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.

The proposed research is relevant to public health because it will advance development of a first-in-class drug for asthma, a global disease afflicting approximately 26.5 million persons in the US (over 8% of the population) and incurring annual health care costs of over $56 billion. Innovative therapies are needed to improve symptom control and quality of life, reduce adverse effects, improve treatment compliance, and control costs. The research is relevant to the NIH mission by exploring the physiological effects of GABAA receptor modulation in the lung and pharmaceutically targeting these receptors as a fundamentally novel mechanism of action for oral asthma medications.