The Therapeutic Role of Biologics in Chronic Rhinosinusitis with Nasal Polyps (CRSwNP): A Review of the Current Evidence

Abstract

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a complex inflammatory condition that is primarily categorized as either Type 2 (T2) or non-T2. The T2 inflammatory pathway plays a pivotal role in the pathogenesis of T2 CRSwNP. A significant proportion of patients do not respond to systemic glucocorticoid regimens or repeated surgical interventions, which severely impacts their long-term quality of life and presents a therapeutic challenge. Recent studies confirm that biologics are an effective treatment for severe or refractory CRSwNP. This review systematically collates the latest advances in biological therapies for CRSwNP by conducting extensive searches of the PubMed, Embase, and Cochrane Library databases from the inception of these databases up to October 2025. The review focuses on elucidating the pathological mechanisms of CRSwNP and the classification and target mechanisms of biologics. It also examines the current research landscape regarding variability in biologics efficacy. Substantial clinical evidence indicates that these biologics can effectively alleviate symptoms of sinusitis, reduce turbinate volume, and improve patients’ quality of life. They also demonstrate potential in improving comorbid conditions, offering novel therapeutic options for severe or refractory CRSwNP. However, challenges remain in identifying biomarkers and selecting suitable biologics, requiring further research to enable personalized treatment strategies.

Introduction

Chronic rhinosinusitis (CRS) is a heterogeneous chronic inflammatory disease that commonly affects the mucosa of the nasal cavity and paranasal sinuses. It is characterized by symptoms that persist for over 12 weeks, including nasal congestion, rhinorrhea, a diminished sense of smell, and facial pressure or pain. Endoscopic examination typically reveals nasal polyps, mucopurulent secretions in the middle meatus, and/or mucosal edema and changes to the mucosa on CT scans.1 It can severely impair patients’ quality of life.1,2 According to the EPOS 2020 guidelines, CRS can be classified into two phenotypes based on endoscopic examination and CT: Chronic Rhinosinusitis with Nasal Polyps (CRSwNP) and Chronic Rhinosinusitis without Nasal Polyps (CRSsNP). CRS is also classified as Type 2 (T2) or non-Type 2 based on the type of cytokines released.1 Chronic sinusitis affects approximately 8–10% of the global population, with CRSwNP accounting for 20–30%.3,4

Since the beginning of the 21st century, people have focused on the inflammatory mechanisms of CRSwNP. It has been discovered that T2 CRSwNP is the primary subtype of refractory CRSwNP.5 The pathophysiological characteristics of T2 CRSwNP are defined by tissue eosinophils ≥10/HPF or blood eosinophils ≥250×10⁹/L or IgE ≥100 IU/ml¹. This condition is driven by Th2 cells, type 2 innate lymphoid cells (ILC2), and Type 2 cytokines (IL-4, IL-5, and IL-13), which regulate the T2 inflammatory response.6 Elevated eosinophil counts exacerbate sinusitis symptoms and increase the risk of postoperative recurrence several-fold.7 In Western countries, approximately 80% of CRSwNP cases are due to T2 inflammation, whereas in Asian countries it constitutes 40%.8 However, research over the past two decades has revealed that regional variations in T2 inflammation expression evolve. Within numerous Asian countries, there has been a marked increase in T2 inflammation expression among CRSwNP patients, with T2 CRSwNP or mixed-type CRSwNP becoming increasingly prevalent.9 This shift may contribute to a greater disease burden.

In recent years, monoclonal antibodies (mAbs) targeting key inflammatory mediators such as IL-4/IL-13, IL-5, IgE, and thymic stromal lymphopoietin (TSLP) have transformed the therapeutic landscape for CRSwNP. Its efficacy has been demonstrated in patients who have had a poor response to endoscopic sinus surgery (ESS) or who have surgical contraindications or concomitant asthma.1 In summary, this review summarizes the relevant literature and analyzes current advances in the treatment of CRSwNP using biologics.

Material and Methods

This study retrieved relevant literature on CRS, nasal polyps, and biologics from English-language literature via the PubMed, Embase, and Cochrane Library databases from the inception of these databases up to October 2025. Keyword combinations included: sinusitis, nasal polyps, Type 2 inflammation, diagnosis, prognosis, classification, phenotype, genotype, biologics, monoclonal antibodies. Non-human studies were excluded. This review covers details of the pathogenesis of different CRS subtypes, the mechanisms of action of various biologics, the efficacy of biologics in treating CRSwNP, and advances in biologic therapies for T2 inflammation. The data were synthesized descriptively. This was because of the heterogeneity of the study designs and endpoints. As a review article, this study is exempt from Institutional Review Board (IRB)/ethical review.

