Depemokimab: toward biannual biologic therapy for severe eosinophilic asthma

Abstract

Severe eosinophilic asthma remains a major therapeutic challenge despite advances in biologic therapies targeting type 2 inflammation. Depemokimab (Exdensur®), a novel ultra-long-acting anti-interleukin-5 (IL-5) monoclonal antibody, introduces a new treatment paradigm through sustained eosinophil suppression and twice-yearly administration. Engineered with enhanced IL-5 binding affinity and fragment crystallizable (Fc) modifications that prolong systemic persistence, depemokimab achieves durable pharmacodynamic activity and extended dosing intervals. Phase III SWIFT-1 and SWIFT-2 trials demonstrated significant reductions in annualized asthma exacerbations, with efficacy comparable to established anti-IL-5 agents and a favorable safety profile. However, benefits in lung function, symptom control, and quality of life have been less consistent, underscoring the complex relationship between eosinophilic inflammation and broader disease manifestations. The principal advantage of depemokimab lies in its potential to reduce treatment burden, improve adherence, and decrease healthcare utilization. As severe asthma management evolves, depemokimab represents a promising patient-centered option, although optimal patient selection and long-term outcomes require further investigation.

Severe eosinophilic asthma remains a major unmet clinical challenge despite the availability of targeted biologic therapies. Although monoclonal antibodies (mAbs) directed against immunoglobulin E, interleukin (IL)−5, IL-5 receptor α, IL-4/IL-13 signaling, and thymic stromal lymphopoietin have transformed outcomes in selected patients, a substantial proportion continue to experience exacerbations, treatment burden, and suboptimal adherence [1]. Depemokimab (trade name Exdensur®), a novel ultra-long-acting anti-IL-5 mAb, introduces a distinct pharmacological paradigm by combining enhanced cytokine neutralization with extended systemic persistence, enabling twice-yearly administration [2]. This unique profile positions depemokimab as a potentially transformative therapy within the evolving landscape of severe asthma management.

Depemokimab is a humanized immunoglobulin G, subclass 1, κ light chain (IgG1κ) mAb derived from mepolizumab but optimized through affinity maturation and fragment crystallizable (Fc) engineering. Specifically, amino acid substitutions within the complementarity-determining regions increase IL-5 binding affinity, while YTE (M252Y/S254T/T256E) mutations in the Fc domain enhance neonatal Fc receptor (FcRn) binding, prolonging antibody recycling and serum half-life (Fig. 1) [3]. This dual engineering strategy results in markedly improved pharmacokinetics and pharmacodynamics compared with earlier anti-IL-5 agents. In preclinical studies, depemokimab demonstrated significantly enhanced IL-5 neutralization potency and prolonged suppression of circulating eosinophils in vivo, supporting its development as a biannual therapy [3]. Given the central role of IL-5 in eosinophil maturation, activation, and survival, sustained cytokine blockade leads to durable reductions in eosinophilic inflammation, a key driver of type 2 (T2) asthma [3–5].

Fig. 1.

Depemokimab’s mechanism of action. Depemokimab is a humanized IgG1κ mAb structurally derived from mepolizumab but containing seven amino acid substitutions in the heavy chain. Four substitutions are located within the Fab variable region and enhance ITableL-5 affinity, while three YTE substitutions (M252Y/S254T/T256E) in the Fc region increase binding to the FcRn at acidic endosomal pH. This promotes reduced lysosomal degradation and increased recycling, resulting in prolonged systemic exposure and enabling biannual dosing. Compared with non-YTE modified anti-IL-5 mAbs, such as mepolizumab, depemokimab demonstrates enhanced IL-5 neutralization potency, increased FcRn binding affinity, and prolonged half-life. Fab: fragment antigen-binding; Fc: fragment crystallizable; FcRn: neonatal Fc receptor; IgG1κ: immunoglobulin G, subclass 1, κ light chain; IL-5: interleukin-5; mAb: monoclonal antibody; YTE: tyrosine (Y) at position 252, threonine (T) at position 254, glutamic acid (E) at position 256. Created in BioRender.com. Papavassiliou, K. (2026) https://BioRender.com/7vp20c4

The biological effects of depemokimab are consistent with its mechanism of action but are distinguished by their duration. Early-phase clinical studies demonstrated dose-dependent reductions in blood eosinophil counts of approximately 80%, sustained for up to 26 weeks following a single administration [2]. This prolonged pharmacodynamic effect reflects both the enhanced binding affinity and extended half-life of the molecule. Beyond eosinophil depletion, IL-5 blockade may influence broader inflammatory networks, including epithelial dysfunction, mucus production, and airway remodeling, although these downstream effects remain incompletely characterized [3]. The capacity to maintain continuous suppression of eosinophilic activity over extended intervals represents a critical advance, as fluctuations in drug exposure with shorter-acting biologics may permit intermittent disease activity.

