There are two kinds of biologics, dupilumab and stapokibart, targeting IL-4 Rα, blocking IL-4 and IL-13 signalling. In dupilumab's two phase 3 trials—LIBERTY NP SINUS-24 (24-week follow-up) and LIBERTY NP SINUS-52 (52-week follow-up), dupilumab has been shown to reduce nasal polyp score (NPS), need for systemic corticosteroid (SCS) therapy, and ESS, while also improving nasal congestion score (NCS), the 22-item Sinonasal Outcome Test (SNOT-22), Lund-Mackay computed tomography score, and the University of Pennsylvania Smell Identification Test (UPSIT) score, compared with placebo. Efficacy shown in SINUS-24 diminished after discontinuation while effects shown in SINUS-52 kept improving to week 52, highlighting the need for sustained type 2 inflammation suppression (5). Many real-world studies further validate the efficacy of dupilumab, with the longest follow-up duration reaching 4 years (6). Specifically, a real-world study with a 96-week (2-year) follow-up has shown that dupilumab's efficacy for CRSwNP has been principally established within the first 24 weeks, has persisted through the entire follow-up period, and has yielded only marginal additional improvements thereafter; tapering dupilumab by prolonging the interdose interval—implemented every 24 weeks, conditional on the assessment of biological response and CRS control—can be applied in the vast majority of patients, which may ultimately enhance cost-effectiveness (7).

In the phase 3 clinical trial of stapokibart found that patients with severe CRSwNP treated with a daily intranasal INCS, stapokibart reduced polyp size and severity of nasal symptoms at 24 weeks. CROWNS-2 follow-up duration is 52 weeks. Lack of longer follow-up duration. However, only patients in China were enrolled, limiting generalizability to other populations (8).

Omalizumab, an anti-IgE antibody, has demonstrated efficacy in patients with CRSwNP and comorbid asthma previously. In the phase 3 study with a 24-week follow-up duration evaluating the efficacy and safety of omalizumab in patients with severe CRSwNP despite daily INCS therapy, enhancements in NPS and NCS were coincident with important improvements in Total Nasal Symptom Score, SNOT-22 score, sense of smell, postnasal drip, runny nose and UPSIT score (9). After this stage, subjects in both the placebo and omalizumab arms received 28 weeks of open-label omalizumab together with baseline nasal mometasone therapy, and were then monitored for 24 weeks subsequent to the cessation of omalizumab administration. Following omalizumab withdrawal, scores exhibited a gradual decline throughout the 24-week follow-up phase, yet values in both groups still remained superior to the pretreatment baseline (10). Multiple real-world studies of omalizumab in patients with CRSwNP demonstrate similar efficacy to the phase 3 studies (11, 12).

Two monoclonal antibodies, mepolizumab and depemokimab, inactivate IL-5, thereby inhibiting eosinophilic inflammation. In the phase 3 trial SYNAPSE of mepolizumab, which incorporated a 52-week follow-up duration, mepolizumab improved nasal polyp size and nasal obstruction, reduced need for ESS and SCS use, and improved sinonasal symptoms and HRQoL. This trial included only patients with prior surgery, which may be different from other trials (13). The MERIT study of mepolizumab, a 52-week follow-up trial focusing on patients from Japan, China, and Russia with CRSwNP/eosinophilic CRS, has also demonstrated significant improvements in nasal obstruction, sinonasal symptoms, and HRQoL. There are differences in disease profiles between populations in Asia and Europe, and this trial demonstrates efficacy and safety in patients with CRSwNP in these countries (14).

Depemokimab is the first ultra-long-acting anti-IL-5 biological drug allowing biannual administration and sustained suppression of Type 2 inflammation. In the phase 3 ANCHOR-1 and ANCHOR-2 trials, which incorporated a 52-week follow-up duration, participants on depemokimab had significantly greater improvements in the coprimary endpoints of total NPS and participant-reported mean nasal obstruction verbal response scale score, versus placebo. Secondary endpoints also favoured depemokimab, all with nominal significance in pooled analysis (15).

Benralizumab targets the α subunit of the interleukin-5 receptor (IL-5Rα). This process leads to the swift, nearly total depletion of blood eosinophils and a decrease in basophil counts. In the phase 3 OSTRO study—which included 48 weeks of benralizumab administration and a total 80-week follow-up period (with 32 weeks of extended post-treatment monitoring)—benralizumab led to a significant reduction in NPS and nasal blockage compared with placebo, with efficacy sustained even during the post-discontinuation follow-up phase. Additionally, this study enrolled patients with a total SNOT-22 score ≥ 30, which may lead to an underestimation of the actual effectiveness of these treatments (16, 17).

Tezepelumab is a human monoclonal antibody that specifically prevents thymic stromal lymphopoietin (TSLP) from engaging with its heterodimeric receptor. It is approved for maintenance therapy of severe asthma, regardless of the T2 endotype. In the phase 3 trial of tezepelumab for severe CRSwNP (WAYPOINT), which featured a 52-week follow-up duration, tezepelumab therapy led to significantly greater reductions in the size of nasal polyps, the severity of nasal congestion and sinonasal symptoms, and the use of ESS and SCS than placebo in adults with severe, uncontrolled chronic rhinosinusitis with nasal polyps (18).

