a 28-item instrument specifically designed to assess the QOL status in adult patients with rhinoconjunctivitis; each item score ranges from 0 to 6, and total score ranges from 0 to 168, with lower score indicating a higher QOL

Table 4 presents the results of GEE analyzing the temporal trends of rTNSS, rTOSS, VAS, and RQLQ scores among 94 participants who completed follow-up at both 2 weeks and 12 weeks after treatment. Time was included as a categorical variable in the models, with adjustments for baseline demographic and clinical characteristics.

Table 4.

Evaluation of the therapeutic effect of stapokibart based on generalized estimating equations

Variables	Coefficients	Std.error	Z.value	95%CI of coefficients		P values
				lower	upper
rTNSS model
Sex (Ref = male)	0.048	0.056	0.718	-0.063	0.158	0.397
Age	-0.001	0.003	0.072	-0.008	0.006	0.789
Duration of SAR	0.008	0.006	2.122	-0.003	0.019	0.145
Allergen (Ref = non-dust mite)	0.030	0.065	0.208	-0.098	0.158	0.648
Asthma	-0.109	0.104	1.089	-0.314	0.096	0.297
Conjunctivitis	-0.078	0.069	1.275	-0.212	0.057	0.259
2 weeks	-0.698	0.067	109.395	-0.829	-0.567	< 0.001
12 weeks	-0.805	0.082	97.136	-0.965	-0.645	< 0.001
rTOSS model
Sex (Ref = male)	0.006	0.110	0.003	-0.210	0.222	0.958
Age	0.009	0.007	1.473	-0.006	0.023	0.225
Duration of SAR	0.012	0.011	1.111	-0.010	0.033	0.292
Allergen (Ref = non-dust mite)	0.260	0.123	4.477	0.019	0.500	0.034
Asthma	0.004	0.176	0.001	-0.341	0.348	0.983
Conjunctivitis	0.416	0.109	14.458	0.202	0.630	< 0.001
2 weeks	-0.698	0.113	38.185	-0.919	-0.477	< 0.001
12 weeks	-1.475	0.210	49.136	-1.887	-1.063	< 0.001
VAS model
Sex (Ref = male)	-0.083	0.055	2.313	-0.190	0.024	0.128
Age	0.001	0.003	0.001	-0.006	0.006	0.975
Duration of SAR	0.009	0.005	2.654	-0.002	0.020	0.103
Allergen (Ref = non-dust mite)	-0.010	0.061	0.029	-0.130	0.109	0.864
Asthma	-0.096	0.096	0.989	-0.285	0.093	0.320
Conjunctivitis	-0.084	0.065	1.663	-0.213	0.044	0.197
2 weeks	-0.712	0.066	117.733	-0.840	-0.583	< 0.001
12 weeks	-0.752	0.076	97.243	-0.901	-0.602	< 0.001
RQLQ model
Sex (Ref = male)	-0.006	0.082	0.005	-0.166	0.154	0.943
Age	0.003	0.005	0.279	-0.008	0.013	0.597
Duration of SAR	0.011	0.008	2.103	-0.004	0.026	0.147
Allergen (Ref = non-dust mite)	0.054	0.084	0.412	-0.111	0.220	0.521
Asthma	-0.018	0.128	0.020	-0.269	0.233	0.888
Conjunctivitis	-0.021	0.086	0.058	-0.189	0.148	0.809
2 weeks	-0.835	0.088	90.000	-1.007	-0.662	< 0.001
12 weeks	-1.315	0.142	85.364	-1.594	-1.036	< 0.001

SAR seasonal allergic rhinitis, rTNSS reflective total nasal symptom score, rTOSS reflective total ocular symptom score, VAS visual analogue scale, RQLQ Rhinoconjunctivitis Quality of Life Questionnaire, QOL quality of life

rTNSS was calculated by summing up the individual scores for nasal congestion, runny nose, nasal itching and sneezing; the individual nasal symptom score ranges from 0 (no symptom) to 3 points (severe); total score ranges from 0 to 12, with lower score indicating less severe nasal symptoms. rTOSS was calculated by summing up the individual scores for itching and burning eyes, eye redness and tearing and watering eyes; the individual nasal symptom score ranges from 0 (no symptom) to 3 points (severe); total score ranges from 0 to 9, with lower score indicating less severe nasal symptoms. VAS was calculated by summing up the individual pain scores; total score ranges from 0 to 10, with lower score indicating less pain symptoms. RQLQ is a 28-item instrument specifically designed to assess the QOL status in adult patients with rhinoconjunctivitis; each item score ranges from 0 to 6, and total score ranges from 0 to 168, with lower score indicating a higher QOL

