The functionality is limited to basic scrolling. The time to the first asthma exacerbation was longer in the tezepelumab groups than in the placebo group. A total of 2 patients in the medium-dose group, 3 in the high-dose group, and 1 in the placebo group discontinued the trial regimen because of adverse events. Reslizumab for inadequately controlled asthma with elevated blood eosinophil counts: results from two multicentre, parallel, double-blind, randomised, placebo-controlled, phase 3 trials. [, Chastek B, Korrer S, Nagar SP, Albers F, Yancey S, Ortega H, et al. Tezepelumab Monograph for Professionals - Drugs.com Study to evaluate tezepelumab on airway inflammation in adults with uncontrolled asthma (CASCADE). Benralizumab, an anti-interleukin-5 receptor monoclonal antibody, as add-on treatment for patients with severe, uncontrolled, eosinophilic asthma (CALIMA): a randomised, double-blind, placebo-controlled phase 3 trial. Sci Rep. 2013;3:2301. Following OCS dose optimization, the 48-week treatment period comprises: a 4-week induction phase during which tezepelumab is introduced; a 36-week OCS reduction phase during which the OCS dose is tapered (dependent on the patient continuing to meet asthma control criteria); and an 8-week maintenance phase in which patients continue on their final OCS dose. Safety was monitored at each trial site by asking participants whether they had had any adverse events from enrollment through follow-up at week 64. Immunol Res. eCollection 2022. Careers. Patients were assigned to receive subcutaneous injections of tezepelumab at a dose of 70 mg every 4 weeks (low dose), 210 mg every 4 weeks (medium dose), or 280 mg every 2 weeks (high dose) or of placebo every 2 weeks for the duration of the trial. Bleecker ER, FitzGerald JM, Chanez P, Papi A, Weinstein SF, Barker P, et al. Asthma control, severity, and quality of life: quantifying the effect of uncontrolled disease. Michael Lairmore no LinkedIn: Experimental cat allergy shots provide Available from: https://clinicaltrials.gov/ct2/show/, ClinicalTrials.gov. [Last accessed: February 2021]. Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. NAVIGATOR ({"type":"clinical-trial","attrs":{"text":"NCT03347279","term_id":"NCT03347279"}}NCT03347279) [58] is a pivotal phase 3 study assessing the potential efficacy of tezepelumab in adults and adolescents with severe, uncontrolled asthma spanning a broad range of phenotypes, aiming to build on the findings of PATHWAY. official website and that any information you provide is encrypted Cigarette smoke extract induces thymic stromal lymphopoietin expression, leading to T(H)2-type immune responses and airway inflammation. The heterogeneity of severe asthma makes management of the disease highly challenging, and intensive treatment regimens involving multiple medications are required. 24. Patients were also required to have a history of at least two asthma exacerbations that led to systemic glucocorticoid treatment, or one severe exacerbation that led to hospitalization, in the 12 months before trial entry. Veeva ID: Z4-46798Date of next review: August 2024. J Immunol. Price D, Fletcher M, van der Molen T. Asthma control and management in 8,000 European patients: the REcognise Asthma and LInk to Symptoms and Experience (REALISE) survey. Eligibility for these therapies is partly determined by meeting specific inflammatory biomarker thresholds (and, by extension, phenotypes) for which efficacy of the particular biologic treatment was demonstrated in clinical trials. NEW! Federal government websites often end in .gov or .mil. Expert Opin Ther Targets. Nagata Y, Kamijuku H, Taniguchi M, Ziegler S, Seino K. Differential role of thymic stromal lymphopoietin in the induction of airway hyperreactivity and Th2 immune response in antigen-induced asthma with respect to natural killer T cell function. 8600 Rockville Pike Tezepelumab-ekko is a human monoclonal antibody that acts as a thymic stromal lymphopoietin (TSLP) blocker. Thymic stromal lymphopoietin (TSLP) is an innate cytokine, belonging to the group of alarmins, which plays a key pathogenic role in . S5B in the Supplementary Appendix). 2018;378(26):248696. . 