Pathological Mechanisms of CRSwNP

CRSwNP is a multifactorial disease with a highly heterogeneous pathogenesis. It is currently recognized that nasal polyps may be associated with numerous inflammatory cells, including eosinophils, neutrophils, B cells, T cells, and lymphocytes. EPOS 2020 categorizes CRSwNP into three types based on its inflammatory cells: Type 1, dominated by T_H1 cells, represents IL-2, IFN-γ, and TNF-α-driven T1 inflammation, primarily defending against intracellular pathogens such as viruses and microorganisms; Type 2, dominated by T_H2 cells, represents IL-4, IL-5, and IL-13-driven T2 inflammation, primarily acting against parasitic infections and extracellular allergens; Type 3, dominated by T_H17 cells, represents IL-17, IL-6, and IL-8-driven T3 inflammation, mainly targeting extracellular bacteria and fungi. Among these, Type 1 and Type 3 are collectively termed non-Type 2 inflammations. We have compiled a simplified mechanism diagram (see Figure 1 for details). The T2 inflammatory pathway is regarded as the most significant subtype within the CRSwNP classification.1 The pathogenesis of T2 CRSwNP may be broadly categorized into two stages: innate immunity and adaptive immunity.10 Firstly, when external pathogens such as bacteria or viruses cause damage to the nasal mucosal epithelium, this induces the production of nasal epithelial cytokines, including IL-25, IL-33, and TSLP. These subsequently stimulate ILC2s to produce IL-4 and IL-13.11 At the same time, Macrophages phagocytose allergens and present them to dendritic cells (DCs), which then stimulate undifferentiated T cells to differentiate into T_H2 cells. These T_H2 cells secrete IL-4 and IL-13. Consequently, cells stimulate the production of associated factors through the combined action of innate and adaptive immunity, thereby activating downstream pathways. Then, the IL-4 and IL-13 stimulate B cells to differentiate into plasma cells and produce IgE. IgE binds to FcεRIa receptors on mast cells and basophils. Upon subsequent allergen re-exposure in the nasal cavity, cross-linking occurs, triggering degranulation and release of multiple inflammatory mediators from mast cells and basophils. This particularly involves the release of eosinophil chemotactic factors such as IL-5, RANTES (CCL5 Protein), and eosinophil activation chemotactic factor.12 Due to eosinophil infiltration, substances within eosinophil cytoplasmic granules exert toxic effects on host cells, including eosinophil cationic protein (ECP) and eosinophil peroxidase (EPO).13 The release of these toxic substances causes damage to the sinus mucosal tissue, including abnormal proliferation and differentiation of basal cells. This subsequently promotes the growth of nasal polyps, leading to the development of CRSwNP.14

Figure 1.

Inflammatory pathways and therapeutic targets in chronic rhinosinusitis with nasal polyps (CRSwNP).

Abbreviations: ILC-2, type 2 innate lymphoid cell; IL, interleukin; IFN, interferon; TNF, tumour necrosis factor; Th, helper T cell; G-CSF, granulocyte colony-stimulating factor; TSLP, thymic stromal lymphopoietin; PGD₂, prostaglandin D2; cDC, conventional dendritic cell; LTs, Leukotrienes.

Classification of Biologics

Anti-IgE Therapy

A representative drug is Omalizumab, which binds to IgE and prevents its interaction with FcεRIa, thereby downregulating its expression and modulating cellular function.15 We summarize various mAbs’ binding sites, key trial results, and approved indications in Table 1, including Omalizumab. Currently, Omalizumab has been approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) in 2020 for use in adult patients with CRSwNP.16 In the open-label extension (OLE) study following the Omalizumab Phase III clinical trials (POLYP 1 and POLYP 2), results demonstrated that after 52 weeks of treatment with Omalizumab, all patients showed significant improvement in the Nasal Polyps Score (NPS)(Mean Differences [MD] −1.31; 95% credible interval [95% CI], −1.60 to-1.03), the Sino-nasal Outcome Test-22 (SNOT-22)(MD −28.47; 95% CI, −31.52 to −25.42), and the Total Nasal Symptom Score (TNSS)(MD −3.83; 95% CI, −4.31 to −3.34). Besides, after switching to Omalizumab, no significant differences were observed between the placebo and Omalizumab groups in NPS (MD −0.34; 95% CI, −0.74 to 0.06) or Nasal congestion scores (NCS) (MD −0.14; 95% CI, −0.36 to 0.09). Furthermore, the study participants have 57% comorbid asthma, and Omalizumab also improved their Asthma Quality of Life Questionnaire scores (AQLQ).17 We also found that in the additional analysis of OLE, regardless of whether asthma or aspirin-exacerbated respiratory disease (ARED) was present, the effect on NPS and NCS improvement was similar.17 This indicates that for CRSwNP, the efficacy of Omalizumab is independent of the current allergic status. Chinthrajah et al previously demonstrated efficacy even in “non-IgE-mediated” diseases, suggesting low dependence on serum IgE levels.37 Omalizumab has also demonstrated comparable advantages in real-world studies. A multicenter retrospective study conducted in Spain involving 23 adult patients with mild asthma and concomitant CRSwNP showed significant improvements in NPS and SNOT-22 after 12 months of treatment. Furthermore, polyp resolution was associated with the duration of Omalizumab therapy (OR=0.61).38

