mega-md 原貌：Drugs 86-6 (2026) — 13 篇 bundler 自動抽取

Drugs — 2026-05-26 全期 raw bundle

13 篇文章，5 篇 open access。

Article 1 — Oral Gut-Restricted Targeted Therapy for IBD: A Pipeline Review

DOI: 10.1007/s40265-026-02309-x
Section: Leading Article
OA: no
Article URL: https://link.springer.com/article/10.1007/s40265-026-02309-x
PDF URL: https://link.springer.com/article/10.1007/s40265-026-02309-x.pdf
Authors: Roseira, Joana

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Abstract

Oral gut-restricted therapies are being explored as a drug delivery strategy for inflammatory bowel disease (IBD), with the aim of achieving therapeutic effects within the intestinal mucosa while minimizing systemic exposure. Advances in molecular engineering and formulation technologies have enabled the development of orally administered agents intentionally designed to act locally within the gastrointestinal tract. This narrative review examines the biological, pharmacokinetic, and formulation principles underlying oral gut-restricted drug delivery in IBD, including an analysis of discontinued clinical development programs in ulcerative colitis and Crohn’s disease. Across locally acting antibodies, peptides, and small molecules, the analysis of these programs reveals recurring factors contributing to discontinuation. These include limited or absent clinical efficacy despite evidence of mucosal target engagement, challenges in achieving consistent and adequate intestinal exposure, constraints related to formulation or delivery technologies, and trial-related factors such as high placebo response rates. In several cases, manufacturing variability or strategic considerations also influenced development outcomes. The review of the current clinical trial pipeline suggests an evolution in development strategies relative to earlier programs, with increasing emphasis on the confirmation of local tissue drug levels, incorporation of mucosal pharmacodynamic readouts, and selection of endpoints aligned with localized mechanisms of action, including endoscopic and histologic outcomes. These elements appear critical for interpreting early phase efficacy signals for agents designed to have minimal systemic activity. Effective translation requires alignment between mechanism of action, intestinal drug delivery, tissue-level pharmacodynamics, and clinical trial design. Incorporating these lessons may improve the likelihood of success for future oral gut-restricted therapies in IBD.

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Bidirectional Interplay Between IBD Therapies and the Gut Microbiota: A Pharmacomicrobiomic Approach to Personalized Treatment

Article 03 October 2025

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Inflammatory bowel diseases: pathological mechanisms and therapeutic perspectives

Article Open access 07 January 2026

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Understanding the therapeutic toolkit for inflammatory bowel disease

Article 31 January 2025

Discover the latest articles, books and news in related subjects, suggested using machine learning.

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Authors and Affiliations

Gastroenterology Department, Unidade Local de Saúde do Algarve, Unidade de Portimão, Portimão, Portugal

Joana Roseira

ABC—Algarve Biomedical Center, Faro, Portugal

Joana Roseira

Univ. Grenoble Alpes/Hepato-Gastroenterology and Digestive Oncology department, CHU Grenoble Alpes/Institute for Advanced Biosciences, CNRS UMR 5309-INSERM U1209, Grenoble, France

Marianne Hupé

Division of Gastroenterology, Department of Medicine, Western University, London, ON, Canada

Yuhong Yuan & Vipul Jairath

CINTESIS@RISE, Department of Community Medicine, Information and Health Decision Sciences (MEDCIDS), Faculty of Medicine, University of Porto (FMUP), Porto, Portugal

Fernando Magro

Department of Gastroenterology, Unidade Local de Saúde São João (ULSSJ), Porto, Portugal

Fernando Magro

Department of Epidemiology and Biostatistics, Western University, London, ON, Canada

Vipul Jairath

Department of Medicine, Schulich School of Medicine and Dentistry I Western University, University Hospital, Room A10-219, London, ON, N6A 5B6, Canada

Vipul Jairath

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Conflicts of Interest

JR received advisory board fees and speaker’s fees from Abbvie and Janssen; MH received advisory board fees and speaker’s fees from Takeda, Celltrion Healthcare, Amgen, Abbvie, Pfizer, and Johnson & Johnson; YY none to declare. FM served as speaker for Abbvie, Arena, Biogen, Bristol Myers Squibb, Falk, Ferring, Hospira, Janssen, Laboratórios Vitoria, Pfizer, Lilly, Merck Sharp & Dohme, Sandoz, Takeda, UCB, and Vifor. VJ has received has received consulting/advisory board fees from AbbVie, Alimentiv, Anaptyis Bio, Arena Pharmaceuticals, Asahi Kasei Pharma, Asieris, Astra Zeneca, Bristol Myers Squibb, Celltrion, Eli Lilly, Endpoint Health, Enthera, Ensho, Ferring, Flagship Pioneering, Fresenius Kabi, Galapagos, GlaxoSmithKline, Genentech, Gilead, Innomar, JAMP, Janssen, Merck, Metacrine, Mylan, MRM Health, Pandion, Pendopharm, Pfizer, Protagonist, Prometheus Biosciences, Reistone Biopharma, Roche, Roivant, Sandoz, Second Genome, Sorriso, Spyre, Synedgen, Takeda,Teva, Ventyx, and Vividion and speaker’s fees from, Abbvie, Ferring, Bristol Myers Squibb, Eli Lilly, Fresenius Kabi, Janssen, Pfizer, Shire, Takeda, and Tillotts.

Author Contributions

JR, MH, YY, FM, and VJ contributed to the outline. The first draft of the manuscript was written by JR and MH. JR, MH, YY, FM, and VJ commented on previous versions of the manuscript. All authors have read and approved the final version of the manuscript and agree to be accountable for the work.

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Roseira, J., Hupé, M., Yuan, Y. et al. Oral Gut-Restricted Targeted Therapy for IBD: A Pipeline Review. Drugs 86, 779–795 (2026). https://doi.org/10.1007/s40265-026-02309-x

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Article 2 — Targeting Inflammation in Bronchiectasis

DOI: 10.1007/s40265-026-02314-0
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Article URL: https://link.springer.com/article/10.1007/s40265-026-02314-0
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Authors: Mac Aogáin, Micheál

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Abstract

Bronchiectasis is defined by chronic infection, dysregulated inflammation and impaired mucociliary clearance underpinning progressive structural lung injury. While airway infection remains a clinical hallmark, numerous studies demonstrate that excessive neutrophil-dominated inflammation is a key determinant of disease severity, exacerbation risk and quality of life. Recent developments have transformed our understanding of inflammatory drivers uncovering distinct inflammatory endotypes defined by dominant microbial species, pattern-recognition receptor activation, inflammasome signalling, Th17-associated cytokine networks and failures of mucosal immunity. The emerging roles of viral–bacterial interactions, fungi, pathobionts and the broader microbiome challenge the conventional infection-only paradigm and highlight gaps in current therapeutic strategies. Such developments underpin the rationale behind anti-inflammatory strategies in bronchiectasis, ranging from suppression of neutrophil-driven injury through direct neutrophil elastase or upstream dipeptidyl peptidase-1 (DPP-1) inhibition, to immunomodulatory macrolides, toward therapies aimed at recalibrating epithelial and mucosal homeostasis. While several antibacterial and anti-infective trials have produced mixed results, this is likely to reflect unresolved heterogeneity in microbiome composition and host immune signalling. In contrast, emerging anti-inflammatory strategies show strong positive signals, reinforcing the need for better endotyping and biomarker-guided patient selection. Here we synthesize recent mechanistic and clinical insights to propose a more integrated framework for understanding and ultimately targeting airway inflammation in bronchiectasis.

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Pathophysiology, Immunology, and Histopathology of Bronchiectasis

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The cellular triangle in bronchiectasis: the interplay network and regulatory mechanisms of neutrophils, macrophages, and epithelial cells

Article Open access 11 December 2025

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Fungal-Associated Endotypes as a Treatable Trait in Bronchiectasis

Article Open access 29 December 2025

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Acknowledgements

The authors thank The Academic Respiratory Initiative for Pulmonary Health (TARIPH) and the Lee Kong Chian School of Medicine Centre for Microbiome Medicine for collaboration support. Figures in this paper were created with BioRender.com.

Funding

This research is supported by the National Research Foundation Singapore under its Open Fund-Large Collaborative Grant (MOH-001636) administered by the Singapore Ministry of Health’s National Medical Research Council; the Singapore Ministry of Health’s National Medical Research Council under its Clinician-Scientist Individual Research Grant (MOH-001356) (S.H.C) and Clinician-Scientist Award (CSA) Investigator (INV) category (MOH-001855). The funders had no role in study design, data collection, analysis, or manuscript preparation.

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Department of Biochemistry, St. James’s Hospital, Dublin, Ireland

Micheál Mac Aogáin

Clinical Biochemistry Unit, School of Medicine, Trinity College Dublin, Dublin, Ireland

Micheál Mac Aogáin

Division of Respiratory Medicine and Gastroenterology, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK

Amy Gilmour & James D. Chalmers

Radcliffe Department of Medicine, University of Oxford, Oxford, UK

James D. Chalmers

Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore

Sanjay H. Chotirmall

Department of Respiratory and Critical Care Medicine, Tan Tock Seng Hospital, Singapore, Singapore

Sanjay H. Chotirmall

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J.D.C reports grants or contracts from AstraZeneca, Boehringer Ingelheim, Genentech, Gilead Sciences, GlaxoSmithKline, Grifols, Insmed, Novartis and Trudell Medical Group; consulting fees from Antabio, AstraZeneca, Boehringer Ingelheim, Chiesi Farmaceutici, GlaxoSmithKline, Grifols, Insmed, Janssen, Novartis, Pfizer, Trudell Medical Group and Zambon. S.H.C has served on advisory boards for CSL Behring, Pneumagen Ltd., Zaccha Pte Ltd, Boehringer-Ingelheim, GSK, Chiesi Farmaceutici and Sanofi, on DSMBs for Inovio Pharmaceuticals and Imam Abdulrahman Bin Faisal University and has received personal fees from Astra-Zeneca, Boehringer-Ingelheim, CSL Behring and Chiesi Farmaceutici, all unrelated to this work. All other authors have no potential conflicts of interest to disclose.

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Mac Aogáin, M., Gilmour, A., Chalmers, J.D. et al. Targeting Inflammation in Bronchiectasis. Drugs 86, 797–812 (2026). https://doi.org/10.1007/s40265-026-02314-0

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Article 3 — Current and Emerging Biologic Therapies for Severe Asthma

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Abstract

Severe asthma is a heterogeneous disorder characterized by persistent symptoms, frequent exacerbations, and corticosteroid dependence despite optimized therapy. Seven monoclonal antibodies are currently approved, targeting immunoglobulin E (IgE; omalizumab), interleukin (IL)-5 or IL-5 receptor α (mepolizumab, reslizumab, depemokimab, benralizumab), IL-4 receptor α (dupilumab), and the epithelial alarmin thymic stromal lymphopoietin (TSLP; tezepelumab). These therapies have demonstrated substantial reductions in exacerbation rates and oral corticosteroid use, along with improvements in lung function and patient-reported outcomes. Safety profiles are generally favorable across populations. Key predictors of response include blood eosinophil counts, fractional exhaled nitric oxide, and phenotype-specific biomarkers. Despite these advances, unmet needs remain. Current biologics only partially address type 2-low, neutrophilic, and mixed granulocytic phenotypes, as well as airway remodeling and persistent exacerbations in type 2-high patients. Emerging strategies aim to overcome these limitations by targeting upstream alarmins (TSLP and IL-33), dual or trispecific cytokine pathways, and IgE-producing B cells. Novel Fc-engineered and dual-receptor anti-IgE monoclonal antibodies enhance the magnitude and durability of IgE suppression. Multi-target constructs, including bispecific and trispecific agents, simultaneously block overlapping type 2 and non-type 2 pathways, which could improve outcomes in heterogeneous and refractory populations. Preclinical and early-phase clinical studies suggest that these approaches may provide disease-modifying effects and support biomarker-guided personalized therapy. This review summarizes the current landscape of approved biologics and the rationale for next-generation therapies in severe asthma. It highlights mechanistic insights, clinical efficacy, and future directions for precision-targeted treatment strategies.

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Abstract

Biologic Therapies in Severe Asthma: Current Landscape, Clinical Evidence, and Future Directions

Article Open access 28 December 2025

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Biological therapy for severe asthma

Article Open access 13 August 2021

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Therapeutic interventions in severe asthma

Article Open access 28 November 2016

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Antibody therapy
Biological Therapy
Biologics
Recombinant Protein Therapy
Targeted therapies
Therapeutics
Asthma Phenotyping and Immune Mechanisms

FormalPara Key Points

Currently approved biologics provide substantial clinical benefits for patients with type 2-high severe asthma, but they do not address type 2-low and mixed phenotypes.
Next-generation biologics use multi-target, Fc-engineered, and alarmin-directed strategies to improve efficacy, durability, and precision for specific patients.
Biomarker-guided therapy and upstream pathway modulation show promise in addressing refractory disease and enabling personalized treatment.

1 Introduction

Severe asthma (SA) is defined by inadequate asthma control despite optimized inhaled corticosteroid (ICS) and long-acting beta-agonist therapy and management of modifiable risk factors, or by loss of control upon treatment reduction [1]. Although SA affects only 3.6–10% of patients with asthma, it accounts for a disproportionate amount of morbidity, healthcare utilization, and costs [2].

1.1 Burden of Severe Asthma

Severe asthma is defined as requiring a high-dose ICS in combination with another controller medication to maintain asthma control, or as having uncontrolled asthma despite such therapy [3]. Patients with SA are at an increased risk of exacerbations compared with those with milder disease [1, 3]. These exacerbations lead to accelerated airway remodeling, faster lung function decline, and reduced responsiveness to standard therapies [1, 4]. However, some individuals may achieve good control without frequent exacerbations or the need for biologic therapy [1, 4].

Severe asthma imposes a substantial psychological and social burden. Patients can experience impaired quality of life, sleep disturbances, reduced work productivity, and high rates of anxiety and depression. These issues are largely driven by symptoms and oral corticosteroid (OCS) toxicity [5,6,7]. Asthma-related mortality is also significantly higher in patients with severe uncontrolled disease [8]. Economically, SA accounts for a disproportionate share of direct and indirect asthma-related costs, which are further increased by OCS-associated adverse events (AEs), including osteoporosis, diabetes mellitus, cardiovascular disease, and infections, which may occur with both long-term exposure and repeated short courses of OCS [9, 10].

1.2 Rationale for Biologic Therapies

In SA, high-dose ICSs and systemic corticosteroids often fail to achieve optimal disease control and are associated with significant AEs. Low-dose OCSs (≤7.5 mg/day of prednisone equivalent) may be considered as a last-resort add-on therapy for select adults; however, maintenance OCS carries substantial cumulative AEs [1]. These limitations underscore the necessity of therapeutic strategies that target the underlying pathogenic mechanisms of asthma rather than merely alleviating symptoms [1, 11, 12]. Recent advances in immunopathology have revealed that asthma is a heterogeneous condition consisting of various phenotypes and mechanistic endotypes. These are most broadly classified as type 2 (T2)-high and T2-low asthma [13,14,15] (Fig. 1).

[Figure] 40265_2026_2310_Fig1_HTML.png — Fig. 1
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Type 2-high asthma is characterized by eosinophilic airway inflammation and elevated biomarkers, such as fractional exhaled nitric oxide (FeNO), blood and sputum eosinophils, and immunoglobulin E (IgE), driven by interleukin (IL)-4, IL-5, and IL-13, with contributions from alarmins thymic stromal lymphopoietin (TSLP), IL-25, and IL-33, which are epithelial-derived cytokines, IgE-mediated pathways, and mediators, such as prostaglandin D2 and periostin [16,17,18,19]. This endotype includes both allergic and nonallergic forms [20]. The nonallergic form often occurs in adulthood and is more severe. It also encompasses molecular sub-endotypes dominated by IL-5, IL-13, or IgE signaling [21]. Aspirin-exacerbated respiratory disease [22] and comorbid chronic rhinosinusitis with nasal polyps [23] are also frequently observed within the T2-high spectrum.

In contrast, T2-low asthma is characterized by the absence of eosinophilic inflammation and is associated with neutrophilic or paucigranulocytic patterns involving heterogeneous mechanisms, such as IL-17, IL-6, and tumor necrosis factor-alpha (TNF-α) signaling; neurogenic inflammation; and microbiome alterations [24,25,26]. Type 2-low features may represent a distinct endotype or emerge from long-standing T2-high disease, particularly following prolonged corticosteroid exposure [3, 27, 28]. Inflammatory phenotypes may also shift or coexist over time within a “mixed” endotype [29].

The recognition of these pathways has enabled the development of targeted biologic therapies, including monoclonal antibodies (mAbs) targeting IgE, IL-5, IL-5 receptor α (IL-5Rα), IL-4/IL-13 receptor complex, and upstream epithelial-derived alarmins such as TSLP. These agents reduce exacerbations, improve lung function, decrease dependence on OCS, and enhance quality of life in selected patients with SA [11, 30, 31]. Biomarker-guided biologic therapy is a significant step toward precision medicine in SA [32]. However, challenges remain in predicting responses, managing nonresponders, and addressing unmet needs in T2-low asthma [32]. Therefore, this review aims to summarize the current landscape of approved biologic therapies for SA and to discuss emerging next-generation biologics, focusing on their mechanisms of action, clinical evidence, and potential role in advancing biomarker-guided precision medicine.

2 Targets for Biologic Intervention

The persistence of airway inflammation and remodeling in patients with SA, even with optimized standard therapy, underscores the need for precise cellular and molecular targets for biologic intervention. Understanding the pathways that drive immune activation and structural changes has enabled the development of therapies that selectively modulate disease-relevant mechanisms.

2.1 Type 2 Inflammatory Pathway

Environmental triggers induce the release of alarmins (TSLP, IL-33, and IL-25) from epithelial cells, which activate dendritic cells and group 2 innate lymphoid cells (ILC2s). This initiates downstream innate and adaptive T2 immune responses [33]. Activated T helper 2 (Th2) cells and ILC2s secrete IL-4, IL-5, and IL-13, orchestrating interconnected pathogenic processes [34, 35]. Interleukin-4 and IL-13 signal via IL-4Rα and the Janus kinase/signal transducer and activator of transcription 6 pathway, promoting IgE class switching, eosinophil recruitment, and airway remodeling through mediators such as periostin, while IL-5 acts via IL-5Rα and signal transducer and activator of transcription 5 to facilitate eosinophil maturation, survival, and trafficking.

Mast cells and basophils further amplify inflammation and bronchoconstriction through high-affinity immunoglobulin E receptor (FcεRI)-mediated degranulation and the release of histamine, leukotrienes, and prostaglandin D2 [36]. Structural airway cells, including airway smooth muscle (ASM) and fibroblasts, respond to IL-13 and IL-4 signaling by producing periostin and other matrix proteins, thereby contributing to subepithelial fibrosis, airway stiffening, smooth muscle hypertrophy, and persistent airflow limitation [34].

Clinically, T2 activation is reflected by increased blood and airway eosinophils, FeNO levels, and serum IgE levels [31]. This provides the rationale for biologics that target IL-5, IL-5Rα, and IL-4Rα. These biologics reduce exacerbations, OCS dependence, and airway remodeling in select patients [1, 35].

2.2 Type 2-Low (Non-Type 2) Pathway

Type 2-low asthma is mechanistically heterogeneous and lacks a single dominant driver [37]. It is commonly associated with Th1/Th17-mediated inflammation, in which IL-17A/F, TNF-α, interferon-gamma, and IL-6 promote neutrophil recruitment and activation, as well as chronic airway inflammation [38]. Neutrophilic asthma is often associated with elevated levels of IL-8, IL-1α, and granulocyte colony-stimulating factor, potentially driven or maintained by low-grade infection and airway microbiome dysbiosis [39]. Neuroimmune interactions mediated by neuropeptides, such as substance P and calcitonin gene-related peptide, released from sensory nerves, contribute to airway hyperresponsiveness, mucus secretion, and inflammation, and also to corticosteroid resistance and airway remodeling [40]. Corticosteroid resistance is linked to IL-17A/Th17 pathways, which induce proinflammatory mediators (e.g., lipocalin-2, serum amyloid A) that corticosteroids poorly suppress, perpetuating neutrophilic inflammation [41].

Clinically, T2-low asthma is characterized by persistent symptoms and a poor response to existing biologics that primarily target T2 pathways [35]. This has prompted investigation of alternative potential targets, including IL-17, IL-6, TNF-α, and IL-1β [38], as well as microbiome-modifying strategies, such as macrolide therapy [42].

2.3 Upstream Mediators: Thymic Stromal Lymphopoietin and Other Alarmins

Thymic stromal lymphopoietin, IL-33, and IL-25 are upstream epithelial-derived mediators that amplify T2 inflammation and, to some extent, non-T2 inflammation. They do this by activating dendritic cells, ILC2s, mast cells, and basophils [43, 44]. These alarmins act early in the inflammatory cascade and represent attractive therapeutic targets with broader efficacy than a downstream cytokine blockade [45]. Blocking TSLP has been shown to significantly reduce asthma exacerbations, improve lung function, and decrease the need for systemic corticosteroids in patients with SA, including those with low blood eosinophil counts (BECs) who are not eligible for other biologics [35]. An IL-33 blockade also shows promise, but its impact on T2-low asthma is less clear [46].

2.4 Integration of Pathways and Biologic Targets

Severe asthma is best viewed as a dynamic network of interacting inflammatory pathways rather than a collection of isolated mechanisms [11]. The integration of T2-high, T2-low, and alarmin-driven mechanisms, each characterized by distinct cellular and molecular mediators that interact and evolve over time, provides the biological rationale for mechanism-based treatment selection guided by biomarkers such as BEC, FeNO, and IgE [35, 47]. Combining clinical phenotyping based on factors such as age of onset, comorbidities, and exacerbation history with molecular endotyping enables personalized therapeutic strategies that optimize clinical outcomes and resource utilization [48].

3 Currently Approved Biologic Therapies for Severe Asthma

Seven biologic agents, omalizumab, mepolizumab, reslizumab, depemokimab, benralizumab, dupilumab, and tezepelumab, are currently approved for the treatment of SA (Table 1) [1], each targeting specific components of disease-relevant inflammatory pathways [11] (Fig. 2).

[Figure] — Table 1 Currently approved biologic therapies for severe asthma

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3.1 Anti-Immunoglobulin E Therapy: Omalizumab

Omalizumab, a recombinant humanized mAb, binds to the Cε3 domain of IgE, preventing its interaction with both the high-affinity IgE receptor (FcεRI) on mast cells and basophils and dendritic cells, and the low-affinity receptor (CD23/FcεRII) on B cells and other antigen-presenting cells [49]. Omalizumab binding induces large-scale conformational changes in the Cε3 domains of IgE-Fc, allosterically inhibiting FcεRI interaction, while CD23 binding is inhibited sterically because of overlapping binding sites on each Cε3 domain. This dual mechanism is clinically significant, as inhibition of CD23 binding disrupts IgE-facilitated allergen presentation and upstream Th2 immune activation, which may contribute substantially to therapeutic efficacy beyond FcεRI-mediated effects alone [49]. By binding to free IgE, omalizumab reduces circulating IgE levels by greater than 96% and induces sustained downregulation of FcεRI expression on mast cells, basophils, and dendritic cells, thereby inhibiting chronic aspects of allergic inflammation involving T-cell activation [50].

Omalizumab is the first approved anti-IgE biologic for allergic SA. It reduces exacerbations, decreases the use of OCS, and improves quality of life, particularly in patients with elevated IgE and allergic sensitization [50]. GINA recommends using omalizumab as add-on therapy for patients aged ≥6 years with perennial allergen sensitization and uncontrolled disease despite high-dose ICSs and additional controller medications [1]. Omalizumab is administered subcutaneously every 2–4 weeks, and the dosage is based on body weight and baseline IgE levels. However, the IgE level does not predict response [1].

Real-world and observational studies report a 59% reduction in exacerbations and a 41% reduction in maintenance OCS use, with improvements in lung function and patient-reported outcomes [50]. Long-term data demonstrate sustained efficacy without tachyphylaxis for 5–10 years, with long-lasting improvements in asthma control, significant decrements in exacerbation rates, and reductions in the use of OCSs [41].

A better response is associated with higher BEC (≥260/μL), elevated FeNO (≥19.5 ppb), childhood-onset asthma, and allergen-driven symptoms [52], although clinical benefit is observed across a broad biomarker range [53]. Omalizumab is generally well tolerated. Anaphylaxis is rare (approximately 0.2%) and usually occurs during the initial stages of treatment [54]. Long-term safety has been established for up to 5 years [55]. Treatment response should be assessed after at least 4 months [1]. Emerging evidence also suggests corticosteroid-sparing effects and the potential to reverse airway remodeling [56]. Self-administration is increasingly feasible, subject to local regulatory and payer requirements [57].

3.2 Anti-Interleukin-5 and Interleukin-5 Receptor-Targeted Therapies

Anti-IL-5 (mepolizumab, reslizumab, and depemokimab), and anti-IL-5Rα (benralizumab) therapies are established as add-on maintenance treatments for severe eosinophilic asthma in adults and children. These agents target the IL-5 pathway, reducing eosinophilic inflammation and thereby decreasing asthma exacerbations, improving symptom control, and enabling OCS sparing [35, 47].

3.2.1 Mepolizumab

Mepolizumab, a humanized mAb that targets IL-5, is administered subcutaneously at a dose of 100 mg every 4 weeks for adults and adolescents, and 40 mg every 4 weeks for children aged 6–11 years, with self-administration available. It is approved for treating eosinophilic SA, particularly in patients with elevated BECs [58,59,60].

A recent meta-analysis of ten randomized controlled trials (RCTs) [n = 4471] demonstrated that mepolizumab significantly reduces exacerbations and improves lung function (forced expiratory volume in 1 second [FEV1]) [61]. It also enhances asthma control, as measured by Asthma Control Questionnaire (ACQ)-5 scores, with a safety profile comparable to placebo. Another meta-analysis of real-world studies corroborates these findings, showing reductions in exacerbations and hospitalizations, improvements in asthma control (ACQ and Asthma Control Test [ACT]), modest FEV1 gains, and substantial OCS-sparing effects [62]. In children, the MUPPITS-2 trial reported reduced exacerbations, though improvements in lung function were not significant [63].

Real-world evidence indicates that approximately 73% of patients respond to mepolizumab, with 28% classified as “super responders” (exacerbation free and off OCSs at 1 year) [64]. Annual exacerbation reductions of 72–80% have been observed over 12 months, with additional benefits in patients with comorbid chronic rhinosinusitis with nasal polyps [65]. Mepolizumab also demonstrates corticosteroid-sparing effects and improves airway remodeling by reducing reticular basement membrane thickness and ASM mass after 12 months [66].

Data from the REALITI-A study further confirm that mepolizumab consistently decreases clinically significant exacerbations by 53–79%, lowers the use of OCSs, and improves symptom scores and lung function [67]. The greatest benefits are seen in patients with an older age at onset, a lower body mass index, and who do not smoke [67]. An extended follow-up suggests reductions in healthcare resource utilization, as well as improved productivity and daily functioning [68]. Baseline BEC strongly predicts response. Patients with a BEC ≥500 cells/μL experience a 73% reduction in exacerbations compared with 36–39% in those with a BEC ≥150 cells/μL [69].

Mepolizumab is well tolerated, even in OCS-dependent patients [70]. The most common AEs are headache (up to 32%) and nasopharyngitis (18%), while injection-site reactions are uncommon (1–3%) and generally mild.

3.2.2 Reslizumab

Reslizumab, another humanized anti-IL-5 mAb, is administered intravenously at 3 mg/kg every 4 weeks. Pivotal trials and meta-analyses demonstrate that reslizumab reduces asthma exacerbations by approximately 50–54% in adults with eosinophilic SA and BECs ≥400 cells/μL and a history of exacerbations [71,72,73]. Reslizumab is more effective in patients with higher baseline BECs. While lung function gains are statistically significant, they are limited. Patient-reported outcomes show modest yet meaningful improvements. The minimal clinically important difference is achieved for the Asthma Quality of Life Questionnaire, but not for ACQ.

Real-world studies confirm these benefits, reporting reductions in exacerbations, improvements in lung function, and decreased OCS use in adults with eosinophilic SA [74,75,76]. Data from the Dutch SA registry (RAPSODI) indicate that both biologic-naïve patients and those switched from another T2 biologic derive benefit, with nearly 60% achieving a “good” or “excellent” overall clinical response [75].

The overall incidence of AEs is lower with reslizumab than with placebo [70]. Common AEs include mild asthma worsening, nasopharyngitis, upper respiratory tract infection, and headache.

3.2.3 Depemokimab

Depemokimab is a humanized IgG1 kappa mAb that acts as an IL-5 antagonist. It is engineered with a triple YTE amino acid substitution in the Fc region to enhance neonatal Fc receptor binding and prolong the half-life. This enables subcutaneous dosing every 6 months for the treatment of eosinophilic SA [77]. Model-informed drug development studies have shown that a single 100-mg subcutaneous dose results in BEC reductions like those of mepolizumab and maintains sustained pharmacodynamic effects throughout the 26-week dosing interval [78].

Phase IIIA multicenter, double-blind, placebo-controlled RCTs SWIFT-1 and SWIFT-2 included 762 patients with uncontrolled eosinophilic SA despite medium- or high-dose ICSs and additional controllers [79]. Patients were randomized 2:1 to receive depemokimab 100 mg or placebo at weeks 0 and 26. The primary endpoint was the annualized rate of clinically significant asthma exacerbations over 52 weeks. Depemokimab significantly reduced the annual exacerbation rate by 54% compared with placebo (rate ratio 0.46, 95% confidence interval 0.36–0.59) and rapidly and sustainably suppressed BECs by 83% in SWIFT-1 and 82% in SWIFT-2at week 52. Safety outcomes were comparable to placebo, with no drug-related serious AEs or deaths. Immunogenicity was low, with binding antibodies detected in 5–12% of patients and neutralizing antibodies in only two cases. Liver-related discontinuations were rare and not attributable to the drug. Long-term efficacy and safety were confirmed in the AGILE open-label extension, which demonstrated sustained benefits over 2 years with twice-yearly dosing [80]. Depemokimab has entered the regulated asthma market in key regions and is expected to expand further as global regulatory reviews conclude in 2026.

3.2.4 Benralizumab

Benralizumab is a humanized afucosylated mAb that binds to the IL-5Rα subunit on eosinophils and basophils, inducing antibody-dependent cell-mediated cytotoxicity and resulting in near-complete eosinophil depletion. This mechanism leads to rapid and sustained eosinopenia, as demonstrated in the ABRA study, highlighting the potent eosinophil-depleting activity of benralizumab and its potential relevance for the early control of eosinophilic airway inflammation [81]. The approved dosing regimen is 30 mg subcutaneously every 4 weeks for the first three doses, followed by every 8 weeks, and self-administration is an option.

Efficacy was demonstrated in two pivotal phase III trials, the 48-week SIROCCO trial [82] and 56-week CALIMA trial [83]. These trials collectively enrolled over 2500 patients with uncontrolled SA. In patients with a baseline BEC ≥300 cells/μL, benralizumab significantly reduced the annual exacerbation rates (SIROCCO: 45–51%; CALIMA: 28–36%), increased the prebronchodilator FEV1 by 106–159 mL, and improved asthma symptom scores, particularly with the every-8-week regimen. The OCS-sparing effect was demonstrated in the 28-week ZONDA trial, which reported a median 75% reduction in the daily OCS dose and a 70% reduction in exacerbations compared with the placebo group [84].

Real-world evidence corroborates these findings. After 48 weeks of therapy, benralizumab reduced annual exacerbation rates by 72.8% (from 4.92 to 1.34 per year), with 43.8% of patients remaining exacerbation free; 51.4% of patients on maintenance OCS were able to discontinue therapy [85]. Overall, 86% of patients met responder criteria, and 39% were classified as “super responders” (no exacerbations or OCS use). The multinational XALOC-1 program demonstrated similar reductions in exacerbations and corticosteroid use, and improvements in symptom control and lung function, across diverse subgroups, including patients with prior biologic exposure [86]. The ANANKE observational retrospective cohort study reported sustained improvements over 96 weeks: the annualized exacerbation decreased by 94.9% (any) and 96.9% (severe), the median FEV1 increased by 400 mL, and the ACT scores improved from 14 to 23. Additionally, 60% of patients discontinued OCS therapy [87]. However, the ANANKE study lacked a control group.

Emerging evidence suggests that patients who do not respond well to mepolizumab may benefit from transition to benralizumab. In a retrospective multicenter cohort study of patients with eosinophilic SA and nasal polyposis, switching to benralizumab improved ACT scores, reduced daily rescue inhaler use, and decreased maintenance corticosteroid requirements compared with the patients’ prior response to mepolizumab [88]. The imPROve Asthma study revealed that rates of clinical asthma remission with benralizumab vary depending on the instrument and threshold applied [89]. After 12 months, four-component remission was achieved in 42.7% of patients using an ACQ-6 score of ≤1.5, compared with 21.5% using an ACT score of ≥23. Intermediate rates were observed with an ACQ-6 score of 0.75 (24.4%) and an ACT score of ≥20 (36.9%). These trends persisted at 24 months, with lenient criteria yielding nearly double the remission rate of stricter thresholds.

Benralizumab is generally well tolerated. Adverse events are generally mild to moderate and include nasopharyngitis, headache, sinusitis, bronchitis, and fever. Serious AEs and discontinuations are uncommon. Long-term safety data up to 5 years have revealed no new safety concerns [90]. However, hypersensitivity reactions, including rare anaphylaxis, have been reported; therefore, post-administration monitoring is suggested as a precautionary measure [91].

3.3 Anti-Interleukin-4 Receptor α Therapy: Dupilumab

Dupilumab is a fully human mAb that targets the IL-4Rα, thereby inhibiting signaling mediated by both IL-4 and IL-13, central drivers of T2 inflammation in asthma [92]. By blocking this shared receptor component, dupilumab exerts a broader immunomodulatory effect than agents that target either cytokine individually. This disrupts downstream T2 effector pathways and attenuates airway inflammation at multiple levels in T2-high asthma phenotypes.

Dupilumab is approved for asthma treatment as an add-on maintenance therapy at doses of 200 mg or 300 mg administered subcutaneously every 2 weeks for patients aged ≥6 years with moderate-to-severe asthma characterized by an eosinophilic phenotype or dependence on OCS [92, 93]. Self-administration is permitted.

The efficacy of dupilumab in SA has been demonstrated in multiple phase III clinical trials within the LIBERTY ASTHMA program. In the QUEST trial, dupilumab reduced the annual rate of severe exacerbations by 47% overall and by 67% in patients with baseline BECs of at least 300 cells/μL. Improvements in pre-bronchodilator FEV1 were observed as early as 2 weeks, with mean increases of 140 mL in the overall population and 230 mL in the high-eosinophil subgroup [94]. In the VENTURE trial, dupilumab achieved a median 70% reduction in daily OCS dose, with 52% of patients discontinuing OCSs entirely while maintaining asthma control and experiencing fewer exacerbations [95]. Post hoc and long-term analyses from the QUEST trial and the single-arm, open-label TRAVERSE extension study cohorts demonstrated that FEV1 improvements emerged by week 2 and were sustained for at least 52 weeks, irrespective of recent exacerbation history [96]. This suggests that dupilumab mitigates exacerbation-related lung function decline.

