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.

拟议的研究将确定第一类新化学物质的制造性和非临床安全性哮喘治疗的实体。 PI301药物调节伽马氨基丁酸A型受体（GABAAR）在肺中，代表了一种从根本上进行哮喘药物靶向和设计的新方法。该药物是被开发为用于控制哮喘症状的口服药物。几种动物的药效研究哮喘模型显示出发炎和非肺肺和人类肺部外植体。 PI301治疗还减少了Th2高的肺部炎症和 Th2-low小鼠哮喘模型。这项创新的意义是一种减轻两个的化合物哮喘，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，并在当前的哮喘组合疗法范围内改善控制。这项研究的长期目标是FDA批准PI301，PI301是哮喘的第一类口服药物。这目的是使用微囊化策略优化PI301的口服药代动力学。一系列将开发微囊化的药物制剂，并基于体外溶解的最佳配方将通过大鼠口服剂量进一步评估以评估改进的药代动力学。选择的准备 ICH Q1A（R2）将经过稳定性测试。大鼠用微封装的PI301的剂量研究将建立药物安全性和最大耐受剂量，并为未来的辅助GLP研究的设计提供信息。我们的假设是优化的配方（微封装PI301）将维持长时间的治疗方法 PI301血液浓度并减少由于高峰值浓度而导致的安全责任的可能性重复给药。基本原理是使用可接受的FDA药物微囊封装方法（持续释放和肠涂层），它可以增加口服生物利用度并提供可以轻松的药物形式在非临床啮齿动物和非岩体物种中口服，并在胶囊中进一步配制人类研究。我们的假设将在三个特定目的中进行检验：（1）开发微包装的形式 pi301; （2）证明了临床前大鼠毒性研究的PI301安全性；（3）证明了一个安全的PI301 遗传毒理学特征。这项研究的意义是开发一种安全有效的药物控制哮喘症状，避免对当前疗法的抵抗，并提高依从性。进步进入临床试验的PI301将建立外围Gabaars作为引人注目的新药物目标，并启用开发其他Gabaar配体作为其他免疫炎性疾病的治疗方法。创新这项研究是一种新型药物，可以减少过敏原或感染性引起的哮喘性肺部炎症起源以及跨越哮喘疾病内型。可以口服PI301，达到高组织选择性对于肺部和有限的大脑暴露。这项研究将扩大旁分泌Gabagagic的横切知识肺部的系统可以用于其他肺部疾病治疗。