2 Anti-TSLP: Tezepelumab (AMG157) Phase III in asthma: . Available from: https://clinicaltrials.gov/ct2/show/, ClinicalTrials.gov. Tezepelumab is a human monoclonal antibody that binds to TSLP, inhibiting its . Expert Opin Ther Targets. Several studies with this mAb are ongoing. Global strategy for asthma management and prevention. DESTINATION: a phase 3, multicentre, randomized, double-blind, placebo-controlled, parallel-group trial to evaluate the long-term safety and tolerability of tezepelumab in adults and adolescents with severe, uncontrolled asthma. No other potential conflict of interest relevant to this article was reported. In relation to these phenotypes, it should be noted that corticosteroid therapy reduces eosinophil counts and may also increase neutrophil counts [16]; thus a patients apparent phenotype may be a product of treatment choices rather than a true reflection of the underlying disease mechanisms. Thymic stromal lymphopoietin (TSLP) is an innate cytokine, belonging to the group of alarmins, which plays a key pathogenic role in asthma by acting as an upstream activator of cellular and molecular pathways leading to type 2 (T2-high) airway inflammation. Tezepelumab given as an add-on-therapy to patients with severe uncontrolled asthma has shown safety, tolerability and efficacy. When asthma-related adverse events were removed from the above analysis, the overall incidence of adverse events was similar across the trial groups (Table 3). TSLP is thought to play a role in neutrophilic airway inflammation by activating dendritic cells to induce polarization of nave T cells towards a Th17 phenotype, which subsequently release IL-17 [45, 46]. Efficacy and safety of tralokinumab in patients with severe uncontrolled asthma: a randomised, double-blind, placebo-controlled, phase 2b trial. The statistically significant and clinically meaningful exacerbation rate reductions demonstrated with tezepelumab in patients with baseline eosinophil counts less than 300 cells per microlitre support the US Food and Drug Administration Breakthrough Therapy Designation granted to tezepelumab in September 2018 for patients with severe asthma, without an eosinophilic phenotype.2,3 Tezepelumab is being developed by AstraZeneca in collaboration with Amgen. eosinophilic or allergic) or biomarker limitations (3) Reference: 2017;9:CD010834. Mast cell-airway smooth muscle crosstalk: the role of thymic stromal lymphopoietin. The median dose was 400 g per day of fluticasone administered by means of a dry-powder inhaler or equivalent in the medium-dose inhaled glucocorticoid stratum, with 73 patients in the placebo group, 67 in the low-dose tezepelumab group, 70 in the medium-dose group, and 71 in the high-dose group, and 1000 g per day of fluticasone administered by means of a dry-powder inhaler or equivalent in the high-dose inhaled glucocorticoid stratum, with 65, 71, 67, and 66 patients in the respective trial groups. 2022 May 4;10(5):1064. doi: 10.3390/biomedicines10051064. This article was updated on April 18, 2019, at NEJM.org. Coexpression of type 2 immune targets in sputum-derived epithelial and dendritic cells from asthmatic subjects. AstraZeneca is an established leader in respiratory care, and its inhaled and biologic medicines reached more than 53 million patients in 2019. Tezepelumab specifically blocks TSLP from binding to its heterodimeric receptor, thereby inhibiting the production of various inflammatory cytokines and cell types. J Allergy Clin Immunol 2008;122:1208-1214, 34. Epithelial cell alarmin cytokines: Frontline mediators of the asthma Ziegler SF, Artis D. Sensing the outside world: TSLP regulates barrier immunity. TSLP signaling pathway map: a platform for analysis of TSLP-mediated signaling. Cao L, Liu F, Liu Y, Liu T, Wu J, Zhao J, et al. This trial was performed in accordance with the ethical principles of the Declaration of Helsinki, International Conference on Harmonisation Good Clinical Practice guidelines, and applicable regulatory requirements. Perspectives in Therapy of Chronic Rhinosinusitis. 