Table 1.

Clinical Studies on Biologics for the Treatment of Chronic Rhinosinusitis with Nasal Polyps

Category	Drug	Mechanism of Action	CRSwNP Indication Approval	NPS (vs Placebo)	AEs (%) (vs Placebo)
Anti-IgE	Omalizumab	Inhibits the binding of IgE to FcεRIα; downregulates IgE-mediated inflammatory responses.15	FDA/EMA/ NMPA16	POLYP 1:17 –1.14 (95% CI: –1.59 to –0.69); POLYP 2:17 –0.59 (95% CI: –1.05 to –0.12)	50.4% VS 58.5%17
Anti-IL-4/IL-13	Dupilumab	Targets IL-4Rα; Inhibits IL-4/IL-13 signaling; reduces Th2 cell differentiation and IgE production.18	FDA/EMA19	LIBERTY:20–2.40 (95% CI: –2.77 to –2.02)	69% VS 74%20
	Stapokibart (CM310)	Same target (IL-4Rα)18	NMPA21	CROWNS-2:22 −2.3 (95% CI: −2.6 to −1.9)	77.8% VS 69.7%22
Anti-IL-5	Mepolizumab	Directly binds to IL-5; Inhibits eosinophil activation.23	FDA/EMA/ NMPA24	SYNAPSE:25–0.73 (95% CI: –1.11 to –0.34)	82% VS 84%25
	Benralizumab	Binds to IL-5Rα, inducing antibody-dependent cellular cytotoxicity; eliminates eosinophils.26	Completed Phase III trials	OSTRO:27 −0.57 (95% CI:-0.85 to −0.29)	77.3% VS 78.8%27
	Depemokimab	Long-acting anti-IL-5, enhanced binding affinity.28	Completed Phase III trials	ANCHOR-1:29 –0.7 (95% CI: –1.1 to –0.3); ANCHOR-2:29 –0.6 (95% CI: –1.0 to –0.2);	ANCHOR-1: 74% VS 79%; ANCHOR-2: 76% VS 80%.29
Anti-TSLP	Tezepelumab	Blocking TSLP-receptor binding inhibits multicellular inflammatory networks.30	FDA/EMA	WAYPOINT:31 −2.07(95% CI: −2.39 to −1.74)	78.3% VS 77.1%31
Other biologics	SB010	Inhibit the GATA-3 transcription factor to block the production of Th2 cytokines (IL-4/IL-5).32	Data unavailable	——	——
	Etokimab	Inhibit IL-33/ST2 signaling to reduce type 2 inflammation.33	Completed Phase II trials (NCT03614923)	Etokimab q4w: −0.38(95% CI: −1.01 to 0.25): Etokimab q8w: −0.41(95% CI: −1.03 to 0.22)	28.57%(q4w) VS 22.86%(q8w) VS 17.14%
	Fevipiprant	Antagonize IL-17A to inhibit neutrophilic inflammation.34	Completed Phase IIIb trials35	Fevipiprant 150 mg:35 0.05(95% CI: 0.59 to 0.70): Fevipiprant 450 mg: −0.25(95% CI: −0.88 to 0.39)	53.1% (150 mg)35 VS 38.2% (450 mg) VS 34.4%
	Brodalumab	Blocking the PGD2/CRTH2 pathway to inhibit mast cell inflammation.36	Data unavailable	——	——

Abbreviations: FDA, US Food and Drug Administration; EMA, European Medicines Agency; NMPA, National Medical Products Administration of China.

