SBIR-STTR Award

Alzheimer's disease (AD) is the largest unmet medical need in the US and the only major cause of death that cannot be prevented, cured, or slowed. Arviat Pharmaceuticals, Inc. is developing oral small-molecule inhibitors of the 12/15-lipoxygenase (12/15-LO) enzyme family to reduce microglia driven neuroinflammation and, thereby, slow progression of AD. Inhibition of 12/15-LO activity to reduce neuroinflammation has been validated in human clinical trials in Parkinson's disease and orphan pediatric neurodegenerative diseases, in human genome wide association studies, and in animal models of AD and other adult neurodegenerative diseases. Vatiquinone™, a first generation 12/15-LO inhibitor discovered and developed by the PI, is now used to treat children with Leigh syndrome, a rare, otherwise fatal pediatric neurodegenerative disease characterized by severe neuroinflammation, microgliosis, and gliotic scarring of the brain. With their extreme neuroinflammation, this pediatric population can be viewed as accelerated models of adult neurodegenerative disease (e.g. AD). Vatiquinone™ is not well-suited for treating AD or Parkinson's disease, leading to the plans,under this proposed SBIR, to develop second-generation oral small-molecule inhibitors of 12/15-LO with significantly greater efficacy than Vatiquinone™. These efforts will leverage existing and generate new intellectual property, covering novel agents potentially suitable for treating large populations with AD and other adult neurodegenerative diseases. In addition to LO inhibitors developed internally, Arviat has an option on a portfolio covering 5 compound families (7 US patents (issued 2013-2019) and several pending applications),which claim compositions of matter with the same novel redox mechanism of action as Vatiquinone™. This proposed Phase I SBIR research will lead to rapid prioritization of compounds from these 6 families, through an iterative screening funnel, consisting of these Specific Aims: (1) To prepare ≥100 compounds, selected tothoroughly sample the patent portfolios; (2) To test these compounds for (i) potency and selectivity as 12/15-LO (vs 5-LO) inhibitors in enzyme assays and (ii) suppression of cytokine production in activated human microglial cultures (iPSC-microglia); (3) To test ≥20 compounds, advanced based on Aim 2 criteria (IC50<50nM for 12/15-LO, and >500 nM for 5-LO and IC50 ≤75 nM in cellular assays), in a functional neuroprotectionassay (prevention of axonal degeneration in NGF-deprived mouse primary neurons); and (4) To test ≥6compounds, advanced based on the Aim 3 criterion (IC50≤75 nM), for oral bioavailability and brain permeability in rats (criteria for advancement, brain/plasma ratios ≥0.5 and oral availability ≥20%). If successful, this research will identify at least 3 compounds for further evaluation in Phase II, to include synthetic scale-up,toxicology screening, off-target activities, formulation development, confirmatory PK and brain permeabilitystudies, and in vivo AD model efficacy studies, leading to identification of a lead compound for IND-enabling research supporting clinical trials in AD patients, as a potential disease-modifying treatment. Shrader, William D.

Project narrative:
Alzheimer's disease (AD) is the largest unmet medical need in the US, affecting ~5.8M aging Americans, and there are no treatments to prevent, slow, or cure its devastating, fatal progression, only drugs to partially improve its symptoms. Over the past three decades, many proposed AD drugs, mostly focused on one hypothesized disease mechanism, have failed in the clinic. The goal of this SBIR project is to discover new drugs for treating AD, based on the novel anti-inflammatory mechanism of a lead compound that is already used successfully to treat a rare, otherwise fatal, neurological disease in children. Adult ; 21+ years old ; Adult Human ; adulthood ; Affect ; Age ; ages ; Aging ; Alzheimer's Disease ; AD dementia ; Alzheimer ; Alzheimer Type Dementia ; Alzheimer disease ; Alzheimer sclerosis ; Alzheimer syndrome ; Alzheimer's ; Alzheimer's disease dementia ; Alzheimers Dementia ; Alzheimers disease ; Primary Senile Degenerative Dementia ; dementia of the Alzheimer type ; primary degenerative dementia ; senile dementia of the Alzheimer type ; inhibitor/antagonist ; inhibitor ; Anti-Inflammatory Agents ; Anti-Inflammatories ; Anti-inflammatory ; Antiinflammatories ; Antiinflammatory Agents ; antiinflammatory ; Arachidonate 15-Lipoxygenase ; 15-LOX ; 15-Lipoxygenase ; Arachidonate Omega-6 Lipoxygenase ; Arachidonic Acid 15-Lipoxygenase ; Reticulocyte Arachidonate 15-Lipoxygenase ; Biological Assay ; Assay ; Bioassay ; Biologic Assays ; Biological Availability ; Bioavailability ; Biologic