2019;199:A2621. Extension Study to Evaluate the Safety and Tolerability of Tezepelumab in Adults and Adolescents With Severe, Uncontrolled Asthma (DESTINATION) The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. An experimental approach that combines cat allergy shots with a monoclonal antibody led to more effective relief that continued a year after treatment ended. 2019;56(10):111019. Menzies-Gow A, Wechsler ME, Brightling CE. Tezepelumab-ekko has the following limitations of use: Not for relief of acute bronchospasm or status asthmaticus. Meta-analysis of genome-wide association studies of asthma in ethnically diverse North American populations. Introduction: Thymic stromal lymphopoietin (TSLP) is overexpressed in the airways of severe asthmatics and is an upstream cytokine that orchestrates inflammatory responses in asthma. 2022 Sep 29;12(10):1520. doi: 10.3390/life12101520. Global Initiative for Asthma (GINA) guidelines (treatment steps 4 and 5) recommend a combination medium-to-high-dose inhaled corticosteroid (ICS) and long-acting 2 agonist (LABA) as maintenance therapy to prevent exacerbations and to control symptoms in these patients, with additional relief from a short-acting 2 agonist as needed (or an ICS/LABA combination as both maintenance and reliever therapy, in the case of formoterol-containing combinations) [18]. 2018;34(12):207588. Lancet. Compared with placebo, tezepelumab also reduced asthma-exacerbation-related hospitalizations and improved lung function, asthma control and patient HRQoL [52]. ); and MedImmune, Cambridge, United Kingdom (R.M.). Menzies-Gow A, Wechsler ME, Brightling CE. Dr. Corren reports receiving grant support, lecture fees, and honoraria from Genentech, receiving lecture fees from and serving on an advisory board for Teva Pharmaceuticals, receiving grant support from Sanofi, receiving consulting fees from and serving on an advisory board for Vectura Group, and receiving grant support and consulting fees from Regeneron; Dr. Parnes, being employed by and owning stock in Amgen and being named as an inventor on a patent (US 20170082608 A1) licensed to AstraZeneca Collaboration Ventures on a method for detecting helper T-cell or cytotoxic T-lymphocyte subpopulations in persons affected by a disease or disorder having an immune component; Dr. Wang, being employed by MedImmuneAstraZeneca and owning stock in AstraZeneca; Ms. Mo, being employed by and owning stock in Amgen; Ms. Roseti, being employed by MedImmuneAstraZeneca and owning stock options in AstraZeneca; Dr. Griffiths, being employed by MedImmune and owning stock and stock options in AstraZeneca; and Ms. van der Merwe, being employed by MedImmune and owning stock and stock options in AstraZeneca. [. N Engl J Med 2014;371:1198-1207, 9. However, these treatments are not effective in patients with asthma activated by other pathways. Asthma is a chronic inflammatory disease characterized by variable airflow limitation and airway hyperresponsiveness. All analyses were carried out with the use of SAS software, version 9.3. Varricchi G, Pecoraro A, Marone G, Criscuolo G, Spadaro G, Genovese A, Marone G. Front Immunol. Allergy 2008;63:932-938, 4. The annualized asthma exacerbation rate was lower in some, but not all, tezepelumab groups than in the placebo group when patients were stratified according to the number of asthma exacerbations in the previous 12 months and, in post hoc analyses, according to smoking history (Table S10 in the Supplementary Appendix). Generating an ePub file may take a long time, please be patient. Ann Intern Med 2011;154:573-582, 15. Tezepelumab reduces serious exacerbations in severe asthma J Manag Care Spec Pharm. The safety analyses were based on the as-treated population and included all the patients who received at least one dose of tezepelumab or placebo; patients were evaluated according to the trial agent received. Dieses Wissen wurde genutzt, um den Antikrper Tezepelumab (Anti-TSLP) als Wirkstoff gegen allergisches Asthma zu entwickeln, Tezepelumab wurde 2021 zugelassen. Post hoc analyses included stratification of the primary end point according to baseline blood eosinophil count (<400 or 400 cells per microliter) and patient smoking history. There is now a strong body of evidence showing the benefit of targeting the top of the inflammatory cascade with tezepelumab, and we look forward to bringing this potential first-in-class medicine to a broad population of severe asthma patients as soon as possible., Tezepelumab demonstrated statistically significant improvements in every key secondary endpoint compared to placebo, including lung function measurements, asthma control and health-related quality of life.2, There were no clinically meaningful differences in safety results between the tezepelumab and placebo groups. J Allergy Clin Immunol 2012;129:Suppl:S88-S123, 29. 