Anti-IL-4/IL-13 Therapy

The IL-4Rα serves as a common receptor component for IL-4 and IL-13. Anti-IL-14Rα biologics can simultaneously inhibit the signaling pathways of both cytokines, thereby suppressing Th2 differentiation and IgE class switching in B cells.18 Representative drugs include Dupilumab and Stapokibart (CM310). In 2019, the FDA and EMA approved Dupilumab for the treatment of CRSwNP in adults. Stapokibart was launched in China in 2025 and received approval for the treatment of adult CRSwNP (Table 1). The indication for this condition remains under review in European and American countries. Results from the Phase III clinical trials of Dupilumab (LIBERTY NP SINUS-24 and LIBERTY NP SINUS-52) showed significant improvements in patients’ NPS (LSMD −2.40; 95% CI, −2.77 to −2.02), NCS (MD −0.98; 95% CI, −1.17 to −0.79), and SNOT-22 (MD −20.96; 95% CI, −25.03 to −16.89) compared to placebo after 52 weeks.20 Although eotaxin-3 and ECP levels decreased at week 24 compared to baseline, there was a transient increase in eosinophil counts that was not statistically significant compared to baseline, with levels returning to baseline by week 52. This may be due to Dupilumab inhibiting IL-4/IL-13-mediated migration of eosinophils from the blood to tissues, resulting in elevated blood eosinophil counts.19,39 Similarly, in clinical practice, the degree of symptom improvement aligns with RCT evidence and may even be superior to it. The DUPIREAL trial conducted a retrospective study involving 648 patients with severely uncontrolled CRSwNP. Dupilumab significantly reduced NPS (Median difference: −5.0) and SNOT-22 (Median difference: −46.0) compared to the baseline on 12 months. Besides, the study demonstrated superior efficacy in patients with concomitant asthma and AERD, although the difference did not reach statistical significance.40 This result indicates that biologics hold potential for synergistic treatment in CRSwNP patients with concomitant other T2 inflammatory diseases. Notably, the LIBERTY trial observed a rebound in NPS and NCS scores, as well as symptom recurrence, after treatment was discontinued at 24 weeks. Maximum efficacy was not achieved by week 52. However, the DUPIREAL trial results further confirm that Dupilumab is a chronic treatment that requires administration for at least six months to one year. Nevertheless, defining treatment success at these time points remains controversial, highlighting the need for long-term follow-up in real-world studies in the future. Additionally, China’s domestically developed Stapokibart completed Phase III trials (CROWNS-2) in the Chinese population in 2025 and was subsequently approved for marketing in China. Stapokibart demonstrated significant efficacy in reducing NPS, with the Stapokibart group showing an improvement of 2.6 points from baseline at 24 weeks, compared to an improvement of only 0.3 points in the placebo group (P<0.01).22 The results of the CROWNS-2 trial demonstrated a more significant improvement in NPS from baseline compared to Dupilumab (SINUS-24) (MD=2.6 VS MD=1.89), a highly encouraging finding. We can observe that both mAbs demonstrate favorable safety and tolerability profiles. The most common adverse event (AE) for Dupilumab was nasopharyngitis, with incidence rates showing no statistically significant difference compared to placebo. The incidence of adverse events for Stapokibart was comparable to that of the placebo (75% VS 79%), with upper respiratory tract infection being the most common AE, and no serious adverse events (SAEs) occurred. These findings introduce the Chinese treatment approach for CRSwNP to the global community,41 offering promising innovative options for patients with refractory or severe T2 CRSwNP. However, further exploration is required regarding its application in populations from other countries and regions.

