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Unmet need in severe, uncontrolled asthma: can anti-TSLP therapy with tezepelumab provide a valuable new treatment option?

ABSTRACT: Despite treatment with standard-of-care medications, including currently available biologic therapies, many patients with severe asthma have uncontrolled disease, which is associated with a high risk of hospitalization and high healthcare costs. Biologic therapies approved for severe asthma have indications limited to patients with either eosinophilic or allergic phenotypes; there are currently no approved biologics for patients with eosinophil-low asthma. 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. Targeting an upstream mediator of the inflammatory response may have a broader effect on airway inflammation and provide more effective asthma control. One such potential target is thymic stromal lymphopoietin (TSLP), an epithelial-derived cytokine released in response to multiple triggers associated with asthma exacerbations, such as viruses, allergens, pollutants and other airborne irritants. Mechanistic studies indicate that TSLP drives eosinophilic (including allergic) inflammation, neutrophilic inflammation and structural changes to the airway in asthma through actions on a wide variety of adaptive and innate immune cells and structural cells. Tezepelumab is a first-in-class human monoclonal antibody that blocks the activity of TSLP. In the phase 2b PATHWAY study (NCT02054130), tezepelumab reduced asthma exacerbations by up to 71% compared with placebo in patients with severe, uncontrolled asthma across the spectrum of inflammatory phenotypes, and improved lung function and asthma control. Phase 3 trials of tezepelumab are underway. NAVIGATOR (NCT03347279), a pivotal exacerbation study, aims to assess the potential efficacy of tezepelumab further in patients with a broad range of severe asthma phenotypes, including those with low blood eosinophil counts. SOURCE (NCT03406078) aims to evaluate the oral corticosteroid-sparing potential of tezepelumab. DESTINATION (NCT03706079) is a long-term extension study. In addition, an ongoing phase 2 bronchoscopy study, CASCADE (NCT03688074), aims to evaluate the effect of tezepelumab on airway inflammation and airway remodelling in patients across the spectrum of type 2 airway inflammation. Here, we summarize the unmet therapeutic need in severe asthma and the current treatment landscape, discuss the rationale for targeting TSLP in severe asthma therapy and describe the current development status of tezepelumab.

SUBMITTER: Menzies-Gow A

PROVIDER: S-EPMC7560289 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Unmet need in severe, uncontrolled asthma: can anti-TSLP therapy with tezepelumab provide a valuable new treatment option?

Menzies-Gow Andrew A Wechsler Michael E ME Brightling Chris E CE

Respiratory research 20201015 1

Despite treatment with standard-of-care medications, including currently available biologic therapies, many patients with severe asthma have uncontrolled disease, which is associated with a high risk of hospitalization and high healthcare costs. Biologic therapies approved for severe asthma have indications limited to patients with either eosinophilic or allergic phenotypes; there are currently no approved biologics for patients with eosinophil-low asthma. Furthermore, existing biologic treatmen ...[more]

PMID: 33059715

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Project description:Patients with severe uncontrolled asthma still experience acute asthma symptoms and exacerbations, particularly those with non-eosinophilic inflammation who take the maximum amount of standard drug therapy. Tezepelumab, a human monoclonal antibody, can improve lung function and enhance control of asthma symptoms in those patients, regardless of the disease's baseline characteristics. This study aims to investigate the safety and efficacy of using tezepelumab in controlling severe symptoms of uncontrolled asthma. We performed a comprehensive literature search in several databases, including PubMed, Scopus, Web of Science, Cochrane Library, and clinicaltrial.gov, using a well-established search strategy to include all relevant publications. According to our inclusion criteria, we searched for randomized controlled trials comparing tezepelumab versus placebo in patients with severe, uncontrolled asthma. We analyzed the data using The Revman 5.4 program software. The search identified 589 potential articles. After excluding studies inconsistent with selection criteria, four studies were included and analyzed qualitatively and quantitatively. The pooled effect demonstrated the better performance of tezepelumab over the placebo regarding the decrease in annualized asthma exacerbation rate (MD = - 0.74, (95% CI [- 1.04, - 0.44], p < 0.00001)), asthma control questionnaire-6 (ACQ-6) Score MD = - 0.32, (95% CI [- 0.43, - 0.21], p < 0.00001)), blood eosinophil count (MD = - 139.38 cells/mcL, (95% CI [- 150.37, - 128.39], p < 0.00001)), feNO (MD = - 10 ppb, (95% CI [- 15.81, - 4.18], p = 0.0008)) and serum total IgE (MD = - 123.51 UI/ml, (95% CI [- 206.52, - 40.50], p = 0.004)). All tezepelumab groups had higher pre-bronchodilator forced expiratory volume in 1 s than the placebo group (MD = 0.16, (95% CI [0.10, 0.21], p < 0.00001)). Higher efficacy and safety profile was detected for tezepelumab to control the exacerbations of severe uncontrolled adult asthmatics.

