Targeting the Immunometabolic Hub Nlrx1 as a Novel Therapeutic for Allergic AsthmaBiotherapeutics Inc (BTI) is an emerging biotech company that synergistically combines the power of advancedcomputational modeling with translational experimentation to accelerate the development of novel products for precisionmedicine and health. This SBIR application stems from data showing a vital role for nucleotide-binding oligomerizationdomain, leucine rich repeat containing X1 (NLRX1) as a new therapeutic target for allergy and asthma.Our Product: BTI has developed first-in-class, small-molecule therapeutics that bind and activate the novel regulatorymolecule, NLRX1. The goal of this project is to validate NLRX1 as a target for allergic asthma and develop NX-73 as anoral therapeutic to treat mild to moderate to severe asthma.Significance: Asthma is a chronic disease afflicting over 330 million individuals globally and 40 million in the U. S. Asthmais a chronic, widespread allergic disease with total expenses exceeding $80 billion annually in the U.S. In particular,neutrophilic, non-type 2 asthma has a lower responsiveness to current treatments. Though recent years have witnessed anincrease in the number of biologics for asthma, these biologics are specific to certain endotypes, are very costly, and requireup to 26 visits per year for treatment via injections. Inhaled corticosteroids, another common form of treatment havemoderate to serious adverse side-effects and are thought to reduce in effectiveness overtime. Thus, there is an unmet medicalneed for safer and more efficacious oral therapeutics for asthma. This SBIR Phase I application will develop NX-73 as anovel NLRX1-binding product candidate and validate its safety, efficacy, and specificity for the NLRX1 target. Successin this project will launch a new drug development program centered on NLRX1-activating orally active therapeutics witha long-term goal of entering clinical trials for asthma by 2022. The Specific Aims are to:Aim 1. Determine the in vivo proof-of-concept therapeutic efficacy of NX-73 in mouse models of allergic asthma.Aim 2. Evaluate whether NX-73 reduces Th2 and/or Th17 responses by dendritic cells and airway epithelial cells.Aim 3. Conduct preliminary pharmacokinetic (PK) and toxicity studies with NX-73 to determine the oralbioavailability and pulmonary distribution and 7-day repeat-dose toxicity in rats.Expected Successful Outcomes: i) Validation of the therapeutic efficacy of NX-73 as a lead molecule for suppressingasthma by targeting Nlrx1; ii) Reduction of asthma symptoms with oral doses of NX-73 ⤠10 mg/kg; iii) Loss of NX-73function in Nlrx1-/- mice and cells; and iv) Benign safety profile with NOAEL ⥠1,000 mg/kg oral in rats.SBIR Phase II: Will validate the translation of NX-73 effects in human CD141hi dendritic cells and airway epithelial cellsfrom individuals with mild-to-moderate and moderate-to-severe asthma, assess the therapeutic efficacy of NX-73 in a guineapig model of asthma, and advance NX-73 to IND-enabling GLP toxicology studies.Commercial Application: At the conclusion of this R&D effort BTI will have the preliminary validation necessary to selectNX-73 as an IND-ready lead NLRX1-targeting small molecule. The impact of new oral, NLRX1-activating asthmatherapeutics has the potential to disrupt a $56 billion industry that is anticipated to compound annual growth rate of 7%.
Public Health Relevance Statement: PUBLIC HEALTH RELEVANCE
Asthma is a common disease affecting nearly 10% of the U.S. population with high proportions of patients unresponsive to
current medications. This SBIR Phase I has the potential to rapidly develop a novel class of oral therapeutics that target the
Nod-like leucine rich repeat protein, Nlrx1, for the long-term control of allergy and asthma, and advance them through the
FDA-regulatory pipeline into IND and clinical testing by 2022. The proposed studies will provide both the physiological
relevance, safety profile, and mechanistic foundation for how NX-73 targets Nlrx1in the lungs to enhance immunometabolic
effects that reduce the development of respiratory allergy and asthma.
