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      Lebrikizumab in moderate-to-severe asthma: pooled data from two randomised placebo-controlled studies

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          Abstract

          Introduction

          In a subset of patients with asthma, standard-of-care treatment does not achieve disease control, highlighting the need for novel therapeutic approaches. Lebrikizumab is a humanised, monoclonal antibody that binds to and blocks interleukin-13 activity.

          Methods

          LUTE and VERSE were replicate, randomised, double-blind, placebo-controlled studies, evaluating multiple doses of lebrikizumab in patients with uncontrolled asthma despite the use of medium-to-high-dose inhaled corticosteroid and a second controller. Patients received lebrikizumab 37.5, 125, 250 mg or placebo subcutaneously every four weeks. The primary endpoint was the rate of asthma exacerbations during the placebo-controlled period. Analyses were performed on prespecified subgroups based on baseline serum periostin levels. Following the discovery of a host-cell impurity in the study drug material, protocols were amended to convert from phase III to phase IIb. Subsequently, dosing of study medication was discontinued early as a precautionary measure. The data collected for analysis were from a placebo-controlled period of variable duration and pooled across both studies.

          Results

          The median duration of treatment was approximately 24 weeks. Treatment with lebrikizumab reduced the rate of asthma exacerbations, which was more pronounced in the periostin-high patients (all doses: 60% reduction) than in the periostin-low patients (all doses: 5% reduction); no dose–response was evident. Lung function also improved following lebrikizumab treatment, with greatest increase in FEV 1 in periostin-high patients (all doses: 9.1% placebo-adjusted improvement) compared with periostin-low patients (all doses: 2.6% placebo-adjusted improvement). Lebrikizumab was well tolerated and no clinically important safety signals were observed.

          Conclusions

          These data are consistent with, and extend, previously published results demonstrating the efficacy of lebrikizumab in improving rate of asthma exacerbations and lung function in patients with moderate-to-severe asthma who remain uncontrolled despite current standard-of-care treatment.

          Trial registration numbers

          The LUTE study was registered under NCT01545440 and the VERSE study under NCT01545453 at http://www.clinicaltrials.gov

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          Most cited references13

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          Lebrikizumab treatment in adults with asthma.

          Many patients with asthma have uncontrolled disease despite treatment with inhaled glucocorticoids. One potential cause of the variability in response to treatment is heterogeneity in the role of interleukin-13 expression in the clinical asthma phenotype. We hypothesized that anti-interleukin-13 therapy would benefit patients with asthma who had a pretreatment profile consistent with interleukin-13 activity. We conducted a randomized, double-blind, placebo-controlled study of lebrikizumab, a monoclonal antibody to interleukin-13, in 219 adults who had asthma that was inadequately controlled despite inhaled glucocorticoid therapy. The primary efficacy outcome was the relative change in prebronchodilator forced expiratory volume in 1 second (FEV(1)) from baseline to week 12. Among the secondary outcomes was the rate of asthma exacerbations through 24 weeks. Patient subgroups were prespecified according to baseline type 2 helper T-cell (Th2) status (assessed on the basis of total IgE level and blood eosinophil count) and serum periostin level. At baseline, patients had a mean FEV(1) that was 65% of the predicted value and were taking a mean dose of inhaled glucocorticoids of 580 μg per day; 80% were also taking a long-acting beta-agonist. At week 12, the mean increase in FEV(1) was 5.5 percentage points higher in the lebrikizumab group than in the placebo group (P = 0.02). Among patients in the high-periostin subgroup, the increase from baseline FEV(1) was 8.2 percentage points higher in the lebrikizumab group than in the placebo group (P = 0.03). Among patients in the low-periostin subgroup, the increase from baseline FEV(1) was 1.6 percentage points higher in the lebrikizumab group than in the placebo group (P = 0.61). Musculoskeletal side effects were more common with lebrikizumab than with placebo (13.2% vs. 5.4%, P = 0.045). Lebrikizumab treatment was associated with improved lung function. Patients with high pretreatment levels of serum periostin had greater improvement in lung function with lebrikizumab than did patients with low periostin levels. (Funded by Genentech; ClinicalTrials.gov number, NCT00930163 .).
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            Endotyping asthma: new insights into key pathogenic mechanisms in a complex, heterogeneous disease.

