Development of microencapsulated PI301 targeting lung GABAergic signaling

开发针对肺 GABA 信号传导的微囊 PI301

基本信息

批准号：
10478543
负责人：
Douglas C. Stafford
金额：
$ 25.58万
依托单位：
PANTHERICS INCORPORATED
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-03 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10478543
关键词：
Address Adrenal Cortex Hormones Adrenergic Agonists Advanced Development Adverse effects Affect Agonist Allergens Animals Asthma Biological Biological Availability Biological Products Blood Brain Bronchial Spasm Bronchodilator Agents Butyric Acids Chemicals Chronic Clinical Trials Collaborations Combined Modality Therapy Cost Control Data Development Disease Dose Drug Compounding Drug Controls Drug Costs Drug Design Drug Kinetics Drug Stability Drug Targeting Enteral Eosinophilia Formulation Future Genes Goals Health Care Costs Human Hyperactivity Immune Immunomodulators In Vitro Inflammatory Inhalation Inhalators Injectable Innovative Therapy Knowledge Lead Leukotriene Antagonists Leukotrienes Ligands Literature Lung Lung diseases Maximum Tolerated Dose Medical Methods Microencapsulations Mission Monoclonal Antibodies Mus Oral Oral Administration Outcome Particle Size Patients Peripheral Persons Pharmaceutical Preparations Pharmacodynamics Pharmacologic Substance Pharmacology Pharmacology Study Phase Physiological Population Preparation Public Health Pulmonary Inflammation Quality of life Rattus Relaxation Research Residual state Resistance Risk Rodent Safety Series Signal Transduction Solvents Steroids Stimulus Symptoms System Testing Therapeutic Tissues Toxic effect Toxicogenetics Treatment Failure United States National Institutes of Health Validation Variant airway hyperresponsiveness airway inflammation airway obstruction airway remodeling animal safety asthma model asthmatic asthmatic patient base beta-2 Adrenergic Receptors capsule compliance behavior cost design effective therapy first-in-human genotoxicity global health improved in vivo innovation manufacturability medication safety new therapeutic target novel novel strategies novel therapeutics paracrine patient population pre-clinical receptor reduce symptoms respiratory smooth muscle safety study stability testing symptomatic improvement

项目摘要

The proposed research will establish the manufacturability and non-clinical safety of a first-in-class new chemical entity for asthma treatment. The drug, PI301, modulates gamma amino butyric acid type A receptors (GABAAR) in the lung and represents a fundamentally novel approach to asthma drug targeting and design. The drug is being developed as an oral medication for asthma symptom control. Pharmacodynamic studies in several animal asthma models have shown significant relaxation of constricted airway smooth muscle (ASM) in inflamed and non-inflamed lung and in human lung explants. PI301 treatment also reduced lung inflammation in Th2-high and Th2-low mouse asthma models. The significance of this innovation is a single compound that alleviates two hallmark symptoms of asthma, bronchospasm and lung inflammation, which avoids the use of corticosteroids and inhaled bronchodilators and improves upon the current paradigm of combination therapies for asthma control. The long-term goal of this research is FDA approval of PI301, a first-in-class oral drug for asthma. The objective is to optimize the oral pharmacokinetics of PI301 using microencapsulation strategies. A series of microencapsulated drug preparations will be developed, and the best formulation based on in vitro dissolution will be evaluated further by oral dosing in rats to assess improved pharmacokinetics. The chosen preparation will undergo stability testing following ICH Q1A(R2). Rat dosing studies with microencapsulated PI301 will establish drug safety and the maximum tolerated dose and inform the design of future IND-enabling GLP studies. Our hypothesis is that an optimized formulation (microencapsulated PI301) will sustain a prolonged therapeutic PI301 blood concentration and reduce the possibility of safety liabilities due to high peak concentrations with repeated dosing. The rationale is to use FDA-acceptable drug microencapsulation methods (sustained release and enteric coating), which can increase oral bioavailability and provide a drug form that can be readily administrated orally in non-clinical rodent and non-rodent species and formulated further in capsules for first in human studies. Our hypothesis will be tested within three Specific Aims: (1) Develop a microencapsulated form of PI301; (2) Demonstrate PI301 safety in pre-clinical rat toxicity studies; and, (3) Demonstrate a safe PI301 genetic toxicology profile. The significance of this research is development of a safe and effective drug that controls asthma symptoms, avoids resistance to current therapies, and improves compliance. Advancement of PI301 into clinical trials will establish peripheral GABAARs as compelling new drug targets and enable development of other GABAAR ligands as treatments for other immune-inflammatory diseases. The innovation of this research is a novel drug that can reduce asthmatic lung inflammation arising from allergen or infectious origins and across asthma disease endotypes. PI301 can be administered orally, achieving high tissue selectivity for lung and limited brain exposure. This research will expand crosscutting knowledge of a paracrine GABAergic system in the lung that can be exploited therapeutically for other lung disorders.

拟议的研究将确定一流新化学品的可制造性和非临床安全性治疗哮喘的实体。该药物 PI301 可调节 γ 氨基丁酸 A 型受体 (GABAAR) 在肺部，代表了一种全新的哮喘药物靶向和设计方法。该药物是被开发为用于控制哮喘症状的口服药物。多种动物的药效学研究哮喘模型显示，在发炎和哮喘患者中，收缩的气道平滑肌 (ASM) 显着松弛。非发炎的肺部和人肺外植体中。 PI301 治疗还可以减少 Th2 高和 Th2 型患者的肺部炎症 Th2低小鼠哮喘模型。这项创新的意义在于单一化合物可以减轻两种哮喘、支气管痉挛和肺部炎症的标志性症状，避免使用皮质类固醇和吸入支气管扩张剂，并改进了当前哮喘联合治疗的范例控制。这项研究的长期目标是 FDA 批准 PI301，一种治疗哮喘的一流口服药物。这目的是使用微胶囊化策略优化 PI301 的口服药代动力学。一系列开发微囊药物制剂，根据体外溶出度确定最佳剂型将通过大鼠口服给药进一步评估，以评估药代动力学的改善。所选择的准备工作将按照 ICH Q1A(R2) 进行稳定性测试。微囊 PI301 的大鼠剂量研究将确定药物安全性和最大耐受剂量，并为未来支持 IND 的 GLP 研究的设计提供信息。我们的假设是，优化的配方（微囊 PI301）将维持长期的治疗效果。 PI301 血药浓度并降低因高峰浓度而导致安全责任的可能性重复给药。其基本原理是使用 FDA 可接受的药物微囊化方法（缓释和肠溶衣），它可以增加口服生物利用度并提供易于吸收的药物形式在非临床啮齿动物和非啮齿动物物种中口服给药，并进一步配制为胶囊，用于首次人类研究。我们的假设将在三个具体目标内得到检验：(1) 开发微胶囊形式 PI301；（2）在临床前大鼠毒性研究中证明PI301的安全性； (3) 展示安全的 PI301 遗传毒理学概况。这项研究的意义在于开发一种安全有效的药物控制哮喘症状，避免对当前治疗产生耐药性，并提高依从性。的进步 PI301 进入临床试验将确立外周 GABAAR 作为引人注目的新药靶点，并使开发其他 GABAAR 配体作为其他免疫炎症疾病的治疗方法。创新这项研究的成果是一种新药，可以减少过敏原或感染引起的哮喘性肺部炎症起源和跨哮喘疾病内型。 PI301可以口服，实现高组织选择性对于肺部和有限的大脑暴露。这项研究将扩展旁分泌 GABA 能的横切知识肺部系统，可用于治疗其他肺部疾病。