SBIR-STTR Award

Vivreon Biosciences is an innovative life sciences company that is developing a series of novel small molecule, Ca2+ channel inhibitors for the treatment of Alzheimer's disease (AD). Our lead compound series achieves neuroprotection by an entirely new mechanism - inhibition of Ca2+ release-activated Ca2+ (CRAC) channels to block microgliosis. Vivreon seeks NIA funding to bridge the gap between discovery and development. We will perform a series of functional safety pharmacology and in vitro efficacy screens to identify promising candidate compounds in our library of small molecule CRAC channel inhibitors. Upon successful completion of the program, our preclinical candidate will be the first to specifically target the CRAC pathway for neuroprotection in AD, thus comprising an entirely new tool in the battle against AD. Vivreon has discovered a lead compound series with oral bioavailability that penetrates into the central nervous system (CNS) very efficiently, shows no neurotoxicity in the Irwin test of CNS integrity, and demonstrates neuroprotection in a mouse model of microgliosis (experimental autoimmune encephalitis). The lead series inhibits microgliosis by blocking CRAC channel activity with nM potency; suppressing M1-like NF- κB activity, while preserving M2-like phagocytosis. We will now test select candidates from our lead compound series in innovative safety and efficacy screens using screening technology from patient-derived induced pluripotent stem cells (iPSCs). iPSCs will first be grown and differentiated into microHearts and screened for functional safety pharmacology to detect potential cardiac toxicity liabilities. Finally, iPSCs from persons with Alzheimer's disease will be differentiated into microglia-like cells to monitor the anti-neuroinflammatory capacity of our candidate drugs. The final aim for this proposal is the preliminary preclinical characterization of the first CRAC channel inhibitor for AD therapy and identification of key inflammatory cytokines that may be used as surrogate biomarkers for target engagement in future clinical studies.

Public Health Relevance Statement:
Vivreon Biosciences, LLC 7558 Trade St. San Diego, CA 92121 vivreonbiosciences@gmail.com Vivreon Biosciences - NIA SBIR # PAS-18-187 Project Narrative Current Alzheimer's disease (AD) therapies act on neurons only to alleviate symptoms of the disease without slowing disease progression. Microglial-associated genes are risk factors for AD, and chronic microgliosis contributes to progressive neurodegeneration in AD. Vivreon Biosciences is testing candidate neuroprotective therapeutics in human AD microglia to explore biomarkers that will guide our future AD clinical approach. .

Project Terms:
Alzheimer's Disease; senile dementia of the Alzheimer type; primary degenerative dementia; dementia of the Alzheimer type; Primary Senile Degenerative Dementia; Alzheimers disease; Alzheimers Dementia; Alzheimer's; Alzheimer syndrome; Alzheimer sclerosis; Alzheimer disease; Alzheimer Type Dementia; Alzheimer; inhibitor/antagonist; inhibitor; Biological Availability; Physiologic Availability; Biologic Availability; Bioavailability; Biological Sciences; Life Sciences; Bioscience; Biologic Sciences; Brain; Encephalon; Brain Nervous System; capsule; Capsules; plasmalemma; Plasma Membrane; Cytoplasmic Membrane; Cell membrane; Cell Body; Cells; Clinical Study; Clinical Research; Clinical Trials; Disorder; Disease; Dosage Forms; drug/agent; Pharmaceutic Preparations; Medication; Drugs; Pharmaceutical Preparations; Investigational New Drugs; Investigational Drugs; autoimmune encephalomyelitis; Experimental Autoimmune Encephalitis; Experimental Allergic Encephalomyelitis; Experimental Allergic Encephalitis; EAE; Experimental Autoimmune Encephalomyelitis; Foundations; Future; Goals; Grant; Modern Man; Human; In Vitro; Kinetics; heavy metal lead; heavy metal Pb; Pb element; Lead; Libraries; Mission; Persons; neuronal degeneration; neurological degeneration; neurodegenerative; neurodegeneration; neural degeneration; Neuron Degeneration; Nerve Degeneration; neuronal; Neurocyte; Neural Cell; Nerve Unit; Nerve Cells; Neurons; Patients; Phagocytosis; Pharmacology; Risk; Risk Management; Safety; Tablets; Technology; Testing; Toxicology; Work; soluble amyloid precursor protein; beta amyloid fibril; amyloid-b protein; amyloid beta; abeta; a beta peptide; Aß; Amyloid ß-Protein; Amyloid ß-Peptide; Amyloid ß; Amyloid Protein A4; Amyloid Beta-Peptide; Amyloid Alzheimer's Dementia Amyloid Protein; Alzheimer's amyloid; Alzheimer's Amyloid beta-Protein; Alzheimer beta-Protein; Amyloid beta-Protein; cytokine; surrogate biomarkers; surrogate bio-markers; Surrogate Markers; Muscular Weakness; Muscle Weakness; Chronic; Clinical; Phase; Series; Microglia; perivascular glial cell; microgliocyte; microglial cell; mesoglia; gitter cell; Hortega cell; Disease Progression; Funding; Therapeutic; Inflammatory; tool; Impaired cognition; cognitive loss; cognitive dysfunction; Disturbance in cognition; Cognitive function abnormal; Cognitive decline; Cognitive Impairment; Cognitive Disturbance; Knowledge; programs; Oral; treatment duration; treatment days; Treatment Period; muscle strength; interest; small molecule libraries; chemical library; neuroprotection; Animal Model; model organism; model of animal; Animal Models and Related Studies; Toxic effect; Toxicities; novel; Property; Cardiotoxicity; Cardiotoxic; Cardiac Toxicity; drug discovery; Neuraxis; Central Nervous System; CNS Nervous System; Pharmacological Substance; Pharmaceuticals; Pharmaceutical Agent; Pharmacologic Substance; preventing; prevent; small molecule; Address; Data; Applications Grants; Grant Proposals; Small Business Innovation Research Grant; Small Business Innovation Research; SBIR; Monitor; Cardiac; Development; developmental; Pathway interactions; pathway; pre-clinical; preclinical; National Institute on Aging; National Institute of Aging; neuroinflammation; neuroinflammatory; innovation; innovative; innovate; clinically relevant; clinical relevance; neurotoxic; neurotoxicity; neuronal toxicity; neuron toxicity; Alzheimer's disease risk; alzheimer risk; Alzheimer risk factor; mouse model; murine model; progressive neurodegeneration; induced pluripotent stem cell; iPSCs; iPSC; iPS; commercialization; new therapeutic target; novel therapy target; novel therapeutic target; novel pharmacotherapy target; novel druggable target; novel drug target; new therapy target; new pharmacotherapy target; new druggable target; new drug target; patient population; Biological Markers; biomarker; biologic marker; bio-markers; lead series; drug candidate; Regimen; risk variant; risk locus; risk loci; risk genotype; risk gene; risk allele; Risk-associated variant; screening; Drug Targeting; targeted treatment; targeted therapy; targeted therapeutic agents; targeted therapeutic; targeted drug treatments; targeted drug therapy; Patient risk; targeted biomarker; potential biomarker; potential biological marker; clinical biomarkers; clinically useful biomarkers; reduce symptoms; symptom relief; symptom reduction; symptom alleviation; relieves symptoms; fewer symptoms; decrease symptom; ameliorating symptom; alleviate symptom; clinical translation; therapeutic candidate; preservation; novel lead compound; lead candidate; side effect; infection risk