The phase IV VESTIGE trial enrolled patients with T2 asthma and evidence of active IL-13-driven inflammation (BEC ≥300 cells/μL and FeNO ≥25 ppb) [97]. At week 24, dupilumab significantly increased the proportion of patients achieving FeNO <25 ppb and reduced airway inflammation and mucus plugging. The most pronounced improvements in pre- and post-bronchodilator FEV1 and FVC were seen in patients with high baseline mucus plug scores (≥4), indicating that those with a greater mucus burden derived the greatest benefit [98]. Dupilumab also improved small airway function, as reflected by increased forced expiratory flow at 25–75% of forced vital capacity, and reduced airway wall thickness and air trapping [99]. The EVEREST trial was a multicenter, randomized, double-blind, head-to-head phase IV study comparing dupilumab and omalizumab in patients with chronic rhinosinusitis with nasal polyps and coexisting asthma [100]. Dupilumab demonstrated greater reductions in nasal polyp size, symptom scores, and improvements in lung function compared with omalizumab, while both treatments were generally well tolerated over 24 weeks.

Real-world evidence further supports the clinical benefits of dupilumab. In a multicenter cohort with up to 3 years of follow-up, patients who continued dupilumab treatment experienced significant reductions in the frequency of annual exacerbations, improvements in ACT scores, percent increases in predicted FEV1, and meaningful reductions in the dose of OCS [101]. A subset of patients achieved remission based on established criteria. The US ADVANTAGE study reported a 44% lower exacerbation rate and a 28% reduction in systemic corticosteroid prescriptions compared with omalizumab [102]. Comparative effectiveness analyses suggest that dupilumab is associated with a lower risk of exacerbations than mepolizumab or benralizumab, especially in patients with BECs ≥300 cells/μL [103].

Dupilumab has broad effects on T2 biomarker profiles, including rapid reductions in FeNO and progressive decreases in BECs. However, the relationship between biomarker changes and exacerbation reduction is complex. While improvements in lung function correlate with reductions in biomarkers, a reduction in exacerbation risk does not appear to depend strictly on the magnitude of biomarker changes [104].

Dupilumab is generally well tolerated. The most frequently reported AEs include injection-site reactions, transient blood eosinophilia, and nasopharyngitis. There are rare cases of eosinophilic granulomatosis with polyangiitis. Conjunctivitis is more commonly observed in patients treated for atopic dermatitis, but its incidence does not appear to be increased in asthma populations [92]. Systematic reviews of phase III evidence indicate a favorable safety profile in pediatric patients, with no new safety signals observed in children aged 6–11 years with moderate-to-severe T2 asthma [93].

3.4 Anti-Thymic Stromal Lymphopoietin Therapy: Tezepelumab

Tezepelumab is a fully human mAb that selectively blocks TSLP by preventing its interaction with the TSLP receptor complex and the recruitment of IL-7Rα required for downstream signaling [105]. By blocking TSLP upstream, it modulates multiple effector pathways involved in airway inflammation, eosinophil trafficking, and airway remodeling. Tezepelumab is approved as an add-on maintenance treatment for uncontrolled SA in adults and adolescents aged ≥12 years, without biomarker-based eligibility thresholds, which is a distinguishing feature among biologics for SA.

The efficacy of tezepelumab across the spectrum of T2 inflammatory status has been demonstrated within the PATHFINDER clinical development program. In the pivotal RCTs PATHWAY [106] and NAVIGATOR [107], tezepelumab significantly reduced annualized severe exacerbation rates compared with placebo, with consistent benefits observed across baseline biomarker strata. However, a pooled analysis of the PATHWAY and NAVIGATOR trials showed no statistically significant reduction in patients with both BEC <150 cells/μL and FeNO <25 ppb who were not receiving maintenance OCSs [108], suggesting that the apparent efficacy in T2-low populations may be less robust than initially perceived, and could represent a chance finding in specific subgroups. Additional benefits included improvements in pre-bronchodilator FEV1, asthma control measures, and reductions in healthcare resource use [109]. These trials established the approved dosing regimen of 210 mg administered subcutaneously every 4 weeks.

The SOURCE trial evaluated the OCS-sparing efficacy of tezepelumab in adults with OCS-dependent SA, but it did not meet its primary endpoint [110]. No statistically significant difference was observed between tezepelumab and placebo in the proportion of patients achieving greater percentage reductions in daily OCS dose at week 48 without loss of asthma control in the overall population. However, post hoc and subgroup analyses indicated a greater likelihood of OCS dose reduction among patients with baseline BECs ≥150 cells/μL. In contrast, the WAYFINDER multicenter, single-arm, open-label, OCS-sparing study demonstrated that tezepelumab enabled nearly 90% of OCS-dependent patients to reduce their daily corticosteroid dose to ≤5 mg and more than 50% to discontinue OCS entirely over 52 weeks, while maintaining asthma control and demonstrating a favorable safety profile across biomarker and allergy subgroups [111]. Long-term data from the DESTINATION extension study further confirmed the sustained efficacy and stable safety profile of tezepelumab treatment for up to 2 years, including persistent reductions in exacerbation rates among patients previously enrolled in NAVIGATOR or SOURCE, including those with prior OCS dependence [112].

Overall, while tezepelumab demonstrates robust efficacy in many patients with T2-high asthma, the benefit in T2-low populations appears less consistent, highlighting the need for careful patient selection and further real-world evaluation, although real-world evidence supports these findings, demonstrating improvements in asthma control, reductions in exacerbation frequency and OCS use, and gains in lung function and biomarker profiles in both T2-high and T2-low SA populations, including patients transitioning from other biologic therapies [113,114,115].

The safety profile of tezepelumab has remained consistent throughout clinical trials [105]. The most commonly reported AEs are nasopharyngitis, headache, and bronchitis. Serious AEs occur at low rates, comparable to placebo in controlled settings. Recent real-world data, including prolonged treatment durations, have not revealed new or unexpected safety signals [104,105,106].

4 The Interleukin-17/T Helper 17 Axis in Asthma: Biological Rationale and Unsuccessful Clinical Translation

The IL-17 cytokine family has attracted considerable attention in SA owing to its association with neutrophilic inflammation, corticosteroid resistance, and mixed granulocytic phenotypes [116]. The family comprises six cytokines (IL-17A-F), which signal through heterodimeric receptor complexes consisting of five receptor subunits (IL-17RA-RE). Interleukin-17A, the prototypical member of the family, is predominantly produced by Th17 cells, but is also produced by γδ T cells, natural killer cells, and neutrophils. Elevated airway levels of IL-17A, IL-17F, and IL-17E (IL-25) have been reported in the airways of patients with SA [41]. Interleukin-17RA is the most ubiquitously expressed receptor subunit and forms functional complexes with other IL-17 receptors. These complexes include IL-17RA-RC, which mediates signaling of IL-17A, IL-17F, and IL-17AF, and IL-17RA-RB, which binds IL-17E and promotes Th2 immune responses [117].

Despite this strong mechanistic rationale, biologic therapies targeting the Th17/IL-17 axis have yielded largely disappointing clinical results in asthma treatment. Secukinumab, a human IgG1 mAb that neutralizes IL-17A (and IL-17AF with lower affinity), was evaluated in a phase II RCT in adults with uncontrolled moderate-to-severe asthma and BECs <400 cells/µL [118]. The study failed to demonstrate improvement in asthma control, as assessed by the ACQ-6, compared with placebo at 12 weeks.

Brodalumab, a human IgG2 monoclonal antibody that targets IL-17RA and inhibits signaling of multiple IL-17 family ligands, was evaluated in two phase II studies in patients with moderate-to-severe asthma [119, 120]. Neither study demonstrated clinically meaningful improvements in asthma control, and a subsequent phase IIb trial was terminated early following an interim futility analysis.

Upstream modulation of the Th17 axis has also been explored. Risankizumab, an anti-IL-23p19 mAb, was evaluated in a phase IIa trial in patients with uncontrolled SA [121]. The study failed to meet its primary endpoint (time to first asthma worsening) and was associated with a significantly increased risk of asthma worsening compared with placebo, with the median time to first asthma worsening being approximately 50% shorter in the risankizumab group (40 days vs 86 days).

Given the close relationship between IL-6 signaling and Th17 differentiation, tocilizumab, an anti-IL-6 receptor mAb, was investigated in a small proof-of-concept study in mild allergic asthma [122]. Tocilizumab did not attenuate allergen-induced late asthmatic responses or airway inflammatory biomarkers, leading to early termination of the study for futility.

Collectively, although extensive mechanistic data link the IL-17/Th17 pathway to severe and corticosteroid-resistant asthma, clinical studies targeting IL-17A, IL-17RA, IL-23, or IL-6 have not demonstrated a therapeutic benefit to date. These findings suggest that Th17-driven inflammation may act as a disease modifier rather than a dominant targetable driver in unselected asthma populations, underscoring the need for improved patient stratification and biomarker-guided therapeutic approaches.

5 Emerging Biologic Therapies

Despite the availability of multiple biologic therapies for SA, a substantial proportion of patients continue to experience persistent symptoms, frequent exacerbations, and dependence on OCSs, which are associated with morbidity and AEs [123]. This residual disease burden reflects the substantial heterogeneity of SA and the persistence of inflammatory mechanisms that are not adequately targeted by currently approved biologics [124].

Patients with T2-low asthma, which is characterized by neutrophilic or paucigranulocytic airway inflammation and driven by cytokines such as IL-6, IL-17A, and epithelial-derived alarmins including IL-33, demonstrate limited responsiveness to existing biologics [124, 125]. This results in persistent symptoms and exacerbations despite optimized treatment. Even among patients with T2-high asthma, subgroups may exhibit additional proinflammatory activity mediated by non-canonical T2 cytokines (e.g., IL-1β and IL-6), epithelial alarmins, and neutrophil activation, which are not effectively suppressed by current therapies, as demonstrated by proteomic analyses of airway samples from patients receiving anti-IL-5 therapy [124, 125].

These observations highlight several unmet needs in the management of SA, including inadequate disease control in T2-low and mixed granulocytic phenotypes, persistent exacerbations despite the apparent suppression of downstream T2 inflammation, limited effects on airway remodeling, and the absence of robust biomarker-guided strategies to support precision medicine. These needs are summarized in Table 2.

[Figure] — Table 2 Unmet needs and rationale for emerging biologic strategies in severe asthma

While some emerging agents improve pharmacokinetics or dosing convenience for established biologic targets, substantial advances in SA management are more likely to come from therapies that address upstream or complementary inflammatory pathways. Accordingly, there has been an increase in attention on biologics that target epithelial alarmins, such as TSLP and IL-33, either alone or in combination with downstream cytokines (Table 3). These approaches aim to suppress early disease drivers and attenuate the amplification of multiple inflammatory cascades.

[Figure] — Table 3 Emerging biologic therapies for severe asthma

In parallel, the development of multi-specific biologic constructs has gained momentum in response to the need to overcome the therapeutic ceilings associated with single-pathway inhibition. These agents have the potential to address the complex and overlapping inflammatory endotypes characteristic of SA by simultaneously targeting multiple cytokines or signaling axes. Figure 3 summarizes mAbs that have reached clinical evaluation and exhibit potential for treating SA, while Fig. 4 depicts biologic candidates that remain at the preclinical stage but show mechanistic promise.

[Figure] 40265_2026_2310_Fig3_HTML.png — Fig. 3
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[Figure] 40265_2026_2310_Fig4_HTML.png — Fig. 4
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Concurrently, next-generation strategies targeting IgE are being developed to enhance the magnitude and durability of IgE suppression, although the EVEREST trial suggests that targeting IgE alone may be insufficient in more complex T2-low or mixed phenotypes [100]. Unlike first-generation anti-IgE therapies, which primarily neutralize circulating IgE, these novel approaches aim to coordinately inhibit free IgE and IgE-producing B cells (Figs. 3 and 4). This provides more sustained modulation of IgE-driven immune responses. Future trials of next-generation anti-IgE agents, ideally head-to-head against other biologics across different T2 asthma phenotypes, will be needed to clarify whether enhanced IgE inhibition translates into a broader or greater clinical benefit.

5.1 Novel Anti-Immunoglobulin E Agents

In addition to established anti-IgE therapy with omalizumab, next-generation biologics that target IgE have been developed to improve efficacy, durability, and convenience for patients with allergic SA.

5.1.1 Enhanced Immunoglobulin E Neutralizers

Ligelizumab, a high-affinity anti-IgE mAb, binds to IgE more strongly than omalizumab. In a Phase IIb trial for chronic spontaneous urticaria, ligelizumab showed numerically superior efficacy compared with omalizumab for outcomes such as complete hives response at week 12 (51% vs 26% for 72 mg ligelizumab vs omalizumab) [126]. However, in asthma, ligelizumab failed to demonstrate superiority over placebo or omalizumab [127]. This may be because of its weaker inhibition of IgE:FcεRII (CD23) interactions, which could result in incomplete suppression of CD23-mediated inflammatory pathways [128]. The clinical development of ligelizumab has been discontinued, as it did not demonstrate clear superiority over existing therapies [129].

Ozureprubart (formerly RPT904) is a half-life-extended anti-IgE mAb that targets the same epitope as omalizumab. Early clinical studies indicate extended pharmacokinetics and pharmacodynamics compared with omalizumab [130], although no peer-reviewed asthma trial data are currently available.

PRO98498 (HAE1) is a structurally modified anti-IgE mAb with nine amino acid substitutions in the complementarity-determining regions. This results in approximately 23-fold higher affinity for IgE than omalizumab [131]. Preclinical models have demonstrated that it has comparable systemic exposure to omalizumab and suppresses free IgE at lower serum levels [132]. This suggests that it has the potential to be more potent and require less frequent dosing.

LP-003 is a novel humanized anti-IgE mAb designed to block the interaction of IgE with both FcεRI and CD23, thereby preventing effector cell activation and modulating IgE production [133]. In a multicenter, placebo-controlled, phase II RCT of patients with inadequately controlled seasonal allergic rhinitis, LP-003 significantly suppressed free IgE, improved nasal and ocular symptoms, reduced the use of rescue medication, and exhibited a safety profile comparable to placebo [133]. Its high affinity and dual-receptor blockade suggest potential to suppress IgE more effectively than first-generation anti-IgE therapies.

5.1.2 Immunoglobulin E Production Modulators (CD23 Dependent)

UB-221 binds to both free IgE and CD23-occupied IgE, enabling enhanced CD23-mediated downregulation of IgE production [134]. Preclinical studies have shown that UB-221 is more effective than ligelizumab and omalizumab at downregulating IgE production via CD23, and more effective than omalizumab at neutralizing IgE. In a first-in-human trial for chronic spontaneous urticaria, a single dose produced rapid reductions in free IgE and long-lasting symptom relief [134]. However, no asthma-specific phase II/III data are currently available.

5.1.3 Immunoglobulin E-B-Cell-Targeting Therapies

Quilizumab targets the M1-prime segment of membrane IgE, thereby depleting IgE-switched and memory B cells [135]. In adults with inadequately controlled allergic asthma despite taking high-dose ICSs and a second controller, quilizumab reduced serum IgE by 30–40% [136]. However, it did not significantly reduce asthma exacerbation rates, improve lung function, or alleviate patient-reported symptoms compared to placebo [136].

5.1.4 Fc-Active Immunomodulatory Anti-Immunoglobulin E Biologics

Xmab7195 is an Fc-engineered anti-IgE mAb that binds to free IgE and suppresses its production by B cells. It is optimized to co-engage the inhibitory FcγRIIb receptor on IgE+ B cells, which inhibits their activation and differentiation into IgE-secreting plasma cells. The effects of Xmab7195 are mediated through IgE sequestration and FcγRIIb-dependent suppression of IgE production rather than direct modulation of CD23-IgE interactions [133]. In preclinical models, Xmab7195 reduced total human IgE by up to 40-fold compared with omalizumab, without affecting other immunoglobulin isotypes [137]. Clinical safety and efficacy data in humans are pending.

YH35324, a long-acting IgETrap-Fc fusion protein, consists of the extracellular domain of FcεRIα fused to an Fc region that binds to free IgE, preventing interaction with FcεRI on mast cells and basophils and inhibiting allergic responses [138]. Studies have shown that YH35324 suppresses FcεRIα expression on these cells more effectively than omalizumab does; significant reductions have been observed for up to 14 days after administration. YH35324 mechanistically binds to IgE-unbound FcεRIα, inducing internalization and recycling via actin-dependent endocytosis and FcRn binding in the lysosome [139]. This provides a novel mode of action beyond IgE sequestration. A first-in-human, randomized, double-blind, placebo- and omalizumab-controlled phase I study evaluated YH35324 in healthy subjects and atopic adults with mild allergic rhinitis, atopic dermatitis, food allergy, or urticaria with serum total IgE levels of 30–700 IU/mL (Part A) or >700 IU/mL (Part B) [140]. YH35324 demonstrated dose-proportional pharmacokinetics, rapid and sustained suppression of free IgE, and a favorable safety profile in atopic subjects without serious AEs or anaphylaxis. Its efficacy lasted longer than that of omalizumab. Further clinical studies are needed to establish its efficacy and safety in patients with allergic diseases.

5.2 Next-Generation Anti-Interleukin-5-Based Therapies

Next-generation anti-IL-5-based therapies are being developed to address unmet needs in SA, especially those beyond the traditional eosinophilic phenotypes. In this context, depemokimab has recently received regulatory approval for use in SA, representing the first example of a long-acting IL-5-targeting strategy designed to improve treatment durability and dosing convenience. In parallel, additional biologics with broader immunomodulatory profiles are in clinical development, aiming to extend therapeutic benefits to more complex and treatment-resistant asthma phenotypes. Although these approaches are conceptually promising, their ultimate clinical impact remains to be fully established.

CSL311 is a human mAb that targets the common beta subunit (βc, CD131), which is shared by the receptors for IL-5, IL-3, and granulocyte-macrophage colony-stimulating factor [141]. By blocking the cytokine-binding site of βc, CSL311 simultaneously inhibits signaling mediated by all three cytokines. This results in the coordinated suppression of eosinophilic and neutrophilic inflammatory pathways. These cytokines collectively drive the survival, activation, and recruitment of eosinophils, neutrophils, and interstitial macrophages within the airways, thereby contributing to persistent airway inflammation [141].

CSL311 is particularly promising for treating asthma phenotypes characterized by mixed granulocytic inflammation because these phenotypes are often corticosteroid-resistant and associated with airway remodeling and fibrotic changes. Preclinical and ex vivo studies have shown that CSL311 mitigates airway inflammation and fibrosis, as well as improves lung function in models of chronic allergen exposure and acute corticosteroid-resistant asthma [142]. CSL311 normalizes extracellular matrix (ECM)-related gene expression and reverses fibrosis-associated transcriptional signatures, suggesting potential benefit in SA with established airway remodeling.

Preclinical and early translational studies indicate that CSL311 has a favorable safety profile, with no major safety concerns identified to date. Importantly, CSL311 does not appear to compromise antiviral immunity, as it preserves type I, II, and III interferon responses and natural killer cell expansion, and does not increase susceptibility to infection in animal models [143]. However, comprehensive human safety data are still lacking, and further clinical trials are needed to fully define its safety and efficacy in patients with asthma.

5.3 Novel Dual Antagonists for Interleukin-4 and Interleukin-13

Nanobodies, or single-domain antibodies, are small antibody fragments derived from camelids or produced through recombinant engineering. They represent an emerging class of inhalable biologics for asthma therapy [144]. Their small size, high stability, and favorable tissue penetration make them particularly suited for pulmonary delivery.

5.3.1 Nanobody-Based Inhalable Dual Interleukin-4/Interleukin-13 Antagonists

LQ036 is a bivalent nanobody construct comprising two HuNb103 units. It potently and selectively inhibits IL-4Rα signaling and is specifically designed for inhalation [145]. Preclinical studies using humanized mouse models revealed that inhaled LQ036 markedly suppressed T2 airway inflammation. This is evidenced by reductions in serum ovalbumin-specific IgE, CCL17 in bronchoalveolar lavage fluid, and bronchial goblet cell hyperplasia. In addition, LQ036 inhibited TF-1 cell proliferation and signal transducer and activator of transcription 6 phosphorylation in T cells derived from asthmatic patients, confirming the effective blockade of both the IL-4 and IL-13 pathways. Structural analyses revealed an overlapping binding epitope with dupilumab, but with a higher affinity that translates into more efficient inhibition of downstream signaling. Notably, inhaled administration of LQ036 achieved high concentrations in pulmonary and bronchial tissues with favorable pharmacokinetics, minimal systemic exposure, and an acceptable safety profile.

5.3.2 Bifunctional Cytokine-Neutralizing Constructs

In parallel, dual IL-4/IL-13 antagonists based on bifunctional scaffolds, such as single-chain variable fragment constructs, have been developed to directly neutralize both cytokines in their soluble forms, thereby preventing receptor engagement [146]. These agents reduce airway hyperresponsiveness, mucin gene expression, and inflammatory cytokine release. They have systemic half-lives of several days. However, compared with inhaled nanobody platforms, their pharmacokinetic profiles are characterized by broader systemic distribution and lower lung selectivity. Nevertheless, bifunctional cytokine neutralization is still of interest for complex T2 endotypes and mixed inflammatory phenotypes that may respond suboptimally to receptor-directed therapies.

5.3.3 Bispecific Nanobodies Targeting Upstream and Downstream Type 2 Pathways

Bispecific antibodies further expand multi-target approaches by inhibiting multiple cytokines involved in asthma pathogenesis simultaneously. Lunsekimig, a bispecific nanobody that targets TSLP and IL-13, was evaluated in a phase Ib RCT involving 36 participants with mild-to-moderate asthma and elevated FeNO ≥25 ppb [147]. A single subcutaneous dose of 400 mg was well tolerated, with no serious treatment-emergent AEs. Treatment resulted in a significant reduction in FeNO from day 8 to day 29 (mean change −40.9 ppb; 90% confidence interval −55.43 to −26.39; p < 0.0001 vs placebo) and decreased circulating T2 biomarkers. Participants with a baseline impairment showed numerical improvements in lung function, particularly in small airway indices. These results suggest that a dual TSLP/IL-13 blockade may suppress T2 inflammation more robustly than single-cytokine inhibition, potentially overcoming therapeutic efficacy ceilings.

5.3.4 Trispecific and Extended Multi-Target Biologics

PF-07264660 is a trispecific mAb designed to simultaneously inhibit IL-4, IL-13, and IL-33. This represents an advanced multi-targeted strategy for broadly targeting T2 inflammatory pathways [148]. Safety and translational studies are ongoing, but clinical efficacy in asthma has yet to be established.

5.3.5 Combined Thymic Stromal Lymphopoietin and Interleukin-4 Receptor α Blockade

Additional bispecific approaches include a novel antibody that targets both TSLP and IL-4Rα, thereby inhibiting signaling mediated by TSLP, IL-4, and IL-13. In preclinical models, this agent suppressed T-cell proliferation and CCL17 release, and in a TSLP/ovalbumin-induced asthma model using humanized transgenic mice, it attenuated all major allergic and inflammatory features [149]. In contrast, single-target antibodies produced only partial effects, which supports the hypothesis that simultaneously blocking upstream epithelial cytokines and downstream T2 effector pathways may provide broader disease control.

5.3.6 Interleukin-13-Targeted Monotherapies and Receptor-Directed Strategies

Beyond dual receptor-directed strategies, several anti-IL-13 mAbs and IL-13 pathway inhibitors have been investigated in T2-high asthma phenotypes [150]. Cendakimab (RPC4046), a humanized IgG1 mAb, neutralizes IL-13 by preventing its interaction with both IL-13Rα1 and IL-13Rα2. This results in the potent suppression of IL-13-dependent gene transcription in preclinical asthma models, as well as favorable safety and pharmacokinetics in first-in-human studies involving healthy subjects and asthmatic patients [151]. These findings support continued evaluation of cendakimab in allergic inflammatory conditions, including eosinophilic esophagitis and potentially asthma. CNTO 5825 similarly inhibits IL-13 binding to IL-13Rα1 and IL-13Rα2 and has shown acceptable safety, linear pharmacokinetics, and pharmacodynamic evidence of target engagement, including reductions in serum IgE and T2 biomarkers [152]. However, definitive efficacy data in asthma remain limited. Abrezekimab (VR942/CDP7766) is a humanized, high-affinity anti-IL-13 mAb fragment formulated for inhalation. It has demonstrated acceptable safety and tolerability, as well as pharmacodynamic activity in phase I asthma studies, supporting the feasibility of a localized pulmonary IL-13 blockade [153]. Finally, eblasakimab (ASLAN004), which targets the IL-13Rα1 subunit of the type II receptor complex, has shown the ability to inhibit signal transducer and activator of transcription 6 phosphorylation in early human studies [154] and reduce T2 biomarkers such as total IgE and TARC in atopic dermatitis [155]. Emerging translational evidence supports further investigation of eblasakimab in airway inflammatory diseases driven by IL-13 and IL-4 signaling.

5.4 Novel Anti-Alarmin Monoclonal Antibodies

The clinical validation of alarmin blockade in asthma has stimulated the development of next-generation anti-alarmin mAbs. These mAbs aim to enhance efficacy, durability, and tissue-specific targeting beyond first-generation agents.

5.4.1 Emerging Anti-Thymic Stromal Lymphopoietin/Thymic Stromal Lymphopoietin-Targeting Candidates

Inhaled anti-TSLP antibody fragments, such as ecleralimab (CSJ117), have demonstrated potent attenuation of allergen-induced bronchoconstriction and airway inflammation in adults with mild atopic asthma. In a double-blind, placebo-controlled phase IIa RCT, once-daily inhaled ecleralimab (4 mg) reduced the late asthmatic response by 64% and allergen-induced sputum eosinophils by 64% and 52%, respectively, at 7 and 24 hours post-allergen challenge [156]. The treatment had a favorable safety profile with no significant systemic AE. These results suggest that the inhaled delivery of anti-TSLP biologics can achieve local efficacy while minimizing systemic exposure [157].

A broad pipeline of next-generation anti-TSLP agents employing diverse strategies to enhance potency, durability, and tissue targeting is under investigation [158]. Nanobody-based inhaled constructs, such as LQ043, demonstrate high-affinity TSLP-TSLP receptor (TSLPR) inhibition, favorable pharmacokinetics, and reassuring safety profiles in animal models and phase I human studies [159]. Biparatopic nanobodies, such as CRNB909, block both TSLPR (site I) and IL-7Rα (site II). This yields a binding affinity for human TSLP that is approximately 40-fold higher and 9.2-fold greater inhibition of TSLP-mediated JAK-STAT signaling than tezepelumab [160]. Monospecific mAbs, such as solrikitug, selectively inhibit TSLP binding to IL-7Rα and demonstrate ten-fold higher in vitro potency than tezepelumab, likely owing to epitope-specific effects on downstream signaling [161]. Other inhaled strategies include dry-powder Fab formulations, such as AZD8630 (AMG104), which reduced FeNO in patients with moderate-to-severe asthma while maintaining low systemic exposure in phase I–II studies [162, 163].

Anti-TSLP and anti-TSLPR mAbs administered systemically are also progressing through early-phase development. Verekitug (UPB-101, ASP7266), a human anti-TSLPR antibody, demonstrated near-complete receptor occupancy and reductions in blood eosinophils (up to 65%) and FeNO (up to 54%), and a favorable safety profile, with a mean half-life of ~20 days [164, 165]. Half-life-engineered mAbs, such as TAVO101 [166, 167] and CM326 [168, 1590], exhibit prolonged pharmacokinetics, linear exposure, low immunogenicity, and flexible dosing intervals. This supports potential extended administration schedules. Other investigational anti-TSLP mAbs, including bosakitug and GB-0895, are mentioned in the emerging pipeline, though detailed preclinical or clinical data are unavailable [170]. Dual-targeted constructs, such as the bispecific nanobody lunsekimig (SAR443765), inhibit both TSLP and IL-13, significantly reducing FeNO by 40.9 ppb from baseline at day 29 after a single subcutaneous dose in patients with mild-to-moderate asthma and demonstrating good tolerability [147]. These developments collectively underscore the rapidly evolving anti-TSLP therapeutic landscape and its potential applicability across T2-high and T2-low asthma phenotypes.

5.4.2 Targeting the Interleukin-33/Suppression of Tumorigenicity 2 Axis

Interleukin-33, an epithelial-derived alarmin, is released in response to airway injury caused by allergens, pollutants, and respiratory infections and activates immune responses by binding to its receptor suppression of tumorigenicity 2 (ST2), also known as IL-1 receptor-like 1 (IL1RL1), which is expressed on a broad range of innate and adaptive immune cells, including ILC2s, Th2 lymphocytes, mast cells, basophils, and eosinophils [171]. Activation of the IL-33/ST2 axis promotes the release of T2 cytokines (IL-5, IL-13), contributing to airway eosinophilia, mucus hypersecretion, bronchial hyperresponsiveness, and asthma exacerbations [172]. It also contributes to non-T2 responses, airway remodeling, and heightened susceptibility to exacerbations [173]. Therapeutic strategies targeting this pathway include ligand neutralization (anti-IL-33 mAbs) and receptor blockade (anti-ST2 mAbs).

5.4.2.1 Anti-Interleukin-33 Monoclonal Antibodies

Several anti-IL-33 mAbs are in clinical development for moderate-to-severe asthma. Itepekimab reduced loss-of-control events, improved lung function, and decreased BECs in adults receiving medium-to-high dose ICSs plus a long-acting beta-agonist in a phase II RCT [174]. Efficacy was observed in both high- and low-eosinophil subgroups, with greater improvements experienced by patients with higher baseline BECs. Combination therapy with dupilumab did not demonstrate an additive benefit.

Etokimab (ANB020) showed proof-of-concept efficacy in a phase IIa study of severe eosinophilic asthma, with a single intravenous dose rapidly improving lung function, reducing BECs, and enhancing asthma control [175]. However, no phase II or III studies have been published, and development in asthma remains limited to early-phase trials.

Tozorakimab (MEDI3506) is a next-generation anti-IL-33 mAb with a dual mechanism of action. It binds to both reduced and oxidized forms of IL-33, thereby inhibiting IL-33 signaling via ST2 and the receptor for advanced glycation end products**/**epidermal growth factor receptor complex [176]. This attenuates inflammation and promotes epithelial repair. Preclinical and phase I studies have demonstrated a potent blockade of IL-33-driven inflammatory responses and reductions in serum IL-5 and IL-13, as well as epithelial repair, in vitro and in murine models [176]. However, in the phase IIa FRONTIER-3 study of adults with early-onset moderate-to-severe asthma (diagnosed before age 25 years), tozorakimab did not meet its primary endpoint of change in pre-bronchodilator FEV1 from baseline at week 16 [177]. Nevertheless, patients with a history of two or more exacerbations in the previous year showed numerical improvements in FEV1, reduced use of rescue medication, and significant reductions in T2 inflammatory biomarkers, including FeNO and BECs, supporting effective engagement of the IL-33 pathway.

5.4.2.2 Anti-Suppression of Tumorigenicity 2 Monoclonal Antibodies

Anti-ST2 mAbs represent a distinct approach by targeting the IL-33 receptor (ST2), thereby inhibiting the downstream signaling initiated by IL-33. Astegolimab, a fully human IgG2 antibody, binds to ST2 with high affinity, thereby preventing IL-33 receptor activation. In a phase IIb RCT, astegolimab significantly reduced annualized asthma exacerbation rates in adults with SA, including those with low BECs (T2-low asthma) [178]. The reduction in exacerbations was dose dependent, with the highest dose (490 mg subcutaneously every 4 weeks) yielding an overall 43% reduction, and a 54% reduction in the eosinophil-low (<300 cells/mL) subgroup. Astegolimab did not improve lung function (FEV1), but its safety profile was comparable to placebo, with no increase in infections or major cardiac events. Current clinical development in asthma appears limited, with the focus having shifted toward chronic obstructive pulmonary disorder.

Melrilimab is another anti-ST2 mAb in early development. Preclinical studies demonstrate suppression of ILC2 activation and airway inflammation. However, clinical efficacy in asthma remains unproven, with no significant improvements in asthma control or biomarkers reported to date [179, 180].

5.4.3 Anti-Interleukin-25 Therapy

Interleukin-25 is increasingly regarded as an epithelial-derived alarmin, although its classification remains debated because of differences in release mechanisms compared with classical alarmins such as IL-33 and TSLP [181]. Unlike these alarmins, IL-25 can be produced constitutively or in response to specific immune stimuli, and its release is not associated with acute cell death or necrosis [182]. Nevertheless, IL-25 plays a key pathogenic role in asthma through activation of the IL-25/IL-17RB axis, which is a major driver of T2 inflammation and airway remodeling [183]. Interleukin-25 is predominantly produced by airway epithelial cells in response to allergens and environmental triggers. It promotes Th2 cytokine production (IL-4, IL-5, IL-13), eosinophilic inflammation, airway hyperresponsiveness, and structural remodeling.

Preclinical data support the concept that IL-25 contributes to airway inflammation and that its neutralization attenuates hallmark features of allergic airway disease in animal models [184, 185]. Accordingly, mAbs targeting IL-25 or its receptor IL-17RB are under early investigation for allergic and T2-mediated diseases. Available data suggest that IL-25 blockade can safely modulate T2 immune responses, which supports further exploration in allergic and eosinophilic disorders. However, no anti-IL-25 agents advanced to phase II clinical trials for asthma treatment.

XKH001, a humanized anti-IL-25 mAb, is currently in phase II development for atopic dermatitis. It has demonstrated favorable safety and pharmacokinetics in single- and multiple-ascending-dose studies in healthy volunteers, with a half-life of 22–25 days and no detectable anti-drug antibodies [186]. Pharmacodynamic activity was observed, with a marked reduction in total IgE levels at the 600-mg dose compared with placebo.

SM17, a humanized IgG4 mAb targeting IL-17RB, effectively inhibited IL-25 signaling in preclinical models. It reduced eosinophilic airway inflammation, T2 cytokine secretion, and collagen deposition in a house dust mite-induced asthma model [187]. In a phase I study of healthy volunteers, SM17 was generally well tolerated, with a half-life of 10.5–15 days, and was associated primarily with mild headache as the most common AE [188].

5.5 Immune Checkpoint Modulators for Severe Asthma

Immune checkpoint pathways play a role in the immunopathogenesis of asthma by regulating Th cell polarization, tissue-resident memory T-cell persistence, and regulatory T-cell function [189]. Dysregulation of these pathways, through excessive co-stimulatory signaling or impaired inhibitory signaling**,** leads to chronic airway inflammation and loss of immune homeostasis in asthma [189].

Several co-stimulatory receptors, including OX40 (CD134), inducible T-cell co-stimulator (ICOS), and TNF superfamily members such as CD30, are upregulated on activated CD4⁺ T cells, including Th2 and Th17 subsets [190,191,192]. The engagement of OX40/OX40 ligand (OX40L) and ICOS/ICOS ligand pathways promotes Th2 polarization, enhances the production of key T2 cytokines (IL-4, IL-5, and IL-13), and supports the survival and persistence of TRMs in the lung, processes that are implicated in asthma exacerbations and disease chronicity [190, 191]. Inducible T-cell co-stimulator signaling also plays a critical role in generating and maintaining the suppressive function of Tregs, which are essential for respiratory tolerance [193]. Engagement of CD30 by CD30L on antigen-presenting cells further amplifies Th2 and Th17 responses, partly through downregulation of IL-2 production. This process promotes TRM persistence and sustains allergic inflammation and contributes to asthma exacerbations [194, 195]. Conversely, immune checkpoint inhibitory receptors such as programmed cell death-1 (pd-l1) and its ligands (pd-l1/pd-l2) modulate Th2 and Th17 responses. A pd-l1 enhances Th17-mediated inflammation, while the effects on Th2 responses appear to be context dependent [196].

