Developing IN-007 as a Widely Deployable Inhaled Treatment Against Pathogens Utilizing Human ACE2 for Viral Attachment and Entry

Background: We propose to incorporate some key elements for Warfighter use as we continue the development of our inhaled antibody-based drug, IN-007, as a preventative or therapeutic against any ACE2- binding pathogen of pandemic potential. Leveraging the fact that all viruses target a limited number of common receptors for infectivity, this work will serve as a prototype for our platform approach to proactively develop interventions for new and emerging respiratory pathogens, which addresses the FY23 focus area FA2.13: antivirals for the prevention and/or treatment of infectious diseases (broad spectrum and prevention preferred). Inhaled delivery (rather than intravenous infusion or intermuscular injection) offers several key advantages for the prevention or treatment of respiratory infectious diseases, including lowering the dose of monoclonal antibodies (mAb) required to achieve the same dose in the airway mucus, providing immediate therapeutic concentrations in the airways without waiting for biodistribution from the serum, and allowing convenient dosing at home or in the field. Inhalon Biopharma, a world leader in inhaled biologics formulation, has designed IN-007 to be dosed by inhaled delivery within minutes using an ultraportable handheld nebulizer in a formulation that is thermal stable. Inhalon's inhaled antibody platform is at TRL 6 having completed phase 1a and phase 1b studies including evaluation of safety, aerosol delivery efficiency, PK and PD. Hypothesis/Objective: The objective of this proposal is to conduct a suite of activities that would make IN-007 a Warfighter-friendly option for treating and preventing current and emerging ACE2-binding respiratory pathogens with pandemic potential. These activities include the following Specific Aims: Aim 1: Drug Product Formulation Optimized for Extreme Ambient Temperature Storage. (A) Develop an optimal, thermal stable liquid formulation. (B) From the liquid formulation(s), develop a thermal stable lyophilized formulation. (C) Conduct shelf-life stability product quality assessment after nebulization of IN-007. Aim 2: Improved Nebulizer Design. (A) Team formation, knowledge transfer, and requirements building. (B) Identify sources for prototype nebulizer systems and/or components. (C) Acquire nebulizer(s) and or component(s) and assemble prototype devices. (D) Prototype nebulizer testing. Aim 3: Perform Feasibility Assessment of Soft Mist Inhalation (SMI). (A) Assessment of the two types of SMI delivery for optimal IN-007 delivery. (B) Optimization of formulation and development of an optimal performance profile for the soft mist inhaler. (C) Evaluation of the "robust" formulation identified in Aim 1. Aim 4: Optimization of Drug Product Manufacturing. (A) Increased IN-007 production yield from the upstream cell fermentation process. (B) Improved efficiency and recovery of IN-007 product in the downstream purification steps. Study Design: We will work with our partners to develop: (1) a drug product formulation for storage at extreme ambient temperatures; (2) an improved, Warfighter-friendly, optimized vibrating mesh nebulizer design; (3) a feasibility assessment of non-battery-operated alternate delivery via soft mist inhalation (SMI); and (4) process optimization for large-scale, pandemic-ready, drug product manufacturing. Impact: The immediate impact of the proposed project would be advancement of the first pan-variant, inhaled immunodecoy therapeutic for any present and future variant of SARS-CoV-2 into clinical studies. Another relatively near-term impact of the project would be the availability of a treatment for any ACE2- binding pathogen of pandemic potential that may spill over to humans from natural reservoirs, dramatically shortening the time between the outbreak of a future pandemic and the availability of safe and effective therapeutics. Further, the proposed work would provide broad validation to a new field of host attachment decoy-based treatments for emerging respiratory infectious pathogens via an immunodecoy prioritization scheme based on current active programs of animal virus vector sampling. Less