For all efficacy indicators, both 2 weeks and 12 weeks after treatment were associated with statistically significant reductions in scores compared to baseline (all P < .001), confirming progressive and durable therapeutic effects. Specifically, the rTNSS model showed coefficients of -0.698 (95% CI: -0.829 to -0.567) at 2 weeks and − 0.805 (95% CI: -0.965 to -0.645) at 12 weeks, indicating a gradual decrease in nasal symptom severity. The rTOSS model exhibited a more pronounced reduction at 12 weeks (-1.475, 95% CI: -1.887 to -1.063) than at 2 weeks (-0.698, 95% CI: -0.919 to -0.477), reflecting continued improvement in ocular symptoms. Similarly, the VAS model demonstrated consistent reductions at 2 weeks (-0.712, 95% CI: -0.840 to -0.583) and 12 weeks (-0.752, 95% CI: -0.901 to -0.602), while the RQLQ model showed the most substantial decline at 12 weeks (-1.315, 95% CI: -1.594 to -1.036) versus 2 weeks (-0.835, 95% CI: -1.007 to -0.662), highlighting ongoing enhancements in quality of life. Among the adjusted covariates, only a limited number, such as comorbidity of conjunctivitis in the rTOSS model showed significant associations (P < .001), but these did not undermine the consistent and robust temporal trends of the efficacy outcomes.

Safety outcomes were comprehensively evaluated by monitoring TEAEs throughout the entire study period, including the 2-week treatment phase and the subsequent 12-week follow-up period. A total of 8 patients (6.30%) reported TEAEs, all of which occurred during the treatment phase; no new or additional AEs were identified during the 12-week follow-up, indicating sustained safety of stapokibart after treatment completion. All TEAEs were graded as Grade 1 (mild) per the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, with no SAEs, life-threatening events, or TEAEs leading to treatment discontinuation or patient withdrawal observed. The specific events included transient injection site erythema (3 cases, 2.36%), injection site pruritus (3 cases, 2.36%), and mild injection site pain (2 cases, 1.57%), all of which resolved spontaneously within 1–3 days without the need for additional medical intervention or treatment interruption.

Discussions

This real-world study evaluated stapokibart in 127 adults with moderate-to-severe SAR inadequately controlled by SoC, with 94 patients completing 12-week follow-up. All key efficacy outcomes, including rTNSS, rTOSS, VAS, as well as RQLQ, showed meaningful improvements at both 2 weeks and 12 weeks post-treatment, with progressive improvements in nasal and ocular symptoms, overall symptom severity and quality of life over the observation period, validated by GEE analyses. Besides, multivariable generalized linear regression models revealed limited significant correlates with post-treatment symptom severity scores across most indicators, while RQLQ was more strongly associated with baseline demographic, clinical, and symptom-related characteristics. From a safety perspective, stapokibart was well-tolerated, with only mild, transient injection site-related treatment-emergent adverse events reported during the treatment phase, no severe adverse events, and no new adverse events identified during the 12-week follow-up.

This real-world study contributes valuable evidence to the clinical utility of stapokibart for moderate-to-severe, SoC-refractory SAR. While the phase 3 PHECDA RCT [28, 29], the largest randomized study of stapokibart to date, demonstrated significant symptom improvements at 2 and 4 weeks, its maximum follow-up duration of 4 weeks limited insights into the durability of therapeutic effects beyond the short term. In contrast, our study’s 12-week follow-up period revealed sustained and even progressive improvements across all efficacy endpoints, including nasal symptoms remained stably reduced from 2 to 12 weeks, while ocular symptoms and quality of life showed further enhancements at 12 weeks. GEE analyses confirmed these robust temporal trends, with both 2-week and 12-week time points showing statistically significant reductions relative to baseline (all P < .001). This extension is clinically meaningful, as SAR patients often require sustained symptom control throughout the pollen season; our data provide novel evidence that stapokibart’s efficacy persists beyond the 4-week window evaluated in RCTs, supporting its utility for long-term symptom management in real-world settings.

