Effect of tralokinumab, an interleukin-13 neutralising monoclonal antibody, on eosinophilic airway inflammation in uncontrolled moderate-to-severe asthma (MESOS): a multicentre, double-blind, randomised, placebo-controlled phase 2 trial (original) (raw)
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The Cochrane library, 2021
BackgroundTargeting the immunoglobulin E pathway and the interleukin‐5 pathway with specific monoclonal antibodies directed against the cytokines or their receptors is effective in patients with severe asthma. However, there are patients who have suboptimal responses to these biologics. Since interleukin‐4 and interleukin‐13, signalling through the interleukin‐4 receptor, have multiple effects on the biology of asthma, therapies targeting interleukin‐4 and ‐13 (both individually and combined) have been developed.ObjectivesTo assess the efficacy and safety of anti‐interleukin‐13 or anti‐interleukin‐4 agents, compared with placebo, anti‐immunoglobulin E agents, or anti‐interleukin‐5 agents, for the treatment of children, adolescents, or adults with asthma.Search methodsWe identified studies from the Cochrane Airways Trials Register, which is maintained by the Information Specialist for the Group and through searches of the US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform. The search was carried out on the 16 October 2020.Selection criteriaWe included parallel‐group randomised controlled trials that compared anti‐interleukin‐13 or ‐4 agents (or agents that target both interleukin‐13 and interleukin‐4) with placebo in adolescents and adults (aged 16 years or older) or children (younger than 16 years), with a diagnosis of asthma; participants could receive their usual short‐ or long‐acting medications (e.g. inhaled corticosteroids (ICS), long‐acting beta adrenoceptor agonists (LABA), long‐acting muscarinic antagonists (LAMA), and/or leukotriene receptor antagonists) provided that they were not part of the randomised treatment.Data collection and analysisWe used standard methods expected by Cochrane.Main resultsWe identified and included 41 RCTs. Of these, 29 studies contributed data to the quantitative analyses, randomly assigning 10,604 people with asthma to receive an anti‐interleukin‐13 (intervention) or anti‐interleukin‐4 agent (intervention), or placebo (comparator). No relevant studies were identified where the comparator was an anti‐immunoglobulin agent or an anti‐interleukin‐5 agent. Studies had a duration of between 2 and 52 (median 16) weeks. The mean age of participants across the included studies ranged from 22 to 55 years. Only five studies permitted enrolment of children and adolescents, accounting for less than 5% of the total participants contributing data to the present review. The majority of participants had moderate or severe uncontrolled asthma. Concomitant ICS use was permitted or required in the majority (21 of 29) of the included studies. The use of maintenance systemic corticosteroids was not permitted in 19 studies and was permitted or required in five studies (information not reported in five studies). Regarding the most commonly assessed anti‐interleukin‐13/‐4 agents, four studies evaluated dupilumab (300 mg once every week (Q1W), 200 mg once every two weeks (Q2W), 300 mg Q2W, 200 mg once every four weeks (Q4W), 300 mg Q4W, each administered by subcutaneous (SC) injection); eight studies evaluated lebrikizumab (37.5 mg Q4W, 125 mg Q4W, 250 mg Q4W each administered by SC injection); and nine studies (3259 participants) evaluated tralokinumab (75 mg Q1W, 150 mg Q1W, 300 mg Q1W, 150 mg Q2W, 300 mg Q2W, 600 mg Q2W, 300 mg Q4W, each administered by SC injection; 1/5/10 mg/kg administered by intravenous (IV) injection); all anti‐interleukin‐13 or‐4 agents were compared with placebo.The risk of bias was generally considered to be low or unclear (insufficient detail provided); nine studies were considered to be at high risk for attrition bias and three studies were considered to be at high risk for reporting bias.The following results relate to the primary outcomes. The rate of exacerbations requiring hospitalisation or emergency department (ED) visit was probably lower in participants receiving tralokinumab versus placebo (rate ratio 0.68, 95% CI 0.47 to 0.98; moderate‐certainty evidence; data available for tralokinumab (anti‐interleukin‐13) only). In participants receiving an anti‐interleukin‐13/‐4 agent, the mean improvement versus placebo in adjusted asthma quality of life questionnaire score was 0.18 units (95% CI 0.12 to 0.24; high‐certainty evidence); however, this finding was deemed not to be a clinically relevant improvement. There was likely little or no difference between groups in the proportion of patients who reported all‐cause serious adverse events (anti‐interleukin‐13/‐4 agents versus placebo, OR 0.91, 95% CI 0.76 to 1.09; moderate‐certainty evidence).In terms of secondary outcomes, there may be little or no difference between groups in the proportion of patients who experienced exacerbations requiring oral corticosteroids (anti‐interleukin‐13/‐4 agents versus placebo, rate ratio 0.98, 95% CI 0.72 to 1.32; low‐certainty evidence). Anti‐interleukin‐13/‐4 agents probably improve asthma control based on asthma control questionnaire score (anti‐interleukin‐13/‐4 agents versus placebo, mean difference ‐0.19; 95% CI ‐0.24 to ‐0.14); however, the magnitude of this result was deemed not to be a clinically relevant improvement. The proportion of patients experiencing any adverse event was greater in those receiving anti‐interleukin‐13/‐4 agents compared with those receiving placebo (OR 1.16, 95% CI 1.04 to 1.30; high‐certainty evidence); the most commonly reported adverse events in participants treated with anti‐interleukin‐13/‐4 agents were upper respiratory tract infection, nasopharyngitis, headache and injection site reaction. The pooled results for the exploratory outcome, the rate of exacerbations requiring oral corticosteroids (OCS) or hospitalisation or emergency department visit, may be lower in participants receiving anti‐interleukin‐13/‐4 agents versus placebo (rate ratio 0.71, 95% CI 0.65 to 0.77; low‐certainty evidence).Results were generally consistent across subgroups for different classes of agent (anti‐interleukin‐13 or anti‐interleukin‐4), durations of study and severity of disease. Subgroup analysis based on category of T helper 2 (TH2) inflammation suggested greater efficacy in patients with higher levels of inflammatory biomarkers (blood eosinophils, exhaled nitric oxide and serum periostin).Authors' conclusionsBased on the totality of the evidence, compared with placebo, anti‐interleukin‐13/‐4 agents are probably associated with a reduction in exacerbations requiring hospitalisation or ED visit, at the cost of increased adverse events, in patients with asthma. No clinically relevant improvements in health‐related quality of life or asthma control were identified. Therefore, anti‐interleukin‐13 or anti‐interleukin‐4 agents may be appropriate for adults with moderate‐to‐severe uncontrolled asthma who have not responded to other treatments. These conclusions are generally supported by moderate or high‐certainty evidence based on studies with an observation period of up to one year.