The clinical efficacy of depemokimab has been established in the pivotal Phase III SWIFT-1 and SWIFT-2 trials, which evaluated twice-yearly subcutaneous administration in patients with severe eosinophilic asthma [6]. Across these replicate, randomized, placebo-controlled studies, depemokimab significantly reduced the annualized rate of exacerbations by approximately 54% compared with placebo, with rate ratios of 0.42 and 0.52, respectively [6]. These reductions were consistent across key subgroups and were observed early, with sustained benefits throughout the 52-week study period [7]. Importantly, the magnitude of exacerbation reduction is comparable to that reported with established anti-IL-5 therapies, suggesting that extending the dosing interval does not compromise efficacy. A summary of the key efficacy and safety findings from the SWIFT-1 and SWIFT-2 trials is provided in Table 1.

Table 1.

Key efficacy and safety outcomes of depemokimab in the Phase III SWIFT-1 and SWIFT-2 trials

Outcome	SWIFT-1 (Depemokimab vs Placebo) [Ref. 6]	SWIFT-2 (Depemokimab vs Placebo) [Ref. 6]
Patients randomized, n	250 vs 132	252 vs 128
Baseline blood eosinophil count, cells/μL	298 vs 310	339 vs 330
Blood eosinophil reduction at week 52	− 83% from baseline	− 82% from baseline
Annualized exacerbation rate	0.46 vs 1.11	0.56 vs 1.08
Exacerbation rate ratio (95% CI)	0.42 (0.30–0.59)	0.52 (0.36–0.73)
Reduction in annualized exacerbation rate	58%	48%
Placebo-adjusted change in prebronchodilator FEV₁ at week 52	+ 54 mL	+ 68 mL
Change in SGRQ total score at week 52	− 13.03 vs − 9.67	− 14.80 vs − 12.49
Change in ACQ-5 score at week 52	− 0.82 vs − 0.77	− 0.81 vs − 0.70
Exacerbations leading to hospitalization or emergency department visit, n	5 vs 13	16 vs 18
Any adverse event, n (%)	183 (73%) vs 97 (73%)	180 (72%) vs 101 (78%)

ACQ-5 Asthma Control Questionnaire-5, FEV₁ Forced Expiratory Volume in 1 second, CI Confidence Interval, SGRQ St. George’s Respiratory Questionnaire

However, the clinical profile of depemokimab is characterized by a notable dissociation between exacerbation reduction and improvements in secondary outcomes. In both SWIFT trials, no statistically significant differences were observed in health-related quality of life, asthma control scores, or lung function, precluding formal inference on these endpoints [6]. Similar findings have been reported in systematic analyses, which confirm robust reductions in exacerbations but inconsistent effects on symptom control and spirometric parameters [8]. The limited effects of depemokimab on lung function may reflect its predominant action on eosinophilic inflammatory pathways rather than on the structural airway alterations associated with severe asthma. In addition, the modest improvements observed in spirometric indices suggest that persistent airflow limitation related to airway remodeling may not be substantially modified by IL-5 blockade alone. Whether prolonged eosinophil suppression with depemokimab can influence remodeling processes over longer treatment periods remains an important area for future investigation. This divergence also raises important questions regarding the mechanisms underlying exacerbations versus daily symptom burden and suggests that IL-5-driven eosinophilic inflammation may be more directly linked to exacerbation risk than to chronic symptomatology.

Additional insights are provided by pooled and subgroup analyses. Early and sustained efficacy has been demonstrated across dosing intervals, with reductions in exacerbation risk maintained over successive 26-week periods [7]. Greater benefits have been observed in patients with shorter disease duration, moderate inhaled corticosteroid exposure, or comorbid chronic rhinosinusitis with nasal polyps, indicating potential phenotypic predictors of response [7]. Moreover, depemokimab has shown efficacy in patients with overlapping T2 conditions, further supporting its role in systemic eosinophilic disease [9]. The NIMBLE trial extends these findings by demonstrating that switching from existing anti-IL-5 or anti-IL-5 receptor therapies to depemokimab maintains disease control, highlighting its potential as a convenient alternative in stable patients [10].