Anti-IL-5 Therapy

This includes Mepolizumab, Benralizumab, and the long-acting Depemokimab (see Table 1). IL-5 is produced by B cells during T2 inflammatory processes, acting on the IL-5Rα on downstream eosinophils, B cells, and mast cells to further intensify the severity of Type 2 inflammation. IL-5 mAbs block signal transduction by binding to this receptor, thereby inhibiting IL-5-mediated activation and recruitment of eosinophils and mast cells, and alleviating Type 2 inflammation.23 Mepolizumab binds directly to IL-5, reducing downstream eosinophil activation. Depemokimab not only binds directly to IL-5 but also enhances IL-5 binding affinity, exhibits high potency, and possesses an extended half-life, requiring administration only twice yearly.28 Meanwhile, Benralizumab binds directly to IL-15 Rα expressed on eosinophils, directly enhancing antibody-dependent cellular cytotoxicity and inducing apoptosis.26 Among these agents, Mepolizumab has received approval from the FDA and EMA for treating adult CRSwNP inadequately controlled by systemic corticosteroids or surgery.24 The remaining mAbs remain in development for CRSwNP, though their research findings hold considerable promise. Results from the SYNAPSE trial showed that 206 patients received Mepolizumab treatment while 201 received a placebo. At the 52-week follow-up, the treatment group demonstrated marked improvements in the NPS (MD −0.73; 95% CI, −1.11 to −0.34), the Nasal Congestion Visual Analogue Scale (VAS) (MD −3.14; 95% CI, −4.09 to −2.18), and SNOT-22 (MD −16.49; 95% CI, −23.57 to −9.42). Additionally, during the 52-week treatment period, the risk of undergoing endoscopic sinus surgery in the Mepolizumab group was significantly lower (hazard ratio (HR) 0.43; 95% CI, 0.25 to 0.76; P=0.0032) and the need for rescue systemic corticosteroids (HR 0.58; 95% CI, 0.36 to 0.92; P=0.0020) compared with the placebo group. Concurrently, it significantly alleviated symptoms and reduced eosinophil counts in patients with comorbid asthma. There was no significant difference in the incidence of adverse events between the two groups (82% in the Mepolizumab group vs 84% in the placebo group).25 Subsequently, a single-center retrospective real-world study conducted in Spain indicated that following treatment with Mepolizumab, patients exhibited a significant reduction in SNOT-22 compared to baseline, relative to placebo (MD −63; 95% CI, −68 to −58). Notably, this study also indicated that patients with concomitant AERD experienced greater reductions in NPS and eosinophil counts compared to those without AERD.42 The results of the Depemokimab trials (ANCHOR-1, ANCHOR-2) demonstrated that 540 CRSwNP were randomized to treatment and control groups. Following 52 weeks of Depemokimab therapy, significant improvements were observed in endpoints including the NPS, NCS, and SN0T-22 compared to the placebo. Furthermore, the risk of surgery compared to the placebo was reduced (16% VS 22%).29 The OSTRO study enrolled patients with severe CRSwNP. Benralizumab demonstrated significant improvements in NPS (MD −0.570; 95% CI, −0.852 to −0.289) and NCS (MD −0.270, 95% CI −0.458 to −0.083) compared with the placebo group at the 40-week follow-up. Meanwhile, the trial found that the Benralizumab group improved the Asthma Control Questionnaire 6(ACQ-6) scores in patients with comorbid asthma and exhibited a 47% lower asthma exacerbation rate than the placebo group. Interestingly, the study also suggested that the presence of nasal polyps may enhance the efficacy of Benralizumab in treating severe asthma.27 In a real-world pilot study, Benralizumab demonstrated significant improvements compared to baseline in the NPS and Asthma Control Test (ACT) (P<0.05; P<0.01) after 12 months of treatment in patients with severe CRSwNP and concomitant eosinophilic asthma (SEA).43

Anti-TSLP Therapy

TSLP is a multifunctional cytokine that acts upon multiple cellular lineages, including dendritic cells, T cells, B cells, neutrophils, mast cells, eosinophils, and ILC, influencing their maturation, survival, and recruitment. Furthermore, in allergic diseases, TSLP promotes the release of T_H2 cytokines by dendritic cells, eosinophils, and mast cells. Simultaneously, it stimulates the differentiation of CD4+ T cells into T follicular helper cells, which can induce memory B cells to secrete IgG and IgE. This establishes a link between TSLP and IgE production in allergic processes.30 Compared with healthy individuals, asthma patients and CRSwNP patients exhibit elevated TSLP expression in airway or polyp tissue, sufficient to induce airway inflammatory responses.33 Tezepelumab is a human mAb that blocks the binding of thymic stromal lymphopoietin to its heterodimeric receptor (TSLP receptor and IL-7Rα), thereby inhibiting its signaling pathway. The FDA and the EMA have currently approved Tezepelumab for the treatment of asthma, as well as CRSwNP in patients aged 12 years and older with inadequately controlled disease (Table 1). 31,44,45 In the post-hoc analysis of the Phase IIb PATHWAY study (NCT02054130)46 and the Phase III NAVIGATOR study (NCT03347279),47 patients receiving Tezepelumab demonstrated greater reductions in blood eosinophil counts, FeNO, IL-5, and IL-13 levels compared with placebo, regardless of nasal polyp status. This resulted in fewer asthma exacerbations and decreased Type 2 inflammatory biomarkers. Building upon this research foundation, Han et al investigated the application of Tezepelumab in adults with CRSwNP (the WAYPOINT study). The findings of the trial provided substantial corroboration for the aforementioned conclusions, whilst simultaneously delivering an exhaustive appraisal of the efficacy of Tezepelumab in the context of CRSwNP. In week 52, patients treated with Tezepelumab exhibited a decrease in NPS of 2.07 points (95% CI, −2.39 to −1.74) in comparison to placebo, accompanied by a NCS reduction of −1.03 points (95% CI, −1.20 to −0.86). The treatment demonstrated favorable safety, with nasopharyngitis being the most common adverse event. The incidence of serious adverse events was lower in the Tezepelumab group than in the placebo group (10 cases VS 12 cases).31