3,10 NAVIGATOR is the first Phase 3 trial to show benefit in severe asthma by targeting TSLP. "adding a monoclonal antibody called tezepelumab to standard therapy could improve results. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Epub 2020 Jan 21. Click cancel to return to AstraZenecas site or continue to proceed. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. 2005;174(12):818390. The authors received no remuneration for the authorship or publication of this article. Dupilumab and tezepelumab in severe refractory asthma: new N Engl J Med. Omalizumab in severe allergic asthma inadequately controlled with standard therapy: a randomized trial. sharing sensitive information, make sure youre on a federal A possible explanation for this lack of complete efficacy may be that these biologics target individual, downstream elements of the asthma inflammatory response, leaving other components untreated. The https:// ensures that you are connecting to the Tezepelumab regulatory submission accepted and granted FDA Priority From the David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles (J.C.), and Amgen, Thousand Oaks (J.R.P., M.M.) Download scientific diagram | Biologics target type 2 airway inflammation in childhood asthma. Eur Respir J. Tezepelumab's benefit for asthma exacerbation reduction may be more robust than previously thought. Online ahead of print. 1) [5153]. 2020 Aug;24(8):777-792. doi: 10.1080/14728222.2020.1783242. Curr Med Res Opin. Respir Res. An asthma exacerbation was defined as a worsening of asthma symptoms that led to any of the following: the use of systemic glucocorticoids (oral or injectable) or, in the case of a stable maintenance regimen of oral glucocorticoids, a doubling of the dose for 3 or more days; an emergency department visit due to asthma that led to systemic glucocorticoid treatment; or an inpatient hospitalization due to asthma. Castro M, Zangrilli J, Wechsler ME, Bateman ED, Brusselle GG, Bardin P, et al. Studies in progress will provide further evidence of whether tezepelumab can be an effective treatment for a broad population of patients with severe asthma. The treatment effect was observed as early as week 4 (the first time point assessed) and was sustained for the duration of the trial (Fig. Tezepelumab is a thymic stromal lymphopoietin (TSLP) blocker, human monoclonal antibody (IgG2), indicated for the add-on maintenance treatment of adult and pediatric patients aged 12 years and older with severe asthma. Li Y, Wang W, Lv Z, Li Y, Chen Y, Huang K, et al. Tezepelumab is a potential first-in-class human monoclonal antibody that inhibits the action of TSLP, a key epithelial cytokine that sits at the top of multiple inflammatory cascades and is critical in the initiation and persistence of allergic, eosinophilic and other types of airway inflammation associated with severe asthma.3,10 TSLP is released in response to multiple triggers associated with asthma exacerbations, including allergens, viruses and other airborne particles.3,10 Expression of TSLP is increased in the airways of patients with asthma and has been correlated with disease severity.3,25 Blocking TSLP may prevent the release of pro-inflammatory cytokines by immune cells, resulting in the prevention of asthma exacerbations and improved asthma control.3,25 Tezepelumab acts at the top of the inflammation cascade and has the potential to treat a broad population of severe asthma patients regardless of their type of inflammation.3,25. 