Although several mAbs targeting immune checkpoint pathways have entered development for allergic and T2-mediated diseases, clinical experience in asthma remains limited. Preclinical studies indicate that inhibiting OX40/OX40L signaling reduces airway eosinophilia, mucus hypersecretion, and Th2 cytokine production, while limiting the accumulation and activity of lung tissue TRMs, which are associated with asthma exacerbations and chronicity [191, 197, 198]. Inhibition of OX40 signaling has also been shown to suppress IgE class switching by attenuating IL-4-driven B-cell responses [191]. An anti-OX40L mAb was evaluated in a phase II trial involving 28 adults with mild atopic asthma undergoing an allergen challenge [199]. Despite demonstrating clear pharmacologic activity, including reductions in serum IgE (17%) and sputum eosinophils (75%) after 16 weeks, the treatment did not attenuate early- or late-phase asthmatic responses. More recently, biologics targeting the OX40/OX40L pathway, including the anti-OX40 antibodies (rocatinlimab and GBR830) and the anti-OX40L antibody amlitelimab, have demonstrated efficacy in suppressing pathogenic T-cell responses in atopic dermatitis [200, 201]. However, they have not advanced to late-phase trials or received regulatory approval for asthma treatment

Targeting the ICOS/ICOS ligand pathway has also shown promise in preclinical models of established allergic asthma. Disruption of T follicular helper cell responses and IgE-driven immune memory led to the amelioration of airway inflammation [190]. Furthermore, pd-l1 agonism has demonstrated therapeutic potential in preclinical studies by suppressing ILC2 activity and reducing airway hyperresponsiveness [202]. Analyses of single-cell RNA sequencing of lung CD4⁺ T cells from asthmatic patients have identified ICOS, OX40, and CD30L expression in TRM, supporting their role in disease persistence [198]. Preclinical data further suggest that the combined inhibition of ICOS ligand with OX40L or CD30L can limit TRM accumulation and induce hyporesponsiveness to allergen re-exposure. However, these approaches have not yet been evaluated in clinical trials for asthma.

5.6 Anti-Transforming Growth Factor-β and Anti-Remodeling Biologics

Transforming growth factor-β (TGF-β) is a key mediator of airway remodeling in asthma. It drives fibroblast proliferation, ECM deposition, goblet cell hyperplasia, and smooth muscle hypertrophy through Smad signaling pathways [203]. Elevated TGF-β levels correlate with key structural abnormalities in SA, including subepithelial fibrosis, reticular basement membrane thickening, and persistent airflow limitation [204].

Eosinophils substantially contribute to airway remodeling by inducing collagen and fibronectin synthesis and stimulating ASM proliferation via TGF-β1, with resident-like eosinophils exhibiting pronounced profibrotic activity [205, 206]. Consistent with this mechanism, anti-IL-5 biologics reduce eosinophilic infiltration and are associated with decreases in basement membrane thickness, smooth muscle mass, proliferating cells, and profibrotic markers such as tenascin-C and fibulin-1 [66]. In contrast, tezepelumab reduces eosinophilic inflammation and airway hyperresponsiveness without significantly affecting established airway remodeling, suggesting predominantly anti-inflammatory rather than antifibrotic activity [207].

Theoretically, directly targeting TGF-β is an attractive strategy because it addresses the central profibrotic mediator and may uncouple structural remodeling from inflammation. In preclinical models, pan-TGF-β neutralizing antibodies have been shown to reduce peribronchiolar collagen deposition, ASM proliferation, and mucus production, even when administered after eosinophilic inflammation is established [203]. In a murine model of asthma, isoform-specific neutralizing antibodies against TGF-β1 and TGF-β inhibited the ovoalbumin-induced subepithelial collagen deposition by ~60–70% compared with control antibodies. Both also reduced allergen-induced eosinophil and lymphocyte increases, while TGF-β1 inhibition uniquely reduced macrophage influx [208]. Fresolimumab (GC1008), a pan-TGF-β1/2/3 neutralizing mAb, has been developed for fibrotic diseases and cancer but has not been tested in asthma [209].

Thus far, no anti-TGF-β mAb has progressed to clinical trials for asthma, largely because of safety concerns related to systemic TGF-β inhibition. Broad inhibition of multiple TGF-β isoforms, especially a dual TGF-β2/3 blockade, can lead to severe toxicities, including cardiac valvulopathies, hemorrhage, and anemia in animal models. However, selective inhibition of individual isoforms or dual TGF-β1/2 inhibition appears to be better tolerated [210]. Furthermore, blocking TGF-β1 can paradoxically worsen airway hyperresponsiveness despite reducing fibrosis, reflecting the complex immunoregulatory role of TGF-β1 in suppressing allergen-induced bronchoconstriction in experimental asthma [211].

Considering these challenges, researchers are exploring downstream profibrotic mediators as alternative therapeutic targets. Connective tissue growth factor (CTGF/CCN2) amplifies the fibroblast-to-myofibroblast transition and the ECM production. Airway smooth muscle cells from patients with asthma exhibit heightened CTGF responses to TGF-β stimulation compared with cells from non-asthmatic individuals [212]. Pamrevlumab (FG-3019), an anti-CTGF mAb, has shown efficacy in idiopathic pulmonary fibrosis [213] and reduced airway remodeling in preclinical asthma models [214]. Lysyl oxidase-like 2 (LOXL2), which is upregulated in asthmatic ASM and bronchial tissue, promotes ECM cross-linking, tissue stiffness, and secondary activation of TGF-β signaling [215]. In experimental asthma models, LOXL2 inhibition reduced collagen deposition and ASM thickening [216]. Although the anti-LOXL2 antibody simtuzumab failed clinically [217], LOXL2 remains a potential therapeutic target, particularly considering emerging evidence implicating nuclear LOXL2 in fibroblast-to-myofibroblast differentiation [218].

6 Conclusions

Despite the availability of seven mAbs currently approved for the treatment of SA by targeting IgE, IL-5, IL-5Rα, IL-4Rα, and TSLP, approximately 21–29% of patients treated with biologics remain uncontrolled, and only 19% achieve clinical remission after 12 months of therapy [219]. This residual disease burden reflects the marked biological heterogeneity of SA, the presence of overlapping inflammatory endotypes, and the persistence of upstream epithelial and non-T2 immune pathways that existing biologic therapies only partially address [35]. Moreover, emerging evidence suggests that neuroinflammation may contribute to asthma pathophysiology. Systemic and central nervous system effects of airway inflammation, including activation of neural pathways, can alter neural activity and impact mood and cognition [220]. Airway inflammation, particularly involving eosinophils and Th cell subsets such as Th17, appears capable of triggering neuro-inflammatory signaling [219]. However, current studies have not included intervention arms with biologic therapies, leaving it unclear whether modulation of these pathways could mitigate neuroinflammation or improve neurocognitive outcomes [221].

The latest American College of Chest Physicians clinical practice guideline suggests either omalizumab or dupilumab for adult patients with moderate-to-severe allergic asthma and a history of one or more exacerbation per year requiring OCSs [222]. However, for patients with frequent exacerbations (two or more per year) or any severe exacerbation requiring hospitalization, the guideline suggests dupilumab over omalizumab, for those with more severe impairments in quality of life, (and fewer than two exacerbations per year), omalizumab over dupilumab and for patients with a greater impairment in lung function (FEV <70% predicted), dupilumab over omalizumab. In adult patients with SA who are corticosteroid dependent, the panel suggests either anti-IL5/5Rα therapy or dupilumab, and dupilumab over tezepelumab. In those who have not demonstrated a clinical response to omalizumab after 4–6 months, the suggestion is to use either anti-IL5/5Rα therapy or dupilumab, and in the case of no clinical response to anti-IL5/5Rα therapy after 4–6 months, to use either dupilumab or tezepelumab, utilizing post-treatment FeNO ≥25 ppb for advising changes in therapy to dupilumab and preferring dupilumab over tezepelumab for patients who are corticosteroid dependent. In adult patients with SA who have not demonstrated a clinical response to dupilumab after 4–6 months, the guideline suggests either anti-IL5/5Rα or tezepelumab, preferring anti-IL5/5Rα over tezepelumab for those who are corticosteroid dependent.

Nevertheless, as highlighted in Table 2, important unmet needs persist across multiple asthma phenotypes. Patients with T2-low or mixed granulocytic inflammation, in particular, benefit little from currently approved agents that predominantly target eosinophilic or canonical T2 pathways. [118]. Similarly, exacerbations that persist in patients with seemingly well-controlled T2-high disease highlight the role of epithelial alarmins, redundant cytokine networks, and immune memory mechanisms that perpetuate airway inflammation despite the blockade of downstream effectors [223].

In this context, emerging biologic strategies are shifting toward inhibiting upstream pathways, engaging multiple targets, and modulating immune networks more effectively. Novel approaches targeting alarmins such as TSLP and IL-33, either alone or with downstream cytokines, aim to suppress inflammatory cascades more broadly across both T2-high and T2-low endotypes [224]. Similarly, next-generation anti-IgE agents and Fc-engineered constructs aim to enhance the depth and durability of IgE suppression by neutralizing circulating IgE and modulating IgE-producing B-cell responses simultaneously [217]. Biologics directed against shared receptor subunits, such as the βc subunit common to IL-3, IL-5, and granulocyte-macrophage colony-stimulating factor receptors, are a promising strategy for concurrently attenuating eosinophilic and neutrophilic inflammation. This approach addresses phenotypes characterized by corticosteroid resistance and airway remodeling [141].

Beyond efficacy, several of these emerging therapies introduce conceptual and practical advances, including inhaled delivery platforms, nanobody-based constructs, extended half-life engineering, and bispecific or trispecific designs [124]. Depemokimab (extended half-life anti-IL-5) [79], lunsekimig (anti-IL-13/TSLP bispecific) [147], and PF-07264660 (anti-IL-4/IL-13/IL-33 trispecific) [148] are good examples of these advances. These innovations have the potential to improve lung selectivity, reduce systemic exposure, and overcome the therapeutic ceilings observed with single-cytokine inhibition. Nevertheless, their ultimate clinical value will depend on a robust demonstration of safety, long-term disease modification, and meaningful improvement in patient-centered outcomes [35, 124].

Collectively, the evolving biologic landscape in SA reflects a transition from phenotype-driven treatment to a more nuanced, endotype- and pathway-oriented paradigm. Future progress will depend on refined biomarker-guided patient stratification, integration of multi-omics approaches, and strategic deployment of multi-target biologics to match the complex immunopathology of SA [1, 225]. These advances are crucial for moving beyond merely controlling symptoms and achieving durable disease modification in this heterogeneous and burdensome condition.

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Open access funding provided by Università degli Studi di Roma Tor Vergata within the CRUI-CARE Agreement. No funding was received for the preparation of this article. Open access funding was provided by Università degli Studi di Roma Tor Vergata within the CRUI-CARE Agreement.

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Unit of Respiratory Medicine, Department of Experimental Medicine, University of Rome ‘Tor Vergata’, Via Montpellier, 1, 00133, Rome, Italy

Mario Cazzola, Josuel Ora & Paola Rogliani

Unit of Pharmacology, Department of Experimental Medicine, University of Campania ‘Luigi Vanvitelli’, Naples, Italy

Maria Gabriella Matera

Unit of Respiratory Clinical Pharmacology, Department of Clinical Science and Translational Medicine, University of Rome ‘Tor Vergata’, Rome, Italy

Luigino Calzetta

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Cazzola, M., Matera, M.G., Ora, J. et al. Current and Emerging Biologic Therapies for Severe Asthma. Drugs 86, 813–840 (2026). https://doi.org/10.1007/s40265-026-02310-4

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Article 4 — Developments in Pharmacotherapy for Acromegaly: Current and Emerging Approaches

DOI: 10.1007/s40265-026-02312-2
Section: Review Article
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Article URL: https://link.springer.com/article/10.1007/s40265-026-02312-2
PDF URL: https://link.springer.com/article/10.1007/s40265-026-02312-2.pdf
Authors: Tritos, Nicholas A.

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Abstract

Pituitary surgery is the primary therapy for most patients with acromegaly. Medical therapy has an important, albeit adjunctive role in the management of patients with persistent disease after surgery. However, primary medical therapy can be appropriate as an option in select patients. Medical therapies in current use for acromegaly are somatostatin receptor ligands (SRLs) (octreotide long-acting release [LAR], octreotide acetate, lanreotide depot, octreotide subcutaneous (SC) depot, pasireotide LAR, oral octreotide, paltusotine), dopamine agonists (cabergoline) and growth hormone receptor antagonists (pegvisomant). These are often efficacious and generally well tolerated. However, a particular pharmaceutical agent may not meet the needs of individual patients because of intolerance, contraindications to their use, lack of sustained efficacy, or decreased quality of life. Several investigational drugs are in development towards addressing unmet needs of patients with acromegaly, including new formulations of SRLs (lanreotide prolonged-release formulation, Debio 4126, pasireotide SC depot), novel SRLs (somatoprim, HTL0030310), monoclonal antibodies against growth hormone, and new growth hormone receptor antagonists. Current and emerging therapies are offering renewed hope for disease control. More studies including comparator agents, identification of accurate biomarkers and models predictive of clinical effectiveness may further improve the care of patients with acromegaly.

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Real-world burden of disease, treatment, and healthcare resource utilization in acromegaly: a quantitative survey of patient experiences

Article Open access 05 December 2025

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Acromegaly

Article 21 March 2019

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Pituitary Tumor Behavior and Disease Severity in Patients with Acromegaly

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Neuroendocrine Unit and Neuroendocrine and Pituitary Tumor Clinical Center, Massachusetts General Hospital, 100 Blossom Street, Cox 140, Boston, MA, 02114, USA

Nicholas A. Tritos & Beverly M. K. Biller

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Nicholas A. Tritos & Beverly M. K. Biller

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NAT has no conflicts of interest to disclose. BMKB has been the PI of grant support to Mass General Hospital from Alexion, Crinetics and DebioPharm; and has received occasional consulting honoraria from Alexion, Camurus, Crinetics, and Recordati.

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Tritos, N.A., Biller, B.M.K. Developments in Pharmacotherapy for Acromegaly: Current and Emerging Approaches. Drugs 86, 841–850 (2026). https://doi.org/10.1007/s40265-026-02312-2

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Article 5 — Advances in Immune-Based Approaches for the Cure of HIV Infection

DOI: 10.1007/s40265-026-02311-3
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Abstract

Despite significant advances in antiretroviral therapy, the need for a cure for HIV persists because of factors such as long-term antiretroviral therapy-related comorbidities, disease stigma, and inequities in access to care. Most cure efforts focus on inducing durable HIV remission (antiretroviral therapy-free viral control) either by augmenting immune function or reducing the HIV reservoir. In this review, we highlight immune-based cure interventions currently under investigation with a particular focus on those that have demonstrated the ability to induce durable HIV remission after analytic treatment interruption, here termed “post-intervention control”. While current cure interventions are generally complex, expensive, and not easily scalable, they provide critical “proof of principle” that a cure for HIV is possible. Continuing to make studies of HIV cure a funding priority is important, we believe, as continued optimization of cure interventions should eventually lead to a cure that is simple, safe, effective, affordable, and scalable. In addition, we highlight critical features in clinical trial design and pharmacokinetics/pharmacodynamics that should be considered prior to clinical trial implementation.

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Abstract

The potential impact of a “curative intervention” for HIV: a modelling study

Article Open access 12 June 2019

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Pediatric HIV: the Potential of Immune Therapeutics to Achieve Viral Remission and Functional Cure

Article 01 May 2020

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HIV Cure: How Far We Have Come?

Article 13 August 2024

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AIDS
Antibody therapy
Gene Therapy
Immunotherapy
Targeted Gene Repair
HIV infections
Immunological Responses in HIV Infection

FormalPara Key Points

Despite significant advances in antiretroviral therapy and HIV treatment, the need for a simple, safe, effective, affordable, and scalable cure persists.
Most HIV cure approaches target immune activation and reservoir reduction to achieve durable remission, which can be interrogated using an analytic treatment interruption.
Clinical trial design and pharmacokinetic/pharmacodynamic factors must be carefully considered to maximize what can be learned from HIV cure clinical trials.

1 Introduction

What began with the identification of people who could suppress HIV without antiretroviral therapy (ART, “elite controllers”) and the description of the first eradicative cure (Timothy Ray Brown, the “Berlin Patient”) has led to a robust clinical trials agenda focused on inducing durable HIV remission (ART-free viral control) [1,2,3]. Here, we review therapeutic approaches currently under investigation as components of potential HIV cure strategies. We focus on those that have demonstrated the potential to induce durable ART-free viral control after an analytic treatment interruption (ATI). See Table 1 of the Electronic Supplementary Material for an overview of select published trials highlighted in this review. We also discuss clinical trial design optimization for future cure studies.

1.1 What Might a Cure for HIV Look Like?

There has been extensive debate as to what an HIV cure or remission strategy must achieve, and these goals are actively evolving with the optimization of standard-of-care HIV treatment. Although early ART regimens had complex dosing schedules and unfavorable side-effect profiles, modern ART has excellent efficacy and tolerability for most individuals. People with HIV (PWH) whose virus is suppressed by ART are unable to transmit the virus via sexual contact (“Undetectable = Untransmittable”) [4]. Until recently, most modern ART regimens required daily dosing of oral medications but even this is changing: long-acting formulations of injectable ART that can be administered as infrequently as every-other-month are now available [5] and regimens requiring even less frequent dosing are on the horizon [6]. In many ways, the continued optimization of ART is blurring the line between treatment and cure.

Still, the need for a cure persists. While much safer and better-tolerated than before, PWH on long-term ART continue to experience increased rates of co-morbidities such as kidney disease, osteoporosis, and cardiac disease [7]. A cure for HIV could also limit the number of new infections (estimated at 1.3 million people in 2023) and decrease stigma [8]. Too many individuals are unable to access ART — in the most recent UNAIDS assessment, 9.3 of the nearly 40 million PWH worldwide (including 120,000 children) were not on effective ART; this rate is even higher in key populations like children, female sex workers, people who inject drugs, and transgender women, particularly in Sub-Saharan Africa [9]. Finally, for many PWH on ART, continued access is not guaranteed as demonstrated by the severe disruptions caused by the coronavirus disease 2019 pandemic and the dismantling of crucial programs such as PEPFAR and USAID, which were responsible for delivering ART to tens of millions of people worldwide. A widely available cure for HIV would likely improve the health of PWH, avoid the uncertainty related to ongoing ART access, and could play a key role in ending the HIV epidemic.

Currently, no cure strategy is as safe and effective as ART. This was acknowledged in a multi-stakeholder target product profile initiative, which argued that it is not necessary for first-generation remission strategies to compete with or attempt to replace ART [10]. Instead, it was suggested that a cure should be a reasonable option for those who are unable or unwilling to achieve sustained viral suppression with current regimens. The ultimate goal is to develop an intervention that is simple, safe, effective, affordable, and scalable. This long-term need does not preclude investments in more complex cure regimens, as once proof-of-concept is achieved, optimization will follow. Such an approach should, we argue, guide how we invest funds in HIV cure research.

2 Immunotherapeutic Approaches for HIV Cure

Multiple strategies could play a role in a cure for HIV (Fig. 1) with most functioning to promote reservoir reduction or host-mediated immune control. In the absence of complete viral eradication, both will likely be needed (“reduce and control”). We discuss the potential of these strategies to achieve “post-intervention control” (PIC) of HIV, which we define as the ability of a PWH, following an experimental intervention beyond standard-of-care ART, to maintain a plasma HIV viral load “set point” (i.e., average viral load over a sustained period of time) that is low or unquantifiable. How low the “set point” needs to be for an intervention to be considered impactful has yet to be defined, but at the very least it needs to be below the level at which HIV is transmissible (200–1000 copies/mL) [11]. Post-intervention control has been observed in several clinical trials, though in a minority of trial participants [12]. Nevertheless, these studies provide “proof-of-concept” that we can alter the natural history of post-ART viral replication. A single therapy is unlikely to achieve long-term control of HIV; combination approaches will most likely be needed. A comprehensive review of recent combination immunotherapy trials designed for an HIV cure has been published by our group [12].

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2.1 Reservoir-Targeting Therapies

The HIV reservoir is the primary barrier to cure [13]. There are two goals for any reservoir-targeted cure strategy: eliminate all virus or reduce the reservoir size to facilitate sustained immune control. Complete viral eradication may one day be possible in allogeneic stem cell transplantation, but for now is aspirational.

2.1.1 Early ART and Latency Prevention

HIV post-exposure prophylaxis prevents reservoir establishment, and with the improvement in diagnostics and the advent of widely available ART in the 2000s, there was hope that early HIV treatment might as well. This was not the case, as even individuals treated during acute or hyperacute infection exhibited viral rebound following ART interruption [14, 15]. The only examples of early ART leading to a cure are in studies of maternal-to-child HIV transmission [16, 17].

2.1.2 Allogeneic Stem Cell Transplantation

The only eradicative cures of people with established infection have been in allogeneic stem cell transplant recipients, ten of whom have now had undetectable viral loads off ART for at least 7 months, most for over 2 years [2, 18,19,20,21,22,23,24,25,26]. While most transplants involved CCR5-deficient stem cells, eradicative cure has also been seen in recipients of wild-type cells. While this provides inspiring proof-of-concept for a cure, such a strategy is not safe or scalable, and furthermore, not all stem cell transplants in PWH are curative [27].

2.1.3 Reservoir Reduction Strategies

Various factors, including the tissues in which HIV-infected cells reside, reservoir cell resilience, virus transcriptional activity, and location of viral integration sites are barriers to reservoir eradication that will need to be overcome [28]. HIV latency reversal is a key part of reservoir reduction strategies, as reactivation of the dormant virus renders it susceptible to immune-based clearing. Latency reversal agents include histone deacetylase inhibitors, Toll-like receptor (TLR) agonists (TLR-7/9), and second mitochondria-derived activator of caspases mimetics; while these agents reactivate HIV in vivo or ex vivo, their impacts on the viral reservoir in clinical trials have been limited [29, 30]. Novel approaches to reservoir reduction are also emerging. Integrated HIV proviruses can be specifically targeted with messenger RNA-lipid nanoparticle-based delivery of the transcription-promoting HIV Tat [31]. Interestingly, CD8+ T-cell depletion has been shown to enhance latency reversal in non-human primates (NHPs) through incompletely understood mechanisms [32]. An alternate approach to reducing the rebound competent reservoir is via silencing with latency-promoting agents [33].

Reservoir cells can also be directly targeted for immune based clearing. For example, dual affinity re-targeting proteins bind gp120 (part of the HIV envelope glycoprotein [Env]) and CD3 promoting killing of HIV-infected cells [34, 35]. Bispecific T-cell receptors in early clinical investigation redirect T cells towards cells expressing HIV Gag presented on HLA molecules [36]. A study of combination dual affinity re-targeting/latency reversal agents in NHPs with SHIV on ART did not show a change in the viral reservoir, possibly owing to low latency reversal [37].

2.2 Broadly Neutralizing Antibodies (bNAbs) and Post-ART Control

Broadly neutralizing antibodies (bNAbs) are monoclonal antibodies (mAbs) that target exposed Env epitopes and confer potent cross-clade viral neutralization [38]. Initially isolated from PWH, bNAbs are being developed for prevention, treatment, and cure [39]. Given Env’s variability and plasticity, bNAb escape is a major limitation so bNAbs are generally administered in combinations of two or three with complementary specificities [40].

Like all mAbs, bNAbs comprise a variable (Fab) and constant (Fc) region. The variable region confers antibody specificity while the constant region permits interaction with Fc receptor-expressing cells [41]. While the first generation of bNAbs tended to have a short half-life, Fc modification allows them to be engineered to persist for long durations (months or longer) in the blood. LS modification (introduction of Met428Leu and Asn434Ser), for instance, enhances binding affinity for the neonatal Fc receptor and can extend in vivo half-life by 2.7- to 4.1-fold [42].

2.2.1 Mechanisms of Viral Control

There are at least three mechanisms through which bNAbs may contribute to HIV cure/remission: reservoir reduction, immune complex formation, and blunting of viral rebound (Fig. 2).

[Figure] 40265_2026_2311_Fig2_HTML.png — Fig. 2
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2.2.1.1 Reservoir Reduction

Antibodies have functions beyond neutralization. Antibody-dependent cellular cytotoxicity and phagocytosis responses can target both neutralizing and non-neutralizing epitopes and promote cell death. Somes studies suggest that antibody-mediated responses may shape the reservoir over decades of ART, [43, 44] but whether bNAb administration contributes to reservoir reduction is unclear. In five studies of bNAb administration in PWH who underwent an ATI, three reported no significant change in the viral reservoir, [45,46,47] one reported a small reduction in the intact proviral reservoir, [48] and one reported a possible acceleration of intact reservoir decay time [49]. It is likely that Env expression under ART-mediated viral suppression is too low for bNAbs to clear the reservoir. Combinations of bNAbs and latency reversal agents have shown promise in NHP models [50, 51].

2.2.1.2 Immune Complex Formation

Another mechanism by which bNAbs may promote HIV control is by potentiating endogenous HIV-specific immune responses, a phenomenon known as the “vaccinal effect” [52]. In the contexts of cancer and infection with non-HIV viral pathogens, mAbs have been shown to induce immunologic (T- and B-cell-mediated) protection long after infused antibody levels wane [53,54,55,56,57,58]. Mechanisms underlying the vaccinal effect, at least in the context of cancer, involve Fc/FcR-based interactions between antigen:antibody immune complexes and immune cells like dendritic cells and macrophages that internalize immune complexes and present antigens to prime new or pre-existing T- and B-cell responses [56]. Fc modification strategies that promote binding to particular FcRs are areas of active investigation in HIV and beyond [57,58,59,60,61,62]. Some population-based studies have demonstrated a role for Fc/FcR interactions in clinical outcomes following HIV infection, [63,64,65] but evidence supporting a role for the vaccinal effect in PIC of HIV is more limited.

2.2.1.3 Blunted Rebound

Broadly neutralizing antibodies effectively suppress the virus and can delay, or blunt, rebound from latently infected cells. Most simplistically, slowing the typically exponential viral rebound may allow the immune system to “keep up” rather than becoming overwhelmed. Supporting this hypothesis, in a recent study of ART interruption in both elite controllers and non-controllers, elite controllers demonstrated both a delay in viral rebound and slower rates of viral increase compared with non-controllers [66].

2.2.2 Clinical Studies of Post-Intervention Control

2.2.2.1 Non-human Primates

Perhaps the most robust evidence supporting a role for the vaccinal effect in immune control of HIV comes from NHP studies, where bNAb administration shortly after SHIV infection was shown to lead to high rates (>50%) of post-intervention control [67]. This control was CD8+ T-cell mediated as depletion of these cells resulted in rapid viral rebound [67]. The NHP model has also demonstrated that the timing of antibody administration is critically important, as bNAb administration during suppressive ART results in much lower rates of SHIV control after ART is stopped, [50] suggesting that bNAbs need to be administered when at least some amount of virus is present.

2.2.2.2 Clinical Trials in PWH

In five recent trials of bNAb administration that involved an ATI (0906, 180115, T003, 0965, and RIO), participants received multiple infusions of two or three bNAbs over several weeks to months [45,46,47,48, 68, 69]. 0906, 180115, 0965, and RIO used the bNAbs 3BNC117 and 10-1074, which recognize the CD4 binding site and the V3 glycan site of Env, respectively [70, 71]. T003 utilized the bNAbs PGT121, VRC07-523LS, and PGDM1400, which recognize the V3 glycan site, CD4 binding side, and V2-apex of Env [72, 73]. Participants generally underwent an ATI around the first bNAb infusion. Viral suppression was typically maintained provided bNAb levels remained therapeutic, though some breakthrough viremia on bNAb therapy occurred. Often, these individuals had baseline viral reservoirs that demonstrated reduced susceptibility to one or more administered bNAbs (0906, T003), [45, 47] though bNAb susceptibility analyses could not uniformly predict the time to rebound (0965) [48]. Indeed, the extent to which clinical assays to assess baseline sensitivity to bNAbs should inform clinical trial eligibility or therapeutic decisions is debated [74]. Incorporating such testing into clinical trial workflows presents practical challenges including assay availability, turnaround time, cost, and the potential need for repeat testing because of viral evolution. Identifying unique binding features that make bNAbs resistant to common escape mutants is an area of active investigation [75]. Even when two or three bNAbs were combined, at least partial bNAb resistance tended to emerge in a rebounding virus (180115, T003) [46, 47]. In 4/5 studies, PIC (viral suppression maintained for weeks after bNAb levels waned), occurred at rates of 10–40% of participants (0906, T003, 0965, RIO) [45, 47, 48, 69]. Notably, in the one clinical trial that compared outcomes of bNAb infusion on or off ART, PIC was only seen in the off ART group, supporting the hypothesis that bNAbs may need to be administered when at least some virus is present (0965) [48]. Results from Arm B of RIO were presented at CROI 2026, wherein participants who had received placebo followed by an ATI and resumed ART were offered dual bNAb therapy followed by a second ATI; viral rebound was delayed in 13/25 participants [76].

It is worth noting that post-infusion antiviral effects have been observed even among individuals whose autologous virus demonstrated a lack of neutralization by bNAbs in vitro, suggesting that bNAbs may exert additional immune-modulating or Fc-mediated functions. In the clinical trials above with immune correlates, two observed no change in autologous HIV-specific CD4+ or CD8+ T-cell responses after bNAb therapy (T003), [47] or in markers of CD8+ T-cell activation (180115) [46]. One observed a transient early increase in the magnitude of Gag-specific CD8+ T-cell responses, though this was not clearly related to viral control (0906) [68]. In RIO, participants who demonstrated long-term viral control had an increase in the magnitude and in vitro proliferative responses of Gag-specific CD8+ T cells after bNAb administration at the time of ATI [77]. As an alternate method of interrogating immune activation, two studies looked at changes in plasma inflammatory cytokine levels during viral suppression by bNAbs after an ATI. One saw no change in levels of cytokines, chemokines, or markers of immune activation (180115) [46]. Another observed increases in plasma proteins associated with cellular metabolism, but less so inflammation, specifically in post-intervention controllers (T003) [47]. Thus, the precise role of bNAbs in PIC remains unclear; they may need to be administered in combination with other immune modulators to induce endogenous immune responses.

2.3 Therapeutic Vaccines

Therapeutic vaccines aim to stimulate pre-existing or generate new HIV-specific immune responses. This section will focus primarily on T-cell vaccines, which have been better studied with regard to post-intervention control, with a brief overview of B-cell vaccines at the end.

2.3.1 T-Cell Vaccines

CD8+ T cells are thought to play a central role in spontaneous control of HIV, [78,79,80,81] so creating a vaccine that elicits optimal T-cell responses, particularly cytotoxic T cells capable of killing HIV-infected cells, will likely be important for PIC [82]. Drawing on what has been observed in spontaneous HIV control, the ideal features of a vaccine-elicited CD8+ T-cell response have recently been reviewed [83]. CD8+ T-cell recognition of mutationally constrained epitopes by cross-reactive T-cell receptors, localization near viral reservoirs, polyfunctionality, and proliferative capacity may all contribute to T-cell-mediated HIV control. Studies investigating the immunogenicity of T-cell-based HIV vaccines were recently reviewed by our group and others [84,85,86]. Here, we focus on vaccine design considerations and outcomes of T-cell therapeutic vaccine trials that included an ATI.

2.3.1.1 Design Considerations

Epitope Targeting

T-cell epitope specificity is important for viral control as HIV control is associated with T-cell responses against Gag and Pol (and possibly Vif), but not Env or Nef [87, 88]. Several different approaches to epitope targeting have been employed [84, 86]. For example, the HIVACAT T-cell immunogen (HTI) was designed to elicit T-cell responses found in individuals with lower viral loads; it contains sequences that cover over 100 optimal T-cell epitopes and has been tested in therapeutic vaccines for PWH [89,90,91,92]. Importantly, the studies underlying the HTI design involved large numbers of people with diverse HLA types and so it does not appear to be biased towards specific HLA alleles. An alternate approach targets highly conserved regions of the HIV proteome, such as the larger HIVConsVx or smaller conserved element immunogens. HIVConsVx [93] includes highly conserved regions of Gag and Pol and has recently been tested in a first-in-human, phase I clinical trial in people without HIV where it demonstrated the ability to elicit broad T-cell responses [94]. The conserved element immunogens, which contain sequences from relatively small conserved Gag elements, have been shown to elicit T-cell responses to conserved element epitopes in NHP with SHIV [95] as well as in people with HIV alone [96] or in combination with other immunotherapies [97]. Another approach is to target “networked” amino acid residues [98]. This approach identifies residues of greatest topologic importance, which correlates with mutational tolerance and functional importance. A clinical trial evaluating a networked epitope vaccine in people with and without HIV (NCT06617091) is underway. Other important considerations in the design of therapeutic vaccines include platform delivery, adjuvants, and dosing strategy; a comprehensive discussion of these topics can be found elsewhere [99,100,101,102].

2.3.1.2 Clinical Studies of Post-Intervention Control

Non-Human Primates

Two platforms have demonstrated promise in terms of PIC of SIV/SHIV. Studies of RhCMV/SIV vaccination (an SIV protein-expressing rhesus cytomegalovirus vaccine) followed by SIV infection in macaques reliably results in ~50% rates of long-term SIV control [103]. This vaccine elicits robust, long-lived, SIV-specific CD4+ and CD8+ T-cell responses. Interestingly, while the magnitude of the SIV-specific CD8+ T-cell response post-vaccination is associated with long-term control, viral rebound does not occur in the setting of CD8+ or CD4+ depletion. Further studies have revealed that, unexpectedly, CD8+ T-cell responses to SIV in this model tend to be restricted by the conserved and ubiquitously expressed MHC-E, which raises the intriguing possibility of generating a more universal CD8+ T-cell response unrestricted by an individual’s HLA type [104]. Separately, an messenger RNA/SIVgag vaccine administered to macaques with SIV on ART followed by an ATI induced Gag-specific CD8+ T-cell responses in multiple tissues and lengthened the time to viral rebound [105].

Clinical Trials in PWH

The first vaccine study to show a significant vaccine effect on post-ART viral dynamics was the AELIX-002 study, a phase I randomized, double-blinded, placebo-controlled trial in which participants who had initiated ART during early HIV infection received DNA then modified vaccinia virus (MVA) vaccines, with or without subsequent chimpanzee adenovirus and MVA vector vaccines (all using the HTI immunogen) [92]. The vaccines were safe and well tolerated. Vaccination resulted in a significant increase in the magnitude and breadth of HIV-specific T-cell responses. While all participants rebounded after ART interruption, post-hoc survival analyses of participants without a protective HLA allele revealed a trend towards a longer time off ART in individuals who had received the therapeutic vaccination compared with placebo. Time off ART also correlated significantly with the magnitude of the HTI-specific T-cell response at the start of the ATI.

2.3.2 B-Cell Vaccines

Most B-cell vaccines have attempted to elicit bNAbs in order to protect against HIV acquisition, with limited success to date [106]. A successful bNAb-eliciting vaccine would have to overcome significant challenges, such as being able to generate long-lived plasma cells for durable antibody responses and being able to reproduce the large number of rare B-cell receptor mutational events involved in natural bNAb evolution [106]. Broadly neutralizing antibodies have unusual characteristics such as a long heavy chain complementarity determining region 3 and demonstrate extensive somatic hypermutation, traits that make them hard to generate in people, [106] and indeed bNAbs emerge rarely and only after years of HIV infection. A recent phase I clinical trial involving messenger RNA-encoded nanoparticles administered in a prime-boost format has shown some promise at eliciting increased antibody somatic hypermutation, antigen affinity, and HIV neutralization capacity [107].

2.3.3 Combination Vaccines

Vaccines that induce both CD8+ T- and B-cell responses may be needed. In combination, antibodies could neutralize HIV protecting cells from infection, while T cells could eliminate cells infected with HIV that escaped bNAb neutralization [108]. The neutralizing antibody titer required for effective protection may indeed be lower if a cellular immune response is also induced [109]. One Ad26/MVA vaccine, containing a mosaic sequence insert designed to increase coverage of circulating HIV strains and to elicit both CD8+ T-cell and antibody responses [110, 111] was studied in PWH started on ART during acute infection. The vaccine did not significantly impact viral rebound kinetics after the ATI [112]. However, it did temporarily increase autologous antibody levels at the time of peak post-vaccine immunity and higher antibody-dependent cellular phagocytosis responses were associated with a longer time to viral rebound [113]. While it may be desirable to have a single vaccine regimen elicit T- and B-cell responses, it is possible that separate vaccines with distinct immunogens, delivery systems, adjuvants, and/or delivery schedules will be required to optimally induce these distinct HIV-specific responses [114].

