Preclinical Development of a New Kinase Inhibitor for Postviral Lung Disease

Background: Respiratory viral infection is a leading cause of morbidity and mortality throughout the world, and the current viral pandemic of SARS-CoV-2 infection is the third leading cause of death in the U.S. This type of infection routinely can cause acute lung injury but can also progress to a remodeling disease process that we designate as post-viral lung disease (PVLD). In the case of SARS-CoV-2 infection, PVLD can progress in the short-term with hypoxic respiratory failure or in the long term (so-called long-COVID) with less mortality but still debilitating respiratory symptoms. Moreover, respiratory viral infection and PVLD cause problems that are distinct to military health and readiness due to high levels of close-contact and low-mask conditions, exposure to unvaccinated populations, and preexisting lung disease. Current therapeutic approaches (antivirals, antibodies, and vaccines) cannot fully address these issues for the present or future viruses. The massive impact of PVLD on military and civilian health and economic issues requires a new approach to defining pathogenesis and treatment. Rationale: To respond to this need, we offer a new pathway for pathogenesis and a corresponding therapeutic for precision medicine in PVLD. This disease pathway features a basal-epithelial stem cell (basal-ESC) subset that can overgrow normal airway sites and invade alveolar sites to form bronchiolar-alveolar remodeling regions as a basis for hypoxia. We defined this paradigm in mouse models of PVLD using the natural pathogen Sendai virus (SeV) but the same features are found in mice using influenza A virus (IAV) and are present uniformly in autopsies of COVID-19 patients. Human cell and animal models show the PVLD process depends critically on a stress kinase known as MAPK13. This relatively orphan kinase was missed in favor of conventional inflammatory pathways and was untargeted in previous kinase-inhibitor screens. Therefore, we used structure-based drug design to engineer proprietary small-molecule kinase inhibitors against MAPK13 and selected a lead candidate compound (NuP-400) based on physical-chemical attributes, cell toxicity, enzyme inhibition, binding mechanism, interaction kinetics, kinome selectivity, pharmacokinetics, and safety. Consistent with these attributes, NuP-400 provides highly potent and safe correction of PVLD in human cell and animal models. Notably, NuP-400 treatment blocks the basal-ESC overactivation that drives the disease, and this benefit is equivalent to Mapk13-deficiency or combined Mapk13-14 blockade in our mouse model of PVLD. NuP-400 also shows no observed adverse effect level (NOAEL) that predicts a satisfactory safety margin and provides a firm basis to move NuP-400 to the next stage of drug development. New models of PVLD using native SeV and adapted IAV in mice and native SARS-CoV-2 in hamsters (that also manifest PVLD) combined with smart delivery using parenteral and inhaled dosing will guide an effective, safe, and practical continuum of care for PVLD in humans. Hypothesis/Aims/Study Design: We propose a new paradigm for PVLD that depends on MAPK13-dependent basal-ESC reprogramming after viral infection, and we offer a precision medicine approach to correct this abnormality using a proprietary MAPK13-inhibitor lead candidate (NuP-400). We aim to move NuP-400 to the next stage of development for a breakthrough therapeutic for PVLD including COVID-19. Our objective is threefold: (i) define pathogenesis to identify druggable targets and biomarkers of both airway and alveolar components of PVLD; (ii) optimize effectiveness of a lead candidate compound using PVLD models; and (iii) engage inhaled dosing with a unique particulate preparation for aerosol generation. Accordingly, we designed the following aims: Aim 1; Animal model and human studies will establish NuP-400 efficacy, mechanism, dosing guidelines, and biomarkers that together will establish disease-modifying and precision-medicine endpoints. Aim 1a will use mouse models of PVLD after IAV and SeV infections taking advantage of new conventional and conditional Mapk13-gene and basal-ESC knockout mice and single-cell strategies to functionalize key drug targets. Aim 1b will use a hamster model of PVLD after SARS-CoV-2 infection and apply similar approaches adapted to this model. Aim 1c will analyze lung tissue from COVID-19 patients compared to other lung disease and non-disease controls to validate findings from cell and animal models. Aim 2: Pharmacology-toxicology and chemistry, manufacturing, and control (CMC) work will complete regulatory testing and CMC information for NuP-400. Aim 2a for pharmacology-toxicology will build on data from parenteral dosing to complete the additional regulatory process using experts for inhaled drug formulation, delivery, pharmacology, and toxicology. Aim 2b on CMC will engage drug manufacturing capabilities for animal studies (Aim 1a, b) and regulatory goals (Aim 2a). Aim 3: Investigational New Drug (IND) application work will assemble preclinical data and other documents for IND application to launch clinical trials of NuP-400 across the time and severity spectrum of PVLD. Impact: We will develop a new small-molecule kinase inhibitor (SMKI) to treat PVLD for the benefit of Service Members, military families, Veterans, and the American public with the intent of Food and Drug Administration (FDA) approval and commercial availability. In the short term, we will develop to our knowledge the first disease-modifying drug for PVLD to launch first-in-human clinical trials. In the long term, we will provide the basis for the next phase of drug development towards delivery and implementation of a safe and effective precision medicine in PVLD. The link to other current viruses and future new viruses should translate to broad benefit across chronic lung diseases. Relevance to Topic Areas: This proposal addresses the topic area of respiratory health, specifically in relation to the area of encouragement of acute and chronic lung injury/disorders due to viral infections such as SARS-CoV-2 that is presently a critical need for military and civilian populations. Less