A second critical strength of this study lies in its alignment with routine clinical practice, addressing the limitations of RCTs in generalizability. The PHECDA RCT employed strict inclusion/exclusion criteria, such as requiring a baseline peripheral blood eosinophil count ≥ 300 cells/µL, excluding patients with comorbid asthma, and restricting background therapy to a standardized regimen of mometasone furoate aqueous nasal spray. In contrast, our real-world design adopted more inclusive and clinically relevant criteria; we enrolled patients with comorbidities common in clinical practice (23.62% with conjunctivitis, 8.66% with asthma), did not impose eosinophil count thresholds, and only required stable-dose SoC medications. Additionally, 25.20% of our cohort was sensitized to dust mite allergens, reflecting the unique allergen profile of Southwest China, a region with a high SAR prevalence but underrepresented in existing RCTs. The consistent efficacy observed in this diverse, less selected population confirms that stapokibart’s benefits are not confined to the idealized patient groups of RCTs, providing external validity evidence to support its use in routine clinical care for heterogeneous SAR patients.

The Stapokibart’s main mechanism of action is to form a high-affinity binding with IL-4Rα, thereby blocking the signals of IL-4 and IL-13. This mechanism addresses an important need of SAR patients, namely the difficulty in achieving adequate relief of nasal congestion; this is also a limitation commonly faced by traditional SoC [33, 34]. In our study, the median nasal congestion subscore was halved from baseline (2.00) to 2 weeks (1.00) and remained low at 12 weeks (1.00), outperforming the modest congestion improvements reported with SoC in real-world observational studies. Furthermore, the improvements across nasal, ocular, and quality-of-life endpoints underscore stapokibart’s ability to target the systemic Th2 inflammatory cascade underlying SAR, rather than just isolated symptoms. This comprehensive efficacy aligns with its mechanism and extends the RCT findings to a population with greater clinical complexity, reinforcing its role as a valuable therapeutic option for patients with SoC-refractory SAR.

Collectively, our results complement the rigorous but narrow evidence from RCTs by demonstrating that stapokibart is effective, durable, and well-tolerated in the heterogeneous patient groups encountered in daily clinical practice, particularly in regions with unique allergen profiles like Southwest China. These findings strengthen the evidence base for stapokibart and provide clinicians with greater confidence in its use for SoC-refractory moderate-to-severe SAR.

Limitations

Despite the valuable insights provided by this real-world study, several limitations should be acknowledged when interpreting the findings. First, the single-center design, conducted exclusively at a hospital in Southwest China, may restrict generalizability to other regions or global populations, as geographic variations in allergen profiles, patient demographics, and clinical practice patterns could influence treatment responses. Second, the absence of a control group, such as placebo, continued SoC, or alternative biologics prevents direct comparative efficacy assessments, a inherent limitation of single-arm real-world studies. However, this constraint is mitigated because of our study enrolled patients with SoC-refractory moderate-to-severe SAR, a population for whom conventional therapies like antihistamines or intranasal corticosteroids have been consistently shown to yield inadequate symptom control [35, 36]. Additionally, such patients rarely experience spontaneous symptom resolution, especially during the peak pollen season, and prior evidence from the phase 3 PHECDA RCT demonstrated minimal symptom improvement with placebo [29], further supporting that the substantial and sustained improvements observed herein are unlikely to be attributed to placebo effects or natural symptom fluctuation. Finally, potential selection bias cannot be excluded, namely participants were recruited from outpatient allergy clinics, which may overrepresent patients with more severe symptoms or higher treatment-seeking behavior, rather than reflecting the broader spectrum of individuals with inadequately controlled SAR in the community. These limitations highlight the need for future multicenter real-world studies with control groups to further validate the comparative effectiveness of stapokibart in diverse patient populations.

Conclusions

This RWS confirms that stapokibart is clinically effective and well-tolerated in adults with moderate-to-severe, SoC-refractory SAR. Significant improvements in nasal symptoms, ocular symptoms, overall symptom severity, and quality of life were observed as early as 2 weeks post-treatment and sustained or further enhanced at the 12-week follow-up. Notably, these therapeutic benefits were consistent across a heterogeneous real-world cohort, including patients with common comorbidities and region-specific allergen sensitization patterns, validating the usability of RCT findings to routine clinical practice. Future multicenter studies with extended follow-up and comparative designs are warranted to further confirm its long-term safety and relative effectiveness, but the current evidence supports stapokibart as a valuable treatment option for SoC-refractory SAR requiring reliable, prolonged symptom relief.

