Development of a Novel Calcium Channel Therapeutic for the Treatment of Asthma

开发治疗哮喘的新型钙通道疗法

• 批准号: 10603554
• 负责人: Milton L Greenberg
• 金额: $ 35.2万
• 依托单位: VIVREON BIOSCIENCES, LLC
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-15 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10603554
• 关键词: Ablation; Achievement; Adolescent; Adopted; Adult; Adult asthma; Air; Air Movements; Anti-Inflammatory Agents; Asthma; Biological; Biological Response Modifier Therapy; Biological Sciences; Calcium Channel; Cardiac; Cells; Chemicals; Chemistry; Chronic; Clinical; Complex; Development; Disease; Disease model; Dosage Forms; Dose; Drug Kinetics; Drug or chemical Tissue Distribution; Dryness; Epithelium; Exhibits; Fibrosis; Forced expiratory volume function; Formulation; Funding; Gatekeeping; Genes; Genetic Transcription; Goals; House Dust Mite Allergens; House mice; Immune; Immunity; In Vitro; Infiltration; Inflammation; Inflammation Mediators; Inflammatory; Inhalators; Intercept; Intranasal Administration; Investigational Therapies; Ion Channel; Irritants; Lead; Leucocytic infiltrate; Leukocytes; Lung; Maintenance; Metered Dose Inhaler Device; Methods; Mission; Modeling; Monitor; Mucous body substance; National Heart, Lung, and Blood Institute; Nebulizer; Oral; Pathologic; Pathology; Pathway interactions; Patient risk; Patients; Persons; Pharmaceutical Preparations; Phase; Phenotype; Plasma; Positioning Attribute; Powder dose form; Preparation; Process; Production; Proliferating; Property; Pulmonary Inflammation; Regimen; Regulatory T-Lymphocyte; Relaxation; Respiratory Tract Infections; Risk; Route; Safety; Severity of illness; Signal Transduction; Small Business Innovation Research Grant; Smooth Muscle; Smooth Muscle Myocytes; Structure of parenchyma of lung; Symptoms; Testing; Therapeutic; Tissues; Toxicology; Validation; Virus Diseases; airway remodeling; asthma model; asthmatic patient; cell type; commercialization; efficacy study; experimental study; human model; improved; improved outcome; in vitro activity; in vivo; knockout animal; minimal risk; muscle form; nanomolar; novel; novel strategies; nuclear factors of activated T-cells; patient population; pharmacologic; preservation; programs; respiratory smooth muscle; response; scale up; senescence; side effect; small molecule; standard of care; success; therapeutic candidate; treatment duration

Vivreon Biosciences, LLC 4940 Carroll Canyon Rd., Ste. 110 San Diego, CA 92121 [e-mail] NHLBI PA-21-259 Project Summary Severe asthma is a potentially lethal disease that is not fully controlled by anti-inflammatory small molecule or biologic therapies. Recent evidence indicates that severe asthma patients exhibit substantial airway remodeling (AR) where the epithelial, goblet and smooth muscle cells adopt atypical phenotypes that lead to airway restriction with airway tissue thickening and fibrosis, smooth muscle mass expansion (SMR), mucus accumulation and airway hyper reactivity to irritants. These tissue remodeling changes are not responsive to standard of care anti-inflammatory (small molecule or biologic) or airway relaxing agents. SMR masses are responsive to ablation by bronchial thermoplasty and clinical improvements are documented suggesting that reducing SMR is a novel means to control severe asthma. Recent studies indicate that the Ca2+ release-activated Ca2+ (CRAC) channel is a critical driver of SMR and that inhibition of CRAC could control SMR. Vivreon Biosciences is pursuing a novel approach to deliver a novel and potent CRAC modulator development candidate locally to the airways to obtain maximal tissue distribution and efficacy to control SMR. Other orally delivered, systemically active CRAC blockers showed efficacy in models of asthma by inhibiting the inflammatory mediators of the disease. Vivreon will surpass these early successes via intranasal delivery to achieve maximal local delivery to the tissue to reduce both SMR and local inflammation. The CRAC pathway regulates many genes through activation of NFAT and NF-B transcriptional activity. These attributes make the CRAC channel a suitable target for development of a drug that can suppress SMR and inflammation that drives severe asthma. Vivreon’s experimental therapeutic exhibits sub nanomolar potency at CRAC and a favorable safety profile (no CYP inhibition, acceptable off-target activity profile, no evidence of cardiac ion channel inhibition) upon oral dosing. In this SBIR Phase 1 project we will confirm in vitro activity against airway smooth muscle cell and leukocyte production of proinflammatory mediators. In Aim 2 we will confirm achievement of lung tissue levels that exceed CRAC IC50 values following intranasal administration. We will also monitor plasma exposure in this experiment to appreciate the potential for systemic activity with this dosing regimen. In Aim 3 we will quantify the efficacy and dose response of our CRAC modulator delivered by the intranasal route (confirmed in Aim 2) on the SMR process and smooth muscle mass, as well as inflammatory processes, in a model of asthma. Successful completion of these Aims will position the program to advance further into IND-enabling studies such as formulation and inhaler delivery optimization, advanced toxicology testing, chemistry scale up and dose-range finding with Phase II SBIR funding and other external support.

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