Project Summary / Abstract Uncontrolled inflammation in the small airways remains a major unmet need in clinical pulmonology. Severely asthmatic patients suffer from life-threatening symptoms and exacerbations requiring costly emergency hospital treatments. Although asthma patients are prescribed large numbers of inhalers, these current devices deliver very little medication into the lungs, with often less than 1% being deposited into small airways, which remain untreated. Therefore, we are developing a new method of delivering medication to the small airways which will perform significantly better than current products, including extra-fine formulations. We will create a novel dry powder formulation containing budesonide, a well-studied and FDA approved corticosteroid medication and a hygroscopic excipient (inactive ingredient) resulting in an excipient enhanced growth (EEG) formulation. This EEG formulation will be able to uniquely treat inflammation in small airways in order to significantly reduce related symptoms of severe asthma. By creating extra-fine submicron and micrometer sized drug powder particles combined with a hygroscopic excipient, the particles are able to avoid depositing in the throat and grow hygroscopically during inhalation to an optimal size to target the small airways with high efficiency. Hygroscopic growth of the particles is essential to prevent exhalation of these small particles and to allow targeted deposition in the small airways. The powder formulation will be delivered by a high efficiency dry powder inhaler including a novel 3D rod array structure that was demonstrated to best disaggregate carrier-free powder formulations. These new formulation and inhaler combinations have been shown to achieve emitted doses greater than 75%, fine particle fractions (<5 µm in size) of greater than 90% and initial mass median aerodynamic diameters (MMAD) less than 1.5 µm, which result in mouth-throat depositional losses of less than 5%. The high efficiency drug delivery will increase drug deposition in untreated lung regions and reduce systemic drug exposure compared to current devices, including extra-fine formulations. We have previously demonstrated feasibility by manufacturing and testing a series of dry powder formulations for chemical stability, physicochemical characteristics, and aerosol performance in a realistic airway in-vitro model in order to identify pharmaceutically acceptable formulations. From these studies, we have selected the lead formulation to move forward in this Phase II effort. We will produce adequate amounts of the lead formulation in order to conduct pre-clinical efficacy tests and IND-enabling toxicology tests to demonstrate the safety of our novel budesonide formulation. Pre- clinical proof of safety will allow for first-in-human testing, the next major phase of development toward significantly controlling symptoms of severe asthma. The translation of this technology into a clinically beneficial product will revolutionize drug delivery and symptom control for severe asthma patients by delivering medicine to currently untreated regions of the airways.

Project Narrative Severe asthma is a long-term debilitating and life-threatening disease with no cure that remains difficult to treat using current inhalers because they deliver very little medication to the small airways. There is consensus that delivery of anti-inflammatory medication to under-treated small airways will have a major impact on reducing pulmonary inflammation in severe asthmatics and reducing side effects associated with undesired mouth-throat deposition. Based on previous in-vitro data we have selected a lead formulation to continue in-vivo development of a novel dry powder corticosteroid formulation and delivery inhaler to target small airway inflammation in order to significantly improve control of severe asthma symptoms.