Phase 2 randomized clinical trial of astegolimab in patients with moderate to severe atopic dermatitis

Maurer, Marcus; Cheung, Dorothy; Theess, Wiebke; Yang, Xiaoying; Dolton, Michael; Guttman, Anna; Choy, David F.; Dash, Ajit; Grimbaldeston, Michele A.; Soong, Weily

doi:10.1016/j.jaci.2022.08.015

Cited by 25 publications

(12 citation statements)

References 27 publications

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“…Non‐significant treatment difference was observed between groups for the primary endpoint, percentage of mean EASI change from baseline at week 16 [6.77% (95% CI: −16.57 to 30.11; p = 0 .5624)]. Moreover, no difference was observed in median percentage of change in serum IL‐5 and CCL13 at Week 16 between groups 110 . Given its well established role in asthma, and clinical improvement in patients with asthma treated with anti‐IL‐33 therapies, IL‐33 is likely more important for allergic sensitization rather than ongoing atopic dermatitis inflammation 111 .…”

Section: Th2mentioning

confidence: 93%

The evolving landscape of biologic therapies for atopic dermatitis: Present and future perspective

David

Ungar

Renert‐Yuval

et al. 2023

Clin Experimental Allergy

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Atopic dermatitis (AD) is one of the most common, chronic inflammatory skin diseases. The Global Burden of Disease study showed that approximately 15%-20% of children and up to 10% of adults suffer from AD with prevalence also varying among races and ethnicities. [1][2][3][4] AD belongs to a family of atopic disorders, including food allergy, asthma and allergic rhino-conjunctivitis, which are often comorbid. 5,6 The clinical presentation of AD is highly heterogeneous, influenced by age of onset, disease stage, chronicity, severity, ethnicity and geographical location, with pruritus and eczematous lesions common to all subtypes. 7-9 AD is characterized as an immune-mediated disorder, with corresponding impaired skin barrier function. [10][11][12][13][14][15][16] Th2 immune axis dysregulation is considered central to AD pathogenesis. 17,18 More recently, the understanding of the complex inflammatory processes underlying disease pathogenesis has significantly expanded, challenging the monolithic disease model of AD. Phenotypic differences across patient types have been better elucidated by unique biomarker findings. 19 Comparisons based on age show differing contributions from Th2/Th22 and Th1/Th17 biomarkers, [20][21][22] with differing immune phenotypes also among Asians and African Americans with AD. [23][24][25][26][27] The continuously expanding understanding of AD pathogenesis underlies the rapidly evolving landscape of new therapeutic approaches, among which are biologic therapies (Figure 1). Through

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Section: Th2mentioning

confidence: 93%

The evolving landscape of biologic therapies for atopic dermatitis: Present and future perspective

David

Ungar

Renert‐Yuval

et al. 2023

Clin Experimental Allergy

View full text Add to dashboard Cite

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“…IL-33 is another example of cytokine produced by the innate immune system, highlighting another possible molecular target in different AD endotypes. Nonetheless, another IL-33 antagonist, astegolimab, was not superior to placebo in a 16-week phase II randomized, placebo-controlled trial by Maurer et al [145].…”

Section: Etokimab-an Il-33 Inhibitormentioning

confidence: 98%

Immunopathogenesis of Atopic Dermatitis: Focus on Interleukins as Disease Drivers and Therapeutic Targets for Novel Treatments

Makowska

Nowaczyk

Blicharz

et al. 2023

IJMS

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Atopic dermatitis is a chronic, recurrent inflammatory skin disorder manifesting by eczematous lesions and intense pruritus. Atopic dermatitis develops primarily as a result of an epidermal barrier defect and immunological imbalance. Advances in understanding these pathogenetic hallmarks, and particularly the complex role of interleukins as atopic dermatitis drivers, resulted in achieving significant therapeutic breakthroughs. Novel medications involve monoclonal antibodies specifically blocking the function of selected interleukins and small molecules such as Janus kinase inhibitors limiting downstream signaling to reduce the expression of a wider array of proinflammatory factors. Nevertheless, a subset of patients remains refractory to those treatments, highlighting the complexity of atopic dermatitis immunopathogenesis in different populations. In this review, we address the immunological heterogeneity of atopic dermatitis endotypes and phenotypes and present novel interleukin-oriented therapies for this disease.