2.4 Checkpoint Inhibitors

The discovery that blocking immune inhibitory checkpoint proteins can promote immune activation has revolutionized the field of cancer therapy and checkpoint inhibitors are now approved for the treatment of many different types of cancer [115]. HIV infection is associated with T-cell exhaustion that can persist even on suppressive ART [116,117,118]. The ability of checkpoint inhibitors to promote HIV control by augmenting immune responses or by acting on infected cells to reverse latency is an area of active investigation [119].

2.4.1 Immune Cell Activation

Chronic HIV infection is associated with upregulation of checkpoint proteins such as programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte antigen 4 on HIV-specific CD4+ and CD8+ T cells [120, 121]. Expression of these molecules is associated with increased viral load and decreased T-cell function (proliferation and cytokine production), which can be at least partially restored by checkpoint blockade [120,121,122,123]. An important question is which subsets of immune cells, in particular, are activated by checkpoint blockade. Newer studies in cancer have demonstrated that checkpoint blockade can expand effector-like CD8+ T cells that retain markers of exhaustion but some effector function [124] as well as memory-precursor-like CD8+ T cells with higher functional potential [125]. Engagement of the Fc region of checkpoint inhibitors by Fc receptor-expressing immune cells can also deplete immunosuppressive cellular populations such as exhausted immune effectors and myeloid-derived suppressor cells [61]. Understanding how best to optimize immune activation will help refine immunotherapeutic approaches.

2.4.2 HIV Latency Reversal

Checkpoint proteins such as PD-1, LAG-3, and TIGIT are enriched on CD4+ T cells infected with HIV [126, 127]. Checkpoint inhibitors, particularly when used in combination with other T-cell-activating stimuli, have demonstrated the ability to reverse latency in vitro [128, 129]. Their in vivo impact on the reservoir from some recent clinical trials is detailed below.

2.4.3 Clinical Studies of Post-Intervention Control

2.4.3.1 Non-Human Primates

Programmed cell death protein 1 blockade after an ATI can enhance SIV control and functional responses of SIV-specific CD8+ T cells [130]. Programmed cell death protein 1 blockade has also been studied in combination with other immunotherapies in chronically SIV-infected macaques on ART. In a study of DNA/MVA vaccination with or without PD-1 blockade, PD-1 blockade enhanced CD8+ T-cell magnitude, function, breadth, and B-cell follicle homing following an ATI, resulting in improved control of the rebounding virus [131]. In another study, PD-1 blockade combined with a TLR7 agonist resulted in increased CD8+ T-cell activation shortly (24 hours) after treatment, though the durability of these responses was not reported and this was not observed for PD-1 blockade alone [132]. Upon ART interruption, all animals rebounded and anti-PD-1/TLR7 agonist administration did not significantly impact viral rebound kinetics. Finally, a study combining PD-1 and interleukin (IL)-10 did observe an impact on viral rebound kinetics post-ATI, although the relative contribution of the two drugs is unclear as the study did not include an arm with anti-PD-1 treatment alone [133]. While viral load cut-offs were overall quite permissive, combination treatment resulted in a significantly lower area under the curve out to 24 weeks post-ATI compared with in controls. A subset of animals also displayed enhanced SIV-specific lymph node CD4+ and CD8+ T-cell responses at 24 weeks post-ATI.

2.4.3.2 Clinical Trials in PWH

Until recently, clinical trial data of immune checkpoint blockade in PWH have been limited [119]. Some small studies have hinted at an effect on in vivo latency reversal, though this has not been consistently observed [134,135,136]. Transient enhancement of CD8+ T-cell responses have also been observed in some PWH receiving checkpoint blockade for other indications [137, 138]. In a recent clinical trial of 30 PWH on ART receiving anti-PD-1 therapy (pembrolizumab) for cancer treatment, 64% of participants followed to the end of therapy demonstrated a decrease in the HIV reservoir, which seemed to be at least in part due to sustained expression of interferon-stimulated genes [139]. A randomized trial of the PD-1 inhibitor budigalimab versus placebo in PWH that included an ATI was also recently published [140]. Programmed cell death protein-1 blockade was associated with a delayed viral rebound and/or long-term control in a subset of participants, though there was no clear association between budigalimab and enhanced CD8+ T-cell responses. Results from a separate trial of budigalimab with or without trosunilimab (an anti-integrin antibody) in PWH on ART who underwent an ATI were presented at CROI 2026 [141]. Combination therapy resulted in post-intervention control in 24% of participants, though 89% of participants experienced at least one adverse event, including four serious adverse events.

2.5 Immune Modulators that Activate the Immune Response

Interleukin-15 is an inflammatory cytokine that plays a central role in CD8+ T-cell and natural killer (NK) cell activation. There has been considerable interest in studying how best to use IL-15 (or IL-15 agonists like N-803) to enhance innate and adaptive anti-HIV immune responses. Interleukin-15 may lower viral setpoints, as demonstrated in a study where SIV-infected rhesus macaques were administered an IL-15 agonist or placebo throughout suppressive ART: IL-15 led to markedly lower viral setpoints following an ATI [142]. N-803 has been shown to redirect SIV-specific CD8+ T cells to lymph node B-cell follicles, a primary site of the latent viral reservoir, resulting in a reduction in cell-associated SIV DNA and RNA [143]. In humans, a phase I dose escalation trial demonstrated that N-803 transiently enhances T-cell and NK cell proliferation and activation [144]. In another trial, N-803 administration during suppressive ART resulted in the expansion of cytotoxic CD8+ T cells and NK cells in peripheral blood and lymph nodes [145]. Early results from a trial of N-803 with or without dual bNAbs (10-1074-LS and VRC07-523LS) that included an ATI (ACTG A5386) have recently been reported [146]. Post-intervention control was observed in 4/19 participants in the N-803 + bNAbs group who underwent an ATI; a transient decrease in intact HIV DNA was also seen. Given the more transient effects of IL-15 on CD8+ T-cell and NK cell activation, optimization of dosing strategy and timing will be important.

Toll-like receptors are innate immune receptors that recognize conserved microorganism-associated molecules. Toll-like receptor agonists, particularly TLR7 and TLR9, are being investigated in several different capacities in HIV cure studies, such as latency reversal, as vaccine adjuvants, and to augment the function of other immunomodulatory agents [147]. In a study of the TLR7 agonist vesatolimod versus placebo in viremic controllers on ART followed by an ATI, vesatolimod was associated with increased immune activation, decreased proviral DNA, and a delay in viral rebound [148]. Toll-like receptor agonism is a promising strategy for HIV cure, but the optimal method to use and combine TLR agonists with other therapies remains to be determined.

2.6 Combination Immunotherapy Regimens

2.6.1 bNAbs in Combination

Several trials have investigated the use of bNAbs combined with other immunomodulating therapies such as type I interferons (BEAT2), [149] TLR agonists (TITAN, FRESH cohort study), [150, 151] and latency reversal agents (eCLEAR) [152, 153]. These studies showed rates of PIC on the order of 17–33%. The added benefit of these combinatorial approaches is still not clear; for instance in the TITAN study, 4/6 participants who achieved PIC received only bNAb therapy; only 1/6 received both bNAbs and the TLR9 agonist. Two of the studies (TITAN and BEAT2) observed no impact of immune interventions on HIV-specific T-cell responses. The eCLEAR study noted a possible increase in the magnitude of Gag-specific CD8+ T-cell responses 90 days after ART initiation [152]. With regard to the reservoir, the BEAT2 study did not observe a change in reservoir size, while eCLEAR suggested that bNAbs may accelerate HIV RNA decay. The FRESH study is highly important in that it represents the first HIV cure trial with an ATI conducted in Africa; studies of the HIV reservoir and immune correlates are still underway [151].

2.6.2 Therapeutic Vaccines in Combination

Two notable studies of combination therapy involving vaccines are the AELIX-003 study, which combined an HTI vaccine regimen with a TLR7 agonist, [91] and the UCSF-amfAR combination study, which combined a therapeutic vaccine (Gag conserved element DNA vaccine with an IL-12 adjuvant and MVA62 [Gag, Pol, Env] boost) with a TLR9 agonist and two bNAbs over a 34-week period [97]. The AELIX-003 study observed PIC rates of 33% in the intervention arm and 24% in the placebo arm. The vaccine was immunogenic, however, and the magnitude of HTI-specific T cells at the start of an ATI was associated with viral control in the vaccinated group. The UCSF-amfAR study observed a higher rate of PIC than any reported immune-based interventional study in HIV to date. Seven of ten participants demonstrated durable viral control: one did not rebound at all over the entire study duration and six achieved viral load setpoints sustained around 1000 copies/mL for several months after bNAbs waned. No change in the viral reservoir measurements were observed, although they were low at baseline in most participants. Immunologic studies have demonstrated that post-intervention control was associated with robust proliferation of CD8+ T cells that expressed higher levels of the stem cell memory-promoting transcription factor TCF-1 that has been shown to be important in immune control of several viral infections [118, 154]. These studies are highly promising and reinforce that combination studies that can stimulate multiple immune responses are most likely to achieve sustained HIV remission.

3 Gene and Cell Therapy Approaches

Increasingly, resources in the HIV cure space are shifting toward cell and gene therapy [155]. This is because of (1) the realization that a single-shot strategy may be needed if a cure is to have a transformative public health impact, and (2) the capacity to genetically modify cells in a safe and scalable manner is advancing rapidly in other areas of medicine, providing a clear roadmap for affordable and scalable in vivo gene editing and delivery.

3.1 Cell and Gene Therapy Approaches to Reducing the Reservoir

3.1.1 Provirus Editing

One approach is to directly edit proviral DNA in vivo using CRISPR/Cas9 technology. This was studied in vivo in NHPs where an adenoviral vector was used to deliver a CRISPR/Cas9 editing treatment targeting SIV DNA (EBT-001) [156]. Animals were on suppressive ART throughout the study. The vector and, importantly, genetic excision were detectable not only in blood but also in major tissue sites of the HIV reservoir. No ATI was performed, but EBT-001 at the highest doses was associated with higher absolute lymphocyte counts, which the authors interpreted as a potential sign of lymphocyte recovery. A first in human phase I/IIa clinical trial of EBT-101 administered to PWH on ART (NCT05144386) is currently underway. Preliminary data have shown that EBT-101 is safe and well tolerated but did not prevent viral rebound in the small number of participants who underwent an ATI [155, 157]. Ongoing studies are investigating the combination of CRISPR/Cas9 machinery and transcriptional activators to reverse latency, as well as novel mechanisms of CRISPR/Cas9 delivery such as lipid nanoparticles [31, 155, 158].

3.1.2 CCR5 Disruption

Given its role as a coreceptor for HIV, CCR5 disruption can make host cells resistant to HIV infection, which could decrease the viral reservoir. Over a decade ago, a clinical trial was performed in PWH on ART that involved infusion of autologous CD4+ T cells that had undergone zinc finger modification of the CCR5 locus, followed by an ATI. During the ATI, unmodified CD4+ T-cell numbers decreased to a significantly greater extent than CCR5-modified CD4+ T-cell numbers, demonstrating in vivo resistance to HIV infection [159]. More recent studies have sought to specifically infuse CCR5-deficient memory CD4+ T cells with cyclophosphamide conditioning to promote engraftment. Results from the TRAILBLAZER study were presented at CROI 2025, however, and no differences in the HIV reservoir were observed [160]. Such an approach has been considered a safer, more scalable alternative to CCR5-deficient stem cell transplantation, but significant optimization is still needed.

3.2 Cell and Gene Therapy Approaches to Controlling the Virus

3.2.1 Vectored bNAbs

One potential approach to generate bNAbs in vivo is via recombinant gene transfer. Broadly neutralizing antibody gene delivery with an adeno-associated vector results in successful in vivo antibody production and protection against HIV/SHIV challenge in humanized mice and NHPs [161,162,163,164,165]. Such an approach has also been studied in PWH in phase I clinical trials [166, 167]. In one trial, participants received an adeno-associated vector 8 gene transfer vector encoding the genetic sequence for the bNAb VRC07. All individuals produced detectable levels of VRC-07 in the serum, some for as long as 3 years, and neutralizing activity of the in vivo antibody was estimated to be similar to that of VRC-07 produced in vitro [166]. In the other trial, a recombinant adeno-associated vector 1 vector encoding the gene for the bNAb PG9 was utilized. Serum PG9 was unable to be detected by an enzyme-linked immunosorbent assay, which was attributed at least in part to the development of anti-drug antibodies (ADAs) [167]. Indeed, in both NHP and human studies, ADAs have represented a major impediment to vectored bNAb persistence; how to decrease ADA production is an area of active investigation. Interestingly, a recent study in NHPs showed that in utero exposure to vectored bNAbs can suppress ADA production, likely owing to neonatal and fetal immunological tolerance [165]. Another study showed that the immunoglobulin subtype can influence ADA development, with immunoglobulin G2-isotype bNAbs being less immunogenic than immunoglobulin G1 [168].

3.2.2 Chimeric Antigen Receptor-T Cells (CAR-T)

While chimeric antigen receptor-T cells (CAR-T) therapy has come into its own in the context of cancer and now autoimmunity, [169] the first clinical studies of CAR-T-targeted HIV. These early CAR-T were designed to express CD4 (with the goal of targeting Env on infected cells) fused to the intracellular CD3z signaling domain [170, 171]. While these studies proved that CAR-T therapy was safe and feasible, they demonstrated only modest anti-viral efficacy and no significant impact on viral loads in vivo, likely in part owing to limited sensitivity and efficacy of first-generation CAR-T designs. Significant progress in the realm of CAR-T design and function has since been made, sparking renewed interest in CAR-T and other engineered T-cell approaches for an HIV cure. We have recently reviewed how features of the robust HIV-specific CD8+ T cells from elite controllers might be harnessed in engineered T-cell therapies for HIV [172].

3.2.2.1 Design Considerations

Avoiding Infection

More recent CAR-T designs for HIV employ single-chain variable fragments (scFvs) derived from bNAbs to target Env on infected cells, circumventing the need for CD4 expression [173]. These cells can still be infected by HIV, so many newer CAR constructs also disrupt CCR5 [174, 175]. Chimeric antigen receptor-T cells using bNAb-derived scFVs fused to second-generation intracellular signaling domains demonstrate robust HIV killing in vivo, which is magnified by CCR5 disruption [173].

Epitope Targeting

While attractive in that they are HLA independent, several challenges exist in terms of CAR-T epitope targeting [176]. Chimeric antigen receptor-T cells use bNAb-derived scFVs targeting Env, the only HIV protein thought to be expressed on the surface of infected cells. However, Env expression is very low on suppressive ART and CAR-T require higher antigen density for activation than conventional T cells [177]. Potential solutions under investigation are to combine CAR-T with latency reversal agents to boost HIV antigen expression or using CARs designed to sense very low antigen levels (including HLA-independent T-cell receptors) [178]. A second challenge is the mutability of Env; while bNAbs recognize highly conserved regions of Env, these may not always be visible from a conformational standpoint to CAR-T. Targeting more visible but less conserved regions offers less broad targeting and could permit escape. A newer innovation has been designing CAR-T with “duoCARs” targeting multiple non-overlapping Env regions [179].

Tissue Trafficking

The HIV reservoir persists in diverse tissues including immune-privileged areas such as secondary lymphoid follicles [180, 181]. One approach that has been tested in NHPs is infusion of anti-CD20 CAR-T that disrupt B- cell follicles [182]. While such an approach transiently ablated B-cell follicles and lead to a modest reduction in the splenic viral reservoir, the overall reservoir was unchanged. Furthermore, preemptive immunosuppression was required to prevent cytokine release syndrome, limiting feasibility. A different technique to direct conventional Env-targeting CAR-T to B-cell follicles is by genetically inducing lymphoid tissue-homing CXCR5 expression [183]. In a NHP study where SIV-infected macaques on ART were administered CXCR5-expressing CAR-T then underwent an ATI, CAR-T successfully homed to lymphoid follicles and a CAR-T infusion was associated with lower plasma and likely lymph node viral loads.

3.2.2.2 Clinical Studies of PIC

Clinical Trials in PWH

There have been two recent clinical trials of CAR-T therapy in PWH, one included an ATI [184, 185]. In the first, CAR-T were generated via lentiviral transduction of enriched autologous CD8+ T cells [184]. The CAR construct consisted of a single bNAb-derived scFv targeting Env, two intracellular costimulatory domains (CD28 and 4-1BB), and short hairpin RNA constructs targeting the checkpoint molecules PD-1, LAG3, and TIM-3. No pre-conditioning was performed. Six of 14 study participants underwent an ATI 3 weeks later. Chimeric antigen-T cells were detectable in vivo for up to 44 weeks after infusion and demonstrated anti-viral efficacy as measured by a reported decrease in the intact proviral reservoir, genetic restriction of the rebounding virus, and enhanced HIV-specific CD8+ T-cell responses 3 weeks post-infusion. All participants who underwent an ATI rebounded, though compared with a comparable historical ATI control group, CAR-T therapy prolonged the time to rebound by an unspecified duration. Five of six participants rebounded by week 5 post-infusion, and all by week 10. In a second trial, CAR-T were given in conjunction with the latency reversal agent chidamide, no ATI was performed [185]. This study utilized a trifunctional CAR-T: a duoCAR that recognized two different sites on Env and signaled via CD28 and 4-1BB costimulatory domains, which was also designed to express CXCR5 and to produce a bNAb (with a different Env specificity than the duoCAR). Chimeric antigen receptor-T cells were generated from haploidentical donors. No pre-conditioning was performed. While no immune correlates were performed, a reduction in the latent viral reservoir was reported, and the reservoir demonstrated selection pressure from CAR-T implying some degree of in vivo anti-viral efficacy. Further clinical trials, particularly those involving an ATI, are needed to elucidate the potential for CAR-T-mediated HIV control.

3.3 Other T-Cell Infusion Products

Gag-specific CD4+ T cells are associated with viral suppression [186]. In a phase I clinical trial (NCT03215004), autologous Gag-specific CD4+ T cells were generated from PWH then transduced with the lentivirus AGT103 conferring resistance against HIV infection. Participants underwent non-myeloablative conditioning with cyclophosphamide prior to infusion [187]. Seven participants received either low- or high-dose cellular infusions and no serious adverse events were reported. Infused cells were detectable for at least 6 months post-infusion. A transient increase in HIV-specific CD8+ and CD4+ T-cell responses was observed several weeks post-infusion, including endogenous CD4+ responses. No ATI was performed.

A separate phase I clinical trial (NCT03485963) is investigating an alternate autologous T-cell infusion product consisting of HIV-specific T cells expanded to target conserved epitopes in Gag, Pol, and Nef [188]. The infusion product was primarily CD8+ memory T cells. Six PWH received two infusions of this product without any prior lymphodepletion. HIV-specific T-cell expansion was observed in vivo and genome-intact HIV proviruses reportedly decreased in 3/6 participants. No ATI was performed.

4 Important Considerations in Clinical Trial Design

4.1 Target Population

Early ART initiation confers numerous benefits, including establishment of a smaller, more homogeneous reservoir and more robust immune reconstitution. Individuals who begin ART shortly after HIV acquisition may thus be especially well positioned to benefit from immunotherapeutic strategies aimed at durable remission. However, globally, most PWH initiated ART after years of untreated infection. This population presents challenges for cure-directed interventions, including a larger and more diverse reservoir and varying degrees of immune dysfunction. Consequently, early-phase proof-of-concept trials often prioritize enrolling participants who initiated ART earlier, as they may have a higher likelihood of demonstrating a measurable benefit.

Age-related eligibility criteria are also common in HIV cure trials, and their implications warrant careful consideration as the population of long-term survivors continues to age [189]. Older adults frequently present with comorbidities that may be exclusionary, and may exhibit attenuated immune responses to some immunotherapies. At the same time, older PWH are often highly motivated research participants. Trial designs must balance safety concerns, feasibility, and the potential impact of age on intervention efficacy. Inclusion of older individuals may be appropriate when comorbidities do not pose an additional risk, and their participation is essential to ensuring that cure strategies are generalizable to the broader population of PWH.

In the absence of validated biomarkers that reliably predict a viral rebound, many HIV cure trials incorporate analytic treatment interruptions — highly monitored ART pauses — to assess the impact of investigational interventions on viral rebound dynamics. Studies focused on delaying the time to rebound typically require shorter ATIs, while those evaluating effects on the post-rebound set point necessitate longer ATIs. Updated consensus guidelines related to the conduct of ATIs have recently been published that address issues such as entry criteria (e.g., immune status as determined by CD4+ T-cell count or nadir, medical comorbidities, HIV history), ART resumption criteria (e.g., based on the magnitude and duration of plasma HIV RNA level increases), and sociobehavioral considerations (e.g., status disclosure, transmission risk, psychological harm) [190]. The guidelines also acknowledge the need for flexibility based on the study’s aims and standards in the geographic region in which it is conducted. They further highlight pharmacokinetic (PK) challenges in the modern treatment era, particularly with the increasing availability of long-acting ART regimens (e.g., cabotegravir/rilpivirine, lenacapavir, bNAbs) [191]. Indeed, in the absence of prolonged wash-out periods prior to study entry, we anticipate that long-acting regimens will pose challenges for ATI study design and interpretation, as prolonged drug persistence and PK “tails” may influence the timing and dynamics of a viral rebound.

Recent aggregate analyses also provide an important empirical benchmark for ATI study design and interpretation, including expectations around timing of rebound and virologic control. A meta-analysis of individual participant data from the placebo (or non-intervention) arms of 24 prospective ATI studies evaluated time to viral rebound and the frequency of post-treatment control across diverse trial designs [192]. The analysis found that most participants experienced a viral rebound within the first few weeks (mainly 2–4 weeks) after an ATI. Sustained post-treatment control was rare and observed in only a minority of participants across studies (4% overall, 1–6% depending on timing of ART initiation following HIV acquisition).

The timing of the ATI relative to intervention delivery is also an emerging area of investigation. Most early studies administered one or more interventions during ART suppression, followed by an ATI to evaluate their biological effects. However, accumulating evidence indicates that some interventions may be more effective in the presence of active viral antigen expression. As a result, trial designs are increasingly incorporating ATIs prior to interventions (sometimes referred to as a “transient” treatment interruption), allowing the investigational agents to be delivered during periods of higher viral replication. Our group has developed an approach in which interventions are administered following a transient treatment interruption, either near the time of viral rebound — targeting the critical “intercept” between viral expansion and host immune response — or at the time of ART re-initiation, mimicking the immunologic environment present during initial ART initiation. These alternative ATI-integrated designs offer opportunities to probe mechanistic questions while potentially enhancing intervention efficacy, but require careful safety safeguards and monitoring plans.

4.3 The Importance of Sociobehavioral Research

Sociobehavioral research shapes the key questions that inform cure-related clinical trials, helping to determine not only if a particular intervention is scientifically promising, but also feasible, acceptable, and meaningful to PWH. Sociobehavioral research provides critical insight into participants’ motivations, concerns, and lived experiences — factors that directly influence recruitment, retention, adherence, and the interpretation of trial outcomes. It also helps refine the fundamental questions that define the field: What threshold of viral control would constitute a clinically and socially meaningful cure? How do we design trials that are scientifically rigorous yet maximally inclusive of diverse populations? What level of risk is ethically acceptable, and how do participants weigh those risks in the context of their own lives and relationships? Finally, sociobehavioral research illuminates the unique cultural, social, and structural considerations that shape trial design and implementation in different global settings.

4.4 Standardized Reporting of Trial Outcomes

Most HIV cure-related clinical trials are small, complex, and resource intensive, frequently conducted at a single site, and early phase or uncontrolled in design. While these trials play a critical role in establishing feasibility, safety, and preliminary efficacy signals, this heterogeneity makes it difficult to synthesize findings across studies or draw broader conclusions. To maximize what can be learned from each trial, it is essential to contextualize individual study outcomes within the broader landscape of cure research. To achieve this will require standardization of how trial data — particularly ATI-related outcomes, virologic endpoints, immune correlates, and safety events — are defined, measured, and reported. Efforts such as harmonized monitoring schedules and definitions of viral rebound standardized assays for reservoir quantification, and consensus frameworks for reporting immunologic responses can facilitate cross-trial comparisons. Standardized reporting also enhances transparency and reproducibility, enabling investigators to identify consistent signals, refine hypotheses, and design more targeted downstream studies. Moreover, harmonization supports regulatory stakeholders, who rely on clear comparable metrics to evaluate potential therapeutic strategies.

5 Important Considerations in Pharmacology

Use of the discussed modalities should be accompanied by thorough PK and PK/pharmacodynamic (PD) studies in the target population. Timing of the therapeutic agent washout from plasma and tissues is also important for study design (e.g., timing of an ATI and sampling of immunologic/virologic measures).

5.1 Pharmacokinetics

For small-molecule therapeutics, traditional PK profiles (i.e., absorption, distribution, metabolism, and excretion) should be established for use in PWH, including evaluation of ART–drug interactions, drug-metabolizing enzyme and transporter genetic heterogeneity, and effective concentrations, especially for highly protein-bound drugs. For mAbs, factors such as inflammation and genetic differences in neonatal Fc receptor expression may lead to PK differences [193]. Most bNAbs exhibit 30% variation in plasma PK exposure and half-life, [194, 195] and antigen expression may also impact mAb pharmacokinetics, which may underlie differences in the half-life observed for some bNAbs between people with and without HIV [196].

5.2 Pharmacokinetic/Pharmacodynamic (PK-PD) Studies

Clinical studies are imperative to inform PK-PD relationships for novel agents such as bNAbs, specifically to delineate antiviral and immunomodulatory effects. Defining PK-PD targets requires consideration of participant- and virus-specific factors such as age, sex, weight, concomitant medications including combination bNAb use, [45, 194] virus subtype, HLA type, reservoir size, [197] and virus susceptibility [45, 97, 198]. For viral susceptibility, PK-PD inhibitory quotients have been employed to define bNAb target cut-offs for pre-exposure prophylaxis [199]. In cure studies, these cut-offs may be confounded as waning bNAb levels and virus susceptibility tend to be inversely related in participants who rebound earlier [200].

6 Conclusions

The goal for HIV cure strategies is to achieve sustained viral control at levels where the virus cannot be transmitted and does not confer any ill health consequences to the host in a way that is safe and broadly accessible. Long-acting injectable ART may be able to fill this need for a while, but the need for a cure persists. The current attacks on science and medicine, projected to have devastating effects on HIV prevention and treatment efforts worldwide, particularly highlight the urgent need for a cure. We are making progress towards inducing durable remission with the strategies described above, but major optimization efforts will be needed to move from proof-of-concept to an approach that is simple, safe, effective, affordable, and scalable. We envision that one day, PWH will be able to receive a single injection that eradicates the reservoir while stimulating an immune response to promote durable viral control — a “one-shot” cure for HIV.

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Department of Medicine, University of California, San Francisco, San Francisco, CA, USA

Julia A. Wagner, Demi A. Sandel, Rachel L. Rutishauser, Steven G. Deeks & Michael J. Peluso

Department of Clinical Pharmacy, University of California, San Francisco, San Francisco, CA, USA

Amelia N. Deitchman

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Julia A. Wagner is supported in part through the National Institutes of Health/National Institute of Allergy and Infectious Diseases under Award Number T32AI060530. Demi A. Sandel is supported in part through the National Institutes of Health/National Institute of General Medical Sciences under Award Number T32GM136547. Additional support was provided by the National Institutes of Health UM1AI164560 (DARE, Steven G. Deeks), K23AI157875 (Michael J. Peluso), K23AI162249 (Amelia N. Deitchman), R01AI170239 (Rachel L. Rutishauser), and P01AI178375 (Rachel L. Rutishauser).

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Julia A. Wagner, Demi A. Sandel, Amelia N. Deitchman, Rachel L. Rutishauser have no conflicts of interest that are directly relevant to the content of this article. Michael J. Peluso serves on a DSMB for American Gene Technologies. Steven G. Deeks receives research support from Gilead. He is a member of the scientific advisory board for Tendel. He has consulted for AbbVie and ViiV.

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JAW, RLR, SGD, and MJP conceptualized the manuscript. JAW, DAS, AND, and MJP performed the literature search and drafted the manuscript. All authors critically revised the manuscript.

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Overview of select published HIV cure clinical trials (through 2025) (XLSX 73 KB)

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Wagner, J.A., Sandel, D.A., Deitchman, A.N. et al. Advances in Immune-Based Approaches for the Cure of HIV Infection. Drugs 86, 851–870 (2026). https://doi.org/10.1007/s40265-026-02311-3

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Article 6 — Sequential Use of Trastuzumab Deruxtecan and Sacituzumab Govitecan in Patients with Breast Cancer: A Pharmacological Approach to Support the Clinical Rationale

DOI: 10.1007/s40265-026-02289-y
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Abstract

Antibody-drug conjugates (ADCs) represent a major advance in breast cancer therapy, with trastuzumab deruxtecan and sacituzumab govitecan emerging as leading agents targeting distinct tumor antigens and employing different linker-payload designs. Trastuzumab deruxtecan is a second-generation HER2-directed ADC composed of trastuzumab linked via a cleavable tetrapeptide linker to the camptothecin derivative exatecan, a highly potent topoisomerase I inhibitor. Its high drug-to-antibody ratio (DAR 8:1), membrane-permeable payload, and efficient lysosomal release confer strong antitumor activity, including a robust bystander effect in HER2-low tumors. By contrast, sacituzumab govitecan is a TROP-2-targeted ADC conjugated through a hydrolysable CL2A linker to SN-38, the active metabolite of irinotecan. Sacituzumab govitecan features a high DAR (7.6:1) and allows extracellular as well as intracellular release of SN-38, enhancing bystander killing in tumors with heterogeneous TROP-2 expression, while maintaining a favorable toxicity profile due to the lower intrinsic potency of SN-38 relative to exatecan. Since both these ADCs are conjugated to topoisomerase I inhibitors, concerns about potential cross-resistance regarding their sequencing in clinical practice are being raised, and currently there is a lack of predictive biomarkers providing a rational basis for their sequential administration. Resistance mechanisms exhibit significant heterogeneity: resistance to trastuzumab deruxtecan has been associated with mutations in TOPO I and SLX4, impaired lysosomal function, and efflux via ABC transporters. In contrast, resistance to sacituzumab govitecan is linked to overexpression of multidrug resistance proteins, particularly BCRP-mediated efflux. Clinically, trastuzumab deruxtecan has shown substantial efficacy in both HER2-positive and HER2-low breast cancer, whereas sacituzumab govitecan has demonstrated efficacy across triple-negative and hormone receptor-positive/HER2-negative breast cancers. Collectively, these agents highlight how variations in target antigen, linker chemistry, and payload potency impact ADC activity, therapeutic index, and potential strategies for sequential treatment in advanced breast cancer. Graphical Abstract The alternative text for this image may have been generated using AI.

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Efficacy of administration sequence: Sacituzumab Govitecan and Trastuzumab Deruxtecan in HER2-low metastatic breast cancer

Article 25 June 2024

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Antibody–Drug Conjugate Revolution in Breast Cancer: The Road Ahead

Article Open access 25 March 2023

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Antibody–Drug Conjugates for the Treatment of Solid Tumors: Clinical Experience and Latest Developments

Article 08 November 2017

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Cancer therapeutic resistance
Ceroid
Chemotherapy
Gene targeting
Molecularly targeted therapy
Targeted therapies
Targeted Therapies in HER2-Positive Breast Cancer

FormalPara Key Points

Antibody-drug conjugates (ADCs) have transformed the treatment of breast cancer by combining antibody specificity with potent cytotoxic payloads, along with improved linker chemistry that enables targeted release of toxic molecules within tumors while maintaining stability in plasma.
Trastuzumab deruxtecan and sacituzumab govitecan are next-generation ADCs characterized by high affinity for their respective targets, cleavable linkers—via proteolysis or pH-sensitive hydrolysis—and potent topoisomerase I inhibition.
Mechanistic factors support the rationale for sequencing these ADCs in clinical practice. Despite both utilizing topoisomerase I inhibitors as payloads, which raises concerns about potential cross-resistance, differences in antibody targets (HER2 vs TROP-2), linker chemistry, and antibody scaffolds provide a strong basis for their sequential administration.

1 Introduction

Antibody-drug conjugates (ADCs) have meaningfully changed breast-cancer care by pairing tumor-targeting antibodies with potent cytotoxins to deliver chemotherapy right to cancer cells [1,2,3,4,5]. Clinically, they have improved response rates and survival in human epidermal growth factor receptor 2 (HER2)-positive disease [3] and, more recently, expanded options for patients with HER2-low and hormone-receptor (HR)+/HER2− or triple-negative subtypes after standard therapies (Table 1) [3]. Because the cytotoxic payload is delivered more efficiently to the target tissue, ADCs can achieve high intratumoral drug levels with a different—and often more manageable—toxicity profile than conventional chemotherapy, although class-specific risks (e.g., interstitial lung disease (ILD)/pneumonitis with some topoisomerase I (TOPO I)-targeting ADCs, neutropenia/diarrhea with others) require proactive monitoring. Their rise has also elevated the importance of precise biomarker assessment (e.g., refined HER2 scoring, trophoblast cell surface antigen 2 [TROP-2] expression [6]) and opened questions about optimal sequencing, combination strategies, resistance mechanisms, and earlier use in the disease course [7]. Overall, ADCs have broadened effective, personalized treatment choices and improved outcomes for many patients with breast cancer.

[Figure] — Table 1 ADCs in breast cancer

2 Literature Search Methods

A comprehensive literature review was conducted to identify studies describing structural and pharmacological characteristics and mechanisms of resistance to ADCs in cancer. A systematic search of the PubMed database was performed for articles published between January 1, 2015, and August 31, 2025. The search strategy combined terms related to ADCs and resistance mechanisms, including but not limited to: “antibody-drug conjugate,” “ADC,” “resistance,” “mechanism of resistance,” “target down-regulation,” “payload efflux,” “lysosomal trafficking,” “antigen modulation,” and specific ADC agents (e.g., trastuzumab deruxtecan, sacituzumab govitecan). Boolean operators (AND, OR) were used to refine results and capture relevant combinations of keywords. Reference lists of key articles and recent reviews were manually screened to identify additional pertinent publications.

Inclusion criteria encompassed original research articles, translational studies, clinical trials, case series, abstracts and relevant preclinical investigations that reported molecular or cellular mechanisms associated with intrinsic or acquired resistance to ADC therapy. Review articles, meta-analyses, and expert opinions were included to contextualize findings but were not the primary sources for mechanistic data. Articles not in English or without available full text were excluded.

Data extraction focused on ADC target modulation, payload handling, receptor internalization and trafficking alterations, drug efflux transporters, tumor microenvironment influences, and clinical correlates of resistance. Mechanistic themes were synthesized qualitatively to construct an integrated framework of resistance pathways across ADC platforms.

3 Structural Characteristics of Trastuzumab Deruxtecan and Sacituzumab Govitecan

Trastuzumab deruxtecan (DS-8201a, T-DXd) is a next-generation HER2-directed ADC that employs a distinct cytotoxic payload and a cleavable linker, enabling activity in cells with low HER2 expression and overcoming mechanisms of resistance to trastuzumab emtansine (T-DM1). Part of its payload (DXd, DX-8951f, or exatecan, a water-soluble derivative of camptothecin [8]) can diffuse into the tumor microenvironment, exerting a bystander effect on neighboring cancer cells lacking HER2 expression [9]. As a result, trastuzumab deruxtecan shows efficacy in HER2-low breast cancers and in tumors refractory to trastuzumab emtansine (T-DM1). Although trastuzumab deruxtecan has efficacy across HER2 ultra-low, HER2 low and HER2 positive cancers, the magnitude of benefit correlates with the level of HER2 expression. In the Phase III DESTINY-Breast03 trial, among patients previously treated with trastuzumab and a taxane for HER2-positive metastatic breast cancer, trastuzumab deruxtecan significantly lowered the risk of progression or death compared with trastuzumab emtansine across different stratification groups [10].