Other Monoclonal Antibodies

GATA-3, a zinc finger transcription factor belonging to the GATA family of transcription factors, binds to consensus DNA sequences. Primarily expressed in Type 2 inflammatory cells, its activation upon stimulation enhances the transcription of T_H2 cytokines such as IL-4 and IL-5.48 GATA-3 DNAase can inhibit GATA-3, thereby blocking T_H2 cytokine transcription. This prevents downstream cells from releasing IgE and inhibits inflammatory pathways.49 GATA-3 DNAase reduced the area under the curve (AUC) for forced expiratory volume in 1 second (FEV₁) by 34% in patients with allergic asthma, whereas placebo increased it by 1%. A significant decrease in IL-5 was also observed in the treatment group. Furthermore, no significant difference in adverse events was noted between patients receiving GATA-3 DNAase and those receiving a placebo.32 In the upstream pathway, IL-33 acts as an alarm signal released by airway epithelial cells upon exposure to environmental triggers such as allergens and viruses. It stimulates effector cells within multiple T_H2 pathways, thereby driving the onset of inflammation.33 Astegolimab, a human IgG2 mAb capable of selectively inhibiting the IL-33 receptor, was administered by Kelsen et al to 502 patients with severe asthma. Following 54 weeks of treatment involving injections every four weeks, the annual exacerbation rate (AER) was reduced, with a particularly pronounced effect observed in patients with high-eosinophil asthma. The treatment demonstrated favorable safety and tolerability profiles.50 However, another IL-33 mAb, Etokimab, demonstrated in its Phase II clinical trial (NCT03614923) that after 16 weeks of treatment for CRSwNP, the group receiving Etokimab 150mg every four weeks showed no statistically significant reduction in NPS or SNOT-22 scores compared to the placebo group (P=0.2364; P=0.1330), leading to discontinuation of further trials. For neutrophil-dominant T3 CRSwNP, IL-17 serves as its primary characteristic factor,34 promoting neutrophil recruitment and disrupting the epithelial barrier, among other effects.51 Brodalumab antagonizes IL-17A, blocking its effects. Initially employed in the treatment of moderate-to-severe psoriasis, it demonstrated significant efficacy.52 However, Brodalumab lacks clinical evidence for treating CRSwNP. Additionally, Gevaert et al observed that increased mast cell proliferation in the sinus mucosa of CRSwNP patients leads to heightened prostaglandin D2 (PGD2) release. The PGD2 receptor-2 (DP2) pathway plays a significant role in the pathogenesis of various inflammatory diseases, including CRSwNP, atopic dermatitis, and asthma.36 Fevipiprant (a DP-2 antagonist) blocks the binding of PGD2 to its receptor. Gevaert et al administered Fevipiprant to CRSwNP patients to evaluate its efficacy. After 16 weeks of treatment, no statistically significant difference was observed in the primary outcome measure NPS compared to baseline or versus the placebo group (P=0.223, P=0.656).35 Further research is required to explore the efficacy and mechanisms of DP-2 antagonists in CRSwNP and asthma. These studies further emphasize the complexity of the inflammatory pathways involved in CRSwNP. Disrupting these pathways by blocking a single cytokine may be insufficient, and the synergistic interactions between them warrant further investigation.