Safety data across clinical trials indicate that depemokimab is generally well tolerated. In pooled analyses of Phase III studies, adverse events were predominantly mild or moderate and occurred at rates comparable to placebo, with low incidences of serious adverse events and treatment discontinuation [11]. Immunogenicity appears limited, with infrequent development of anti-drug antibodies and no clear impact on efficacy or safety [11]. These findings are consistent with the established safety profile of IL-5-targeted therapies and support the long-term use of depemokimab in chronic disease management.

The introduction of depemokimab addresses several key unmet needs in severe eosinophilic asthma. First, treatment adherence remains a major challenge with currently available biologics, which require administration every 2–8 weeks. The extended dosing interval of depemokimab has the potential to improve adherence by reducing treatment burden and simplifying therapeutic regimens. Second, healthcare resource utilization associated with frequent clinic visits or injections may be substantially reduced, with implications for both patient convenience and system-level efficiency. Third, sustained eosinophil suppression may provide more consistent disease control, minimizing fluctuations in inflammatory activity.

Nevertheless, depemokimab must be considered within the broader context of existing biologic therapies. Anti-IL-5 agents such as mepolizumab and reslizumab, and the anti-IL-5 receptor antibody benralizumab, have demonstrated similar reductions in exacerbations, along with modest improvements in lung function and quality of life [1]. In contrast, upstream therapies such as dupilumab and tezepelumab target broader inflammatory pathways and have shown efficacy across multiple endpoints, including lung function and symptom control [1]. As such, the primary differentiating feature of depemokimab is not superior efficacy but rather its pharmacokinetic profile and dosing convenience.

This distinction has important implications for therapeutic positioning. Depemokimab may be particularly advantageous in patients with adherence challenges, limited access to healthcare facilities, or preference for less frequent dosing. It may also be considered in patients already well controlled on anti-IL-5 therapies who seek to reduce treatment burden. Conversely, in patients with prominent symptoms, airflow limitation, or T2-low or mixed inflammatory phenotypes, alternative biologics targeting broader pathways may be more appropriate.

Despite its promise, several limitations of depemokimab should be acknowledged. The lack of consistent improvements in patient-reported outcomes and lung function suggests that IL-5 inhibition alone may be insufficient to address all dimensions of severe asthma. Furthermore, long-term data beyond one year remain limited, and the durability of clinical benefits over extended periods requires further investigation. The identification of biomarkers to predict response to depemokimab is also an area of ongoing research, as heterogeneity in treatment response remains a challenge across all biologic therapies [1]. While blood eosinophils remain the primary criterion for anti-IL-5 therapies, emerging evidence indicates that dynamic biomarker profiles and longitudinal changes may better reflect treatment responsiveness than static baseline values [12]. Recent advances in multiomics have enabled the identification of molecular endotypes characterized by distinct transcriptomic, proteomic, and imaging signatures associated with differential outcomes [13, 14]. Notably, integrative approaches combining clinical, molecular, and radiological data have revealed heterogeneous pathways underpinning severe asthma, suggesting that IL-5-driven inflammation represents only one component of a complex disease network [14]. In this context, the application of multiomic stratification could refine patient selection for depemokimab, identify those most likely to benefit from sustained eosinophil suppression, and support the development of personalized treatment algorithms. Such strategies will be essential to maximize therapeutic efficacy and advance precision medicine in severe asthma.

In addition, economic considerations will play a critical role in determining the uptake of depemokimab. While reduced dosing frequency may lower administration costs, the overall cost-effectiveness of the therapy will depend on pricing, healthcare system structures, and comparative effectiveness relative to existing biologics. The potential for reduced exacerbation-related healthcare utilization may offset drug costs, but real-world data are needed to confirm this hypothesis.

In conclusion, depemokimab represents a significant advancement in the treatment of severe eosinophilic asthma by introducing the first ultra-long-acting anti-IL-5 biologic capable of twice-yearly administration. Its innovative molecular design enables sustained eosinophil suppression and substantial reductions in exacerbation risk, addressing critical unmet needs related to adherence and treatment burden. Nevertheless, its clinical profile highlights important limitations, including the absence of consistent improvements in symptoms and lung function, and underscores the need for careful patient selection. As the therapeutic landscape continues to evolve, depemokimab offers a novel and patient-centered option that may reshape the management of eosinophilic asthma while prompting further exploration of long-acting biologic strategies.

Authors’ contributions

KAP, VAG and AGP conceptualized the study and drafted the manuscript. KAP and AGP critically revised the manuscript. All authors have read and approved the content of the manuscript.

Funding

No external funding was received for this work.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.