Sacituzumab govitecan (SG) is an ADC composed of a humanized anti-TROP2 monoclonal antibody conjugated to SN-38, the active metabolite of irinotecan, via a hydrolysable proprietary linker (CL2A) [4]. This linker allows efficient intracellular delivery of SN-38 to TROP2-expressing tumor cells and also permits extracellular release, generating a bystander effect that can eliminate adjacent malignant cells [11, 12]. With a high drug-to-antibody ratio (DAR), the number of cytotoxic molecules conjugated to each antibody, sacituzumab govitecan has secured FDA approval for metastatic triple-negative breast cancer (TNBC), metastatic urothelial carcinoma, and, more recently, hormone receptor-positive/HER2-negative metastatic breast cancer [13]. The favorable pharmacokinetic properties of sacituzumab govitecan allow exploration of model-informed treatment schedules [14].

Determining the optimal sequencing of ADCs has emerged as a critical and unresolved clinical question. The recent approvals of sacituzumab govitecan for HR+/HER2− and TNBC, along with trastuzumab deruxtecan for HER2-positive, low and ultra-low breast cancer, mean that many patients with breast cancer may now be eligible for multiple ADC therapies. However, cross-resistance—whether driven by the antibody target or payload—complicates sequencing strategies.

The ADC-after-ADC (A3) study evaluated 193 patients with metastatic breast cancer treated with ADCs, 32 of whom received more than one ADC (HR+/HER2− = 13, TNBC = 19, HER2-low = 22) [15, 16]. At the time of second ADC initiation, the median patient age was 57 years, and most had undergone multiple prior therapies (median 4, range 2–12). Median progression-free survival (PFS) on the first ADC was 7.55 months, compared with 2.53 months on the second. Patients who switched to an ADC with a different antibody target (from HER2 to TROP2) achieved numerically longer PFS (3.25 vs 2.30 months), although the difference was not statistically significant. Cross-resistance was observed in over half of the evaluable cases. Resistance was more frequent when the same antibody target was re-used (i.e., 69%) compared with a different target (i.e., 50%) [15, 16]. Payload differences also influenced outcomes. These findings suggest that while cross-resistance is common, certain patients can still achieve some benefit with subsequent ADCs, especially when targeting a novel antigen [15].

Resistance to ADCs can arise through several mechanisms, including (1) alterations in antigen expression or accessibility; (2) impaired lysosomal degradation; (3) increased activity of drug efflux pumps; (4) activation of survival and anti-apoptotic pathways; (5) limited drug penetration due to binding site barriers.

Further investigation is required to better understand these resistance mechanisms and refine treatment strategies to exploit the power of sequencing ADCs.

4 Use of Two ADCs in Sequence with Different Payloads Belonging to the Same Pharmacological Category (Topoisomerase Inhibitors)

Evidence suggests that switching ADC payloads mitigates cross-resistance, with improved ORR and PFS2 compared to same-payload sequences [17]. Indeed, resistance to trastuzumab deruxtecan may be linked to diminished sensitivity to its TOPO I inhibitor payload deruxtecan [18]. In one study, researchers developed HER2-ADC-resistant cells by exposing Ba/F3 HER2 YVMA cells to continuous trastuzumab deruxtecan treatment for eight weeks, after which the cells regained rapid growth [19]. Parental Ba/F3 HER2 YVMA cells remained responsive to trastuzumab deruxtecan, with an IC50 of 195 μg/mL, whereas resistant cells exhibited an IC50 exceeding 1000 μg/mL. Furthermore, the resistant cells displayed decreased responsiveness to the TOPO I inhibitor topotecan, with half-maximal inhibitory concentration (IC50) of 200 nM compared to 66 nM in the parental line [19]. These findings indicate that acquired resistance to trastuzumab deruxtecan may arise through reduced sensitivity to its cytotoxic payload. However, the underlying mechanism of resistance to exatecan was not explored in this study [19] and may involve alterations in TOPO I, other components of DNA replication machinery, or changes in cellular transport systems [20].

4.1 Topoisomerase I Mutations

The TOPO I point mutation E418K is one of several described missense variants that confer resistance to clinical TOPO I inhibitors without impairing the intrinsic catalytic activity of the enzyme. This substitution is thought to modify DNA sequence specificity and/or binding affinity, thereby disrupting the precise interaction between the drug and the enzyme-DNA complex [21]. While heterozygous mutations are sufficient to induce resistance, their clinical relevance is highlighted by the detection of a concurrent subclonal TOPO I frameshift mutation in the same metastatic lesions of a patient with TNBC who had developed resistance to sacituzumab govitecan [21]. Such alterations would be expected to promote cross-resistance to multiple novel ADCs incorporating TOPO I inhibitor payloads [21].

Nonetheless, TOPO I mutations remain infrequent. For instance, the R567T missense variant has been reported at a frequency of 0.10% only (TCGA, GDC data portal, accessed September 15, 2025), and no comprehensive studies have yet evaluated the prevalence of these mutations following trastuzumab deruxtecan exposure.

4.2 SLX4 Mutations

The tumor suppressor gene SLX4/FANCP, plays a central role in preserving genome stability, contributing to the repair of interstrand cross-links, homologous recombination, and the cellular response to replication stress—both genome-wide and at specific loci such as fragile sites and telomeres [22]. Functionally, SLX4 serves as a scaffold protein that regulates and coordinates the activity of structure-specific endonucleases, including XPF-ERCC1, MUS81-EME1, and SLX1, across diverse DNA repair and recombination pathways [23]. In addition, SLX4 interacts with multiple DNA repair and cell cycle regulators such as MSH2, PLK1, TRF2, and TOPBP1, as well as with ubiquitin and SUMO [22].

In the biomarker analysis of the DAISY trial, SLX4 mutations were detected in 14% of samples obtained at resistance to T-DXd [24]. The SLX4 mutations were present in three of 89 (3%) pretreatment biopsies and 1.5% in The Cancer Genome Atlas (TCGA) breast cancer [24]. To test whether SLX4 loss directly contributes to resistance against DX-8951-based ADCs, the investigators examined the viability of two breast cancer cell lines (SK-BR-3 and MCF-7) depleted of SLX4 and treated with varying doses of DX-8951 for five days. The SLX4 silencing resulted in a 5- to 20-fold increase in resistance to high-dose exatecan, as reflected in elevated IC80 values: 8.18 versus 167.27 nM (SK-BR-3) and 95.1 versus 502.4 nM (MCF-7) [24]. In contrast, SLX4 loss sensitized cells to the TOPO I inhibitor camptothecin [25].

4.3 Activation of Transport Systems Across Cell Membrane

Preclinical in vitro studies have shown that exatecan is a substrate for several human drug transporters, including organic anion transporting polypeptide 1B (OATP1B) family members, P-glycoprotein (ABCB1), and breast cancer resistance protein (BCRP or ABCG2) [26]. The uptake of exatecan by OATP1B1 and OATP1B3 was evaluated in transporter-expressing cell lines. As expected, the prototypical OATP1B1/1B3 substrate 17β-estradiol was efficiently transported in these cells compared with controls, and its uptake was blocked by rifampicin, a known inhibitor, confirming robust transporter activity. Consistently, the uptake clearance of exatecan was increased 54.9-fold and 5.0-fold in OATP1B1- and OATP1B3-expressing cells, respectively, compared with control cells, and was suppressed by rifampicin [26].

The roles of ABCB1 and ABCG2 in the transport of exatecan was further examined in Caco-2 monolayers. Digoxin, a validated ABCB1 probe, exhibited vectorial transport that was abolished by verapamil (ABCB1 inhibitor) and GF120918 (dual ABCB1/ABCG2 inhibitor). Similarly, estrone sulfate, a ABCG2 substrate, displayed vectorial transport that was completely inhibited by novobiocin (ABCG2 inhibitor) and GF120918. Exatecan also showed vectorial transport from the basolateral to the apical compartment, which was suppressed by verapamil, novobiocin, and GF120918 [26].

Resistance mechanisms to SN-38, the payload of sacituzumab govitecan, have also been extensively studied. Resistant breast cancer cell sublines (T47D/SN120 and T47D/SN150) were generated by gradual exposure to SN-38 [27]. These resistant cells overexpressed multiple efflux transporters, including multidrug resistance-associated protein (MRP) 1, MRP4 and ABCG2. This overexpression appeared to result from reduced epigenetic silencing through DNA hypomethylation and histone deacetylation changes. Functionally, the cells displayed a multidrug resistant phenotype, with cross-resistance to several anticancer agents. Reduced intracellular drug accumulation was observed but could be restored by MRP and ABCG2 inhibitors, confirming the role of these transporters in resistance [27].

Additional studies corroborated the role of ABCG2 in mediating SN-38 resistance. Two resistant sublines (PC-6/SN2-5 and PC-6/SN2-5H) derived from PC-6 small-cell lung cancer cells showed 18-fold and 34-fold resistance to SN-38, respectively, relative to parental cells. Resistance correlated with reduced intracellular accumulation of SN-38 and increased ABCG2 mRNA expression proportional to resistance level [28]. Suppression of ABCG2 mRNA using antisense oligonucleotides restored SN-38 sensitivity, establishing ABCG2 as a direct mediator of efflux-driven resistance. Importantly, UGT1A expression and activity were decreased in resistant cells compared with parental PC-6, ruling out a role for glucuronidation, and no significant upregulation of MRP1-MRP3 was observed. Collectively, these findings indicate that ABCG2 is responsible for exporting SN-38 and/or its glucuronide metabolite, thereby conferring resistance [28].

A separate study confirmed these mechanisms in long-term SN-38-exposed breast cancer sublines (T47D/SN120 and T47D/SN150). Compared with wild-type parental T47D cells, resistant sublines demonstrated 14.5- and 59.1-fold resistance to SN-38, 1.5- and 3.7-fold resistance to irinotecan, and 4.9- and 12-fold resistance to topotecan, respectively [27]. Both sublines exhibited broad cross-resistance to additional anticancer drugs and overexpressed MRP1–MRP4 and BCRP mRNAs. Treatment with the DNA methyltransferase inhibitor 5-aza-2′-deoxycytidine and the histone deacetylase inhibitor trichostatin A upregulated these transporter transcripts in parental cells, supporting an epigenetic regulatory mechanism. Resistant sublines also accumulated less fluorescent dye than wild-type cells, but this phenotype was reversed with known chemosensitizers, which restored intracellular drug accumulation and sensitivity. Together, these findings underscore the role of efflux transporter overexpression, driven in part by epigenetic deregulation, in the development of SN-38 resistance [27].

5 Insights into the Importance of Having a Different Cellular Target, a Different Mechanism of Internalization of the Molecule and of the Release of the Payload

Target antigen expression is a critical determinant of ADC efficacy. Down-regulation or loss of the target antigen represents a key adaptive resistance mechanism, as it directly impairs ADC binding, internalization, and intracellular payload delivery. This mechanism has been clinically documented for trastuzumab deruxtecan (T-DXd) in the Phase II DAISY trial, which provides one of the most comprehensive translational analyses of resistance to a HER2-directed ADC [24]. The DAISY trial evaluated T-DXd in three cohorts of metastatic breast cancer defined by baseline HER2 expression: HER2-positive, HER2-low, and HER2-null tumors. Despite initial responses across all cohorts, paired tumor biopsies obtained at baseline and at progression revealed a consistent pattern of reduced HER2 expression at the time of disease progression, irrespective of initial HER2 status [24]. This decrease was observed both by immunohistochemistry (IHC) scoring and by transcriptomic analyses, supporting true biological down-regulation rather than assay variability.

Importantly, HER2 down-regulation was not limited to complete loss of expression but often involved a quantitative reduction in surface HER2 density, sufficient to compromise ADC binding and uptake. Given that T-DXd efficacy relies on efficient internalization and lysosomal processing to release its membrane-permeable TOPO I inhibitor payload, partial reductions in antigen density may impair intracellular drug delivery.

The DAISY trial further demonstrated that target down-regulation frequently co-occurred with additional resistance mechanisms, including alterations in payload sensitivity and changes in intracellular trafficking pathways. This highlights the multifactorial nature of acquired resistance to ADCs, where antigen modulation may serve as an early adaptive response that facilitates subsequent resistance evolution [24]. These data have important implications for patient selection and treatment sequencing supporting (1) the concept of the dynamic reassessment of target expression for sequencing decisions, (2) the potential vulnerability of ADCs targeting antigens with heterogeneous or plastic expression, and (3) providing the rationale for next-generation ADC strategies, including dual-targeting constructs, bystander-effect optimization, or combination approaches designed to prevent or overcome antigen loss.

Trophoblast cell surface antigen 2 (TROP-2) is a transmembrane glycoprotein with extracellular and intracellular domains that participates in calcium-mediated signal transduction. It has been implicated in multiple signaling pathways, including mitogen-activated protein kinase (MAPK), RAF, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and cyclin D/E, in addition to its role in intracellular calcium regulation [29, 30].

Despite the potential predictive role that TROP-2 may have across different cancers, upregulation of TROP-2 is frequently observed in malignant cells compared with normal tissue, and this overexpression has been documented across a broad range of tumor types, including breast, colorectal, non-small cell lung, esophageal squamous cell, thyroid, and hepatobiliary cancers [31]. Such widespread expression raises the possibility of TROP-2 functioning as a tumor-agnostic biomarker. Although the mechanisms driving TROP-2 upregulation remain unclear, it is hypothesized that the protein exerts critical control over proliferation and invasion, thereby promoting breast cancer progression [32]. Supporting this, preclinical models show that TROP-2 overexpression accelerates tumor growth, whereas knockdown suppresses it [29, 33].

In breast cancer, high TROP-2 expression correlates with poorer survival outcomes. Transcriptomic analyses demonstrate TROP-2 expression across all breast cancer subtypes, with higher levels in HR+/HER2− and TNBC relative to HER2-positive disease. In particular, genomic profiling of TNBC has identified TROP-2 as a promising therapeutic target, leading to its prioritization in drug development [29].

In order to investigate the relationship, if any, of HER2 and TROP-2, a study evaluated archival breast cancer specimens from 986 patients across multiple subtypes using immunohistochemical staining and complemented these findings with analyses from public datasets, including METABRIC, KM Plotter, and ROC Plotter, to assess the prognostic and clinical relevance of TROP-2 in HER2-positive breast cancer [34]. Functional in vitro assays—including transwell migration, invasion, and sphere formation—were performed to evaluate tumor progression, while apoptosis was quantified by annexin V/propidium iodide double staining and flow cytometry.

The HER2-positive tumors exhibited higher TROP-2 protein expression compared with other subtypes. Elevated levels of both TROP-2 and phospho-Akt were observed in HER2-positive tumors relative to normal breast tissue, and TROP-2 expression correlated with tumor stage and phospho-Akt levels. Clinically, high TROP-2 protein levels were associated with worse recurrence-free survival in HER2-positive patients. Consistently, analysis of public datasets demonstrated that elevated TROP-2 transcript expression was linked to shorter recurrence-free and overall survival in HER2-positive breast cancer [34].

In cell models (SK-BR-3 and BT-474), TROP-2 overexpression enhanced migration, invasion, and sphere formation, whereas knockdown reduced these phenotypes. Overexpression also improved cell viability in the presence of lapatinib or neratinib, while TROP-2 knockdown increased apoptosis induced by these HER2-targeted therapies. Importantly, clinical data showed that responders to anti-HER2 therapy had significantly lower TROP-2 transcript expression compared with non-responders [34].

6 The Importance of Different, Functionally Unrelated Cellular Targets: TROP-2 vs HER2

To substantiate the rationale for sequencing anti-TROP-2 and anti-HER2 ADCs, we performed gene-network analysis showing that TACSTD2 (TROP-2) and ERBB2 (HER2) reside in largely disconnected transcriptional modules with minimal co-expression and pathway co-regulation, indicating biological independence and supporting nonredundant, sequential targeting. The network analyses have been generated by using String (https://string-db.org/cgi/input?sessionId=bQ1d2BC8l8Mk&input_page_show_search=on), and network visualization was done with Cytoscape. An ERBB2-TACSTD2 network has been generated in order to understand the biological interaction between the 2 genes. In the network, interconnected genes are represented by “nodes”, and the connection (dialogues) between genes are represented by “edges”. Hub genes were defined based on their degree, centrality and betweenness, i.e., the number of edges connecting each gene to others within the network. For the network analysis, nodes with observed degrees exceeding the 95th percentile of the null distribution were considered statistically significant hubs. The overall ERBB2 and TACSTD-2 gene network reports 32 nodes and 174 edges; ERBB2 and TACSTD-2 display a combined confidence of functional interaction of 0.732 (high) with a co-expression score of 0.087 and a combined confidence of the physical (co-complex) interaction of 0.228, highlighting a weak biological dialogue in between the two genes, but a co-expression evidence only (figure not shown). To confirm the lack of functional network in between ERBB2 and TACSTD-2, a functional cluster analysis was performed by K-means clustering analysis, highlighting and confirming two different clusters: one containing ERBB-2 and one for TACSTD-2 (Fig. 1). Figure 2 reports the most significant dialogues with genes directly interacting with ERBB2, while Figure 3 reports TACSTD2 network (A) and functional clusters (B), showing the most significant dialogues with genes directly interacting with TACSTD-2. While TACSTD-2 mainly functionally interacts with claudin-like genes, ERBB2 network is most related to common oncogenes, such as epidermal growth factor receptor (EGFR), neuregulin (NRG), and fibroblast growth factor receptor (FGFR).

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7 The Importance of a Different Payload: SN-38 vs Exatecan

An effective cytotoxic payload for ADCs requires both tumor sensitivity and a balance between potency and tolerability. Common payload classes include DNA-damaging agents, microtubule/tubulin inhibitors, and TOPO I inhibitors. Although highly potent agents are often favored, moderate potency can sometimes improve safety. For example, sacituzumab govitecan employs SN-38, a moderately toxic payload that provides a more favorable therapeutic index [35, 36]. SN-38 is 100–1000 times more potent than irinotecan [37], but approximately 10-fold less potent than exatecan [29].

The DAR is a critical parameter influencing efficacy and safety. A low DAR reduces activity but improves tolerability, while a high DAR enhances potency but may accelerate clearance and increase toxicity. Trastuzumab deruxtecan has a DAR of 8 molecules of exatecan per antibody [38], compared with a DAR of 7.6 for sacituzumab govitecan. Although SN-38 has a lower cytotoxic potential compared with exatecan, both agents usually have low discontinuation rates in trials with appropriate supportive care. Sacituzumab govitecan is associated with hematological and gastrointestinal toxicities [39], while trastuzumab is instead responsible for rare but serious and potentially life-threatening organ toxicity, the interstitial lung disease [40].

Several features make sacituzumab govitecan particularly effective. First, SN-38 is membrane-permeable, enabling a bystander effect. Second, its hydrolysable linker allows extracellular as well as intracellular release of SN-38, which may be advantageous in tumors with heterogeneous TROP-2 expression [29]. Third, the ADC sustains a high DAR without impairing antibody binding or pharmacokinetics, unlike earlier ADCs such as T-DM1 which was characterized by fist-generation not cleavable linker, a DAR ≤4 and a less potent mertansine (DM1) payload, a combination of molecular characteristics that impaired overall efficacy with respect to trastuzumab deruxtecan [10]. Finally, sacituzumab govitecan shows reduced toxicity relative to other TOPO I inhibitors, particularly less severe diarrhea. This may reflect a lower glucuronidation of antibody-bound SN-38, leading to reduced biliary clearance and less gastrointestinal exposure to bacterial glucuronidase-mediated release, compared with SN-38 generated directly from irinotecan [29, 41].

8 The Importance of a Different Mechanism of Internalization of the Molecule and Release of the Payload

The chemical linker in ADCs connects the cytotoxic payload to the antibody, ensuring stability during circulation. Linker chemistry—defined by functional group and conjugation site—affects ADC pharmacokinetics, pharmacodynamics, and therapeutic index. Common functional groups include disulfide, thioether, and hydrazone, which attach payloads to antibodies through intermolecular interactions. Based on payload release mechanisms, linkers are classified as cleavable or non-cleavable [42]. Cleavable linkers rely on physiological triggers such as acidic pH, proteases, or high glutathione levels. For example, gemtuzumab ozogamicin uses an acid-labile linker, brentuximab vedotin employs a protease-cleavable linker, and mirvetuximab soravtansine relies on disulfide cleavage [42]. In contrast, non-cleavable linkers, such as the thioether linker in T-DM1, require complete lysosomal degradation of the antibody to release the payload, providing enhanced stability and reduced systemic payload release, which may improve safety [43]. Polyethylene glycol (PEG)-based linkers are widely used for their solubility, low immunogenicity, and safety profile [43].

The DAR also determines ADC potency and toxicity. Conjugation usually occurs at lysine side chains or cysteine residues, resulting in heterogeneous DAR values. While a higher DAR can improve efficacy, it may also increase clearance and off-target effects [36, 44, 45]. Protease-cleavable linkers, such as the glycine-glycine-phenylalanine-glycine (GGFG) tetrapeptide linker in trastuzumab deruxtecan, are widely used for their stability in circulation and efficient intracellular release [38, 46].

In sacituzumab govitecan, the CL2A linker was developed from the CL2 prototype by removing a phenylalanine moiety, improving manufacturability while maintaining stability and activity. The CL2A incorporates a short PEG unit for solubility and exhibits intermediate serum stability, enabling SN-38 release both intracellularly and extracellularly [39]. This facilitates bystander killing, particularly in tumors with heterogeneous TROP-2 expression. The linker attaches to the lactone ring of SN-38, conjugated to interchain thiols. Importantly, conjugation preserves SN-38 in its active, closed-lactone form [39].

The benzyl carbonate linker of sacituzumab govitecan can undergo partial hydrolysis in circulation, but its intermediate stability enhances tumor delivery and reduces target-mediated toxicities, such as stomatitis, that were observed with earlier TROP-2 ADCs. Unlike protease-cleavable linkers, hydrolysable linkers may release payload during endosomal trafficking [47], bypassing the requirement for lysosomal degradation [36].

9 Clinical Evidence on the Sequential Use of ADCs in Breast Cancer

One of the key unmet needs in the development of ADCs for breast cancer is to establish their efficacy in the metastatic setting when administered sequentially, and to define the most effective treatment sequence. The DESTINY-Breast02 trial provided important evidence on this question, demonstrating the clinical benefit of trastuzumab deruxtecan in patients previously treated with trastuzumab emtansine [48]. Complementing these findings, the DESTINY-Breast03 trial showed the superiority of trastuzumab deruxtecan over trastuzumab emtansine in the second-line setting for HER2-positive metastatic breast cancer, with unprecedented improvements in both progression-free survival and overall survival. Together, these studies represent important milestones: DESTINY-Breast03 established trastuzumab deruxtecan as the preferred second-line therapy [10], while a retrospective, multicenter, real-world study demonstrated that sequential ADC use directed against HER2—but employing a different linker-payload combination—can still be effective in later lines [49]. These findings support the hypothesis that sequential ADC use can be effective, although the optimal sequence is likely dependent on the specific ADC design and requires validation in prospective clinical trials or large-scale real-world studies.

Recent retrospective and real-world studies evaluating sequential administration of trastuzumab deruxtecan and sacituzumab govitecan consistently demonstrate attenuated efficacy of the second ADC, regardless of sequence and the order of administration. Poumeaud et al [50] reported that while both trastuzumab deruxtecan→sacituzumab govitecan and sacituzumab govitecan→trastuzumab deruxtecan sequences retained antitumor activity, responses were generally short lived and inferior to those achieved when either agent was used earlier in the treatment course. These findings were corroborated by Huppert et al. [51], who demonstrated modest objective response rates (ORRs) and limited PFS with the second ADC in a multicenter cohort, with no clear superiority of one sequence over the other. Tarantino et al. [52] showed that prior exposure to an ADC was associated with reduced efficacy of subsequent ADC across biomarker subgroups, highlighting a potential role for a more aggressive disease biology and therapeutic exhaustion that may follow ADC failure. Table 2 reports a selection of available data on ADC sequencing in breast cancer [15, 50,51,52,53,54,55,56].

[Figure] — Table 2 Summary of selected studies on ADC sequences.

A deeper understanding of the mechanisms of action and resistance of ADCs will be essential for defining treatment algorithms. Several studies have reported the use of trastuzumab deruxtecan and sacituzumab govitecan in combination with pertuzumab or pembrolizumab, respectively, in metastatic breast cancer, demonstrating meaningful clinical responses [57, 58]. With increasing access to these antibody drug conjugates in the second-line setting, mature data from these first-line trials, particularly regarding overall survival, are eagerly awaited. Dedicated trials that directly address the optimal timing of highly effective therapies, such as use in the first line compared with the second line, remain scarce. The SONIA trial, performed on CDK4/6 inhibitors, illustrates the clinical and economic relevance of such sequencing questions and underscores the need for similar studies in the context of antibody drug conjugates, especially given their substantial financial impact [59]. In early breast cancer, adjuvant use of trastuzumab deruxtecan instead of trastuzumab emtansine has demonstrated an improvement in disease-free survival, although overall survival data are currently lacking due to immaturity [60]. Additional challenges are anticipated with the forthcoming survival results of the DESTINY Breast11 trial, which could move trastuzumab deruxtecan into the neoadjuvant setting and already reported an approximately 10% absolute increase in pathological complete response rates [61]. This shift is likely to complicate subsequent adjuvant treatment decisions in patients with residual disease and further highlights the growing complexity of sequencing ADCs across disease stages.

Importantly, the observation that clinical activity is not strictly dependent on target expression—such as trastuzumab deruxtecan showing efficacy even in HER2-low and ultra-low breast cancers, and sacituzumab govitecan demonstrating benefit independent of TROP-2 expression levels [62]—underscores the complexity of their antitumor effects and highlights gaps in our mechanistic knowledge.

The robust activity of second-generation ADCs across diverse breast cancer subtypes provides strong rationale for their investigation in other solid tumors. Both trastuzumab deruxtecan and sacituzumab govitecan are already being studied in multiple malignancies through broad development strategies. The observation that ADC efficacy can extend across tumor types sharing expression of the same antigen mirrors the paradigm of histology-agnostic targeted therapies, as exemplified by the DESTINY-PanTumor02 trial. This suggests that ADCs may ultimately be deployed in a tumor-agnostic manner, independent of biomarker-defined expression thresholds, opening the door to broader applications across oncology [63].

10 Conclusions

The development of ADCs has transformed the therapeutic landscape of breast cancer, with emerging evidence supporting their sequential use to extend survival in the metastatic setting. Clinical data, such as those from the DESTINY-Breast02 trial, demonstrate that even when directed against the same target, ADCs with different linkers and payloads can provide meaningful clinical benefit. This highlights the importance of ADC design elements—including payload selection, linker chemistry, and drug-to-antibody ratio—in shaping therapeutic efficacy and tolerability.

Resistance mechanisms to ADCs are multifaceted. Mutations in TOPO I may confer cross-resistance to deruxtecan and camptothecins, although their frequency after treatment with deruxtecan-containing ADCs remains undefined. Interestingly, SLX4 mutations appear to drive resistance to deruxtecan, but not camptothecins, suggesting distinct resistance profiles even among agents targeting the same pathway. Efflux transporters also play an important role, with OATP1, ABCB1, and ABCG2 implicated in resistance to deruxtecan, while MRP and ABCG2 mediate resistance to camptothecins. Cross-resistance therefore appears to be primarily mediated by ABCG2 activity.

Another layer of complexity arises from the role of TROP-2 expression. Evidence suggests that TROP-2 overexpression in HER2-positive breast cancer may contribute to resistance against anti-HER2 therapies, underscoring the interplay between antigen biology and treatment response. At the same time, payload characteristics substantially influence clinical outcomes. The SN-38 payload of sacituzumab govitecan is less toxic than exatecan, contributing to a more favorable therapeutic index. Furthermore, the linker technology differs between ADCs: sacituzumab govitecan employs a hydrolysable, pH-sensitive linker that enables both intracellular and extracellular release of SN-38, facilitating a bystander effect, whereas trastuzumab deruxtecan uses an enzymatically cleavable peptide linker for exatecan, which relies more on lysosomal degradation. These differences highlight how variations in linker design can shape not only efficacy but also resistance and toxicity profiles.

Collectively, these findings underscore that the future of ADCs lies not only in optimizing their design for enhanced potency and safety but also in refining their sequencing across treatment lines. As second-generation ADCs exhibit activity across various breast cancer subtypes and beyond, their potential is expanding toward tumor-agnostic applications, potentially aligning with the paradigm of histology-independent targeted therapies. Ongoing and future clinical trials will be pivotal in fully defining the optimal use of ADCs, elucidating mechanisms of resistance, and ultimately unlocking their potential for broader, more durable therapeutic benefit across solid tumors.

Change history

16 April 2026

The original article has been updated to update the affiliation Division of Development of New Drugs for Innovative Therapies, European Institute of Oncology IRCCS, Milan, Italy

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Departmental Faculty of Medicine, Saint Camillus International University of Health and Medical Sciences, Rome, Italy

Marzia Del Re

Fondazione Policlinico Universitario IRCCS Agostino Gemelli, Rome, Italy

Marzia Del Re & Emilio Bria

Unit of Clinical Chemistry, ASST Grande Ospedale Metropolitano, Niguarda, Milan, Italy

Elvira Inglese

Università Cattolica del Sacro Cuore, Rome, Italy

Emilio Bria

Department of Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands

Erik J. Blok

Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands

Ron H. J. Mathijssen

Division of Development of New Drugs for Innovative Therapies, European Institute of Oncology IRCCS, Milan, Italy

Giuseppe Curigliano

Department of Oncology and Hemato-Oncology, University of Milan “La Statale”, 7, Via Festa del Perdono, 20122, Milan, Italy

Giuseppe Curigliano & Romano Danesi

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Marzia Del Re: writing—review & editing, writing—original draft, formal analysis, data curation, conceptualization. Elvira Inglese: writing—review & editing, writing—original draft, formal analysis, data curation, conceptualization. Emilio Bria: writing—review & editing, writing—original draft, conceptualization. Erik J. Blok: writing—review & editing. Ron H.J. Mathijssen: writing—review & editing, writing—original draft, conceptualization. Giuseppe Curigliano: writing—review & editing, writing—original draft, conceptualization. Romano Danesi: writing—review & editing, writing—original draft, conceptualization.

Conflict of interest

Marzia Del Re has received speaker’s bureau/advisor’s fees from: Astra Zeneca, Astellas, Bayer, MSD, Daiichi Sankyo, Roche, Novartis, Lilly, Regeneron, Qiagen, Recordati, Qiagen, Amgen. Emilio Bria has received grants or contracts from Astra-Zeneca, Roche and honoraria for lectures from Merck-Sharp & Dome, Astra-Zeneca, Pfizer, Eli-Lilly, Bristol-Myers Squibb, Novartis, Takeda and Roche; he has been member of Data Safety Monitoring Board or Advisory Board of Merck-Sharp & Dome, Pfizer, Novartis, Bristol-Myers Squibb, Astra-Zeneca, Roche, Amgen and Celltrion. Ron H.J. Mathijssen reports relationships with Bayer AG and Novartis Pharma AG that include funding grants (all paid to the institute) and speaking and lecture fees. He reports a relationship with Servier that includes advisory board membership and funding grants, and he reports a relationship with NaDeNo Nanoscience that includes advisory board membership. He also reports funding grants from Astellas Pharma, Boehringer Ingelheim, Cristal Therapeutics, Deuter Oncology, Nordic Pharma, PamGene BV, Pfizer, Roche, and Sanofi (all paid to the institute). Giuseppe Curigliano has received research grants from Merck; has received honoraria from Ellipses Pharma; has received support for attending meetings and/or travel from Roche/Genentech, Pfizer, Daiichi Sankyo and AstraZeneca; has a leadership role for the ESMO, the European Society of Breast Cancer Specialists and ESMO Open; is a speakers’ bureau member for Roche/Genentech, Novartis, Pfizer, Lilly, Foundation Medicine, Samsung, Daiichi Sankyo, Seagen, Menarini, Gilead Sciences, AstraZeneca and Exact Sciences; and has held consulting or advisory roles for Roche/Genentech, Pfizer, Novartis, Lilly, Foundation Medicine, Bristol Myers Squibb, AstraZeneca, Daiichi Sankyo, GlaxoSmithKline, Seagen, Guardant Health, Veracyte, Celcuity, Menarini, Merck, Exact Sciences, Blueprint Medicines and Gilead Sciences. Romano Danesi has received speaker’s bureau/advisor’s fees from AstraZeneca, Amgen, Eisai, EUSA Pharma, Genzyme, Gilead Sciences, Incyte, Ipsen, Janssen, Jazz Pharmaceuticals, Lilly, Roche, Novartis, Pfizer, and Sanofi. All the competing interests are outside the present work. Elvira Inglese and Erik J. Blok declare that they have no conflicts of interest that might be relevant to the contents of this manuscript.

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Del Re, M., Inglese, E., Bria, E. et al. Sequential Use of Trastuzumab Deruxtecan and Sacituzumab Govitecan in Patients with Breast Cancer: A Pharmacological Approach to Support the Clinical Rationale. Drugs 86, 871–885 (2026). https://doi.org/10.1007/s40265-026-02289-y

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Article 7 — The Role of β-Blockers in the Evolving Treatment Landscape of Resistant Hypertension

DOI: 10.1007/s40265-026-02319-9
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Abstract

Resistant hypertension (RHTN) is estimated to affect approximately 15% of all patients with hypertension, although its reported prevalence varies according to the blood pressure (BP) thresholds used for diagnosis, the criteria applied to exclude secondary or pseudoresistant hypertension, and the characteristics of the study populations. Regardless of its current prevalence, RHTN is expected to be encountered with increasing frequency in routine clinical practice, driven by the rising prevalence of conditions that are directly or indirectly linked with its increased risk, such as obesity, diabetes mellitus, and chronic kidney disease (CKD). Consequently, recent clinical trials and hypertension guidelines have devoted substantial attention to RHTN, also considering its association with an increased risk of cardiovascular events and renal failure. In this narrative review, we summarize mechanistic insights and evidence from randomized clinical trials and real-world studies, as well as recommendations from current international guidelines, to provide an updated perspective on the management of RHTN. Among multiple systems, activation of the sympathetic nervous system (SNS) and the renin–angiotensin–aldosterone system represents a central pathophysiological mechanism in RHTN, promoting sodium retention and vascular dysfunction. β-blockers counteract SNS overactivity, a target mechanism not addressed by other first-line therapies, and have compelling indications in most comorbidities associated with RHTN, including coronary artery disease, heart failure, and atrial fibrillation. They can be used across diverse patient populations, including those with advanced CKD, and their side effects can be readily monitored and managed. Evidence from randomized trials and real-world studies supports their efficacy, tolerability, and safety even in high-risk populations. Emerging strategies, including a quadruple single-pill combination containing a β-blocker, may enhance adherence, optimize BP control, and simplify RHTN management.

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Abstract

Hypertension as a Link Between Renal and Cardiac Dysfunction

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Renal autonomic dynamics in hypertension: how can we evaluate sympathetic activity for renal denervation?

