The business objective of Aeon Respire, and the purpose of this SBIR , is to execute key steps towards repurposing niclosamide as a new asthma treatment. The therapeutic rationale for these studies is based on initial findings that niclosamide inhibits an ion channel that is pivotal for airway smooth muscle contraction and mucin hypersecretion. Both of these pathologic processes contribute to airway narrowing and are considered, in addition to inflammation, as the core features of asthma. Existing medications fail to adequately relieve airway narrowing in more severe, treatment refractory patients. In particular, the efficacy of inhaled beta-agonists is compromised at a cellular level by both repeat use desensitization and the indirect effects of inflammation. Therefore, there is need for new treatment approaches. TMEM16A is a calcium-activated chloride channel that regulates calcium signaling in the airways and is required for airway smooth muscle contraction. Niclosamide is an FDA-approved oral drug originally discovered decades ago and safely used as an anti-helminth. It was recently identified in a high throughput unbiased screen as a specific TMEM16A inhibitor. Niclosamide fully relaxes contracted airways via this mechanism and resists desensitization pathways that undermine the effectiveness of beta-agonists. It also reduces mucin release induced by asthma- associated activation signals. TMEM16A inhibition with repurposed niclosamide is therefore an attractive new asthma treatment approach and will benefit from the drug's established human safety record. Niclosamide, however, has poor bioavailability and is unlikely to reach TMEM16A in the airways through oral dosing. The first objective of the project is to reformulate niclosamide through particle engineering to enable inhaled dosing. The next objective is to use the new formulation in inhalation studies to confirm the drug reaches its target locally and will open airways provoked by a contractile agent. Additional studies will establish the pharmacokinetic and initial toxicologic profile of inhaled niclosamide. These studies are crucial to test the scientific hypothesis that inhibiting TMEM16A in the airways is a safe and effective approach to open obstructed airways. They also represent important steps required to move the project closer to discussions with the FDA, filing an IND and testing in human studies.
Public Health Relevance Statement: Project Narrative Completion of this project will achieve important drug repurposing milestones and test the therapeutic hypothesis that TMEM16A inhibition will safely open obstructed airways. It builds on the discovery of an exciting new asthma target by positioning the repurposed drug niclosamide for inhalation and generating in vivo proof of concept.
Project Terms: Adrenal Cortex Hormones; Corticoids; Corticosteroids; airway obstruction; airflow limitation; airflow obstruction; airway limitation; obstructed airflow; obstructed airway; Animals; inhibitor/antagonist; inhibitor; Asthma; Bronchial Asthma; Autopsy; necropsy; postmortem; Biological Availability; Bioavailability; Biologic Availability; Physiologic Availability; Calcium; Calcium Channel Blockers; Calcium Channel Blocking Drugs; Exogenous Calcium Antagonists; Exogenous Calcium Blockaders; Exogenous Calcium Inhibitors; calcium antagonist; capsule; Capsules; Clinical Trials; Disease; Disorder; Canis familiaris; Canine Species; Dogs; Dogs Mammals; canine; domestic dog; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Engineering; Epithelial Cells; Goals; Half-Life; Helminths; Parasitic Worms; Human; Modern Man; Inflammation; Inhalators; Inhaler; Ion Channel; Ionic Channels; Membrane Channels; Lung; Lung Respiratory System; pulmonary; Mucins; Mucus Glycoprotein; Mucous body substance; Mucus; mucous; Muscle Contraction; Muscle Cell Contraction; Muscular Contraction; Particle Size; Pathologic Processes; Pathological Processes; Clinical Pathology; Patients; Drug Kinetics; Pharmacokinetics; Plasma; Blood Plasma; Plasma Serum; Reticuloendothelial System, Serum, Plasma; Powder dose form; Powders; Precipitation; Production; Rattus; Common Rat Strains; Rat; Rats Mammals; Safety; Signal Transduction; Cell Communication and Signaling; Cell Signaling; Intracellular Communication and Signaling; Signal Transduction Systems; Signaling; biological signal transduction; Technology; Testing; Tissues; Body Tissues; Toxicology; Chloride Channels; Chloride Ion Channels; cytokine; Measures; Businesses; Extrinsic asthma; Allergic asthma; atopic asthma; extrinsic allergic asthma; base; Clinical; Refractory; Phase; Biological; pulmonary function; lung function; muscle form; muscle bulk; muscle mass; Patient Selection; chemical property; Agonist; Toxicokinetics; Therapeutic; Contracting Opportunities; Contracts; Inflammatory; Oral; Route; Risk-Benefit Assessment; meetings; particle; bronchial epithelium; methacholine; Calcium Ion Signaling; Calcium Signaling; Allergic; Position; Positioning Attribute; Property; High Throughput Assay; high throughput screening; LC/MS; liquid chromatography mass spectrometry; Involuntary Muscle; Smooth Muscle; Effectiveness; therapeutic testing; therapeutic evaluation; Bronchodilation; Dose; Data; Inhalation Toxicology; in vivo; Small Business Innovation Research Grant; SBIR; Small Business Innovation Research; Process; Pathway interactions; pathway; disease phenotype; burden of illness; burden of disease; disease burden; years of life lost to disability; years of life lost to disease; airway hyperresponsiveness; Airway Hyper-responsiveness; airway hyper-reactivity; airway hyperactivity; airway hyperreactivity; airway hypersensitivity; airway inflammation; airway epithelium inflammation; respiratory smooth muscle; airway smooth muscle; novel strategies; new approaches; novel approaches; novel strategy; desensitization; 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; FDA approved; Biological Markers; bio-markers; biologic marker; biomarker; drug candidate; mucin hypersecretion; Formulation; Inhalation; Inhaling; helminth infection; helminthic infection; infected with helminth; pharmacokinetics and pharmacodynamics; PK/PD; drug repurposing; repurposing agent; repurposing medication
