Hidrosis is the normal physiological sweat response that contributes to thermoregulation during heat stress. Hyperhidrosis is the uncontrolled and excessive production of sweat due to dysregulation of normal sweat control mechanisms. This is an unpleasant and embarrassing condition that affects nearly 5% of the US population and causes significant reduction in performance and economic contribution amongst individuals from all walks of life, and it contributes substantially to debilitating mental health issues like anxiety and depression. Current treatments include powerful anti-perspirants, and topical cholinergic antagonists (Qbrexzaï) and BOTOXï that block innervation pathways that drive primary hyperhidrosis (PHH). These treatments are neither fully effectivenor embraced by the patients due to issues such as inefficacy, inconvenience, side effects, and high cost. Newsolutions are needed to offset the social and emotional impact of PHH. The PHH response is strictly dependent on function of the Ca2+ release activated Ca2+ (CRAC) channels in the sweat gland, and all signals that initiate PHH immediately engage the CRAC pathway to elevate intracellularCa2+ levels in the eccrine sweat gland for sustained periods regardless of the initial stimulus. This elevated Ca2+in turn drives monovalent ion fluxes, creating the osmotic gradient that leads to water release into the gland ductand movement of sweat to the surface for cooling. As such, the CRAC channel is an ideal target for control of hyperhidrosis. Here, Vivreon Biosciences proposes to evaluate a small molecule candidate that potently modulates CRAC channels as a therapeutic candidate for treating PHH. Aim 1 will determine any genotoxic orphototoxic potential using the Ames, chromosomal aberration, and UV-dependent cytotoxicity assays. Aim 2 will develop a suitable topical formulation and measure the topical penetration of the formulation using human skinbiopsies. Aim 3 will measure compound efficacy following topical application alone and in combination with a currently approved therapy against a sweating response elicited in a standard model of hyperhidrosis. Successful conclusion of this project will trigger Vivreon to seek additional funding to advance the PHH program through required development steps culminating in an IND filing and exploration of partnership opportunities with dermatological product companies.
Public Health Relevance Statement: Vivreon Biosciences, LLC Primary hyperhidrosis (PHH), or uncontrollable excessive sweating, is a disruptive and embarrassing condition that impacts nearly 5% of US citizens leading to reduced productivity and mental illnesses such as anxiety and depression. A few treatments are available, but these are frustratingly ineffective, and new treatments in the pipeline are pursuing the same mechanisms of action as these ineffective treatments. Vivreon Biosciences is developing a therapeutic that achieves efficacy through a totally novel and fully validated mechanism of action to provide a more effective product to successfully combat this significantly disruptive condition.
Project Terms: Affect, Anhidrosis, Adiaphoresis, Animals, Anxiety, Automobile Driving, driving, Axilla, Armpit, Axillary, Underarm, Mental disorders, Mental health disorders, Psychiatric Disease, Psychiatric Disorder, mental illness, psychiatric illness, psychological disorder, Biological Assay, Assay, Bioassay, Biologic Assays, Biological Sciences, Biologic Sciences, Bioscience, Life Sciences, Biopsy, Physiologic Thermoregulation, Body Temperature Regulation, Body Thermoregulation, Thermoregulation, Botulinum Toxins, Botulin, Clostridium botulinum Toxins, Chromosome abnormality, Aberrant Chromosome, Chromosomal Aberrations, Chromosomal Abnormalities, Chromosomal Alterations, Chromosome Aberrations, Chromosome Alterations, Chromosome Anomalies, Cytogenetic Aberrations, Cytogenetic Abnormalities, chromosomal defect, chromosome defect, Mental Depression, depression, Dosage Forms, Pharmaceutical Preparations, Drugs, Medication, Pharmaceutic Preparations, drug/agent, Eccrine Glands, Eccrine Sweat Gland, Economics, Goals, Grant, Human, Modern Man, Hyperhidrosis disorder, Hyperhidrosis, nerve supply, innervation, Ions, Mental Health, Mental Hygiene, Psychological Health, Movement, body movement, Mus, Mice, Mice Mammals, Murine, Patients, Pharmacology, Phenotype, Production, Productivity, Rodentia, Rodents Mammals, Rodent, Safety, Cell Communication and Signaling, Cell Signaling, Intracellular Communication and Signaling, Signal Transduction Systems, Signaling, biological signal transduction, Signal Transduction, sudiferous gland, Sweat Glands, Sweating, Synaptic, synapse, Synapses, Testing, Toxicology, Water, Hydrogen Oxide, Measures, Walking, Mediating, Surface, Chronic, Penetration, Physiological, Physiologic, Dermatologic, Dermatological, Autonomic Pathways, Chemicals, Dermal, Stimulus, Individual, Acetylcholine Antagonists, Cholinergic-Blocking Agents, Cholinolytics, Cholinergic Antagonists, Funding, Heat Stress, Heat Stress Syndromes, heat-related illness, Heat Stress Disorders, Therapeutic, Genetic, Attenuated, Life, programs, Reaction, Treatment Period, treatment days, treatment duration, Lytotoxicity, cytotoxicity, Performance, water flow, genotoxicity, Toxicities, Toxic effect, novel, Topical Drug Administration, administer topically, apply topically, deliver topically, topical administration, topical delivery, topical drug application, topical treatment, topically administered, topically applied, topically delivered, topically treated, treat topically, Topical application, Duct, Duct (organ) structure, Prevention, social, Position, Positioning Attribute, Emotional, Modeling, Property, response, Phase I Clinical Trials, Early-Stage Clinical Trials, Phase 1 Clinical Trials, phase I protocol, Skin, Gland, small molecule, Cream, Dose, research clinical testing, Clinical Evaluation, Clinical Testing, clinical test, Small Business Innovation Research Grant, SBIR, Small Business Innovation Research, Knock-out, Knockout, Development, developmental, Phototoxicity, Pathway interactions, pathway, National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIAMS, cost, Population, driving force, combat, patient population, animal efficacy, candidate validation, Regimen, Drug Targeting, Patient risk, Standard Model, Formulation, ineffective therapies, ineffective treatment, clinical candidate, efficacy study, clinical development, therapeutic candidate, druggable target, first-in-human, first in man, side effect, therapeutically effective