Notes: SAR, seasonal allergic rhinitis; rTNSS, reflective total nasal symptom score; rTOSS, reflective total ocular symptom score; VAS, visual analogue scale; RQLQ, Rhinoconjunctivitis Quality of Life Questionnaire; QOL, quality of life.

rTNSS was calculated by summing up the individual scores for nasal congestion, runny nose, nasal itching and sneezing; the individual nasal symptom score ranges from 0 (no symptom) to 3 points (severe); total score ranges from 0 to 12, with lower score indicating less severe nasal symptoms. rTOSS was calculated by summing up the individual scores for itching and burning eyes, eye redness and tearing and watering eyes; the individual nasal symptom score ranges from 0 (no symptom) to 3 points (severe); total score ranges from 0 to 9, with lower score indicating less severe nasal symptoms. VAS was calculated by summing up the individual pain scores; total score ranges from 0 to 10, with lower score indicating less pain symptoms. RQLQ is a 28-item instrument specifically designed to assess the QOL status in adult patients with rhinoconjunctivitis; each item score ranges from 0 to 6, and total score ranges from 0 to 168, with lower score indicating a higher QOL.

Notes: SAR, seasonal allergic rhinitis; rTNSS, reflective total nasal symptom score; rTOSS, reflective total ocular symptom score; VAS, visual analogue scale; RQLQ, Rhinoconjunctivitis Quality of Life Questionnaire; QOL, quality of life.

rTNSS was calculated by summing up the individual scores for nasal congestion, runny nose, nasal itching and sneezing; the individual nasal symptom score ranges from 0 (no symptom) to 3 points (severe); total score ranges from 0 to 12, with lower score indicating less severe nasal symptoms. rTOSS was calculated by summing up the individual scores for itching and burning eyes, eye redness and tearing and watering eyes; the individual nasal symptom score ranges from 0 (no symptom) to 3 points (severe); total score ranges from 0 to 9, with lower score indicating less severe nasal symptoms. VAS was calculated by summing up the individual pain scores; total score ranges from 0 to 10, with lower score indicating less pain symptoms. RQLQ is a 28-item instrument specifically designed to assess the QOL status in adult patients with rhinoconjunctivitis; each item score ranges from 0 to 6, and total score ranges from 0 to 168, with lower score indicating a higher QOL.

Supplementary Information

Below is the link to the electronic supplementary material.

Abbreviations

AR

Allergic rhinitis

IgE

Immunoglobulin E

SAR

Seasonal allergic rhinitis

PAR

Perennial allergic rhinitis

ILC2s

Group 2 innate lymphoid cells

Th2 cells

Types2 helper T cells

TSLP

Thymic stromal lymphopoietin

IL-1β

interleukin-1β

IL-4

Interleukin-4

IL-5

Interleukin-5

IL-9

Interleukin-9

IL-13

Interleukin-13

IL-25

Interleukin-25

IL-31

Interleukin-31

IL-33

Interleukin-33

IL-4Rα

Interleukin-4 receptor alpha subunit

SoC

Standard-of-care

INCS

Intranasal corticosteroids

CRFs

Case report forms

CM310

Stapokibart

rTNSS

Reflective total nasal symptom score

AM

A morning

iTNSS

Instantaneous TNSS

rTOSS

Reflective total ocular symptom score

iTOSS

Instantaneous TOSS

IQR

Interquartile range

CRFs

Case report forms

RQLQ

Rhinoconjunctivitis Quality of Life Questionnaire

QOL

Quality of Life

VAS

Visual analogue scale

RCT

Randomized controlled trial

RWR

Real-world research

STROBE

Strengthening the Reporting of Observational Studies in Epidemiology

TEAEs

Treatment-emergent adverse events

CTCAE

Common Terminology Criteria for Adverse Events

Authors’ contributions

Jia Chen: Writing - original draft, Methodology, Investigation, Conceptualization. Kaifu Lu: Data curation, Methodology, Investigation, Conceptualization. Ping Tang: Data curation, Writing - review & editing, Validation. Yi Liu: Methodology, Writing - review & editing. Dingqiang Huang: Writing - review & editing, Supervision, Methodology, Formal analysis, Data management. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication.

Funding

The authors declare that no financial support was received for the research, authorship, and publication of this article.

Data availability

Due to the nature of this research using data from the hospital’s case management system, the research data is not be made publicly available, further inquiries can be contacted to the corresponding author.

Declarations

Ethics approval and consent to participate

This study received ethical approval from the independent medical ethics committee at Sichuan University affiliated Chengdu Second People’s Hospital (Approval number: No. [KY] PJ2025415), and all participants provided written informed consent before enrollment.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.