            Clinical asthma is very widely assumed to be the net result of excessive inflammation driven by aberrant T-helper-2 (Th2) immunity that leads to inflamed, remodelled airways and then functional derangement that, in turn, causes symptoms. This notion of disease is actually poorly supported by data, and there are substantial discrepancies and very poor correlation between inflammation, damage, functional impairment, and degree of symptoms. Furthermore, this problem is compounded by the poor understanding of the heterogeneity of clinical disease. Failure to recognise and discover the underlying mechanisms of these major variants or endotypes of asthma is, arguably, the major intellectual limitation to progress at present. Fortunately, both clinical research and animal models are very well suited to dissecting the cellular and molecular basis of disease endotypes. This approach is already suggesting entirely novel pathways to disease-eg, alternative macrophage specification, steroid refractory innate immunity, the interleukin-17-regulatory T-cell axis, epidermal growth factor receptor co-amplification, and Th2-mimicking but non-T-cell, interleukins 18 and 33 dependent processes that can offer unexpected therapeutic opportunities for specific patient endotypes.
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              Genome-wide profiling identifies epithelial cell genes associated with asthma and with treatment response to corticosteroids.

              Airway inflammation and epithelial remodeling are two key features of asthma. IL-13 and other cytokines produced during T helper type 2 cell-driven allergic inflammation contribute to airway epithelial goblet cell metaplasia and may alter epithelial-mesenchymal signaling, leading to increased subepithelial fibrosis or hyperplasia of smooth muscle. The beneficial effects of corticosteroids in asthma could relate to their ability to directly or indirectly decrease epithelial cell activation by inflammatory cells and cytokines. To identify markers of epithelial cell dysfunction and the effects of corticosteroids on epithelial cells in asthma, we studied airway epithelial cells collected from asthmatic subjects enrolled in a randomized controlled trial of inhaled corticosteroids, from healthy subjects and from smokers (disease control). By using gene expression microarrays, we found that chloride channel, calcium-activated, family member 1 (CLCA1), periostin, and serine peptidase inhibitor, clade B (ovalbumin), member 2 (serpinB2) were up-regulated in asthma but not in smokers. Corticosteroid treatment down-regulated expression of these three genes and markedly up-regulated expression of FK506-binding protein 51 (FKBP51). Whereas high baseline expression of CLCA1, periostin, and serpinB2 was associated with a good clinical response to corticosteroids, high expression of FKBP51 was associated with a poor response. By using airway epithelial cells in culture, we found that IL-13 increased expression of CLCA1, periostin, and serpinB2, an effect that was suppressed by corticosteroids. Corticosteroids also induced expression of FKBP51. Taken together, our findings show that airway epithelial cells in asthma have a distinct activation profile and identify direct and cell-autonomous effects of corticosteroid treatment on airway epithelial cells that relate to treatment responses and can now be the focus of specific mechanistic studies.
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                Author and article information

                Journal
                Thorax
                Thorax
                thoraxjnl
                thorax
                Thorax
                BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )
                0040-6376
                1468-3296
                August 2015
                22 May 2015
                : 70
                : 8
                : 748-756
                Affiliations
                [1 ]Section of Pulmonary and Critical Care Medicine, Baylor College of Medicine , Houston, Texas, USA
                [2 ]Allergy Associates Research , Portland, Oregon, USA
                [3 ]Asthma and Allergy Research Foundation , Los Angeles, California, USA
                [4 ]Clinical Research Center LLC , St. Louis, Missouri, USA
                [5 ]Genentech Inc. (a Member of the Roche Group) , South San Francisco, California, USA
                Author notes
                [Correspondence to ] Dr Karl Yen, Genentech Inc, 1 DNA Drive, South San Francisco, CA 94080-4990, USA; yen.karl@ 123456gene.com
                Article
                thoraxjnl-2014-206719
                10.1136/thoraxjnl-2014-206719
                4515999
                26001563
                50117672-6580-4bd8-bd1f-52662eb12e82
                Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions

                This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

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                1506
                Respiratory Research
                Original article
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                Surgery
                asthma,cytokine biology,asthma mechanisms
                Surgery
                asthma, cytokine biology, asthma mechanisms

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