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“…However, a subsequent phase II placebo-controlled trial with 302 participants did not show the efficacy of etokimab compared to the placebo at 16 weeks, based on the Eczema Area and Severity Index (EASI) change rate. Additionally, a fully human IgG2 monoclonal antibody, astegolimab, did not show significant differences compared to placebo in a phase II trial ( 27 ). A randomized placebo-controlled phase II trial of astegolimab in adults with moderate to severe AD also failed to show efficacy ( 28 ).…”

Section: Non-lesional Skinmentioning

confidence: 99%

Interplay of cytokines in the pathophysiology of atopic dermatitis: insights from Murin models and human

Yamamura,

Nakashima,

Otsuka

2024

Front. Med.

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The pathogenesis of atopic dermatitis (AD) is understood to be crucially influenced by three main factors: dysregulation of the immune response, barrier dysfunction, and pruritus. In the lesional skin of AD, various innate immune cells, including Th2 cells, type 2 innate lymphoid cells (ILC2s), and basophils, produce Th2 cytokines [interleukin (IL)-4, IL-5, IL-13, IL-31]. Alarmins such as TSLP, IL-25, and IL-33 are also produced by epidermal keratinocytes, amplifying type 2 inflammation. In the chronic phase, not only Th2 cells but also Th22 and Th17 cells increase in number, leading to suppression of filaggrin expression by IL-4, IL-13, and IL-22, which further deteriorates the epidermal barrier function. Dupilumab, which targets IL-4 and IL-13, has shown efficacy in treating moderate to severe AD. Nemolizumab, targeting IL-31RA, effectively reduces pruritus in AD patients. In addition, clinical trials with fezakinumab, targeting IL-22, have demonstrated promising results, particularly in severe AD cases. Conversely, in murine models of AD, several cytokines, initially regarded as promising therapeutic targets, have not demonstrated sufficient efficacy in clinical trials. IL-33 has been identified as a potent activator of immune cells, exacerbating AD in murine models and correlating with disease severity in human patients. However, treatments targeting IL-33 have not shown sufficient efficacy in clinical trials. Similarly, thymic stromal lymphopoietin (TSLP), integral to type 2 immune responses, induces dermatitis in animal models and is elevated in human AD, yet clinical treatments like tezepelumab exhibit limited efficacy. Therapies targeting IL-1α, IL-5, and IL-17 also failed to achieve sufficient efficacy in clinical trials. It has become clear that for treating AD, IL-4, IL-13, and IL-31 are relevant therapeutic targets during the acute phase, while IL-22 emerges as a target in more severe cases. This delineation underscores the necessity of considering distinct pathophysiological aspects and therapeutic targets in AD between mouse models and humans. Consequently, this review delineates the distinct roles of cytokines in the pathogenesis of AD, juxtaposing their significance in human AD from clinical trials against insights gleaned from AD mouse models. This approach will improve our understanding of interspecies variation and facilitate a deeper insight into the pathogenesis of AD in humans.

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Phase 2 randomized clinical trial of astegolimab in patients with moderate to severe atopic dermatitis

Cited by 25 publications

References 27 publications

The evolving landscape of biologic therapies for atopic dermatitis: Present and future perspective

The evolving landscape of biologic therapies for atopic dermatitis: Present and future perspective

Immunopathogenesis of Atopic Dermatitis: Focus on Interleukins as Disease Drivers and Therapeutic Targets for Novel Treatments

Interplay of cytokines in the pathophysiology of atopic dermatitis: insights from Murin models and human

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