Article 02 August 2024

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Resistant Hypertension: Disease Burden and Emerging Treatment Options

Article Open access 16 February 2024

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Cardiac Device Therapy
Cancer therapeutic resistance
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Hypertension Management and Cardiovascular Risk Reduction

FormalPara Key Points

The growing prevalence of resistant hypertension (RHTN), fueled by the increasing burden of obesity, diabetes mellitus, and chronic kidney disease (CKD), constitutes a major clinical challenge owing to its strong association with adverse cardiovascular and renal outcomes.
The overactivated sympathetic nervous system and renin–angiotensin–aldosterone system are key contributors to RHTN. β-blockers target these mechanisms effectively and have demonstrated efficacy and tolerability, even in high-risk populations, including those with heart disease and advanced CKD.
Emerging strategies such as single-pill quadruple combinations may improve adherence, optimize blood pressure control, and simplify the management of RHTN.

1 Introduction

Resistant hypertension (RHTN) is defined as uncontrolled blood pressure (BP) despite maximally tolerated doses of three or more BP-lowering drugs of different classes (one of which should be a thiazide or thiazide-like diuretic), or hypertension controlled with four or more drugs [1,2,3,4]. The BP thresholds defining RHTN vary across guidelines. European guidelines define RHTN using thresholds of ≥ 140 mmHg for systolic BP and/or ≥ 90 mmHg for diastolic BP, whereas US guidelines use lower thresholds of ≥ 130 mmHg and/or ≥ 80 mmHg, respectively [1,2,3, 5].

RHTN is thought to affect approximately 15% of all people with hypertension [6], although its prevalence varies depending on the characteristics of the populations included in different studies, the values used to define controlled BP in different guidelines, and the methods employed for its screening and diagnosis [7]. Indeed, populations with established cardiovascular or kidney disease have a higher prevalence of RHTN [1, 2], and many studies that have reported on the prevalence and characteristics of patients with RHTN have not specified the screening methods used to exclude secondary forms of hypertension or potential causes of pseudoresistant hypertension, such as poor treatment adherence, “white-coat effect”, or inaccurate BP measurement [1, 2]. This is a relevant issue considering that pseudoresistance may account for up to 80% of apparent RHTN cases, while a substantial number of the remaining patients have a secondary cause of hypertension [2, 8]. Therefore, the term “true RHTN” was introduced into the 2023 guidelines of the European Society of Hypertension (ESH) [1]. Accordingly, it is recommended to confirm inadequate BP control ideally by ambulatory BP monitoring (ABPM) or by home BP monitoring (HBPM) if ABPM is not feasible, and after excluding pseudo-RHTN (particularly poor adherence) and secondary causes of hypertension [1].

Despite challenges in the diagnosis of RHTN, its accurate management is crucial because it is associated with an increased risk of cardiovascular and kidney outcomes [1, 2, 9, 10], particularly when it develops before the age of 55 years [11] or remains uncontrolled despite multidrug therapy [12]. This narrative review aims to reexamine the management of RHTN in the context of recent hypertension guidelines, with a particular focus on the potential advantages offered by β-blockers over other available therapies. We integrate pathophysiological insights, clinical trial data, and real-world evidence (RWE) to support the use of this class of drugs within the evolving therapeutic landscape of RHTN. To develop this review, we used our own collective experience and reviewed evidence identified through targeted PubMed searches on RHTN and relevant keywords between June and October 2025.

2 Pathophysiology of RHTN

RHTN arises from a complex interplay of volume and sodium overload, overactivation of multiple neurohormonal systems, including the sympathetic nervous system (SNS) and the renin–angiotensin–aldosterone system (RAAS), and an impaired vascular phenotype characterized by endothelial dysfunction and arterial stiffness (Fig. 1) [13, 14].

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2.1 Sodium and Fluid Retention

Genetic evidence, such as the association between the R563Q mutation in the β-epithelial sodium channel and the risk of severe hypertension, supports a causal role for enhanced sodium reabsorption in RHTN [15, 16]. Beyond intrinsic renal mechanisms, the SNS contributes to sodium retention through both direct and indirect effects. Among the direct mechanisms, stimulation of α₁ and α₂ adrenoceptors enhances sodium reabsorption in the proximal tubule and vasoconstriction of the renal artery [17,18,19]. Indirectly, activation of β₁ adrenoceptors in the juxtaglomerular apparatus promotes renin release, thereby increasing the production of angiotensin II and aldosterone. Additionally, SNS overactivation has been linked to increased recruitment of inflammatory cells within the kidney, increasing parenchymal inflammation, and as a result, enhancing sodium reabsorption [17, 19,20,21].

2.2 RAAS Activation

Genetic studies support a pivotal role of the RAAS in RHTN pathogenesis [22, 23], with recent evidence identifying CASZ1 and WNT2B as loci linked to aldosterone dysregulation in patients with RHTN [22]. Several additional stimuli, such as SNS overactivation and renal hemodynamic alterations, further enhance RAAS activity in these patients, ultimately increasing tubular sodium reabsorption and peripheral vascular resistance through small-vessel vasoconstriction and remodeling [24]. In addition, activation of angiotensin II contributes to SNS overactivity through direct stimulation within the central nervous system, presynaptic enhancement of adrenergic activity, and complex interactions with cardiac and sinoaortic baroreceptors [25, 26]. This may establish a vicious cycle in which SNS activity promotes further angiotensin II release, which in turn amplifies SNS activation.

Activation of aldosterone secretion is a key driver of RHTN, as it promotes sodium retention, volume expansion, and vascular stiffness. Thus, inappropriate or autonomous aldosterone secretion (dysregulation) underlies poor BP control, making its inhibition an essential treatment target in RHTN [1, 2, 27]. While RAAS inhibitors should inhibit aldosterone secretion, sustained aldosterone overproduction might also be observed in patients chronically treated with these drugs and has been attributed to the angiotensin II/aldosterone “escape” phenomenon. This condition is characterized by aldosterone levels that reach or even exceed pretreatment levels despite RAAS blockade, owing to increased renin activity, SNS activity, and/or RAAS-independent stimuli [28, 29]. In these conditions, additional strategies to counterbalance RAAS overactivation might be necessary to obtain adequate BP control. Given that dual blockade of the RAAS with a combination of an angiotensin-converting enzyme inhibitor (ACEi) and an angiotensin receptor blocker (ARB) (or a direct renin inhibitor) is not recommended [1, 2], inhibition of renin secretion by blocking β₁-adrenergic receptors might represent a valuable therapeutic option in patients exhibiting the angiotensin II/aldosterone “escape” phenomenon.

Through microneurography, the gold-standard technique for assessing SNS activity in vivo in humans, it has been demonstrated that muscle sympathetic nerve activity (MSNA) is commonly increased in patients with all forms of hypertension and correlates with both BP values and severity of the clinical presentation of hypertension [30]. Therefore, it should not come as a surprise that SNS overactivation is commonly observed in patients with RHTN.

In a study including 19 normotensive controls, 35 nonresistant hypertensives, and 32 patients with RHTN, Grassi et al. [31] documented a significant and marked increase in MSNA in subjects with RHTN. MSNA was directly related to adiposity measures, clinic/ambulatory/beat-to-beat finger diastolic BPs, plasma aldosterone, Homeostatic Model Assessment (HOMA) index, and markers of hypertension-mediated target-organ damage, including left ventricular mass index, and E/e′ ratio. In turn, inverse relationships were observed with estimated glomerular filtration rate, baroreflex sensitivity, and the E/A ratio. Remarkably, in the stepwise regression analysis, the independent variable most closely related to MSNA values (after adjustment for confounders) was plasma aldosterone, followed by baroreflex sensitivity. These results highlight two important aspects of sympathetic neuroactivation in patients with RHTN. First, although an increased SNS activity in RHTN might be partially related to a high burden of comorbidities characterized by excessive SNS activation (including insulin resistance in obesity, type 2 diabetes, obstructive sleep apnea (OSA), etc. [18, 32]), a primary baroreceptor dysfunction may also play an important role in sustaining SNS overactivation. Second, SNS overactivity is closely intertwined with RAAS activation in patients with RHTN, and the interaction between these two systems likely contributes to persistently elevated BP despite multidrug therapy. These findings were further corroborated by a microneurographic study demonstrating that MSNA was markedly increased in patients with RHTN compared with those with apparent RHTN and controlled hypertension [33]. The same study also confirmed the presence of significant baroreflex dysfunction in RHTN, with impaired baroreflex sensitivity, elevated plasma aldosterone levels, and higher HOMA index values emerging as the variables most strongly associated with MSNA [33].

More recently, a meta-analysis of microneurographic studies confirmed that MSNA is significantly higher in patients with RHTN than in non-RHTN patients, despite more intensive antihypertensive therapy in the former group [30]. In line with previous observations, MSNA in RHTN showed an inverse relationship with baroreflex function, indicating impaired baroreflex-mediated sympathetic modulation. Table 1 reports the most relevant human studies supporting the presence of SNS overactivation in patients with RHTN.

[Figure] — Table 1. Summary of human studies documenting the presence of SNS overactivation in patients with RHTN

Beyond the evidence emerging from observational studies, the presence of SNS overactivation and its strong connection with the RAAS in patients with RHTN are further supported by genetic data. Variants of the β₂-adrenergic receptor (46G>A and 79C>G) have been associated with sodium-sensitive and low-renin hypertension, with the 46AA/79CC diplotype linked to higher levels and impaired suppression of aldosterone during salt loading [45].

The pathophysiological mechanisms through which SNS overactivation promotes persistent BP elevation are likely to be largely mediated by alterations in renal homeostasis. The progressive increase in SNS stimulation in the renal system leads to a stepwise recruitment of mechanisms that elevate BP. At low levels of SNS activation, stimulation of β₁-adrenergic receptors on juxtaglomerular cells enhances renin release, the consequences of which have already been described. As SNS activity increases, α-adrenergic receptors on proximal tubular epithelial cells are activated, promoting sodium and water retention. Further SNS activation results in α₁-adrenoceptor stimulation on the surface of vascular smooth muscle cells, causing vasoconstriction of both afferent and efferent arterioles and consequently reducing renal blood flow and glomerular filtration rate [46].

Beyond its renal effects, increased SNS activity profoundly impacts systemic vascular homeostasis at various organs (the brain, kidney or heart) by promoting vasoconstriction, increasing arterial stiffness, and impairing endothelial function. Most of these alterations have been causally linked to RHTN [22, 47,48,49] and may accelerate hypertension-mediated target-organ damage while inducing systemic hemodynamic disturbances that further contribute to persistent BP elevation (Fig. 1) [50, 51].

3 Clinical Profile

RHTN is more common in males, older adults, individuals of African descent, and in the presence of various comorbidities, some of which can be consequences of the chronic exposure to elevated BP, whereas others can share common disease pathways with RHTN [52,53,54,55,56,57,58] (Fig. 2).

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For example, chronic kidney disease (CKD), obesity, OSA, and type 2 diabetes are characterized by overactivation of the SNS and RAAS, which in turn promotes BP elevation. Conversely, sustained exposure to high BP levels may lead to the development and progression of heart failure and CKD, further complicating the clinical presentation of patients with RHTN. An observational study of 228,406 patients with hypertension found that more patients with RHTN compared with non-RHTN patients had diabetes (34.4% versus 22.8%), heart failure (8.6% versus 2%), atrial fibrillation (19.6% versus 8%), myocardial infarction (4.1% versus 1.8%), or CKD (7.4% versus 2.9%) [57]. These conditions are per se associated with an increased risk of cardiovascular and renal events [59], a risk that is further amplified by the presence of RHTN, as it serves as an independent predictor of adverse outcomes [9,10,11,12, 60]. Therefore, achieving adequate BP control is crucial to mitigate the very high cardiovascular risk in these patients.

Additionally, evidence suggests that even when adequate BP control is achieved, patients with RHTN may remain at higher risk of adverse outcomes compared with those without RHTN [60]. This residual risk is considered to be related to irreversible target-organ damage and the greater burden of comorbidities.

The complex clinical profile of RHTN, characterized by multiple comorbidities and sustained by multifactorial, interacting pathophysiological mechanisms, renders BP control particularly challenging and often requires a substantial pill burden to achieve both adequate BP reduction and comprehensive cardiovascular risk mitigation.

4 Guideline Recommendations

International hypertension guidelines provide similar recommendations on the management of RHTN [1, 2, 5, 61, 62]. Confirmation of elevated BP by out-of-office BP measurements, exclusion of pseudoresistant or secondary hypertension, and consideration of consultation with a hypertension specialist are recommended before adding a fourth drug to a patient’s treatment regimen. Among drugs that can be considered in patients with true RHTN, spironolactone (or another mineralocorticoid receptor antagonist [MRA]) is preferentially recommended [2]. In cases in which spironolactone is contraindicated or not tolerated, β-blockers, extended-release doxazosin or centrally acting α-adrenergic receptor agonists (e.g., clonidine) can be used as alternatives. More recent evidence supports the use of amiloride as an alternative to spironolactone in RHTN [63]. Renal denervation is also recommended as a potential treatment option in these patients [1, 2, 5, 62]. Beyond pathophysiological considerations and guideline recommendations, there is a strong clinical rationale for the use of β-blockers in patients with RHTN, supported by clinical trial data and RWE.

5 The position of β-blockers in the Treatment of RHTN

5.1 Pharmacological and Clinical Rationale for the Use of β-Blockers in Patients with RHTN

Given the central role of SNS overactivity in RHTN, it is intuitive that attenuating sympathetic overdrive through β- and α-adrenergic receptor blockade may exert meaningful antihypertensive effects in patients with difficult-to-control BP. Furthermore, the additive BP-lowering effects of drug combinations rely on complementary mechanisms of action. In this respect, the pro-hypertensive influence of SNS overactivity on the cardiovascular system remains the only major pathway not adequately addressed by the three drug classes currently recommended as first-line antihypertensive therapy in clinical guidelines, namely renin–angiotensin system inhibitors (ACEis/ARBs), calcium channel blockers, and diuretics [1, 2, 5, 61, 62].

β-blockers represent a heterogeneous class of drugs that differ in their selectivity for β₁- versus β₂-adrenergic receptors [64, 65]. Some agents also exert direct vasodilatory effects, either through additional α₁-adrenergic receptor blockade (e.g., carvedilol) or by promoting nitric oxide release via β₃-receptor activation (e.g., nebivolol).

Beyond their selectivity for different adrenergic receptors, β-blockers also vary in key pharmacokinetic properties, including lipophilicity, organ clearance, dialysability, and vasodilatory effects, which together influence blood–brain barrier penetration, dosing flexibility, and safety [66,67,68,69]. Hydrophilic agents such as atenolol have a short half-life and are predominantly renally eliminated. In patients with end-stage renal disease requiring dialysis, these drugs are highly dialysable but their short half‑life and extensive removal during hemodialysis necessitate post‑dialysis or more frequent dosing and careful dose reduction as estimated glomerular filtration rate declines [68, 70, 71]. In contrast, more lipophilic β‑blockers (e.g., metoprolol, carvedilol, propranolol) are primarily hepatically cleared, show greater blood–brain barrier penetration and tissue distribution, are minimally removed by dialysis, and generally do not require dose adjustment in CKD, although interindividual variability in exposure is higher because of first‑pass metabolism and drug–drug interactions [67, 68, 71, 72]. Their greater capacity to cross the blood–brain barrier increases the risk of central nervous system side effects. However, a systematic review and meta-analysis of psychiatric adverse events during β-blocker therapy found no differences in outcomes according to lipophilicity [73]. Bisoprolol occupies an intermediate position, with highly selective β₁‑blockade and roughly balanced renal and hepatic elimination; its half‑life supports once‑daily dosing, and functional organ impairment typically increases exposure by no more than twofold, making it attractive in patients with CKD who require stable, long‑acting β‑blockade [67, 69]. Bisoprolol is substantially dialysable, similar to other hydrophilic agents, which underscores the need for preferential post‑dialysis administration rather than avoidance, and allows the use of thrice‑weekly, dialysis‑synchronized regimens that may enhance adherence in patients with RHTN on hemodialysis [69, 70, 74]. In contrast, vasodilating β‑blockers such as carvedilol and nebivolol are more lipophilic, hepatically cleared, and poorly dialysable [67, 68, 72, 75, 76]. Emerging molecular evidence indicates that biased agonism and receptor heterodimerization further contribute to the pharmacological heterogeneity observed within this drug class [77,78,79].

An important rationale for using β-blockers in the treatment of RHTN is their inclusion in guideline-directed medical therapy (GDMT) for several comorbid conditions frequently encountered in this patient population, including coronary artery disease, heart failure, atrial fibrillation, and other arrhythmias (Table 2, Fig. 2) [1, 80]. Moreover, there are multiple clinical indications that commonly coexist with RHTN and should prompt consideration of β-blocker prescription according to guidelines (Table 3). For some of these conditions, β-blocker therapy was historically considered relatively contraindicated, despite the common presence of compelling indications, due to concerns about potential adverse effects. However, more recent evidence has not demonstrated significant detrimental effects associated with β-blocker use, supporting their safe and appropriate prescription in these settings (Tables 3a) [1, 80]. Other conditions have traditionally been linked to increased SNS activation, thereby providing a pathophysiological rationale for β-blocker therapy (Table 3b). Finally, there are clinical settings in which β-blocker therapy is considered beneficial, either through clinical (symptomatic) improvement or on the basis of observational evidence demonstrating favorable health outcomes (Table 3c, d).

[Figure] — Table 2 Clinical indications or conditions frequently associated with, or observed in, RHTN in which β-blockers have demonstrated benefit [1, 80]

[Figure] — Table 3 Other conditions that should prompt consideration of β-blocker prescription in RHTN according to guidelines [1, 80]

Specifically, in OSA, SNS overactivation is a key mechanism driving nocturnal and daytime hypertension; agents targeting sympathetic pathways, including β‑blockers, are therefore considered mechanistically appropriate for OSA‑related hypertension [56, 81]. Clinical data also indicate that β‑blockers do not increase nocturnal brady-arrhythmias and may blunt apnea‑induced heart rate swings in OSA, supporting their cardiovascular safety in this population [82].

In peripheral arterial disease (PAD) and chronic obstructive pulmonary disease (COPD), historical concerns about the use of β-blockers have not been confirmed in randomized trials or real-world studies. In PAD, β‑blockers (both selective and nonselective) did not significantly worsen claudication distance, maximal walking distance, calf blood flow, vascular resistance, or skin temperature compared with placebo [83,84,85]. A long‑term randomized trial in patients with hypertension with intermittent claudication showed that nebivolol and metoprolol were both well tolerated, with improved ankle–brachial index and claudication distance, while providing effective BP control [86]. Therefore, although β-blockers are not indicated for PAD as PAD-specific therapy per se, they are generally safe in these patients, making their use strongly recommended when compelling cardiovascular indications exist (e.g., post–myocardial infarction, heart failure with reduced ejection fraction) [87, 88]. These conditions are highly prevalent among patients with PAD, given the systemic and multi-territorial nature of atherosclerosis.

In COPD, contemporary evidence, including large meta‑analyses and systematic reviews, shows that cardioselective β‑blockers do not meaningfully reduce forced expiratory volume in 1 second (FEV₁) or increase exacerbation risk, but they are associated with reduced all‑cause mortality and, in some analyses, fewer COPD exacerbations [89,90,91,92]. Cardioselectivity minimizes β₂‑receptor-mediated bronchoconstriction, and current reviews conclude that β‑blockers should not be withheld in COPD when there is a clear cardiac indication, provided nonselective agents are avoided and dosing is carefully titrated [68, 69, 90, 92].

Finally, in patients with uremia (with and without hyperparathyroidism), a marked sympathetic overactivity has been repeatedly documented, together with a high burden of atherosclerotic cardiovascular disease and heart failure, making β-blockers frequently part of GDMT in this population [93,94,95,96,97]. Additionally, the neutral effect of β-blockers on kidney function and circulating potassium levels in patients with CKD supports their use in these subjects, in contrast to MRAs [98].

5.2 Randomized Controlled Trial Evidence Supporting the Use of β-Blockers in Patients with RHTN

A network meta-analysis of 24 trials in 3458 patients with RHTN showed that β-blockers were the third most effective therapy in reducing office systolic BP (standardized mean difference [SMD] − 8.44; 95% confidence interval [CI] − 15.48 to − 1.40) after spironolactone and clonidine [99]. However, β-blockers had the largest effect in reducing office diastolic BP (SMD − 5.57; 95% CI − 8.01 to − 3.13) compared with other treatments such as spironolactone (SMD − 4.50; 95% CI − 6.30 to − 2.69) [99]. In the same analysis, renal denervation (performed either with radiofrequency or ultrasound-based devices) and the α-blocker doxazosin were associated with smaller reductions in office systolic and diastolic BP compared with β-blockers.

It should be emphasized that, to date, bisoprolol is the only β-blocker with robust evidence of a significant BP-lowering effect in patients with RHTN, as demonstrated in both the PATHWAY-2 and the QUADRO trials. Although vasodilating β-blockers have been suggested to provide greater BP-lowering efficacy and a more favorable side effect profile in patients with arterial hypertension [100], no randomized controlled trials (RCTs) have specifically assessed their efficacy and tolerability in patients with RHTN.

As highlighted by current hypertension guidelines [1, 2, 62], therapeutic recommendations for RHTN are primarily supported by evidence from RCTs that have assessed short-term BP-lowering effects of relevant therapies (i.e., with the extent of BP reduction representing the primary outcome) rather than cardiovascular outcomes trials [1, 2]. Indeed, no trial evidence exists to demonstrate a beneficial impact on hard outcomes in patients with RHTN for any of the guideline-recommended antihypertensive therapies. However, the use of β-blockers in the more general population of patients with hypertension is supported by a substantial body of RCT evidence, showing that this drug class significantly reduces the risk of major adverse cardiovascular events (MACE), particularly in patients younger than 65 years [101, 102]. Although these data do not derive from trials specifically enrolling patients with RHTN, it is important to emphasize that none of the other drug classes currently recommended as fourth-line BP-lowering therapies for this condition have a comparable level of evidence supporting cardiovascular protection in hypertensive patients, and it is unlikely that the cardiovascular benefits of β-blockers in preventing MACE differ between patients with hypertension and those with RHTN.

Regarding individual outcomes, some uncertainty persists as to whether β-blockers provide less protection against stroke compared with other BP-lowering medications in the general hypertensive population. Nevertheless, meta-analyses of RCTs have consistently shown a significant reduction in stroke risk with β-blockers compared with placebo [103]. Importantly, no RCT evidence suggests that β-blockers are inferior to other guideline-recommended drug classes for the treatment of RHTN in terms of stroke prevention. Therefore, in patients already receiving RAAS inhibitors, diuretics and calcium channel blockers, whether differences in stroke protection exist between β-blockers and other fourth-line therapies remains to be established.

5.3 Real-World Evidence Supporting the Use of β-Blockers in Patients with RHTN

Given the limitations of currently available RCTs, results from real-world studies are particularly important for guiding the management of patients with RHTN.

In a large retrospective real-world study including 8639 patients from the UK with apparent RHTN [104], β-blockers were associated with a risk of the composite outcome of all-cause mortality, myocardial infarction, and stroke that was not significantly different from that observed with MRAs (propensity score-adjusted hazard ratio 0.81; 95% CI 0.55–1.19) [104]. Although the observational design, the relatively low number of events, and the potential for residual confounding, particularly given the higher comorbidity burden among patients receiving MRAs, limit causal interpretation of these findings, similar results were reported in another real-world study based on a large US administrative database including 80,598 patients [105]. The risk of MACE was comparable in patients with apparent RHTN who initiated MRAs or β-blockers as fourth-line therapy. Notably, in both studies MRA use was associated with a higher incidence of hyperkalemia, and in the study by Desai et al., MRA therapy was also associated with a higher risk of gynecomastia and worsening of renal function compared with β-blockers [105]. These observations differ from the results of the PATHWAY-2 trial, in which β- and α-blockers produced smaller reductions in BP compared with spironolactone, and the rates of adverse events were similar across treatment regimens [106].

The different characteristics of patients included in RCTs versus real-world studies may account, at least partially, for these discrepancies. For example, RCTs in RHTN patients have generally excluded very elderly patients, individuals with advanced CKD, patients at high risk of orthostatic hypotension, patients with atrial fibrillation, and those with comorbidities that provide compelling indications for one of the study drugs (e.g., patients with ischemic heart disease requiring β-blocker therapy), in whom discontinuation of the therapy would have been unfeasible if the patient were assigned to another active treatment or placebo [63, 106, 107]. As a result, patients with RHTN in real-world practice might present with more complex clinical profiles and a greater burden and severity of comorbidities than those recruited in RCTs. Many of these comorbidities might render the use of MRAs challenging owing to a higher risk of adverse effects. For example, while the prevalence of CKD among real-world patients with RHTN is substantially high, the estimated glomerular filtration rate at baseline in the PATHWAY-2 [106] and ReHOT [107] trials was > 85 mL/min/1.75 m2, which may have reduced the likelihood of hyperkalemia and worsening renal function detected during the trials compared with what has been observed in real-world studies.

Similarly, the greater comorbidity burden of real-world patients with RHTN, including conditions associated with SNS overactivation and GDMT indications for β-blocker therapy, may help to explain the similar reductions in BP and risk of MACE observed with MRAs and β-blockers in observational studies. Likely reflecting the high prevalence of comorbidities that may represent compelling indications for β-blocker therapy or contraindications to the use of MRAs [57], β-blockers appear to be used much more frequently than MRAs in real-world patients with RHTN [58].

Finally, it should not be overlooked that the differences observed between real-world studies and RCTs may be related to the larger patient populations (several thousand) and longer follow-up periods in real-world studies compared with RCTs, which typically recruited only a few hundred patients followed for shorter periods (a few months).

Despite evidence from randomized trials and real-world studies confirming the BP-lowering potential of β-blockers in RHTN, this drug class may be associated with adverse effects that can negatively impact adherence in routine clinical practice. Severe bradycardia represents the most frequent adverse effect of β-blocker therapy, reflecting the pharmacodynamic effects inherent to this class of agents. However, RCTs in patients with heart failure have reported that < 1% of patients treated with β-blockers required treatment discontinuation owing to severe bradycardia [108]. Other common side effects that have been related to β-blocker treatment include fatigue, impaired glucose metabolism, cold extremities, sleep disturbances (such as insomnia or nightmares), and sexual dysfunction. Fatigue has been described in patients starting β-blockers, although its severity varies with the specific agent, dose, and individual patient characteristics. Reductions in heart rate and BP, as well as attenuation of the exercise-induced increase in cardiac output, may contribute to exertional fatigue and reduced exercise tolerance [109, 110]. In patients with RHTN, persistently elevated BP and the SNS overactivation that characterize this condition may mitigate the risk of clinically significant hypotension-related fatigue, as the likelihood of excessive BP lowering with β-blocker treatment is generally limited in this population. Depression may also contribute to the fatigue reported during β-blocker therapy. However, recent evidence suggests that the risk of depression associated with β-blockers has likely been overestimated [73]. Careful selection of the specific agent may further reduce the likelihood of these adverse effects. In particular, central-nervous-system-related side effects are more commonly observed with lipophilic β-blockers (e.g., propranolol, metoprolol), which readily cross the blood–brain barrier and may be associated with sleep disturbances, insomnia, nightmares, or somnolence, potentially worsening daytime fatigue.

β-blocker therapy has also been associated with an increased risk of incident diabetes mellitus [111]. This metabolic effect appears to be substantially attenuated with the use of highly β₁-selective agents and vasodilating β-blockers, which have a relatively neutral impact on glucose metabolism [112,113,114].

Furthermore, β-blockers are frequently perceived as carrying a higher risk of erectile dysfunction (ED). Although some earlier reports appeared to support this concern [115, 116], more recent evidence provides a somewhat nuanced perspective. In a nationwide Danish study of newly treated patients with hypertension (approximately 64,700 individuals receiving β-blockers), the 1-year incidence of recorded ED was 4.7% among β-blocker users. However, when compared with calcium-channel blockers, the relative risk (RR) of ED was similar or slightly lower in patients treated with β-blockers (RR 0.91; 95% CI 0.85–0.96) [117]. Other studies have identified β-blocker use as one of several factors associated with a higher prevalence of ED, alongside older age, smoking, and longer duration of hypertension [118]. Nonetheless, the cross-sectional design of these studies precludes distinguishing drug-related effects from ED attributable to the underlying severity of cardiovascular disease. In fact, evidence suggests that the risk of ED related to β-blocker use has likely been overestimated [119].

Irrespective of this evidence, the two most important trials evaluating β-blockers as BP-lowering agents in patients with RHTN did not report a significant increase in the risk of serious adverse events or treatment discontinuation associated with the use of bisoprolol compared with other classes of antihypertensive medications or with BP-lowering triple therapy [106, 120]. Therefore, there is no evidence in patients with RHTN to suggest that β-blockers are poorly tolerated.

6 Challenges in the Management of Patients with RHTN

Despite the availability of effective BP-lowering treatment for RHTN, several challenges continue to complicate patient management. Chief among these are treatment nonadherence and discontinuation, therapeutic inertia, and limited access to specialist care.

Poor adherence and treatment discontinuation are extremely common in patients with RHTN [121,122,123,124,125], as confirmed by RCTs and real-world studies. A UK observational study using chemical adherence testing for antihypertensive drugs in urine of patients with apparent RHTN reported that 55% were nonadherent to prescribed therapy, with 20% being completely nonadherent [122]. In the PRECISION trial, which was designed to evaluate the efficacy of the dual endothelin receptor antagonist aprocitentan in patients with true RHTN, 44.4% of patients with apparent RHTN did not have true RHTN and thus were not eligible for randomization because their systolic BP fell below 140 mmHg following a run-in phase with a triple single-pill combination (SPC) antihypertensive therapy [126]. Similar findings were reported in the RADIANCE-HTN TRIO trial assessing the efficacy and safety of endovascular ultrasound renal denervation in patients with RHTN [127], in which 36% of patients with apparent RHTN were excluded during the run-in period because daytime BP values recorded by ABPM were already within the normotensive range following treatment with BP-lowering triple SPC therapy.

Current guidelines identify nonadherence and drug discontinuation as major barriers to the effectiveness of antihypertensive therapy in apparent RHTN [1, 2, 5, 62]. As in the general hypertensive population, nonadherence in patients with apparent RHTN is also strongly associated with increased risk of adverse cardiovascular outcomes including all-cause mortality, myocardial infarction, stroke, and heart failure [124, 125], and is directly related to total and antihypertensive pill burden [122]. Accordingly, guidelines emphasize the importance of systematic assessment of adherence using, for example, self-report or objective methods [128, 129], and of prescribing BP-lowering drugs at maximally tolerated doses as SPCs before initiating fourth-line therapy [1, 2]. These measures are essential to prevent unnecessary treatment escalation and to avoid costly or inappropriate diagnostic investigations. Nevertheless, adherence to these recommendations remains poor, as demonstrated by a study in patients with uncontrolled hypertension in which only 10.5% of patients received an SPC prescription [130].

Adverse effects associated with fourth-line therapies for RHTN may also substantially increase the risk of treatment discontinuation, and their frequency and impact on discontinuation can vary considerably across drug classes. For example, in a RCT of patients with RHTN and CKD, spironolactone was discontinued in 44% of participants; the addition of a potassium binder reduced this rate by only 20 percentage points [131], at the cost of further increasing the pill burden and the risk of nonadherence (Fig. 3A).

[Figure] 40265_2026_2319_Fig3_HTML.jpg — Fig. 3
https://media.springernature.com/lw685/springer-static/image/art%3A10.1007%2Fs40265-026-02319-9/MediaObjects/40265_2026_2319_Fig3_HTML.jpg

Monitoring for treatment-emergent side effects of β-blockers is relatively simple, and this might explain their more frequent use in clinical practice compared with MRAs. Indeed, the emergence of bradycardia can be readily detected by physicians and even by patients during routine office or home BP measurement, respectively. In contrast, hyperkalemia or renal impairment associated with MRA therapy require laboratory testing and active involvement of healthcare professionals for timely identification, thereby increasing the complexity and costs of patient management (Fig. 3B,C). Likely for these reasons, discontinuation of MRA therapy owing to hyperkalemia is more frequent in real-world settings [132,133,134] than in RCTs [135,136,137,138], and often occurs even at potassium levels not typically associated with severe clinical complications. Although the lower incidence of hyperkalemia observed with the nonsteroidal MRA finerenone compared with more traditional MRAs may increase physicians’ confidence in prescribing this class of drugs, it should be acknowledged that the magnitude of BP reduction achieved with finerenone is modest and unlikely to be clinically meaningful in patients with RHTN [135, 139].

Despite these considerations, treatment with β-blockers in patients with CKD should neither be considered a substitute for ongoing MRA therapy nor delay the initiation of MRAs when these agents have clear, guideline-recommended indications. Recent RCTs with nonsteroidal MRAs have demonstrated significant renal benefits in patients with diabetic kidney disease, establishing them as disease-modifying therapies irrespective of BP control [139]. Similarly, in patients with heart failure with preserved or mildly reduced ejection fraction, MRAs have demonstrated outcome benefits [140], whereas β-blockers lack an equally compelling evidence-based indication in this setting. Therefore, in this subgroup of patients, β-blockers should not be regarded as an alternative to MRAs, which should remain the preferred fourth-line therapeutic option in RHTN. Nevertheless, even in these settings, β-blockers remain a reasonable antihypertensive option in the presence of persistently elevated BP despite appropriate MRA therapy or in patients who are unable to tolerate MRAs.

Patients with RHTN are also at risk of suboptimal treatment owing to therapeutic inertia, defined as failure by the treating physician to initiate or intensify therapy to achieve BP targets. Real-world data suggest that therapeutic inertia affects more than one-third of all patients with hypertension and more than half of those with uncontrolled BP [141]. Although thiazide or thiazide-like diuretics are considered a cornerstone of hypertension management, a large real-world study using an electronic health record–based analysis showed that only 24% (96,691/398,613) of patients with hypertension and 59% (33,525/57,137) of patients with apparent RHTN were prescribed these agents in clinical practice [58].

Finally, although current guidelines recommend referring patients with RHTN to hypertension specialists, limited resources within national health systems increasingly hinder access to specialized centers for disease management [142,143,144]. As a result, the care of patients with RHTN often remains confined to the primary healthcare setting.

7 Emerging Therapeutic Options for RHTN

As our understanding of the pathophysiology and clinical challenges of RHTN advances, novel therapeutic strategies are emerging. These approaches seek either to overcome the limitations of existing treatments or to target new pathways involved in the persistent elevation of BP.

Nonsteroidal MRAs offer greater selectivity for the mineralocorticoid receptor (MR) than steroidal MRAs, especially spironolactone [145]. As mentioned, the nonsteroidal MRA finerenone has demonstrated significant cardiovascular and renal benefits in patients with type 2 diabetes and CKD, as well as in patients with heart failure with moderately reduced or preserved ejection fraction, but its BP-lowering effect is modest, and the risk of hyperkalemia has remained an issue in RCTs [139, 146, 147]. Esaxerenone, another highly selective nonsteroidal MRA, is currently the only nonsteroidal MRA approved for the treatment of hypertension, and only in Japan [1]. A recent systematic review and meta-analysis confirmed the effectiveness of esaxerenone in reducing BP in a dose-dependent fashion, with an associated reduction in albuminuria [148], but also documented an increased risk of hyperkalemia and related drug discontinuation. For these reasons, in the absence of RCTs investigating this drug class in patients with RHTN, their use in this population is currently not recommended.

In turn, aldosterone synthase inhibitors (ASIs) such as baxdrostat and lorundrostat are being specifically tested in patients with difficult-to-control hypertension or RHTN [149]. They represent an alternative therapeutic option that targets and reduces aldosterone production without interacting with the MR and are devoid of sex-hormone-related off-target effects. Although their BP-lowering effect has been confirmed in RCTs [150, 151], the use of ASIs remains associated with an increased risk of hyperkalemia [150, 151], an adverse event that might be of concern particularly in patients with established CKD. In contrast, β-blockers can be prescribed to patients with advanced CKD, with appropriate dose adjustment (Fig. 3D).