Project Terms: Adrenal Cortex Hormones ; Corticoids ; Corticosteroids ; Affect ; Allergens ; Alternaria ; Aspergillus ; Asthma ; Bronchial Asthma ; Autoimmune Diseases ; autoimmune condition ; autoimmune disorder ; Biological Availability ; Bioavailability ; Biologic Availability ; Physiologic Availability ; Biological Response Modifier Therapy ; Biologic Therapy ; Biological Therapy ; biological therapeutic ; biological treatment ; biotherapeutics ; biotherapy ; Biotechnology ; Biotech ; Blood ; Blood Reticuloendothelial System ; Cells ; Cell Body ; Chronic Disease ; Chronic Illness ; chronic disorder ; Clinical Trials ; Communicable Diseases ; Infectious Disease Pathway ; Infectious Diseases ; Infectious Disorder ; Dendritic Cells ; Veiled Cells ; Disease ; Disorder ; Pharmaceutical Preparations ; Drugs ; Medication ; Pharmaceutic Preparations ; drug/agent ; eosinophil ; Blood Eosinophil ; Eosinophilic Granulocyte ; Eosinophilic Leukocyte ; Marrow Eosinophil ; Epithelial Cells ; Foundations ; Goals ; Growth ; Generalized Growth ; Tissue Growth ; ontogeny ; Half-Life ; Helper-Inducer T-Lymphocyte ; Helper Cells ; Helper T-Cells ; Helper T-Lymphocytes ; Helper-Inducer T-Cells ; Inducer Cells ; Inducer T-Lymphocytes ; Human ; Modern Man ; Hypersensitivity ; Allergy ; IgE ; Immunoglobulin E ; Immunoglobulin G ; 7S Gamma Globulin ; IgG ; Immunity ; Industry ; Inflammation ; Interleukin-6 ; B cell differentiation factor ; B cell stimulating factor 2 ; B-Cell Differentiation Factor ; B-Cell Differentiation Factor-2 ; B-Cell Stimulatory Factor-2 ; BCDF ; BSF-2 ; BSF2 ; HPGF ; Hepatocyte-Stimulating Factor ; Hybridoma Growth Factor ; IFN-beta 2 ; IFNB2 ; IL-6 ; IL6 Protein ; MGI-2 ; Myeloid Differentiation-Inducing Protein ; Plasmacytoma Growth Factor ; interferon beta 2 ; Lead ; Pb element ; heavy metal Pb ; heavy metal lead ; Lung ; Lung Respiratory System ; pulmonary ; mast cell ; Marrow Mast Cell ; Tissue Basophils ; mastocyte ; Mitochondria ; mitochondrial ; Mus ; Mice ; Mice Mammals ; Murine ; neutrophil ; Blood Neutrophil ; Blood Polymorphonuclear Neutrophil ; Marrow Neutrophil ; Neutrophilic Granulocyte ; Neutrophilic Leukocyte ; Polymorphonuclear Cell ; Polymorphonuclear Leukocytes ; Polymorphonuclear Neutrophils ; Nucleotides ; Legal patent ; Patents ; Patients ; Drug Kinetics ; Pharmacokinetics ; Plasma ; Blood Plasma ; Plasma Serum ; Reticuloendothelial System, Serum, Plasma ; Pollen ; Program Development ; Rattus ; Common Rat Strains ; Rat ; Rats Mammals ; research and development ; Development and Research ; R & D ; R&D ; Role ; social role ; Safety ; Specificity ; CD4 Positive T Lymphocytes ; CD4 Cells ; CD4 T cells ; CD4 helper T cell ; CD4 lymphocyte ; CD4+ T-Lymphocyte ; CD4-Positive Lymphocytes ; T4 Cells ; T4 Lymphocytes ; Time ; Toxicology ; Translations ; Cavia ; Guinea Pigs ; Guinea Pigs Mammals ; Mediating ; Extrinsic asthma ; Allergic asthma ; atopic asthma ; extrinsic allergic asthma ; Acute ; Benign ; Chronic ; Phase ; Biological ; Physiological ; Physiologic ; Medical ; Individual ; Recovery ; No-Observed-Adverse-Effect Level ; NOAEL ; Immunological response ; host response ; immune system response ; immunoresponse ; Immune response ; Therapeutic ; Ragweed ; Ambrosia ; Exposure to ; Oral ; respiratory ; Visit ; American ; success ; Toxicities ; Toxic effect ; LRR protein ; leucine-rich repeat protein ; novel ; response ; House Dust Mites ; Housedust Mites ; Pyroglyphidae ; Inflammatory Response ; Molecular Interaction ; Binding ; Cellular Immune Function ; immune function ; Effectiveness ; preventing ; prevent ; small molecule ; TSLP ; Thymic Stromal Lymphopoietin ; TSLP gene ; 3-10C ; AMCF-I ; CXCL8 ; GCP1 ; IL-8 ; IL8 ; K60 ; SCYB8 ; TSG-1 ; b-ENAP ; IL8 gene ; Dose ; Symptoms ; Data ; in vivo ; research clinical testing ; Clinical Evaluation ; Clinical Testing ; clinical test ; Leucine-Rich Repeat ; Right-Handed Beta-Alpha Superhelix ; Lower Respiratory System ; Small Business Innovation Research Grant ; SBIR ; Small Business Innovation Research ; Validation ; Development ; developmental ; cost ; asthmatic airway ; asthmatic patient ; asthma patient ; steroid dependence ; steroid addiction ; airway hyperresponsiveness ; Airway Hyper-responsiveness ; airway hyper-reactivity ; airway hyperactivity ; airway hyperreactivity ; airway hypersensitivity ; airway inflammation ; airway epithelium inflammation ; airway remodeling ; Treatment Efficacy ; intervention efficacy ; therapeutic efficacy ; therapy efficacy ; Outcome ; Population ; innovation ; innovate ; innovative ; airway epithelium ; novel therapeutics ; new drug treatments ; new drugs ; new therapeutics ; new therapy ; next generation therapeutics ; novel drug treatments ; novel drugs ; novel therapy ; mouse model ; murine model ; loss of function ; stem ; therapeutic target ; commercial application ; commercialization ; new therapeutic target ; new drug target ; new druggable target ; new pharmacotherapy target ; new therapy target ; novel drug target ; novel druggable target ; novel pharmacotherapy target ; novel therapeutic target ; novel therapy target ; public health relevance ; Allergic Disease ; T cell response ; precision medicine ; precision-based medicine ; small molecule therapeutics ; patient subsets ; patient subgroups ; patient subpopulations ; patient subtypes ; experimental study ; experiment ; experimental research ; Immune signaling ; recruit ; Injections ; Inhalation ; Inhaling ; Precision Health ; Airway Disease ; side effect ; asthma model ; Computer Models ; Computerized Models ; computational modeling ; computational models ; computer based models ; computerized modeling ;