Interleukin 13 and the evolution of asthma therapy
American journal of clinical and experimental immunology, 2012
This is a concise review on Interleukin (IL)-13 and the evolution of asthma therapy, from discovery of the molecule, the identification of its pathogenic role in animal models of asthma, to the development of clinically successful neutralizing agents. The translational path from basic research to clinical application was not sequential as expected but random with respect to the tools (molecular & cell biology, animal models, human studies) used and to the application of academic versus industry research. The experiences with the development of neutralizing anti-IL-13 reagents emphasize the need for inclusion of a biomarker assay in the clinical trials that both identifies individuals that actually have aberrant expression of the pathway of interest and allows determining whether the target of interest is neutralized.
Vaccines
Interleukin-4 (IL-4) and interleukin-13 (IL-13) are key cytokines involved in the pathophysiology of both immune-inflammatory and structural changes underlying type 2 asthma. IL-4 plays a pivotal role in Th2 cell polarization, immunoglobulin E (IgE) synthesis and eosinophil recruitment into the airways. IL-13 synergizes with IL-4 in inducing IgE production and also promotes nitric oxide (NO) synthesis, eosinophil chemotaxis, bronchial hyperresponsiveness and mucus secretion, as well as the proliferation of airway resident cells such as fibroblasts and smooth muscle cells. The biological effects of IL-4 and IL-13 are mediated by complex signaling mechanisms activated by receptor dimerization triggered by cytokine binding to the α-subunit of the IL-4 receptor (IL-4Rα). The fully human IgG4 monoclonal antibody dupilumab binds to IL-4Rα, thereby preventing its interactions with both IL-4 and IL-13. This mechanism of action makes it possible for dupilumab to effectively inhibit type 2 in...
Chest, 2005
Experimental studies on asthma have indicated that interleukin (IL)-13 induces airway hyperreactivity (AHR). However, it remains unproven that IL-13 is responsible for AHR in asthmatic patients. Eosinophilic bronchitis (EB) shows normal airway responsiveness despite eosinophilic airway inflammation of severity similar to that of asthma. This study evaluated the role of IL-13 in asthma by comparing the sputum IL-5 and IL-13 levels in both groups. Comparisons between asthma and EB would clarify the role of IL-13 in AHR. IL-5 and IL-13 were assayed in the sputum and culture supernatants of peripheral blood mononuclear cells (PBMCs) from 22 asthmatic patients, 12 EB patients, and 11 healthy control subjects. IL-13 levels were higher in the asthmatic patients than in the EB patients or healthy control subjects (p = 0.001). IL-5 levels were similar in the asthmatic patients and EB patients, who had significantly higher levels than those of healthy control subjects. Sputum IL-13, but not I...
Respiratory Research
Background Patients with severe, uncontrolled asthma, particularly those with a non-eosinophilic phenotype, have a great unmet need for new treatments that act on a broad range of inflammatory pathways in the airway. Tezepelumab is a human monoclonal antibody that blocks the activity of thymic stromal lymphopoietin, an epithelial cytokine. In the PATHWAY phase 2b study (NCT02054130), tezepelumab reduced exacerbations by up to 71% in adults with severe, uncontrolled asthma, irrespective of baseline eosinophilic inflammatory status. This article reports the design and objectives of the phase 2 CASCADE study. Methods CASCADE is an ongoing exploratory, phase 2, randomized, double-blind, placebo-controlled, parallel-group study aiming to assess the anti-inflammatory effects of tezepelumab 210 mg administered subcutaneously every 4 weeks for 28 weeks in adults aged 18–75 years with uncontrolled, moderate-to-severe asthma. The primary endpoint is the change from baseline to week 28 in airw...