Endothelin receptor antagonists are another class of drugs specifically tested for the treatment of RHTN and target a distinct mechanism from aldosterone inhibition. Unlike MRAs or ASIs, their use is not associated with an increased risk of hyperkalemia, but in the PRECISION trial, the dual endothelin receptor A and B antagonist aprocitentan (12.5 mg and 25 mg) induced only a modest reduction in office systolic BP in patients with true RHTN (−3.8 and −3.7 mmHg, respectively, versus placebo) [152]. Furthermore, the treatment was associated with dose-dependent fluid retention, with peripheral oedema occurring in up to 18% of patients on the 25 mg dose of the drug. Caution is therefore particularly warranted in patients with CKD or heart failure [153], two conditions that are highly prevalent in patients with RHTN.

More recently, a quadruple full-dose SPC containing the ACEi perindopril, the thiazide-like diuretic indapamide, the calcium channel blocker amlodipine, and the β-blocker bisoprolol has been developed and tested for the treatment of RHTN in the QUADRO RCT [120]. In this RCT, patients randomized to the quadruple SPC achieved greater reductions in office systolic BP and 24-h ambulatory systolic BP (−8 mmHg) compared with those receiving the same drugs as triple therapy without bisoprolol [120]. Furthermore, treatment with the quadruple SPC resulted in a significantly higher percentage of patients achieving the BP target than those receiving the triple therapy, as observed in office, home, and 24-h ambulatory BP measurements. Both treatment modalities were well tolerated [120].

8 The Evolving Role of β-Blockers in the Future Treatment Landscape of RHTN

Β-blockers may offer a promising strategy for the future management of RHTN. For instance, the inclusion of a β-blocker in a quadruple SPC allows for easier screening for medication adherence. Indeed, the 2023 ESH guidelines [1] emphasize the value of using pharmacodynamic markers of adherence as objective tools to confirm or exclude nonadherence to antihypertensive therapy [1]. As β-blockers reduce heart rate, incorporating a β-blocker into the SPC not only enhances therapeutic efficacy and adherence, but also allows heart rate monitoring to serve as a practical and easily accessible surrogate for assessing adherence to all drugs (Fig. 3B, C). This feature of the SPC may strengthen physicians’ ability, particularly in primary care settings, to manage patients with apparent RHTN by helping distinguish true RHTN from uncontrolled BP resulting from nonadherence, thereby supporting more accurate diagnostic and therapeutic decision-making. The potential use of a quadruple SPC also allows for a substantial reduction in pill burden, likely resulting in improved adherence, a particular unmet need in this population (Fig. 3A). Additionally, the inclusion of a β-blocker does not increase the risk of hyperkalemia and provides additional cardiovascular protection in patients with RHTN who have comorbidities for which β-blockers are part of their GDMT or may exert favorable effects [80].

In the future, it may be conceivable to develop a personalized approach to the management of RHTN on the basis of the assessment of biomarkers reflecting SNS or aldosterone overactivation. Although this represents an appealing prospect, the adoption of biomarkers to guide tailored therapy in hypertension and RHTN faces several challenges. Sympathetic regulation is regionally heterogeneous and operates across multiple functional levels [154,155,156,157,158], making it unlikely that a single biomarker can reliably capture “global” sympathetic activation. Accordingly, indirect indices such as heart rate, heart rate variability, BP variability, and plasma noradrenaline should be interpreted with caution, particularly when used as surrogates of overall sympathetic drive. In RHTN, this limitation is particularly evident, as microneurographic studies demonstrate marked increases in MSNA that are not paralleled by changes in heart rate or plasma noradrenaline levels [30]. These findings support the complementary role of regional noradrenaline spillover measurements and direct MSNA recording as the most robust methods for characterizing sympathetic overactivity in this high-risk phenotype [155, 157]. However, these techniques remain largely confined to research settings and are not currently applicable in routine clinical practice to guide treatment decisions.

Similar issues apply to biomarkers of aldosterone overproduction, which currently lack consistent evidence supporting their role in treatment personalization. Although low renin and high aldosterone levels have been proposed as potential markers to predict response to MRAs, the evidence supporting their use for personalizing MRA therapy and subsequent monitoring in patients with RHTN remains conflicting. In the PATHWAY-2 trial, approximately 3% of patients had renin levels predicting a better response to α- or β-blockers, yet spironolactone remained the most effective BP-lowering therapy across the entire distribution of baseline plasma renin [106]. In the BaXHTN trial evaluating the BP-lowering effects of the ASI baxdrostat in patients with uncontrolled BP despite treatment with ≥ 2 antihypertensive agents, only 39–40% of patients achieved adequate BP control, despite substantial reductions in circulating aldosterone levels observed with this treatment [150]. Similar considerations emerge from the use of zilebesiran, a novel small interfering ribonucleic acid (siRNA) targeting hepatic angiotensinogen production. Despite this novel approach to antihypertensive treatment being extremely effective in reducing circulating aldosterone levels in phase 1 clinical trials [159], zilebesiran failed to significantly reduce BP in the KARDIA-3 study compared with placebo in a population similar to that of the BaXHTN trial [160].

Taken together, these findings suggest that the mechanisms underpinning SNS-/RAAS-mediated BP regulation are far more complex than previously anticipated and are unlikely to be fully captured by measurements of circulating renin and aldosterone levels or currently available markers of SNS overactivation. Consequently, these markers cannot, for the time being, be relied upon to predict response to therapies targeting aldosterone or SNS signaling.

9 Conclusions

In recent years, substantial progress has been made in elucidating the pathophysiological mechanisms underlying RHTN. Among these, SNS overactivity has emerged as a key driver of sustained BP elevation, acting through direct vascular effects, promotion of sodium and fluid retention, and stimulation of the RAAS. Although RHTN is recognized as an independent risk factor for adverse cardiovascular and renal outcomes, affected patients often present with multiple comorbidities that compound this risk. Poor adherence to antihypertensive therapy is common in this population and adds further complexity to clinical management by accelerating disease progression and increasing the likelihood of complications. Prompt and effective BP control is therefore critical.

Among the therapeutic options currently available, evidence indicates that β-blockers represent a valuable strategy. In addition to mitigating SNS overactivity, they often have compelling or suggested indications in patients with RHTN for many comorbidities commonly encountered in this population and offer side effect profiles that can be more easily monitored in routine practice than those of other fourth-line treatment options. Moreover, the recent development of the first quadruple SPC containing a β-blocker, specifically designed for patients with RHTN, may substantially advance patient management. This innovation not only promises improved BP control and clinical outcomes, but also facilitates distinguishing patients who require specialist referral from those who may primarily benefit from treatment simplification.

Data availability

This is a narrative literature review. To develop the review, we used our own collective experience and reviewed evidence identified through targeted PubMed searches on RHTN and relevant keywords between June and October 2025. Only data already reported in the referenced papers have been used to elaborate the review concepts. Consequently, there is no original data available.

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Acknowledgements

The authors would like to acknowledge Constantinos Bezos of Porterhouse Medical Group for medical writing support. Medical writing support was funded by Servier.

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Authors and Affiliations

Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy

Stefano Masi

National Institute of Cardiology, Interventional Cardiology and Cardiac Surgery (INCCI Luxembourg), Luxembourg City, Luxembourg

Atul Pathak

Centre Hospitalier du Luxembourg (CHL), Luxembourg City, Luxembourg

Atul Pathak

Pharmacology and Hypertension Unit, Hôpital Européen Georges Pompidou, Paris, France

Rosa Maria Bruno

Cardiovascular Center Aalst, AZORG Clinic, Aalst, Belgium

Sofie Brouwers

Department of Experimental Pharmacology, Vrije Universiteit Brussel, Brussels, Belgium

Sofie Brouwers

Department of Hypertension and Diabetology, Medical University of Gdansk, Gdansk, Poland

Krzysztof Narkiewicz

Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy

Stefano Taddei

First Department of Cardiology, National and Kapodistrian University of Athens, Hippokration General Hospital, Athens, Greece

Konstantinos Tsioufis

Institute of Clinical Pharmacology and Toxicology, Charité-University Medicine Berlin, Berlin, Germany

Reinhold Kreutz

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Sofie BROUWERS has received honoraria for consultancy or lectures from Daiichi Sankyo, Novartis, Amgen, Recor, Servier, and Medtronic. Rosa Maria BRUNO has received speaker’s honoraria from Medtronic, Servier, El Kendi, and LXO. Reinhold KREUTZ has received honoraria for consultancy or lectures from AstraZeneca, Bayer, Krka, Menarini Group, Merck, ProMed, PolPharma, Recor, Servier, and Zentiva. Stefano MASI has received consultation fees and honoraria for lectures, editorial activities, and advisory board participation from Servier. Krzysztof NARKIEWICZ has received honoraria for consultancy or lectures from AstraZeneca, Bausch, Berlin-Chemie/Menarini, Egis, Eli Lilly, Gedeon Richter, Krka, Medtronic, Novo Nordisk, Omron, Polpharma, Promed, Recordati, Sandoz, Servier, and Zentiva. Atul PATHAK has received honoraria for consultancy or lectures from AstraZeneca, Bayer, Medtronic, Merck, Novartis, Recor, and Servier. Stefano TADDEI has received honoraria for consultancy or lectures from Servier, Pfizer, Merck Serono, Sandoz, Neopharmed, Sharper, and Medtronic. Konstantinos TSIOUFIS has received research grants from Recor, Medtronic, and Recordatti and honoraria for consultancy or lectures from Medtronic, Servier, Bayer, Menarini, Novartis, AstraZeneca, Boehringer In, Pfizer, Chiesi, Pharmanel, Sanofi, Amgen, VIATRIS, and HIKMA.

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Masi, S., Pathak, A., Bruno, R.M. et al. The Role of β-Blockers in the Evolving Treatment Landscape of Resistant Hypertension. Drugs 86, 887–907 (2026). https://doi.org/10.1007/s40265-026-02319-9

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Article 8 — Large Vessel Vasculitis: Recent Advances in Pathophysiology and Targeted Therapies

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Abstract

Large vessel vasculitides (LVV), including giant cell arteritis (GCA) and Takayasu arteritis (TAK), share common features such as inflammation of large sized arteries but differ in several key aspects, including age of onset and pathogenic mechanism. This narrative review gives an update of recent insights into pathogenesis of GCA and TAK, and discusses emerging targeted therapies based on these insights. It highlights omics-based signatures, ULK3 and SLAMF7 in GCA, EGR1 in TAK, alongside genetic and somatic risk factors such as clonal haematopoiesis (DNMT3A/TET2) linked to relapse and ischaemic vision loss in GCA, and the IL6R-p.Asp358Ala variant as a predictor of reduced interleukin (IL)-6 receptor blockade response. Common mechanisms include CD4⁺ T-cell, monocyte/macrophage, and B-cell infiltration with activation of IL-6, JAK/STAT/interferon, and IL-17 pathways. Giant cell arteritis is characterised by GM-CSF-driven macrophages and disrupted programmed cell death (PD)-1/PD-L1 checkpoint regulation, while TAK shows dominance of CD8⁺ T cells and tumour necrosis factor (TNF)-α signalling. Interleukin-6 receptor inhibitors (e.g., tocilizumab) show robust efficacy in GCA but with notable non-responders; the JAK inhibitor upadacitinib demonstrated efficacy in a Phase III study, whereas IL-17 blockade (secukinumab) yielded inconsistent results. In TAK, TNF inhibitors and tocilizumab are comparably effective; early data suggest Janus kinases (JAK) inhibitors promote remission, imaging improvement, and glucocorticoid sparing. Mavrilimumab (GM-CSF receptor blockade) is promising in GCA. Recent studies have increasingly focused on short-term glucocorticoid therapy in combination with biologic agents. Advances in biomarker research, including investigation of the IL-6 receptor and IL-17A gene polymorphisms, may enable more targeted therapeutic strategies.

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Abstract

Large vessel vasculitides (LVV), including giant cell arteritis (GCA) and Takayasu arteritis (TAK), share common features such as inflammation of large sized arteries but differ in several key aspects, including age of onset and pathogenic mechanism. This narrative review gives an update of recent insights into pathogenesis of GCA and TAK, and discusses emerging targeted therapies based on these insights. It highlights omics-based signatures, ULK3 and SLAMF7 in GCA, EGR1 in TAK, alongside genetic and somatic risk factors such as clonal haematopoiesis (DNMT3A/TET2) linked to relapse and ischaemic vision loss in GCA, and the IL6R-p.Asp358Ala variant as a predictor of reduced interleukin (IL)-6 receptor blockade response. Common mechanisms include CD4⁺ T-cell, monocyte/macrophage, and B-cell infiltration with activation of IL-6, JAK/STAT/interferon, and IL-17 pathways. Giant cell arteritis is characterised by GM-CSF-driven macrophages and disrupted programmed cell death (PD)-1/PD-L1 checkpoint regulation, while TAK shows dominance of CD8⁺ T cells and tumour necrosis factor (TNF)-α signalling. Interleukin-6 receptor inhibitors (e.g., tocilizumab) show robust efficacy in GCA but with notable non-responders; the JAK inhibitor upadacitinib demonstrated efficacy in a Phase III study, whereas IL-17 blockade (secukinumab) yielded inconsistent results. In TAK, TNF inhibitors and tocilizumab are comparably effective; early data suggest Janus kinases (JAK) inhibitors promote remission, imaging improvement, and glucocorticoid sparing. Mavrilimumab (GM-CSF receptor blockade) is promising in GCA. Recent studies have increasingly focused on short-term glucocorticoid therapy in combination with biologic agents. Advances in biomarker research, including investigation of the IL-6 receptor and IL-17A gene polymorphisms, may enable more targeted therapeutic strategies.

Giant cell arteritis: pathogenic mechanisms and new potential therapeutic targets

Article Open access 28 November 2017

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Pathogenesis of Giant Cell Arteritis and Takayasu Arteritis—Similarities and Differences

Article 26 August 2020

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Recent Advances in Giant Cell Arteritis

Article 02 April 2018

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Autoimmune Diseases
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Large Vessel Vasculitis Diagnosis and Management

FormalPara Key Points

Giant cell arteritis (GCA) and Takayasu arteritis are both types of large vessel vasculitis, sharing common features but differing in aspects such as clinical presentation, underlying pathophysiology, and treatment response.
Giant cell arteritis is an age-associated disease and has been linked to somatic mutations related to clonal haematopoiesis, including the TET2 gene.
For both conditions, glucocorticoids remain the standard therapy, often combined with interleukin-6-receptor blockade, while Janus kinase inhibitors show particular promise in GCA. Recent studies have increasingly focused on short-term glucocorticoid therapy in combination with biologic agents specifically for GCA.

1 Introduction

Large vessel vasculitides (LVVs) are classified into two major entities according to the 2012 revised Chapel Hill Consensus Conference: Giant cell arteritis (GCA) and Takayasu arteritis (TAK) [1]. Giant cell arteritis is more common than TAK, but both diseases show marked geographical variation in incidence. A recent meta-analysis reported an overall annual pooled incidence of GCA of 10.0 cases per 100,000 individuals aged over 50 years with a high incidence in Scandinavia [2]. In contrast, TAK is much rarer, with a global annual pooled incidence of 0.11 cases per 100,000 individuals [3], with the highest rates reported in East Asian populations. Giant cell arteritis typically affects individuals aged > 50 years, with a peak incidence around the age of 75 years [4], whereas TAK generally manifests before the age of 40 years, with a median age of 25–30 years [5]. Both diseases demonstrate a female predominance: In GCA, the female-to-male ratio is approximately 2–3:1, while in TAK, it ranges from 6:1 to over 9:1 [6].

Clinically, GCA often affects cranial arteries and presents with cranial ischaemic symptoms such as headache, scalp tenderness, jaw claudication, and visual disturbances, including anterior ischaemic optic neuropathy, which can lead to blindness. However, large vessels such as the thoracic aorta and its proximal branches may also be affected, which can result in complications such as claudication and aneurysm formation. Notably, approximately 60% of GCA patients have concomitant polymyalgia rheumatica (PMR), supporting the concept of a disease spectrum rather than two isolated diseases [7]. Mendelian randomisation analysis of single-nucleotide polymorphism (SNP) indicated potential causal relationship between GCA and PMR at the genetic level, supporting the concept of the disease spectrum [8, 9]. Takayasu arteritis usually begins with non-specific systemic symptoms followed by vascular complications due to large artery involvement of different parts of the aorta and its branches. These include pulselessness, blood pressure discrepancies, renovascular hypertension, and stenoses or occlusions of affected arteries [10]. Both conditions have high relapse rates [11, 12]. Risk factors for relapse in GCA include female sex and large-vessel involvement [11]; in TAK, male sex, elevated C-reactive protein (CRP), and carotidynia have been identified [12]. Glucocorticoids (GC) are the mainstay of treatment for both diseases; however, a deeper understanding of the pathogenesis of LVV has led to the emergence of novel therapeutic approaches [13]. This narrative review delineates recent advances in disease pathogenesis alongside emerging therapeutic strategies based on these insights. While a formal systematic search strategy was not employed, the literature was comprehensively surveyed through key databases and recent relevant publications to provide a balanced and current overview.

2 Pathophysiology and Rationale for Targeted Therapies

Giant cell arteritis and TAK share similar pathophysiological features with CD4⁺ T cell, monocyte and macrophage infiltration in the arterial walls. Importantly, both diseases exhibit the presence of B cells and plasma cells within these inflammatory infiltrates, contributing to the complex immune landscape underlying vascular inflammation [13, 14]. Inflammation involving the adventitia, media, and intima promotes a vascular remodelling process in the affected arteries [15]. In both diseases, CD4⁺ T cells play a crucial role in promoting and sustaining inflammation, as well as in the formation of prototypic granulomas through macrophage differentiation. The CD4⁺ T cells differentiate into interferon-γ-producing Th1 cells and interleukin-17-producing Th17 cells [16]. In contrast to GCA, where CD4⁺ T cells play a central role, TAK involves both CD4⁺ and CD8⁺ T cells, with a higher abundance of CD8⁺ T cells, a reduced CD4⁺/CD8⁺ ratio, and increased numbers of CD20⁺ B cells compared to GCA [17]. The underlying pathophysiology provides the rationale for targeted therapies, which will be outlined in the following section (see Fig. 1 and Table 1).

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[Figure] — Table 1 Main immunopathophysiological pathways and key study findings in giant cell arteritis and Takayasu arteritis

2.1 The Interleukin 6 Pathway

Interleukin-6 (IL-6) is produced by macrophages, monocytes and vascular dendritic cells and infiltrates T cells, promoting CD4⁺ T-cell proliferation within the arterial wall in GCA patients [18]. Elevated levels of IL-6 are associated with active disease [19, 20]. Similarly, IL-6 has a central role in TAK, where it is produced by macrophages and Th17 cells in the arterial wall. Interleukin-6 contributes to inflammation and subsequent fibrosis through activation of adventitial fibroblasts and promotion of extracellular matrix production. In TAK, IL-6 levels also correlate with disease activity and relapse risk [21, 22]. Despite the pivotal role of IL-6 in GCA and TAK, there remains a substantial proportion of patients who fail to achieve clinical remission under IL-6-receptor inhibition [23, 24]. One potential contributing factor is a common coding single nucleotide polymorphism (SNP) in the IL-6 receptor gene, p.Asp358Ala (rs2228145 A>C), which can modulate leukocyte responsiveness to IL-6. This polymorphism is present in approximately 30%–40% of the general population and leads to increased levels of soluble IL-6 receptor (sIL-6R). Zorc et al. [25] demonstrated that the rs2228145 variant is associated with a reduced response to IL-6 receptor blockade and poorer clinical outcomes in GCA, likely driven by enhanced IL-6 signalling in CD4⁺ T cells. These findings suggest that the rs2228145 variant could potentially be used as a biomarker to guide treatment decisions in GCA. Its role in TAK is unclear.

2.2 The Janus Kinase/Signal Transducer and Activator of Transcription Pathway

Janus kinases (JAK) are intracellular tyrosine kinases that bind to cytokine receptors and, upon receptor activation, transmit signals by phosphorylating signal transducer and activator of transcription (STAT) proteins [26]. Interferons activate the JAK/STAT pathway, leading to the transcription of interferon-stimulated genes (ISGs) that have immunomodulatory functions [27]. Vieira et al. [28] showed an upregulation of pathways linked to type I interferon, JAK/STAT signalling, pro-inflammatory cytokines and chemokines in GCA. Furthermore, type I IFN signature genes, STAT1 and STAT2 were significantly upregulated in patients with GCA and INF-α serum concentrations were higher in patients with active symptoms of GCA as compared with patients without symptoms. In a study involving 25 patients with TAK, transcriptome analyses demonstrated that CD4+ and CD8+ T cells showed significant upregulation of genes involved in type I and II interferon responses, JAK/STAT signalling, and cytokine/chemokine pathways [29]. This dysregulation promotes the differentiation of naive CD4+ T cells to pro-inflammatory Th1 and Th17 cells in blood and is associated with disease activity and production of IFNγ and IL-17 [30].

2.3 The Interleukin-17 Pathway

Interleukin-17 (IL-17) is a proinflammatory cytokine mainly produced by Th17 cells as well as CD8+ T cells, γδ T cells, and various innate immune cell populations [31]. I-17-mediated inflammation is normally regulated by regulatory T cells and anti-inflammatory cytokines such as IL-10, transforming growth factor-β (TGF-β), and IL-35. However, dysregulation of IL-17 responses can contribute to immunopathology in autoimmune settings [32]. In active GCA, increased numbers of Th17 cells and IL-17-producing cells have been detected across all layers of affected temporal arteries [16]. Expansion of the Th17 population in the peripheral blood of GCA patients is accompanied by decreased regulatory T cell (Treg) numbers [33]. Interleukin-17 and IL-17 receptor expression are markedly upregulated in GCA arteries exhibiting transmural inflammation, and the level of IL-17 expression correlates directly with the intensity of the systemic inflammatory response [34]. A meta-analysis including over 1000 patients demonstrated that polymorphisms within the IL-17A locus (SNPs rs2275913, rs4711998, and rs7747909) are associated with susceptibility to GCA compared with healthy controls [35]. In TAK, IL-17A correlates with disease activity [30, 36].

2.4 The TNF-Alpha Pathway

In GCA tumour necrosis factor-α (TNF-α) is consistently detectable within inflammatory infiltrates; however, it does not represent the dominant effector cytokine driving disease pathology [37]. In TAK, the inflammatory infiltrate is characterised by an increased contribution of CD8⁺ T cells and natural killer cells, which represent important additional cellular sources of TNF-α alongside activated macrophages. Consequently, TNF-α emerges as a key pathogenic cytokine in TAK, amplifying pro-inflammatory signalling cascades and playing a central role in the maintenance of vascular inflammation and disease activity [38, 39].

2.5 Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF)

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a multifunctional cytokine that regulates the biology of CD4⁺ T cells and dendritic cells and plays a central role in macrophage maturation and function. Increased GM-CSF and GM-CSF receptor-α expression in mRNA and protein level has been demonstrated in GCA lesions [40]. Within the inflamed arterial wall of patients with GCA, GM-CSF is produced by multiple cell types, including B cells, fibroblasts and T cells. Granulocyte-macrophage colony-stimulating factor drives the differentiation and activation of pro-inflammatory macrophage subsets, particularly CD206⁺MMP-9⁺ macrophages, which mediate tissue destruction and folate-receptor-β⁺ macrophages (FRβ⁺), which promote intimal proliferation [41]. Adventitial CD90⁺ fibroblasts have been shown to express both GM-CSF and M-CSF, linking fibroblast activity to the distribution of distinct macrophage subsets. This GM-CSF-dependent crosstalk between macrophages and fibroblasts may contribute to the chronicity and progression of GCA [42].

2.6 The PD-1/PD-L1 Checkpoint Pathway

New-onset GCA has been observed following immune checkpoint inhibitor (ICI) therapy, with a reported prevalence of 0.06% among ICI-treated patients [43]. In this context, Monjo et al. [44] investigated the role of the programmed cell death 1/programmed cell death-ligand-1 (PD-1/PD-L1) co-inhibitory pathway in the pathogenesis of GCA. In this prospective study including 65 patients with newly diagnosed GCA, the authors assessed the frequency of circulating T peripheral helper (cTph) and T follicular helper (cTfh) cells – two CD4⁺ T cell subsets known to be associated with autoimmunity. The study demonstrated increased frequencies of both cTph and cTfh cells in patients with active GCA. Notably, both subsets exhibited high expression of PD-1, which may reflect a compensatory counter-regulatory mechanism. Patients who experienced disease relapse showed significantly lower frequencies of these cell populations compared to those in sustained remission. This suggests that an insufficient capacity to upregulate the PD-1 checkpoint pathway is associated with a poorer prognosis, further supporting a functional role of the PD-1/PD-L1 axis in the pathogenesis of GCA.

3 Molecular and Genetic Factors

3.1 Molecular Signatures of GCA and TAK Revealed by Omics Studies

Recent omics studies have provided important mechanistic insights into GCA and TAK [45]. Plasma proteomic profiling across the LVV spectrum demonstrated shared inflammatory and stromal remodelling signatures in GCA and TAK, including IL-6, monocyte/macrophage-associated proteins (e.g. CCL7, CSF1), tissue remodelling proteins (TIMP1, TNC), and novel mediators such as TNFSF14 and IL-7R, supporting overlapping innate immune activation despite clinical heterogeneity.

Multi-omics analyses in GCA identified Unc-51 like kinase 3 (ULK3) as the strongest protective factor via regulation of autophagy, highlighting its potential role in disease modulation [46]. Additionally, SLAMF7 was recognised as a potential target of elotuzumab. Among the identified targets, five (SLAMF7, ICAM1, IL18, IL6ST, CTSS) already have approved therapeutics. Single-cell analyses showed disrupted gene-immune cell interactions and cell-type-specific inflammatory gene expression in untreated GCA, with TYMP identified as the key hub gene.

In TAK, integrated bulk and single-cell transcriptomic profiling of peripheral T-cell subsets from eight treatment-naive patients and aortic tissue from three patients revealed shared signatures involving cytokine signalling, complement activation, focal adhesion, and extracellular matrix organisation, alongside subset-specific patterns [47]. In CD4⁺ differentially expressed genes (DEGs) were enriched for inflammation, angiogenesis, and platelet activation, whereas CD8⁺ DEGs were linked to cytokine synthesis, notably interleukin-1 signalling. The transcription factor EGR1 was consistently identified in both blood and tissue, underscoring its pivotal role in systemic and vascular inflammation. These omics studies delineate shared and disease-specific molecular signatures in GCA and TAK and provide a foundation for biomarker development and precision-targeted therapies in LVV.

3.2 Genetic Risk Factors in the Pathogenesis of GCA and TAK

Genome-wide association studies (GWAS) have provided important insights into the pathogenesis of inflammatory rheumatologic diseases. In GCA, susceptibility loci have been primarily identified in the human leukocyte antigen (HLA) region on chromosome 6, which confer an increased risk of disease development [48]. In TAK, HLA-B*52 has been confirmed as a major susceptibility allele, alongside four non-HLA susceptibility loci in VPS8, SVEP1, CFL2, and chromosome 13q21. Additionally, IL12B, PTK2B, and a locus on chromosome 21q22 have been confirmed as susceptibility regions [49]. Further, two tag SNPs in the promoter region of IL-18 (rs187238 and rs1946518) and one 3’UTR tag SNP in FGF2 (rs1476217) have been significantly associated with susceptibility to TAK, suggesting their potential role as risk factors for the development of TAK [50].

4 Somatic Mutation in the Pathogenesis of GCA and TAK

Beyond these genetic variations somatic mutations leading to activation of the myeloid cell compartment play a role in GCA pathogenesis. Clonal haematopoiesis (CH), characterised by the expansion of haematopoietic stem cell clones with somatic mutations, can arise due to aging and chronic inflammation. Giant cell arteritis is an age-associated disease, with cumulative incidence increasing significantly in patients harbouring clonal haematopoiesis of indeterminate potential (CHIP) or clonal cytopenia of undetermined significance (CCUS). Among the somatic mutations studied, alterations in the Tet methylcytosine dioxygenase 2 (TET2) gene, which encodes an epigenetic regulator, have been associated with an increased risk of developing GCA and are linked to cases complicated by ischaemic vision loss [48, 51].

Gutierrez et al. [52] investigated the prevalence and functional relevance of CH in patients with GCA and TAK compared to age-matched healthy controls. The incidence of CH was found to be 13% in TAK and markedly higher at 61% in GCA. The most frequently mutated gene was DNA methyltransferase 3 alpha (DNMT3A), followed by TET2. Somatic mutations with a variant allele frequency (VAF) ≥10% were also observed exclusively in older individuals, most commonly in those diagnosed with GCA. Clonal haematopoiesis was significantly more common in patients with GCA compared to age-matched healthy controls. Moreover, patients with CH had a higher risk of disease relapse compared to GCA patients without CH (67% vs 25%, p < 0.01).

5 Overview of Current Targeted Therapies

Several new therapeutic approaches for the treatment of LVV have emerged in recent years. Glucocorticoids (GCs) remain the mainstay for initial treatment of GCA and TAK, with a strategy of slow tapering. However, relapse rates remain high under GC monotherapy and the prolonged treatment duration increases the risk for GC-associated adverse events. Therefore, research has been focusing on the efficacy of immunomodulatory agents to improve clinical outcomes and reduce GC cumulative doses (see Table 1).

5.1 Therapeutic Approaches in GCA

According to the 2018 EULAR recommendations for the management of LVV, induction of remission in GCA should begin with GC therapy (40–60 mg/day prednisone-equivalent) [53]. In cases with acute visual loss or amaurosis fugax, the administration of 250–1000 mg/d intravenous (IV) methylprednisolone for up to three days should be considered. The 2021 ACR guidelines conditionally recommend the use of oral GCs in combination with tocilizumab (TCZ), rather than oral GC alone, for patients with newly diagnosed GCA [13], while EULAR recommendations suggest using TCZ as an add-on in newly diagnosed cases with a high risk of GC-related adverse events or comorbidities, or in patients who experience relapses.

5.1.1 IL-6 Receptor Inhibiton

The GiACTA trial represents a landmark in the management of GCA as the first randomised, double-blind, placebo-controlled Phase III trial. The study involved 251 patients with GCA evaluating TCZ administered weekly or every other week in combination with a 26-week GC taper, compared with placebo combined with either a 26- or 52-week GC tapering regimen [54]. At Week 52, sustained remission (flare free from Week 12 to 52, normalised CRP with protocol GC taper adherence) was achieved in 56% of patients on weekly TCZ and 53% on every-other-week TCZ, compared with 14% and 18% in the placebo groups with 26- and 52-week GC tapers, respectively (p < 0.001). The cumulative median GC dose over 52 weeks was 1862 mg in both TCZ groups versus 3296 mg (placebo 26-week taper) and 3818 mg (placebo 52-week taper; p < 0.001 for both).

Several other studies have investigated the impact of TCZ on GC tapering strategies in GCA. In a prospective, single-arm, open-label study by Unizony et al. [55], the efficacy of TCZ in combination with a short 8-week GC taper was evaluated in 30 patients with new-onset or relapsing GCA. Sustained GC-free remission at Week 52 was achieved in 23 patients (77%) and seven patients (23%) relapsed (mean time to relapse:15.8 weeks [SD 14.7]).

A recent prospective observational study (TOPAZIO) evaluated the impact of an ultra-short GC pulse regimen (IV methylprednisolone 500 mg/day for 3 days) followed by weekly TCZ for 52 weeks in 18 patients with large-vessel GCA [56]. The primary endpoint, a reduction in PET vascular activity score (PETVAS) at Weeks 24 and 52 was met (mean change (95% CI) − 8.6 (− 11.5 to − 5.7) at Week 24 and − 10.4 (− 13.6 to − 7.2) at Week 52; p = 0.001 and 0.002), respectively. In a 26-week observational follow-up after TCZ discontinuation, received TCZ monotherapy was effective in maintaining drug-free clinical remission in large-vessel GCA, with sustained PETVAS reduction compared to baseline; however, PETVAS significantly increased six months after TCZ discontinuation (mean [95% CI] change from Week 52 to 78: + 4.6 [0.7–8.5]) suggesting inflammatory activity [56]. It should be noted that the study excluded patients with cranial symptoms, limiting generalisation of these results to standard clinical practice in GCA. Accordingly, such abbreviated GC-TCZ protocols should currently be restricted to controlled clinical studies at specialised centres with appropriate expertise.

Another study (GUSTO trial) investigated TCZ monotherapy following ultra-short GC administration (500 mg IV methylprednisolone for three days) in new-onset GCA in a single-arm, open-label, proof-of-concept trial. In contrast to the TOPAZIO study [57], which included only patients without ischaemic cranial manifestations, 15 of the 18 enrolled patients in this trial presented with cranial involvement. Remission was achieved in 14 (78%) of 18 patients within 24 weeks; with a relatively long mean time to remission (11.1 weeks [95% CI 8.3-13.9]). Thirteen of 18 (72%) patients remained relapse-free up to Week 52 (95% CI 47–90), while 3 of 18 patients were considered primary treatment failures. Concerningly, one patient developed anterior ischaemic optic neuropathy [58]. In the extension study [59] drug-free remission was maintained in most patients. At Week 52, 13 of 18 patients were in relapse-free remission. Minor relapses occurred in two patients at Weeks 72, 187, and 200, both regaining remission after restarting TCZ monotherapy. By Week 208, 11 of 18 patients remained in relapse-free remission, with 11 of 13 maintaining drug-free remission for 156 weeks.

In a retrospective cohort study by Nielsen et al. [60], which included 155 patients with GCA, relapse rates were compared between tapering and abrupt discontinuation strategies of TCZ. Tocilizumab was primarily initiated due to relapse in 100 of 155 patients (65%). Among the 104 patients who discontinued TCZ, 59% stopped the drug abruptly, 46% of whom experienced a relapse during follow-up (median overall follow-up duration: 854 days from diagnosis and 572 days from TCZ initiation). In contrast, 57 patients underwent tapering, with relapse occurring in 16% (6/38) of those tapering every 2 weeks and in 11% (2/19) of those tapering every 3 weeks. Most relapses (88%; 42 of 48) occurred during the first year of follow-up. Tocilizumab tapering was associated with significantly longer relapse-free survival compared to abrupt discontinuation (p = 0.02). However, relapse rates after discontinuation of treatment were similar between slow and rapid TCZ tapering (21 of 45 [47%] vs 27 of 59 [46%]), respectively.

Interleukin-6-receptor blockade represents an effective and well-tolerated therapeutic option in GCA and is incorporated into international treatment guidelines. Despite this, high relapse rates following discontinuation of IL-6-receptor blockade remain a significant challenge. Further studies are therefore needed to clarify its role in facilitating a standardised GC-tapering regimen in routine clinical practice.

5.1.2 JAK/STAT Inhibition

In the Phase III, randomised, multicentre, double-blind, placebo-controlled SELECT-GCA trial, Blockmans et al. [61] evaluated the efficacy and safety of the JAK inhibitor upadacitinib (15 mg/d and 7.5 mg/d) in combination with a 26-week GC taper, compared to placebo plus a 52-week GC taper, in patients with new-onset or relapsing GCA. A total of 428 patients were enrolled: 209 received upadacitinib 15 mg, 107 received upadacitinib 7.5 mg, and 112 received placebo. The primary endpoint, sustained remission at Week 52 (absence of GCA symptoms Weeks 12–52 with protocol GC taper adherence) was achieved more frequently in upadacitinib 15 mg than placebo (46.4% [95% CI 39.6–53.2] vs 29.0% [95% CI 20.6–37.5]; p = 0.002). Additionally, secondary endpoints including sustained complete remission (defined as sustained remission with normalised ESR and CRP from Weeks 12 to 52), time to disease flare, cumulative GC exposure, and patient-reported outcomes were favouring upadacitinib 15 mg. In contrast, upadacitinib 7.5 mg did not demonstrate superiority for the primary endpoint compared to placebo (41.1% [95% CI 31.8–50.4]).