Project description:IntroductionTezepelumab is a human monoclonal antibody that blocks thymic stromal lymphopoietin (TSLP), an epithelial cytokine implicated in airway inflammation in asthma, from binding to its heterodimeric receptor. In the PATHWAY phase 2b study, tezepelumab significantly reduced exacerbation rates compared with placebo in adults with severe, uncontrolled asthma, irrespective of baseline disease characteristics.ObjectiveTo evaluate the effect of tezepelumab on asthma exacerbations on a seasonal basis.MethodsThis was a post hoc analysis of the PATHWAY study (NCT02054130). Adults (N=550) with severe, uncontrolled asthma were randomized 1:1:1:1 to receive subcutaneous tezepelumab 70 mg every 4 weeks (Q4W), 210 mg Q4W or 280 mg every 2 weeks (Q2W), or placebo Q2W, for 52 weeks. The annualized asthma exacerbation rate (AAER), total number of days with an exacerbation, proportion of patients with at least one exacerbation or 0, 1 or ≥2 exacerbations, and proportion of patients experiencing an exacerbation per day were evaluated by season and over the year, by treatment in the overall study population and in subgroups according to baseline blood eosinophil count (≥300 cells/µL or <300 cells/µL) or atopic asthma status (fluoro-enzyme immunoassay [FEIA]+ or FEIA-).ResultsSeasonal variations in exacerbation rates were found, with peaks observed in fall and winter, and greater variations in patients with high blood eosinophil counts (≥300 cells/µL). Tezepelumab treatment consistently reduced exacerbation rates across all seasons compared with placebo. Furthermore, there was a trend, which was not significant, toward a reduction in the total number of days with exacerbations and in the proportion of patients with exacerbations during each season in patients treated with tezepelumab compared with those who received placebo, irrespective of blood eosinophil count or atopic asthma status.ConclusionTezepelumab reduced exacerbations across all seasons, irrespective of evaluated baseline disease characteristics. These data support the efficacy of tezepelumab in a broad population of patients with severe, uncontrolled asthma.

Project description:BackgroundTezepelumab is an anti-thymic stromal lymphopoietin monoclonal antibody in development for the treatment of severe asthma. This study assessed the functionality and performance of an accessorized pre-filled syringe (APFS) and an autoinjector (AI) for administration of tezepelumab in the clinic and at home.MethodsThis phase 3, multicenter, randomized, open-label, parallel-group study (PATH-HOME, ClinicalTrials.gov identifier: NCT03968978) was conducted in patients aged 12-80 years with asthma that was uncontrolled despite treatment with medium- to high-dose inhaled corticosteroids plus at least one additional controller medication. Patients received six subcutaneous doses of tezepelumab 210 mg via APFS or AI. The first dose was administered by a healthcare professional, and patients or caregivers administered subsequent doses. First, second, third and final doses were administered in the clinic; fourth and fifth doses were administered at home. The primary endpoint was the proportion of successful administrations of tezepelumab. Secondary endpoints included the functionality and performance of the devices, Asthma Control Questionnaire (ACQ)-6 score, pharmacokinetics and safety.ResultsOverall, 216 patients were randomized (APFS, n=111; AI, n=105). Tezepelumab was successfully administered via APFS by 91.7% of the participants (100/109) and via AI by 92.4% (97/105). Overall, 95.4-97.1% of at-home administrations were successful across device groups. Malfunction occurred in 6 of 655 dispensed APFSs and 5 of 624 dispensed AIs. Clinically meaningful improvements in ACQ-6 score were observed after 24 weeks in 81.1% and 76.2% of the patients in the APFS and AI groups, respectively. Tezepelumab pharmacokinetics were consistent between device groups and with previous studies. The most common adverse event was nasopharyngitis (9.3%). Injection-site reactions occurred in 5.7% and 0% of the patients in the AI and APFS groups, respectively.ConclusionThis study demonstrated that the APFS and AI were functional and reliable, and performed equally well at home and in the clinic.

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Unmet need in severe, uncontrolled asthma: can anti-TSLP therapy with tezepelumab provide a valuable new treatment option?

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Unmet need in severe, uncontrolled asthma: can anti-TSLP therapy with tezepelumab provide a valuable new treatment option?

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