Several meta-analyses of randomized controlled trials (RCTs) have indirectly compared the biologics, consistently concluding that dupilumab has superior efficacy (19–23). Notably, in a recent multicentre, randomised, double-blind, phase 4 trial comparing efficacy and safety of dupilumab vs. omalizumab in patients with severe CRSwNP and comorbid asthma, a head-to-head comparison was conducted. Dupilumab showed superiority over omalizumab in meeting the primary endpoints (NPS and UPSIT) and demonstrating significant improvement in all secondary endpoints, including asthma endpoints (24). Further research is warranted to substantiate this conclusion.

A marked increase has been seen in clinical trials assessing the safety and efficacy of novel biologics for the treatment of CRSwNP. As summarized in Table 2, numerous late-phase clinical trials are currently investigating biologics targeting upstream epithelial cytokines such as IL-33 and TSLP. Compared with conventional type 2 cytokine blockade, these emerging therapies may exert broader immunomodulatory effects, representing a potential paradigm shift in the future management of CRSwNP.

These alarmins exert effects on both the innate and adaptive immune systems, thereby holding therapeutic potential for both T2-high and T2-low CRSwNP subtypes. Furthermore, while currently approved biologics provide substantial clinical benefits, their associated economic burden may limit widespread clinical adoption. The development of these novel biologics is expected to provide patients with more cost-effective therapeutic alternatives.

Studies have repeatedly emphasized that the core principle of biologic therapy for CRSwNP lies in targeting the dominant inflammatory pathway: although asthma is well controlled, biologics targeting IL-5 or IgE may on occasion fail to achieve disease remission in CRSwNP. In such cases, switching to biologics that target the IL-4/IL-13 pathway may offer superior efficacy (40, 41, 43). Significant differences exist in the application scenarios and therapeutic characteristics of different biologics, as detailed below:

Dupilumab: This drug exhibits a faster rate of symptom relief than other biologics and serves as the preferred treatment option for cases of urgency (44). It acts on the more upstream IL-4 pathway in the inflammatory cascade, thereby offering distinct advantages for patients with multisystem atopic diseases or those with CRSwNP comorbid with asthma (40). It is capable of simultaneously ameliorating lesions in both the upper and lower airways, thereby achieving dual therapeutic benefits (43–45). For patients who failed initial anti-IL-5 therapy, approximately 50% can achieve effective disease control with dupilumab (43).

Anti-IL-5 agents: It is important to note that if initial anti-IL-5 therapy fails, switching to a second anti-IL-5 agent generally fails to improve patient outcomes (43).

Omalizumab: This agent targets the IgE pathway and is more suitable for CRSwNP patients with comorbid severe allergies, exerting faster and more significant effects in alleviating allergy-related symptoms (46).

In addition, the following key considerations should be integrated into clinical decision-making: clarifying the causes of previous biologic treatment failure is of paramount importance; for patients with multiple comorbid type 2 inflammation-related diseases, priority should be accorded to agents that alleviate the core symptoms most distressing to the patient (40, 41); efficacy assessment must simultaneously address the control of upper and lower airway symptoms, and if a single biologic fails to achieve comprehensive coverage, simultaneous biologic use may be considered (43).

If patients exhibit an incomplete response to biologic therapy or intolerance to AEs, multiple adjustments to the biologic regimen may be necessary. Although the clinical application of biologic combination therapy remains limited, it is suitable for complex cases with inadequate response to monotherapy—particularly in scenarios involving overlapping disease mechanisms, such as severe asthma combined with CRSwNP. For example, the combination of omalizumab and dupilumab can yield additive therapeutic benefits in some refractory cases. The research team reported that, based on their experience to date, this approach could be implemented safely but requires close clinical monitoring (43). In such complex scenarios, individualized treatment plans should be developed, and multidisciplinary decision-making should be adopted to optimize treatment outcomes. Both multiple regimen adjustments and biologic combination therapy are specialized treatment strategies and are only applicable to patients in whom monotherapy fails to achieve disease control (40).

There is currently no clear clinical consensus on whether a washout period is required when switching biologics for the treatment of CRSwNP. Evidence from studies of switching without a washout period has shown that this approach enables rapid symptom improvement and sustained disease control after switching, without increasing the risk of AEs, and is associated with a lower risk of treatment discontinuation and subsequent symptom exacerbation (41, 47). In contrast, studies involving a washout period indicate that symptom control temporarily declines during the washout phase, which may negatively impact HRQoL, and this approach does not demonstrate a clear safety advantage (48). This may be related to the following mechanism: when patients switch from anti-IL-5 therapy to dupilumab, it is recommended to initiate dupilumab directly and leverage the low eosinophil levels induced by prior anti-IL-5 treatment to minimize the risk of eosinophilia-related complications (43). Therefore, provided that there are no contraindications or particular safety considerations, switching biologics without a washout period may serve as a feasible and efficacious strategy for the management of CRSwNP.