In a small prospective, open-label pilot study over 52 weeks, baricitinib was investigated in patients with relapsing GCA [62]. During the observation period, only 1 out of 14 patients (7%) experienced a relapse, while the remaining patients maintained remission under baricitinib, even after GC discontinuation. Therefore, both studies have demonstrated the efficacy of JAK inhibitors, significantly broadening the therapeutic options available in this area.

5.1.3 IL-17 Pathway Blockade

In a randomised, double-blind, placebo-controlled, multicentre Phase II trial (TitAIN), a total of 52 patients with new-onset or relapsing GCA were enrolled and randomised to receive either secukinumab (n = 27) or placebo (n = 25), both in combination with a standardised 26-week GC tapering regimen. The proportion of patients achieving sustained remission at Week 28 (flare free Weeks 12–28, adherence to the GC taper) was significantly higher in the secukinumab group compared to the placebo group (70% [95% credibility interval, 52–85] vs 20% [12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29]). No new safety signals were identified [63]. However, the following Phase III trial (GCAptAIN) did not meet its primary endpoint sustained remission in Week 52 in adults with newly diagnosed or relapsing GCA as communicated by the sponsor of the trial [64]. While all three studies (GIACTA, SELECT-GCA and GCAptAIN) had sustained remission in Week 52 as the primary endpoint, the definition of sustained remission in GCAptAIN significantly differed from the definitions used in SELECT-GCA. Also, the less pronounced effect of secukinumab on CRP-concentrations that were part of the definition of the primary endpoint, might have contributed to the study outcome.

Detailed trial data of the GCAptAIN study have not yet been published. However, a small case series of six patients refractory to TCZ demonstrated clinical and imaging remission. Thus, despite the failure to meet the primary endpoint in the GCAptAIN TITAN study, a potential role for IL-17 blockade cannot be excluded [65]. Additionally, as is well established, PMR and GCA represent a disease spectrum [9]. In patients with PMR treated with secukinumab in the randomised controlled REPLENISH trial, the primary endpoint of sustained remission at Week 52 was met, as reported by the study sponsor [66].

5.1.4 TNF-α Inhibition

Several randomised controlled trials investigating TNF inhibitors, including infliximab, etanercept, and adalimumab, have consistently failed to demonstrate significant clinical benefit or GC-sparing effects in GCA [67,68,69]. These findings suggest that TNF blockade is not an effective therapeutic strategy in GCA.

5.1.5 GM-CSF Pathway Inhibition

Mavrilimumab, a monoclonal antibody targeting the GM-CSF receptor, was evaluated in a Phase II randomised, double-blind, placebo-controlled, multicentre trial in patients with new-onset or relapsing GCA [70]. A total of 70 patients were enrolled (42 received mavrilimumab, 28 received placebo), each in combination with a 26-week GC taper. Mavrilimumab significantly reduced the risk of flare compared with placebo (flare: 19% vs 46%). The primary outcome median time to flare was 25.1 weeks in the placebo group but could not be calculated for patients in the mavrilimumab group because fewer than 50% experienced a flare during the 26 weeks (HR 0.38; 95% CI 0.15–0.92; p = 0.026). Despite these promising results, a Phase III trial has not yet been conducted.

5.1.6 Other Cytokine and Immune Targets

In a multicentre trial, 49 patients with GCA were treated with IV abatacept (a fusion protein that inhibits T-cell activation by blocking costimulatory signals), 10 mg/kg on Days 1, 15, 29, and Week 8, alongside daily GC [71]. At Week 12, patients in remission were randomised in a double-blind manner to continue monthly abatacept or switch to placebo, with both groups following a standardised GC taper ending at Week 28. Abatacept significantly reduced the risk of relapse, with a relapse-free survival rate at 12 months of 48% in the abatacept group versus 31% in the placebo group (p = 0.049).

Although a prospective, open-label 52-week study by Conway et al. [72] demonstrated that ustekinumab, an IL-12/23 inhibitor, may be a promising treatment option, as 25 patients with refractory GCA showed sustained disease control until Week 52, another prospective trial [73] evaluating ustekinumab in 13 patients with active new-onset or relapsing GCA reported a low rate of GC-free remission at Week 52 (23%), defined as absence of relapse and normalisation of ESR and CRP.

The THEIA Phase II trial, which investigated guselkumab, a selective IL-23 blockade, in combination with a 26-week GC taper versus placebo for the treatment of new-onset or relapsing GCA, recently reported that the primary endpoint, GC-free remission, was not significantly different between the treatment arms, leading to termination of the study due to insufficient efficacy, with no new safety signals identified [74].

Three randomised, double-blind, placebo-controlled trials compared methotrexate (MTX) plus GC with placebo plus GC in GCA. Two trials found no significant advantage of MTX [75, 76], whereas one trial demonstrated a reduced risk of relapse in the MTX group [77]. A meta-analysis of these three trials with 161 patients with newly diagnosed GCA (MTX, n = 84; placebo n = 77) was performed [78]. Mean follow-up was 54.7 weeks (SD 39.2), and MTX doses ranged from 7.5–15 mg/week. Methotrexate significantly reduced the risk of first and second relapse compared to placebo, respectively (HR 0.65, 95% CI 0.44–0.98, p = 0.04; and HR 0.49, 95% CI 0.27–0.89, p = 0.02). The number-needed-to-treat (NNT) to prevent one first or second relapse within 48 weeks was 3.6 (95% CI 2.2–56.8) and 4.7 (95% CI 3.3–21.9), respectively. Methotrexate also reduced cumulative prednisolone dose by 842 mg over 48 weeks (p < 0.001). The abstract of the MetoGIA study, an open-label, randomised, controlled, multicentre non-inferiority trial, was recently presented as preliminary data at the ACR 2025 meeting [79]. Among 218 patients (MTX n = 108; TCZ n = 110), the primary endpoint, defined as the proportion of patients without relapse after initial remission and without deviation from the GC taper from baseline to Week 78, was achieved in 37% (MTX) versus 46% (TCZ), corresponding to a 9% difference (95% CI −4% to 22%); thus, MTX did not demonstrate non-inferiority to TCZ.

Leflunomide has been investigated in several studies involving patients in GCA. In a prospective, open-label study, leflunomide was evaluated in 215 patients [80]. At Week 12, 151 patients received leflunomide and GC, while the remaining patients continued GC monotherapy. During the 96-week follow-up, 64 patients (29.8%) experienced a relapse. Among the 51 patients who relapsed after Week 12, 22 of 151 (14.6%) in the leflunomide group versus 29 of 64 (45.3%) in the GC-only group relapsed (p = 0.001; NNT 3.3 for leflunomide). A 2-year follow-up study in an Indian cohort (n = 22) demonstrated that leflunomide effectively reduced GC exposure while maintaining disease control [81]. Additionally, an open-label study showed a GC-sparing effect of leflunomide plus GC compared to GC monotherapy, with significantly fewer relapses during 48 weeks of follow-up (13.3% vs 39.1%, p = 0.02) [82].

5.2 Therapeutic Approaches in TAK

Although the initial GC regimen in TAK closely parallels that of GCA, the clinical course of TAK is often more refractory in terms of delayed treatment response and relapse risk. High relapse rates combined with the frequent challenges of GC tapering and the risk of vascular complications, underscore the need for early initiation of immunosuppressive therapy. According to the 2021 American College of Rheumatology/Vasculitis Foundation (ACR/VF) guideline for the Management of TAK, non-GC immunosuppressive agents such as MTX, azathioprine, and tumour necrosis factor inhibitors (TNFi) may be used in combination with GC [13]. In cases of inadequate response, the use of TCZ is recommended. Randomised controlled trials are limited, and the available evidence remains relatively sparse. As a result, current recommendations are based on low to very low levels of evidence [13, 53].

5.2.1 IL-6 Receptor Inhibiton

Several retrospective and prospective studies have demonstrated the efficacy and safety of IL-6 receptor inhibition [83,84,85,86]. A randomised, double-blind, placebo-controlled Phase III trial (n = 36) in patients with TAK did not achieve the primary endpoint; however, a benefit of TCZ in terms of prolonged time to relapse was observed [87]. Long-term efficacy and a GC-sparing effect without new safety concerns were further confirmed in the open-label extension of this study [88]. Furthermore, in a prospective multicentre open-label study, patients received seven infusions of TCZ followed by a 12-month observation period after treatment cessation [89]. During this follow-up, 45% of patients experienced relapse, suggesting that although TCZ is effective, ongoing maintenance therapy may be necessary. Further research is needed to establish the optimal duration of IL-6-receptor blockade.

In a single-centre retrospective analysis of 63 patients by Liao et al. [90], the disease activity of patients treated with TCZ (n = 31) was lower compared to cyclophosphamide-treated patients (n = 32) (NIH score <1 in TCZ: 50%, 90%, and 96% at 1, 3, and 6 months vs cyclophosphamide: 36%, 30%, and 78%), respectively.

Overall, evidence from clinical trials and observational studies supports TCZ as a safe and effective option for managing TAK, improving disease control and reducing cumulative GC dose.

5.2.2 JAK/STAT Inhibition

Recently published data demonstrated the efficacy of JAK inhibitors in the treatment of TAK. A prospective cohort study evaluated the efficacy and safety of tofacitinib versus leflunomide over 12 months [91]. A total of 67 patients were enrolled, with 35 patients in the leflunomide group and 32 in the tofacitinib group. Complete remission (CR) was defined as no new or worsening systemic or vascular symptoms, ESR ≤40 mm/h, and GC dose ≤15 mg/day at 6 months or ≤10 mg/day at 12 months. Partial remission (PR) required no new or worsening vascular symptoms plus at least two of the other criteria. The effectiveness rate (ER), which included patients who achieved CR or PR, was comparable between the groups (leflunomide 88.57% [31/35] vs tofacitinib 87.50% [28/32], p = 1.00). Furthermore, after 12 months, a significantly higher proportion of patients in the tofacitinib group was in sustained remission under low-dose GC (≤7.5 mg/day) (46.9% vs 17.1%, p = 0.02) and angiographic improvement was more frequent in the tofacitinib group (25.0% vs 5.7%, p = 0.04).

In a prospective observational study involving 53 patients, tofacitinib combined with GC was compared to MTX plus GC over a 12-month observation period [92]. Complete remission rates were higher in the tofacitinib group compared to the MTX group at 12 months (88.46% vs 56.52%, p = 0.02). Furthermore, tofacitinib demonstrated a longer median relapse-free duration and a lower average GC dose.

In a prospective cohort study, the efficacy of baricitinib in combination with GCs was evaluated in patients with refractory TAK [93]. A total of 10 patients received baricitinib. After 6 months, 60% (6/10) of patients achieved an overall treatment response, defined as a CRP level <10 mg/L, absence of angiographic disease progression, and a GC dose <15 mg/day. Four of these patients maintained their response during a median follow-up of 15.3 months (range 4–31). Overall, JAK inhibitors may represent a potential therapeutic option; however, further randomised controlled trials are needed to confirm these results.

5.2.3 IL-17 Pathway Blockade

A prospective, single-centre, open-label cohort study evaluated secukinumab versus TNFi in 53 patients with TAK who were refractory to treatment with GC combined with two conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) or one csDMARD and TCZ. Nineteen patients received secukinumab and 34 patients were treated with TNF inhibitors. Complete response was defined as full clinical remission, normalisation of inflammatory markers, no arterial progression on imaging, and GC dose <15 mg/day. Comparable response rates were observed at 3 months (31.6% for secukinumab vs 58.8% for TNF inhibitors, p = 0.057) and at 6 months (52.6% vs 64.7%, p = 0.389), with similar safety profiles between the two treatment groups [94].

5.2.4 TNF-α Inhibition

Several observational studies have demonstrated a meaningful improvement in disease activity in patients with TAK treated with TNF inhibitors [95,96,97]. Long-term follow-up studies confirmed that infliximab induced a sustained clinical improvement over time, accompanied by significant benefits in health-related quality of life [98,99,100]. More recently, a large retrospective multicentre study directly compared ADA (n = 34) and infliximab (n = 101) in patients with TAK [101]. This study confirmed that both TNF inhibitors are effective in routine clinical practice, with no significant differences observed between the two agents regarding the risk of relapse or the need for revascularisation procedures. Rates of complete response, defined as a National Institutes of Health (NIH) activity score < 2 with a prednisone dose < 7.5 mg/day, were comparable between groups, being achieved in 68% of patients treated with ADA and 73% of those receiving infliximab (p = 0.8).

5.2.4.1 Comparison of TCZ with TNF inhibitors

In a randomised controlled, open-label trial, the efficacy and safety of Adalimumab (ADA) versus TCZ were evaluated in patients with active and severe TAK [102]. A total of 40 patients were enrolled, with 21 receiving ADA and 19 receiving TCZ, both in combination with the same GC tapering schedule and MTX 15 mg/per week. The primary endpoint was the efficacy rate (ER) at 6 months, defined as a GC dose ≤ 15 mg/day without new or worsening systemic symptoms or vascular lesions upon imaging. In the intention-to-treat population, the ER at 6 months was significantly higher in the ADA group compared to the TCZ group (85.71% vs 52.63%, p = 0.02). Nevertheless, efficacy rates at 9 and 12 months did not differ significantly between the groups. However, it should be taken into account that a greater proportion of patients in the ADA group were treatment-naive compared to the TCZ group (28.57% vs 10.53%, respectively), and the median disease duration was approximately 14 months shorter [103].

Several other studies have demonstrated comparable outcomes between TCZ and TNFi, suggesting similar efficacy profiles in TAK. In a multicentre retrospective cohort study conducted across Europe, 209 patients with TAK treated with either TNFi (n = 132) or TCZ (n = 77) were included. At 6 months, CR, defined as National Instituted of Health (NIH) score < 2 and prednisone < 10 mg/day, was achieved in 66% (101/152) of patients receiving TNFi and 70% (75/107) of those treated with TCZ [104]. Similarly, the retrospective analysis by Alibaz-Oner et al. [105] involving 111 patients demonstrated that the efficacy of TNFi and TCZ was comparable in terms of remission rates.

In contrast to the 2021 ACR recommendations [13], a systematic review and meta-analysis of six studies found no significant differences between TCZ and TNFi in clinical remission (RR 1.03, 95% CI 0.91–1.17), angiographic stabilisation (RR 1.00, 95% CI 0.72–1.40), or adverse events (RR 0.84, 95% CI 0.54–1.31), supporting broadly similar effectiveness of both biologic strategies in TAK [106]. Well-designed randomised controlled trials, including adequately powered head-to-head comparisons with standardised GC tapering and longer follow-up, are required to definitively clarify the relative efficacy and safety of TCZ versus TNFi in TAK.

5.2.5 Other Cytokine and Immune Targets

In a randomised controlled study including 34 patients with TAK, those who achieved remission under abatacept combined with a GC tapering schedule by Week 12 underwent double-blind randomisation to continue monthly abatacept or switch to placebo [107]. The addition of abatacept to GC did not reduce the risk of relapse compared with placebo (p = 0.853) and was not associated with a longer median duration of remission (abatacept: 5.5 months vs placebo: 5.7 months).

Methotrexate has already demonstrated therapeutic efficacy in patients with TAK [108]. A retrospective multicentre study compared MTX and azathioprine (AZA) as initial GC-sparing therapies in patients with TAK. Of the 301 patients included, 204 received MTX and 77 received AZA [109]. No differences were seen with regard to remission rates, relapse frequency, radiographic progression (not defined in the manuscript), and drug survival. Higher rates of vascular surgery (AZA: 23% vs MTX: 9%, p = 0.001) were reported in the AZA group; however, higher frequencies of GC treatment in the MTX group and other methodological limitations (i.e., no information on the administered doses and outcomes) make conclusions difficult.

Leflunomide has demonstrated efficacy and safety in TAK, with observational studies reporting clinical improvement and disease activity reduction [110, 111]. A retrospective cohort study by Peron et al. [112] compared the effectiveness and safety of ADA and leflunomide in patients with TAK. A total of 44 patients were included, with 28 receiving leflunomide and 16 receiving ADA. After 15 months, the two groups showed comparable outcomes (CR rate: 62.5% for ADA vs 78.3% for leflunomide; p = 0.307; development of new arterial lesions: 40% vs 25%; p = 0.467). A limitation is that more ADA patients needed baseline IV methylprednisolone, indicating greater disease severity. In comparison, a cohort study of 68 patients demonstrated that leflunomide achieved a faster treatment response and a significantly lower relapse rate compared to MTX over a 12-month follow-up period (7.24% vs 16.67%, p = 0.03) [113]. Additionally, in two prospective cohort studies (n = 131 and n = 929), leflunomide demonstrated superiority over cyclophosphamide in patients with TAK [114, 115]. Leflunomide appears to be a promising therapeutic target in TAK; however, randomised controlled trials are still needed.

6 Therapeutic Pipeline and Ongoing Trials

6.1 Ongoing Clinical Trials of GCA

Several novel and known therapeutic strategies are under current investigation in GCA to improve remission maintenance and reduce GC exposure. In addition to therapies already under investigation in GCA, such as secukinumab (NCT05380453), abatacept (NCT04474847), ustekinumab (NCT03711448) and MTX (NCT05623592), novel agents including the endothelin receptor antagonist bosentan, are also being evaluated (NCT06957002, NCT06887062) (see Table 2 for details).

[Figure] — Table 2 Ongoing and recently completed clinical trials in giant cell arteritis and Takayasu arteritis

6.2 Ongoing Clinical Trials of TAK

The Phase III SELECT-Takayasu trial is evaluating upadacitinib in patients with active TAK (NCT04161898). Deucravacitinib, a selective TYK2 inhibitor targeting Th1/Th17 cytokines and type I interferon pathway, is tested against ADA in relapsing TAK (TYK-TAK trial) (NCT07013838) (see Table 2 for details).

7 Conclusion

Although GCA and TAK are both classified as LVV and share overlapping clinical features, they represent immunologically and therapeutically distinct entities.

Common pathogenic pathways include IL-6, JAK/STAT/interferon, and IL-17 signalling. On the cellular level, GCA is characterised by GM-CSF-dependent macrophage subsets checkpoint dysregulation (PD-1/PD-L1), and age-associated clonal haematopoiesis (CH) of myeloid cells, whereas TAK exhibits dominance of CD8⁺ T cells, disturbance of TNF-α signalling, and a potential pivotal role of the transcriptional factor EGR1, identified through omics analyses.

These divergent mechanisms provide a strong rationale for precision medicine approaches and targeted deployment of novel therapeutic classes. In GCA, IL-6-receptor blockade with TCZ remains first-line therapy, with JAK inhibitors emerging as valid alternatives for patients with inadequate response or intolerance. The GM-CSF receptor blockade (e.g., mavrilimumab) shows promising efficacy but requires further validation. For TAK, current evidence supports the use of both TNF inhibitors and TCZ as effective biologics, despite ACR recommendations favouring IL-6-receptor blockade; TNF inhibitors may serve as important options for refractory cases.

In both diseases, biologics primarily aim to minimise cumulative GC exposure, addressing a major source of morbidity. Biomarker-guided therapeutic decisions are pivotal for precision care. In GCA, the IL6R rs2228145 variant predicts attenuated response to IL-6-receptor inhibition, while CH screening (DNMT3A/TET2 mutations) identifies patients at higher risk of relapse and vascular complications. Molecular signatures reflecting IFN/JAK, IL-17, and GM-CSF pathway activity may further guide tailored treatment. Omics-derived targets such as ULK3 and SLAMF7 in GCA and EGR1 in TAK offer opportunities for drug repurposing and novel interventions. Critical unmet needs include high-quality randomised head-to-head trials comparing biologics and targeted synthetic DMARDs (e.g., TCZ vs TNFi vs JAKi) in TAK, and adaptive, biomarker-stratified trial designs in both GCA and TAK.

Standardised, disease-specific endpoints must be defined, considering nuances such as the impact of IL-6-receptor blockade on CRP concentrations, and protocols for GC tapering and immunosuppressive therapy duration require validation. Safety surveillance is especially important in GCA given the older patient population.

Looking forward, integrating early, biomarker-driven combination therapies with optimised GC strategies promises to improve outcomes. Validation of genetic (IL6R, IL17A), somatic (CH), cellular (Th1/Th17/CD8), and imaging biomarkers is essential to enable individualised treatment, facilitating precise risk stratification and targeted therapy selection.

In summary, while therapeutic advances have transformed LVV management, personalised treatment approaches based on mechanistic insights and biomarker guidance will be key to overcoming current challenges and optimising long-term disease control. Validating genetic, somatic, cellular, and imaging biomarkers will enhance individualised care and improve long-term outcomes in LVV.

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Myriam Reisch, Jens Thiel & Philipp Bosch

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MR: Consultancy: Lilly; Adboard/speaker fees: Alfasigma, Novartis. JT: Consultancy: AbbVie, Janssen, Lilly, Novartis, CSL Behring/Vifor, GSK, AstraZeneca; Speaker Honoraria: AbbVie, Galapagos, Janssen, BMS, Lilly, Vifor, StreamedUp, CSL Behring/Vifor, GSK, AstraZeneca; Research funding: BMS, GSK; Patent application: Pending patent application for the use of secukinumab in GCA. PB: Adboard/speaker fees by Johnsson and Johnsson, AbbVie, Lilly and UCB, Novartis; Project grants: Pfizer.

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Reisch, M., Thiel, J. & Bosch, P. Large Vessel Vasculitis: Recent Advances in Pathophysiology and Targeted Therapies. Drugs 86, 909–925 (2026). https://doi.org/10.1007/s40265-026-02323-z

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Article 9 — Antifungal Treatment Regimens as Primary Therapy for Invasive Aspergillosis: A Systematic Review and Network Meta-analysis

DOI: 10.1007/s40265-026-02316-y
Section: Systematic Review
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Authors: Gu, Qiaoling

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Abstract

Background Invasive aspergillosis (IA) is an invasive fungal disease associated with high mortality. Triazoles are the primary therapy for IA, while amphotericin B, echinocandins, and antifungal combined therapy are commonly considered as alternative treatment options although their efficacy and safety remain subjects of debate. We employed Bayesian network meta-analysis (NMA) to synthesize evidence and evaluate the efficacy and safety of different primary antifungal treatment regimens for IA. Methods A literature search was done in PubMed, EMBASE, Cochrane, and Web of Science databases for clinical studies on primary treatment for patients with IA published before 28 March 2024. We included randomized controlled trials (RCTs) and cohort studies involving patients with proven or probable IA who underwent primary treatment. The primary treatment regimens comprised different types or dosages of monotherapy or combination therapy involving triazoles, echinocandins, and amphotericin B. The primary outcome was cumulative all-cause mortality. Secondary outcomes included all-cause mortality at day 42, day 84, or end of treatment (EOT); the overall response at day 42, day 84, or EOT; invasive aspergillosis-associated mortality on day 42, day 84, and EOT; the incidence of adverse events (AEs), serious adverse events (SAEs), and treatment-related AEs; and treatment discontinuation due to AEs. Results The primary network meta-analysis for cumulative all-cause mortality (5 RCTs, 6 regimens, n = 1293) revealed no statistically significant differences among treatment regimens compared with voriconazole (VOR; surface under the cumulative ranking curve [SUCRA] 56.3%), including VOR combined with anidulafungin (ANI; risk ratio [RR] 0.74, 95% credible interval [CrI] 0.43–1.28; SUCRA 84.3%; moderate confidence), isavuconazole (ISA; RR 0.79, 95% CrI 0.45–1.40; 79.4%; moderate confidence), and posaconazole (POS; RR 1.20, 95% CrI 0.72–2.02; 34.6%; moderate confidence). Sensitivity analyses confirmed the robustness of these findings. Regarding safety, no significant differences were observed in SAEs for ISA (RR 0.91, 95% CrI 0.75–1.11; 85.7%; moderate confidence), POS (RR 1.03, 95% CrI 0.87–1.23; 40.8%; low confidence), and VOR combined with ANI (RR 1.09, 95% CrI 0.88–1.36; 20.8%; moderate confidence) compared with VOR (52.6%). Integrated efficacy-safety analysis suggested a favorable risk–benefit profile for isavuconazole. Conclusions ISA, POS, and VOR are the preferred antifungal agents for primary treatment of IA, with ISA demonstrating a higher likelihood of an optimal efficacy–safety balance. The combination of VOR and ANI may be considered for a subset of severe cases. Registration PROSPERO identifier number CRD42024561215.

Body

Abstract

Background

Invasive aspergillosis (IA) is an invasive fungal disease associated with high mortality. Triazoles are the primary therapy for IA, while amphotericin B, echinocandins, and antifungal combined therapy are commonly considered as alternative treatment options although their efficacy and safety remain subjects of debate. We employed Bayesian network meta-analysis (NMA) to synthesize evidence and evaluate the efficacy and safety of different primary antifungal treatment regimens for IA.

Methods

A literature search was done in PubMed, EMBASE, Cochrane, and Web of Science databases for clinical studies on primary treatment for patients with IA published before 28 March 2024. We included randomized controlled trials (RCTs) and cohort studies involving patients with proven or probable IA who underwent primary treatment. The primary treatment regimens comprised different types or dosages of monotherapy or combination therapy involving triazoles, echinocandins, and amphotericin B. The primary outcome was cumulative all-cause mortality. Secondary outcomes included all-cause mortality at day 42, day 84, or end of treatment (EOT); the overall response at day 42, day 84, or EOT; invasive aspergillosis-associated mortality on day 42, day 84, and EOT; the incidence of adverse events (AEs), serious adverse events (SAEs), and treatment-related AEs; and treatment discontinuation due to AEs.

Results

The primary network meta-analysis for cumulative all-cause mortality (5 RCTs, 6 regimens, n = 1293) revealed no statistically significant differences among treatment regimens compared with voriconazole (VOR; surface under the cumulative ranking curve [SUCRA] 56.3%), including VOR combined with anidulafungin (ANI; risk ratio [RR] 0.74, 95% credible interval [CrI] 0.43–1.28; SUCRA 84.3%; moderate confidence), isavuconazole (ISA; RR 0.79, 95% CrI 0.45–1.40; 79.4%; moderate confidence), and posaconazole (POS; RR 1.20, 95% CrI 0.72–2.02; 34.6%; moderate confidence). Sensitivity analyses confirmed the robustness of these findings. Regarding safety, no significant differences were observed in SAEs for ISA (RR 0.91, 95% CrI 0.75–1.11; 85.7%; moderate confidence), POS (RR 1.03, 95% CrI 0.87–1.23; 40.8%; low confidence), and VOR combined with ANI (RR 1.09, 95% CrI 0.88–1.36; 20.8%; moderate confidence) compared with VOR (52.6%). Integrated efficacy-safety analysis suggested a favorable risk–benefit profile for isavuconazole.

Conclusions

ISA, POS, and VOR are the preferred antifungal agents for primary treatment of IA, with ISA demonstrating a higher likelihood of an optimal efficacy–safety balance. The combination of VOR and ANI may be considered for a subset of severe cases.

Registration

PROSPERO identifier number CRD42024561215.

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Compare the efficacy of antifungal agents as primary therapy for invasive aspergillosis: a network meta-analysis

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Aspergillus Species Causing Invasive Fungal Disease in Queensland, Australia

Article Open access 17 April 2023

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Funding

The study was supported by a grant from the Nanjing Municipal Health Commission’s key development project in medicine (ZKX23020).

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Qiaoling Gu and Yechao Chen have contributed equally to this work and share first authorship.

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Department of Pharmacy, Nanjing Drum Tower Hospital, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, China

Qiaoling Gu, Yechao Chen & Peng Ding

Department of Pharmacy, Nanjing Drum Tower Hospital, Nanjing, Jiangsu, China

Qiaoling Gu, Yechao Chen, Peng Ding, Haixia Zhang & Dayu Chen

Department of Pharmacy, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China

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QG and YC contributed equally to this work. HZ and DC conceived the study and secured funding. QG, YC, PD, and DC designed the search strategy. QG, YC, PD, and DC performed literature searches and screened articles for inclusion. QG, YC, and PD extracted data, conducted analyses, and assessed the quality of eligible studies. QG and YC performed meta-analyses under the supervision of JH and DC. QG and YC drafted the study protocol and manuscript. JH, HZ, and DC contributed to manuscript development through critical review and editing. DC is the guarantor of the study. The corresponding author attests that all listed authors meet authorship criteria and confirms no omissions of eligible contributors.

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Gu, Q., Chen, Y., Ding, P. et al. Antifungal Treatment Regimens as Primary Therapy for Invasive Aspergillosis: A Systematic Review and Network Meta-analysis. Drugs 86, 927–941 (2026). https://doi.org/10.1007/s40265-026-02316-y

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Received: 18 September 2025

Accepted: 22 March 2026

Published: 21 April 2026

Version of record: 21 April 2026

Issue date: June 2026

DOI: https://doi.org/10.1007/s40265-026-02316-y

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Article 10 — Depemokimab: First Approval

DOI: 10.1007/s40265-026-02306-0
Section: AdisInsight Report
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Article URL: https://link.springer.com/article/10.1007/s40265-026-02306-0
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Authors: Lee, Arnold

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Depemokimab (depemokimab-ulaa; EXDENSUR) is an anti-IL-5 antibody being developed by GSK for the treatment of asthma, chronic rhinosinusitis with nasal polyps (CRSwNP), chronic obstructive pulmonary disease, eosinophilic granulomatosis with polyangiitis and hypereosinophilic syndrome. Add-on treatment with depemokimab reduced asthma-related exacerbations in patients with severe asthma with an eosinophilic phenotype, in addition to reducing the severity of nasal polyps and nasal obstruction in patients with CRSwNP. This article summarizes the milestones in the development of depemokimab leading to this first approval in the UK as an add-on maintenance treatment of asthma in adult and adolescent patients aged ≥ 12 years with type 2 inflammation characterised by an eosinophilic phenotype who are inadequately controlled on maximum moderate-dose or high-dose inhaled corticosteroids plus another asthma controller; and as add-on therapy with intranasal corticosteroids for the treatment of adults with severe CRSwNP for whom therapy with systemic corticosteroids and/or surgery do not provide adequate control.

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The preparation of this review was not supported by any external funding.

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During the peer review process the manufacturer of the agent under review was offered an opportunity to comment on the article. Changes resulting from any comments received were made by the authors on the basis of scientific completeness and accuracy. Arnold Lee is a contracted employee of Adis International Ltd/Springer Nature, and declares no relevant conflicts of interest. All authors contributed to this article and are responsible for its content.

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Lee, A. Depemokimab: First Approval. Drugs 86, 943–948 (2026). https://doi.org/10.1007/s40265-026-02306-0

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Received: 29 January 2026

Accepted: 25 February 2026

Published: 26 March 2026

Version of record: 26 March 2026

Issue date: June 2026

DOI: https://doi.org/10.1007/s40265-026-02306-0

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Article 11 — Aficamten: First Approval

DOI: 10.1007/s40265-026-02307-z
Section: AdisInsight Report
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Article URL: https://link.springer.com/article/10.1007/s40265-026-02307-z
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Authors: Shirley, Matt

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Aficamten (MYQORZO™) is a small-molecule cardiac myosin inhibitor being developed by Cytokinetics for the treatment of hypertrophic cardiomyopathy (HCM). Supported by the findings of the phase III, randomised, double-blind, placebo-controlled SEQUOIA-HCM trial, in December 2025 aficamten was approved in both China and the USA to improve functional capacity and symptoms in adults with symptomatic obstructive HCM (oHCM). Subsequently, in February 2026, aficamten was also approved in the EU for the treatment of symptomatic oHCM in adult patients. Aficamten is also in phase III evaluation for use in the treatment of non-obstructive HCM (nHCM) in adults. This article summarises the milestones in the development of aficamten leading to this first approval for symptomatic oHCM.

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Shirley, M. Aficamten: First Approval. Drugs 86, 949–956 (2026). https://doi.org/10.1007/s40265-026-02307-z

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Received: 15 February 2026

Accepted: 10 March 2026

Published: 06 April 2026

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DOI: https://doi.org/10.1007/s40265-026-02307-z

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Article 12 — Tradipitant: First Approval

DOI: 10.1007/s40265-026-02313-1
Section: AdisInsight Report
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Authors: Lee, Arnold

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Abstract

Tradipitant (NEREUS™) is a small molecule neurokinin-1 (NK-1) receptor antagonist being developed by Vanda Pharmaceuticals. NK-1 receptor activation and substance P release in the central nervous system leads to nausea and vomiting symptoms associated with motion sickness. Tradipitant received its first approval in the USA in December 2025 for the prevention of vomiting induced by motion in adults, and is also being developed for the treatment of gastroparesis and prevention of vomiting induced by GLP-1 receptor agonists. In phase III trials, tradipitant reduced the incidence of vomiting associated with motion sickness. This article summarizes the milestones in the development of tradipitant leading to this first approval for the prevention of vomiting induced by motion in adults.

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Lee, A. Tradipitant: First Approval. Drugs 86, 957–961 (2026). https://doi.org/10.1007/s40265-026-02313-1

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Received: 23 February 2026

Accepted: 16 March 2026

Published: 07 April 2026

Version of record: 07 April 2026

Issue date: June 2026

DOI: https://doi.org/10.1007/s40265-026-02313-1

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Article 13 — Zoliflodacin: First Approval

DOI: 10.1007/s40265-026-02308-y
Section: AdisInsight Report
OA: no
Article URL: https://link.springer.com/article/10.1007/s40265-026-02308-y
PDF URL: https://link.springer.com/article/10.1007/s40265-026-02308-y.pdf
Authors: McGuigan, Aisling

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Zoliflodacin (NUZOLVENCE®), a first-in-class, single-dose, oral spiropyrimidinetrione bacterial type II topoisomerase inhibitor, has been developed by Innoviva Specialty Therapeutics in collaboration with the Global Antibiotic Research and Development Partnership (GARDP) and the U.S. National Institute of Allergy and Infectious Diseases (NIAID) for the treatment of uncomplicated urogenital gonorrhea (uUGC). In December 2025, zoliflodacin was approved by the US FDA for the treatment of uUGC due to Neisseria gonorrhoeae in adults and pediatric patients 12 years of age and older weighing at least 35 kg. This article summarizes the milestones in the development of zoliflodacin leading to this first approval for the treatment of uUGC.

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Abstract

Zoliflodacin (NUZOLVENCE®), a first-in-class, single-dose, oral spiropyrimidinetrione bacterial type II topoisomerase inhibitor, has been developed by Innoviva Specialty Therapeutics in collaboration with the Global Antibiotic Research and Development Partnership (GARDP) and the U.S. National Institute of Allergy and Infectious Diseases (NIAID) for the treatment of uncomplicated urogenital gonorrhea (uUGC). In December 2025, zoliflodacin was approved by the US FDA for the treatment of uUGC due to Neisseria gonorrhoeae in adults and pediatric patients 12 years of age and older weighing at least 35 kg. This article summarizes the milestones in the development of zoliflodacin leading to this first approval for the treatment of uUGC.

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Aisling McGuigan

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During the peer review process the manufacturer of the agent under review was offered an opportunity to comment on the article. Changes resulting from any comments received were made by the authors on the basis of scientific completeness and accuracy. Aisling McGuigan is a salaried employee of Adis International Ltd/Springer Nature, and declares no relevant conflicts of interest. All authors contributed to this article and are responsible for its content.

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McGuigan, A. Zoliflodacin: First Approval. Drugs 86, 963–970 (2026). https://doi.org/10.1007/s40265-026-02308-y

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Received: 22 February 2026

Accepted: 12 March 2026

Published: 20 April 2026

Version of record: 20 April 2026

Issue date: June 2026

DOI: https://doi.org/10.1007/s40265-026-02308-y

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Drugs — 2026-05-26 全期 raw bundle

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