2017;151(6):133844. Carr TF, Kraft M. Use of biomarkers to identify phenotypes and endotypes of severe asthma. It is administered SC. Fractional exhaled nitric oxide (FeNO) levels may also be elevated in patients with eosinophilic or allergic phenotypes, although there is not yet a consensus on the threshold that constitutes elevated FeNO. Contacts Extension Study to Evaluate the Safety and Tolerability of Tezepelumab 2020 Aug;24(8):777-792. doi: 10.1080/14728222.2020.1783242. Moore WC, Hastie AT, Li X, Li H, Busse WW, Jarjour NN, et al. Tezepelumab (tezepelumab-ekko; TEZSPIRE) is a first-in-class human IgG2 monoclonal antibody that inhibits the action of TSLP. A full list of inclusion and exclusion criteria is provided in Table S2 in the Supplementary Appendix. Zayed Y, Kheiri B, Banifadel M, Hicks M, Aburahma A, Hamid K, et al. eCollection 2022. Thymic Stromal Lymphopoietin Isoforms, Inflammatory Disorders, and Cancer. Respiratory & Immunology is one of AstraZenecas three therapy areas and is a key growth driver for the Company. FDA Approves First-in-Class Drug for Severe Asthma - Medscape It blocks thymic stromal lymphopoietin (TSLP) and was designed to for the treatment of asthma and atopic dermatitis (AD). Sci Immunol 2016;1:eaaf8471-eaaf8471, 40. HHS Vulnerability Disclosure, Help 2013 Feb;61(2):546-55 Building on the Phase IIb PATHWAY trial, the Phase III PATHFINDER programme included two trials, NAVIGATOR and SOURCE.22,23 The programme includes additional planned mechanistic and long-term safety trials. Tezepelumab is a human monoclonal antibody that blocks the activity of thymic stromal lymphopoietin (TSLP), a key epithelial derived cytokine, which sits at the top of the inflammatory cascade. In some patients with moderate-to-severe asthma, particularly those with noneosinophilic inflammation, the disease remains uncontrolled. Tezepelumab (tezepelumab-ekko; TEZSPIRE) is a first-in-class human IgG2 monoclonal antibody that inhibits the action of TSLP. Similar differences were observed when the prebronchodilator FEV1 was measured as the percent of the predicted value (Table 2). Gao H, Ying S, Dai Y. Pathological roles of neutrophil-mediated inflammation in asthma and its potential for therapy as a target. Secondary end points included the changes from baseline in the prebronchodilator and postbronchodilator FEV1 (an increase in values indicates improved lung function; minimal clinically important difference, 100 to 200 ml),29 ACQ-6 score, AQLQ score, asthma symptom score, and forced vital capacity (FVC), as well as the annualized rate of severe asthma exacerbations at week 52, the time to the first asthma exacerbation, the time to the first severe asthma exacerbation, the percentage of patients with at least one asthma exacerbation, and the percentage of patients with at least one severe asthma exacerbation. Dupilumab efficacy and safety in moderate-to-severe uncontrolled asthma. The safety profile of tezepelumab in PATHWAY was acceptable, with a similar overall frequency of adverse events (including serious adverse events) in patients receiving tezepelumab and those receiving placebo; the most common adverse events were consistent with those expected in a patient population with severe asthma [52]. In patients with asthma, the level of TSLP expression in airway tissue has been shown to correlate with airway obstruction and disease severity. Furthermore, existing biologic treatments decrease exacerbation rates by approximately 50% only, which may be because they target individual, downstream elements of the asthma inflammatory response, leaving other components untreated. Furthermore, 2060% of patients with severe or uncontrolled asthma may receive long-term oral corticosteroid (OCS) therapy [10], which is associated with a range of side effects including infections and cardiovascular, metabolic, psychiatric, ocular, gastrointestinal and bone-related complications [11]. She and colleagues used a monoclonal antibody called tezepelumab to block one of those alarm chemicals, known as thymic stromal lymphopoietin, or TSLP. Effects of steroid therapy on inflammatory cell subtypes in asthma. JCM | Free Full-Text | Severe Eosinophilic Asthma | HTML

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