Masitinib Significantly Decreases the Rate of Asthma Exacerbations in Patients with Severe Asthma Uncontrolled by Oral Corticosteroids: A Phase 3 Multicenter Study

Chanez, Pascal; Israel, Elliot; Davidescu, Lavinia; Ursol, Grigoriy; Korzh, Oleksii; Deshmukh, Vikranth; Kuryk, Łukasz; Nortje, M; Godlevska, O.; Devouassoux, Gilles; Ходош, Э. М.; Hermine, Olivier

doi:10.1164/ajrccm-conference.2020.201.1_meetingabstracts.a4210

Cited by 4 publications

(4 citation statements)

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“…The supporting literature was identified for the 26 compounds. Indacaterol (a beta-2 adrenergic receptor (ADRB2) agonist) and masatinib (a proto-oncogene c-Src (SRC) inhibitor) have undergone phase III clinical trials for asthma 47,48 . There are approved drugs (acetazolamide, fluorouracil, and naproxen and indomethacin, respectively) with the same mechanistic action as cianidanol (a carbonic anhydrase inhibitor) and raltitrexed (a thymidylate synthase inhibitor) for POAG 49 , and piketoprofen and diclofenac (cyclooxygenase 1/2 inhibitors) for gout, respectively.…”

Section: Resultsmentioning

confidence: 99%

A practical guideline of genomics-driven drug discovery in the era of global biobank meta-analysis

Namba

Konuma

et al. 2021

Preprint

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SummaryGenomics-driven drug discovery is indispensable for accelerating the development of novel therapeutic targets. However, the drug discovery framework based on evidence from genome-wide association studies (GWAS) has not been established, especially for cross-population GWAS meta-analysis. Here, we introduce a practical guideline for genomics-driven drug discovery for cross-population meta-analysis, as lessons from the Global Biobank Meta-analysis Initiative (GBMI). Our drug discovery framework encompassed three methodologies and was applied to the 13 common diseases targeted by GBMI (Nmean = 1,329,242). First, we evaluated the overlap enrichment between disease risk genes and the drug-target genes of the disease-relevant medication categories. An omnibus approach integrating the four gene prioritization tools yielded twice the enrichment in the disease-relevant medication categories compared with any single tool, and identified drugs with approved indications for asthma, gout, and venous thromboembolism. Second, we performed an endophenotype Mendelian randomization analysis using protein quantitative trait loci as instrumental variables. After the application of quality controls, including a colocalization analysis, significant causal relationships were estimated for 18 protein–disease pairs, including MAP2K inhibitors for heart failure. Third, we conducted an in silico screening for negative correlations between genetically determined disease case–control gene expression profiles and compound-regulated ones. Significant negative correlations were observed for 31 compound–disease pairs, including a histone deacetylase inhibitor for asthma. Integration of the three methodologies provided a comprehensive catalog of candidate drugs for repositioning, nominating promising drug candidates targeting the genes involved in the coagulation process for venous thromboembolism. Our study highlighted key factors for successful genomics-driven drug discovery using cross-population meta-analysis.

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Section: Resultsmentioning

confidence: 99%

A practical guideline of genomics-driven drug discovery in the era of global biobank meta-analysis

Namba

Konuma

et al. 2021

Preprint

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“…Several promising mast cell-targeted biologics, such as mAbs anti-IL-33 [200] (NTC04570657), anti-ST2 [202], anti-Siglec-8 (NCT03379311; NCT03436797; NCT04322708), and CDX-0159 (NCT04146129) have entered clinical development in asthma or allergic disorders. Moreover, several classes of drugs silencing or depleting mast cells (e.g., TKIs) have shown promising results in patients with severe uncontrolled asthma [262][263][264].…”

Section: Discussionmentioning

confidence: 99%

“…In a phase III trial, masitinib reduced asthma exacerbations compared to placebo in severe asthma patients [263]. Avapritinib (BLU-285), a potent inhibitor of mutant KIT and PDGFRA with activation loop mutations, induces mast cell cytoreduction and remission in the majority of advanced systemic mastocytosis patients [269,270].…”

Section: Depleting Mast Cellsmentioning

confidence: 99%

“…Several classes of KIT-associated tyrosine kinase inhibitors (TKIs) are now available[16,260,261]. Preliminary evidence indicates that prolonged administration of imatinib[262] and masitinib[263,264] can influence airway hyperresponsiveness or reduce asthma exacerbations in asthma patients. These beneficial effects have been tentatively attributed to the inhibition of mast cell activation and/or depletion of mast cells.…”

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confidence: 99%

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Human Lung Mast Cells: Therapeutic Implications in Asthma

Poto

Criscuolo

Marone

et al. 2022

IJMS

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Mast cells are strategically located in different compartments of the lung in asthmatic patients. These cells are widely recognized as central effectors and immunomodulators in different asthma phenotypes. Mast cell mediators activate a wide spectrum of cells of the innate and adaptive immune system during airway inflammation. Moreover, these cells modulate the activities of several structural cells (i.e., fibroblasts, airway smooth muscle cells, bronchial epithelial and goblet cells, and endothelial cells) in the human lung. These findings indicate that lung mast cells and their mediators significantly contribute to the immune induction of airway remodeling in severe asthma. Therapies targeting mast cell mediators and/or their receptors, including monoclonal antibodies targeting IgE, IL-4/IL-13, IL-5/IL-5Rα, IL-4Rα, TSLP, and IL-33, have been found safe and effective in the treatment of different phenotypes of asthma. Moreover, agonists of inhibitory receptors expressed by human mast cells (Siglec-8, Siglec-6) are under investigation for asthma treatment. Increasing evidence suggests that different approaches to depleting mast cells show promising results in severe asthma treatment. Novel treatments targeting mast cells can presumably change the course of the disease and induce drug-free remission in bronchial asthma. Here, we provide an overview of current and promising treatments for asthma that directly or indirectly target lung mast cells.

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Molecular and immunomodulatory actions of new antiasthmatic agents: Exploring the diversity of biologics in Th2 endotype asthma

Okwuofu

Hui

Woei

et al. 2022

Pharmacological Research

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Masitinib Significantly Decreases the Rate of Asthma Exacerbations in Patients with Severe Asthma Uncontrolled by Oral Corticosteroids: A Phase 3 Multicenter Study

Cited by 4 publications

References 0 publications

A practical guideline of genomics-driven drug discovery in the era of global biobank meta-analysis

A practical guideline of genomics-driven drug discovery in the era of global biobank meta-analysis

Human Lung Mast Cells: Therapeutic Implications in Asthma

Molecular and immunomodulatory actions of new antiasthmatic agents: Exploring the diversity of biologics in Th2 endotype asthma

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