Efficacy and Safety of Itepekimab in Patients with Moderate-to-Severe Asthma

Wechsler, Michael E.; Ruddy, Marcella; Pavord, Ian; Israel, Elliot; Rabe, Klaus F.; Ford, Linda; Máspero, Jorge; Abdulai, Raolat M.; Hu, Chih-Chi; Martincova, Renata; Jessel, Andreas; Nivens, Michael; Amin, Nikhil; Weinreich, David M.; Yancopouloš, George D.; Goulaouic, Hélène

doi:10.1056/nejmoa2024257

Cited by 257 publications

(203 citation statements)

References 20 publications

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“…For instance, we are aware that in asthma, IL-4 and IL-5 hold crucial roles, whereas in inflammatory bowel disease and rheumatoid arthritis, TNF-α levels are heightened as a result of chronic inflammation. Further, in chronic obstructive pulmonary disease, cigarette smoke promotes IL-8 production [45][46][47]. In the current COVID-19 pandemic, IL-6 and IL-8 are some of the relevant markers of the cytokine storm and may help in predicting the severity of inflammation [48].…”

Section: Practical Aspects and Unanswered Questionsmentioning

confidence: 99%

Function of Follicular Cytokines: Roles Played during Maturation, Development and Implantation of Embryo

et al. 2021

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A balance within the immune system is necessary for the proper development of ovarian follicles. Numerous cytokines were detected in follicular fluid, the role of which in reproductive physiology seems crucial. They influence the development and maturation of the follicle, ovulation, and corpus luteum formation, as well as embryo implantation and maintenance of pregnancy. The analysis of follicular fluid requires its collection by puncturing of the ovary, which is usually executed in connection with various gynaecological procedures. When interpreting such test results, clinical indications for a given procedure and the method of patient preparation should be taken into account. This review revealed the results of currently available studies on the concentration of pro-inflammatory cytokines in follicular fluid in various forms of infertility. Additionally, it presented cytokines, whose concentration has a significant impact on the size of ovarian follicles, their number, the effectiveness of in vitro fertilisation, development of the embryo, and chances of correct implantation. Despite the many recent publications, the knowledge of follicular fluid immunology in the context of reproductive pathology is superficial and further research is required to extensively understand the roles of individual cytokines in reproductive pathology. In the future, this knowledge may enable patients’ individual qualifications to individual methods of infertility treatment, as well as the possible adjustment of the treatment regimen to the patient’s immune profile.

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Section: Practical Aspects and Unanswered Questionsmentioning

confidence: 99%

Function of Follicular Cytokines: Roles Played during Maturation, Development and Implantation of Embryo

et al. 2021

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“…There are multiple RCTs underway assessing the efficacy of anti-IL-33 biologics to treat asthma, but most results are pending ( Table 7 ). Of note, the first RCT was recently published in 2021 by Wechsler et al which assessed the effect of an anti-IL-33 agent called itepekimab in a phase 2 trial with moderate-to-severe asthma ( Wechsler et al, 2021 ). They found that following 12 weeks of treatment with itepekimab there was an improvement in asthma control and quality of life.…”

Section: Currently Available Biological Therapy and Suboptimal Responses In Severe Asthmamentioning

confidence: 99%

Biologics in Asthma: A Molecular Perspective to Precision Medicine

2022

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Recent developments in therapeutic strategies have provided alternatives to corticosteroids as the cornerstone treatment for managing airway inflammation in asthma. The past two decades have witnessed a tremendous boost in the development of anti-cytokine monoclonal antibody (mAb) therapies for the management of severe asthma. Novel biologics that target eosinophilic inflammation (or type 2, T2 inflammation) have been the most successful at treating asthma symptoms, though there are a few in the drug development pipeline for treating non-eosinophilic or T2-low asthma. There has been significant improvement in clinical outcomes for asthmatics treated with currently available monoclonal antibodies (mAbs), including anti-immunoglobulin (Ig) E, anti-interleukin (IL)-4 receptor α subunit, anti-IL-5, anti-IL-5Rα, anti-IL-6, anti-IL-33, and anti-thymic stromal lymphopoietin (TSLP). Despite these initiatives in precision medicine for asthma therapy, a significant disease burden remains, as evident from modest reduction of exacerbation rates, i.e., approximately 40–60%. There are numerous studies that highlight predictors of good responses to these biologics, but few have focused on those who fail to respond adequately despite targeted treatment. Phenotyping asthmatics based on blood eosinophils is proving to be inadequate for choosing the right drug for the right patient. It is therefore pertinent to understand the underlying immunology, and perhaps, carry out immune endotyping of patients before prescribing appropriate drugs. This review summarizes the immunology of asthma, the cytokines or receptors currently targeted, the possible mechanisms of sub-optimal responses, and the importance of determining the immune make-up of individual patients prior to prescribing mAb therapy, in the age of precision medicine for asthma.

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“…The best evidence for the IL-33/ST2 axis playing a pathogenic role in asthma comes from the results of randomized clinical trials. Blockade of IL-33 with itepekimab, compared to placebo, was shown to reduce exacerbations in patients with moderate-to-severe asthma when treatment with steroids was withdrawn [ 147 ], and blockade of ST2 with astegolimab reduced the annualized asthma exacerbation rate in a broad population of severe asthma patients, including those defined as eosinophil-low [ 148 ]. Importantly, this study highlights the role of IL-33 in inflammation driven by non-T2 pathways.…”

Section: Epithelial Alarmins In Asthmamentioning

confidence: 99%

The Role of Airway Epithelial Cell Alarmins in Asthma

Whetstone

Ranjbar

Omer

et al. 2022

Cells

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The airway epithelium is the first line of defense for the lungs, detecting inhaled environmental threats through pattern recognition receptors expressed transmembrane or intracellularly. Activation of pattern recognition receptors triggers the release of alarmin cytokines IL-25, IL-33, and TSLP. These alarmins are important mediators of inflammation, with receptors widely expressed in structural cells as well as innate and adaptive immune cells. Many of the key effector cells in the allergic cascade also produce alarmins, thereby contributing to the airways disease by driving downstream type 2 inflammatory processes. Randomized controlled clinical trials have demonstrated benefit when blockade of TSLP and IL-33 were added to standard of care medications, suggesting these are important new targets for treatment of asthma. With genome-wide association studies demonstrating associations between single-nucleotide polymorphisms of the TSLP and IL-33 gene and risk of asthma, it will be important to understand which subsets of asthma patients will benefit most from anti-alarmin therapy.

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Efficacy and Safety of Itepekimab in Patients with Moderate-to-Severe Asthma

Cited by 257 publications

References 20 publications

Function of Follicular Cytokines: Roles Played during Maturation, Development and Implantation of Embryo

Function of Follicular Cytokines: Roles Played during Maturation, Development and Implantation of Embryo

Biologics in Asthma: A Molecular Perspective to Precision Medicine

The Role of Airway Epithelial Cell Alarmins in Asthma

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