Availability ; Physiologic Availability ; Blood - brain barrier anatomy ; Blood-Brain Barrier ; Hemato-Encephalic Barrier ; bloodbrain barrier ; Brain ; Brain Nervous System ; Encephalon ; Cause of Death ; Pharmaceutical Chemistry ; Medicinal Chemistry ; Pharmaceutic Chemistry ; Child ; 0-11 years old ; Child Youth ; Children (0-21) ; youngster ; Cicatrix ; Scars ; Clinical Trials ; Cessation of life ; Death ; Disease ; Disorder ; Pharmaceutical Preparations ; Drugs ; Medication ; Pharmaceutic Preparations ; drug/agent ; Endotoxins ; Enzymes ; Enzyme Gene ; Family ; Human Genome ; human whole genome ; Goals ; Hippocampus (Brain) ; Ammon Horn ; Cornu Ammonis ; Hippocampus ; hippocampal ; Human ; Modern Man ; Inflammation ; Interleukin-1 beta ; Beta Proprotein Interleukin 1 ; IL-1 beta ; IL-1 β ; IL-1-b ; IL-1β ; IL1-Beta ; IL1-β ; IL1B Protein ; IL1F2 ; IL1β ; Interleukin 1beta ; Interleukin-1β ; Preinterleukin 1 Beta ; 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 ; Leigh Disease ; Leigh Syndrome ; Subacute Necrotizing Encephalomyelitis ; Subacute Necrotizing Encephalomyelopathy ; Subacute Necrotizing Encephalopathy ; Lipids ; Memory ; Mus ; Mice ; Mice Mammals ; Murine ; Nerve Degeneration ; Neuron Degeneration ; neural degeneration ; neurodegeneration ; neurodegenerative ; neurological degeneration ; neuronal degeneration ; nervous system disorder ; Nervous System Diseases ; Neurologic Disorders ; Neurological Disorders ; neurological disease ; Neurons ; Nerve Cells ; Nerve Unit ; Neural Cell ; Neurocyte ; neuronal ; Oxidation-Reduction ; Redox ; oxidation reduction reaction ; Parkinson Disease ; Paralysis Agitans ; Parkinson ; Parkinson's disease ; Parkinsons disease ; Primary Parkinsonism ; Legal patent ; Patents ; Patients ; Permeability ; Drug Kinetics ; Pharmacokinetics ; Plasma ; Blood Plasma ; Plasma Serum ; Reticuloendothelial System, Serum, Plasma ; Production ; Rattus ; Common Rat Strains ; Rat ; Rats Mammals ; Research ; Research Support ; Signal Transduction ; Cell Communication and Signaling ; Cell Signaling ; Intracellular Communication and Signaling ; Signal Transduction Systems ; Signaling ; biological signal transduction ; Stress ; Testing ; Toxicology ; cytokine ; Generations ; Measures ; Lipoxygenase Inhibitors ; base ; improved ; Phase ; Variant ; Variation ; Biochemical ; Medical ; Microglia ; Hortega cell ; gitter cell ; mesoglia ; microglial cell ; microgliocyte ; perivascular glial cell ; Evaluation ; Childhood ; pediatric ; insight ; Orphan ; Disease Progression ; Intellectual Property ; Intravenous ; cognitive function ; Oral ; Clinic ; brain tissue ; Degenerative Neurologic Diseases ; Degenerative Neurologic Disorders ; Nervous System Degenerative Diseases ; Neural Degenerative Diseases ; Neural degenerative Disorders ; Neurodegenerative Diseases ; Neurologic Degenerative Conditions ; degenerative diseases of motor and sensory neurons ; degenerative neurological diseases ; neurodegenerative illness ; Neurodegenerative Disorders ; Penetrance ; American ; neuroprotection ; Animal Models and Related Studies ; model of animal ; model organism ; Animal Model ; transgenic ; Transgenic Organisms ; novel ; family structure ; Prevention ; (TNF)-α ; Cachectin ; Macrophage-Derived TNF ; Monocyte-Derived TNF ; TNF ; TNF A ; TNF Alpha ; TNF-α ; TNFA ; TNFα ; Tumor Necrosis Factor ; Tumor Necrosis Factor-alpha ; TNF gene ; Modeling ; Sampling ; Pharmaceutical Agent ; Pharmaceuticals ; Pharmacological Substance ; Pharmacologic Substance ; preventing ; prevent ; genetic association ; Dose ; Symptoms ; Cytokine Suppression ; Data ; Ph.D. ; PhD ; Doctor of Philosophy ; in vivo ; Cellular Assay ; cell assay ; Collection ; Small Business Innovation Research Grant ; SBIR ; Small Business Innovation Research ; Preparation ; Process ; Development ; developmental ; axonal degeneration ; axon degeneration ; degenerative axon ; genome wide association study ; GWA study ; GWAS ; genome wide association ; genome wide association scan ; genome wide association studies ; genomewide association scan ; genomewide association studies ; genomewide association study ; whole genome association analysis ; whole genome association studies ; whole genome association study ; neuroinflammation ; neuroinflammatory ; morris water maze ; morris watermaze ; scale up ; Population ; 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 ; Alzheimer's disease model ; AD model ; alzheimer model ; induced pluripotent stem cell ; iPS ; iPSC ; iPSCs ; efficacy testing ; screening ; Formulation ; small molecule inhibitor ; efficacy study ; Alzheimer's disease patient ; Alzheimer's patient ; β-amyloid burden ; Aβ burden ; a-beta burden ; abeta burden ; amyloid burden ; beta amyloid burden ; βamyloid burden ;