The Use of Biologics in Type 2 Diseases

CRSwNP exhibits a complex inflammatory spectrum yet lacks standardized biologic therapies, while CRSwNP patients are more likely to suffer from asthma and other T2 inflammatory diseases. The prevalence of concomitant asthma ranges from 40% to 67%, while aspirin hypersensitivity occurs in 8% to 26% of cases.53 Common T2-mediated inflammatory conditions include atopic dermatitis, asthma, and allergic rhinitis.54 These T2-mediated inflammatory diseases may all coexist with CRSwNP, thereby increasing treatment complexity. What is the current status of research into the biologics mentioned above, which have already been tested in CRSwNP trials, for other T2-mediated inflammatory diseases? In asthma treatment, Dupilumab, Omalizumab, Benralizumab, Mepolizumab, Tezepelumab, and Reslizumab have been approved by the FDA for severe eosinophilic asthma.55 For atopic dermatitis treatment, numerous mAbs have gained approval since 2017. Dupilumab was the first agent approved by both the FDA and EMA for moderate-to-severe atopic dermatitis lasting over six months. Tralokinumab, a fully humanized IL-13-specific mAb, has received FDA approval for treating moderate-to-severe atopic dermatitis in adults. Lebrikizumab is another fully humanized mAb targeting IL-13, approved by the EMA and the FDA for individuals aged 12 years and older. Nemolizumab (IL-31 mAb) has also received FDA approval for atopic dermatitis treatment.56 In allergic rhinitis treatment, the anti-IL-4 mAb (Stapokibart) released its Phase III study (NCT05908032) results in April 2025, showcasing a Chinese solution globally.21 The study demonstrated its efficacy in alleviating moderate-to-severe seasonal allergic rhinitis (SAR) symptoms in patients with moderate-to-severe seasonal allergic rhinitis. Stapokibart achieved a significant improvement in the mean change in daily reflective total nasal symptom score (rTNSS) over the 2 weeks (LSMD = −1.3; 95% CI, −2.0 to −0.6), becoming the world’s first approved IL-4Rα mAb for seasonal allergic rhinitis.57

Comparative Efficacy of Different Biologics

In recent years, a multitude of biologics targeting different sites have emerged, demonstrating promising therapeutic efficacy and safety profiles for CRSwNP. These offer breakthrough treatment options for patients with CRSwNP who have surgical contraindications or experienced recurrence following surgery. However, therapeutic responses vary among different mAbs. Several researchers have conducted systematic reviews and meta-analyses. Wang et al systematically collated all relevant studies up to December 2023 and performed a network meta-analysis. Results indicated that compared with placebo, Dupilumab demonstrated superior efficacy in NPS (MD −1.85; 95% CI, −2.47, −1.24), SNOT-22 (MD −12.56; 95% CI, −22.49, −2.63). Secondly, Omalizumab (MD −1.30; 95% CI, −1.90, −0.70), Benralizumab (MD −0.84; 95% CI, −1.66, −0.03), and Mepolizumab (MD −1.48; 95% CI, −2.22, −0.74) also effectively reduced NPS.58 Moreover, in assessing the risk of AEs when evaluating these mAb therapies for patients with CRSwNP, the systematic review by Aldajani et al indicated that the most common adverse event for Dupilumab was pharyngitis (22.4%), followed by injection site erythema (9.4%) and headache (8.1%). In contrast, the most frequent adverse events for Omalizumab and Mepolizumab were nasopharyngitis, headache, and injection site erythema.59 Chen et al collated long-term data on biologic therapies for CRSwNP up to March 2024, analyzing six studies with follow-up periods of at least 52 weeks. They found no significant difference in adverse event rates between Dupilumab, Omalizumab, Mepolizumab, and Tezepelumab compared with placebo.60 Subsequently, Zhang et al analyzed real-world studies up to July 2024, enrolling 3921 CRSwNP patients. They examined the mean change from baseline (MC) and the proportion achieving the minimal clinically important difference (MCID) at three follow-up time points for four biologics (Dupilumab, Omalizumab, Mepolizumab, Benralizumab). Results demonstrated that during the 16- to 96-week follow-up period, 67% to 99% of patients treated with dupilumab achieved the NPS MCID (NPS score improvement ≥1 point). Regarding primary outcomes, the pooled MC for NPS at 12 months post-baseline was −3.9 (95% CI, −4.2 to −3.5), while SNOT showed −39.1 (95% CI, −42.8 to −35.3). Overall, Dupilumab demonstrated superior efficacy and favorable safety, exhibiting greater therapeutic benefit in real-world settings.61 Additionally, approximately 10% of CRSwNP patients develop AERD,62 and aspirin desensitization (ASA-D) demonstrates significant efficacy for refractory CRSwNP. However, Oykhman et al compared the efficacy of biologics versus ASA-D for CRSwNP and found that Dupilumab, Omalizumab, and Mepolizumab demonstrated superiority over ASA-D in reducing SNOT-22 scores, along with more favorable safety profiles.63 With advancing research into the inflammatory pathways of Type 2 CRSwNP, numerous new mAbs have emerged since 2021. These include anti-IL-4 mAb (Stapokibart), anti-TSLP mAb (Tezepelumab), and long-acting anti-IL-5 mAb (Depemokimab). Stapokibart has demonstrated particular efficacy in reducing NPS. Nasal polyps showed a significant reduction within 2 weeks of initial treatment. By week 24, 81% of patients achieved an improvement of ≥2 points in NPS compared to baseline. The agent also exhibits favorable safety (the most common adverse reactions being conjunctivitis and injection site reactions).22

