Development of microencapsulated PI301 targeting lung GABAergic signaling

开发针对肺 GABA 信号传导的微囊 PI301

• 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
• 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

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.

拟议的研究将建立一流的新化学品的可制造性和非临床安全性 哮喘治疗的实体。药物PI 301调节γ-氨基丁酸A型受体（GABAAR） 代表了一种全新的哮喘药物靶向和设计方法。述药物是 被开发为控制哮喘症状的口服药物。几种动物的药效学研究 哮喘模型已经显示出在炎症和炎症中收缩的气道平滑肌（ASM）的显著松弛， 非炎症肺和人肺外植体中。PI 301治疗还减少了Th 2-高和Th 3-低细胞中的肺部炎症。 Th 2-低小鼠哮喘模型。这种创新的意义在于一种化合物可以将两种 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 和吸入性支气管扩张剂，并改善了目前的哮喘联合治疗模式 控制这项研究的长期目标是FDA批准PI 301，这是一种一流的哮喘口服药物。的 目的：采用微囊化技术优化PI 301的口服药代动力学。一系列 将开发微囊化药物制剂，并根据体外溶出度确定最佳处方 将通过大鼠经口给药进一步评价，以评估改善的药代动力学。选择的准备 将按照ICH Q1 A（R2）进行稳定性试验。微囊化PI 301的大鼠给药研究将 确定药物安全性和最大耐受剂量，并为未来IND使能GLP研究的设计提供信息。 我们的假设是，优化的制剂（微囊化的PI 301）将维持长期的治疗效果。 PI 301血药浓度，并降低由于高峰浓度导致的安全性责任的可能性， 重复给药。基本原理是使用FDA可接受的药物微囊化方法（持续释放 和肠溶包衣），其可以增加口服生物利用度并提供可以容易地 在非临床啮齿类动物和非啮齿类动物种属中口服给药，并进一步配制成胶囊用于首次给药。 人类研究我们的假设将在三个具体目标内进行测试：（1）开发微胶囊形式 （2）证明PI 301在临床前大鼠毒性研究中的安全性;以及（3）证明安全的PI 301 遗传毒理学分析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，避免对当前疗法的抵抗，并提高依从性。推进 PI 301进入临床试验将使外周GABAAR成为引人注目的新药靶点， 开发其他GABAAR配体作为其他免疫炎性疾病的治疗。创新 这项研究的一个新的药物，可以减少哮喘肺部炎症引起的过敏原或传染性 起源和哮喘疾病的内在型。PI 301可口服给药，实现高组织选择性 肺部和大脑接触的风险这项研究将扩大对旁分泌GABA能的横向知识， 肺中的系统，可以在治疗上用于其他肺部疾病。