Limitations and Future Prospects of Biologics

Regarding existing research, we must continue our efforts in several areas moving forward. Firstly, direct comparative efficacy data between biologics remain scarce and limited. To date, only one head-to-head trial comparing Dupilumab and Omalizumab has been published (the EVEREST Phase IV study), yielding results consistent with the direction of the ongoing meta-analysis. After 24 weeks of treatment, Dupilumab demonstrated significantly greater NPS improvement compared to Omalizumab (MD 1.6, p<0.0001).64 Nevertheless, comparisons between the remaining mAbs still rely on integrating indirect comparative results or existing meta-analyses and systematic reviews. Stapokibart and Tezepelumab, which completed Phase III clinical trials in recent years, were not included in the meta-analyses, resulting in an incomplete comparison of biological agents.63 This highlights the necessity for more comprehensive head-to-head trials and updated evidence-based data. Secondly, different intracellular subtypes of CRSwNP require distinct treatment approaches, suggesting that distinguishing between T2 and non-T2 CRSwNP may facilitate personalized therapy. However, current research on biomarkers remains limited. Researchers measuring inflammatory mediators in nasal secretions from CRSwNP patients and establishing predictive models found that IgE, IL-5, and eosinophil counts serve as effective diagnostic markers for T2-type CRSwNP patients.65 Moreover, omics analysis of biological samples from CRSwNP patients is important for identifying phenotypes and therapeutic responses.66 Concurrently, establishing clinical diagnostic and prognostic prediction models for CRS through database-driven approaches and the integration and analysis of multi-omics data may uncover novel therapeutic targets.67 These findings underscore the importance of further research into biomarkers to enhance the precision of treatment for individual patients. Additionally, clinicians need to adopt standardized assessment criteria when evaluating treatment outcomes for CRSwNP. In meta-analyses of biologic therapies for asthma, researchers not only ranked product efficacy but also assessed the probability of achieving or exceeding the minimum clinically important difference (MCID), thereby yielding more clinically meaningful results.68 This differs from conclusions based solely on statistical significance, ensuring that clinical efficacy improvements are aligned with patient symptoms and thereby optimizing treatment outcomes to a greater extent. The cost-effectiveness of biologics requires further research. Brown et al found that adding FESS resulted in an additional total expenditure of $48,838.38, yielding 20.50 quality-adjusted life years (QALYs) and demonstrating greater cost-effectiveness than drug therapy alone.69 Assuming biweekly injections, adding Dupilumab costs $36,234 annually, representing a relatively high expense. Biologics are only cost-effective in a subset of patients with poorly controlled standard therapy. This also prompts otolaryngologists to focus more on refractory CRSwNP, such as postoperative recurrence, where expenditure is more justified.70 Additionally, given the high probability of CRSwNP coexisting with other T2 inflammations, we have summarized approved biologics for common T2 comorbidities associated with CRSwNP. These biologics have been found to treat T2 inflammations coexisting with CRSwNP effectively. This offers significant clinical implications: when treating CRSwNP patients with multiple coexisting T2 inflammations, we may select appropriate biologics based on their comorbidities. This approach achieves multiple therapeutic objectives simultaneously, enhancing treatment efficacy and improving patients’ overall quality of life.

Conclusion

The introduction of biologics represents a paradigm shift in the treatment of CRSwNP, moving from a standardized approach to a precision medicine framework. Simultaneously, biologics offer novel therapeutic options for patients with refractory CRSwNP experiencing postoperative recurrence. Substantial existing research evidence demonstrates that biologics can markedly improve both imaging scores and quality of life in patients. Nevertheless, challenges remain in identifying biomarkers and selecting appropriate biologics. In summary, biologics have yielded substantial outcomes in treating CRSwNP. With the prospect of increasing head-to-head trials and technological innovations in the future, we anticipate that biologics will maximize symptom relief for CRSwNP patients, enhance treatment precision, and reduce the overall disease burden of CRSwNP.

Funding Statement

This work was supported by the Guangdong Medical Association Clinical Research Special Fund under Grant 2024HY-B2015.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

Wenjing Chen and Yanhui Wen are co-first authors for this study. All authors declare no conflicts of interest in this work.