Delaying onset of Alzheimer's Disease (AD) by 5 years would reduce US healthcare costs by one third. In AD, the neurotoxic inflammation of activated brain microglia results in synapse loss and accumulation of improperly aggregated proteins such as amyloid . Productive microglial responses are normally transient, effectively clearing infectious agents or cellular debris, and involve phagocytic and other reparative processes. A therapy that restores the balance of reparative versus damaging neurotoxic microglial responses is hypothesized to reduce synaptic damage, slowing disease progression. The Ca2+ release-activated Ca2+ (CRAC) channel, is supported as a drug target for AD therapy by genetic evidence implicating the CRAC channel signaling pathway. The CRAC channel is activated by multiple receptors on microglia, and downstream signaling drives a multiplicity of biochemical and gene expression events typical of damaging neurotoxic inflammation driven by the NFAT promoter. Vivreon Biosciences seeks to control AD progression by selecting and advancing a lead CRAC modulating compound, VV8325, into the drug development pipeline. VV8325 is orally available and brain penetrant, potent against the CRAC channel and attractive in initial safety tests. Vivreon CRAC channel modulators selectively inhibit neurotoxic microglial inflammation while promoting beneficial phagocytic and survival functions without aggravating a viral challenge. Further, we hypothesize that Aß and cell death associated biomolecules like ADP drive sustained Ca2+ signaling by microglial CRAC channels, resulting in AD pathology, a process intensified in persons with the TREM2-R47H allele. In this Phase 2 project we propose to further qualify VV8325 via completion of drug metabolism and pharmacokinetic studies including, maximal tolerated dose determination, 7-day dose range finding, and optimizing manufacturing parameters towards production of a 100 gram batch. Compound efficacy will be tested in two models of AD. First, we will measure VV8325 efficacy in a validated 5XFAD model to demonstrate a therapeutic dose-response, determine an ED50 and validate our candidate biomarker. Towards guidance of an optimally efficient clinical trial design, VV8325 efficacy against neurotoxic inflammatory activation of human induced pluripotent stem cell microglia (iMGL) bearing the TREM2-R47H variant will be tested in vivo. The TREM2-R47H variant in humans enhances CRAC signaling, is a genetic marker of AD risk and the population may provide a targeted trial cohort. The project will culminate in an in vivo efficacy test of VV8325 in a unique model carrying TREM2-R47H human microglia allowing us to test whether the variant-bearing patients may be more effectively treated by VV8325 and thus point towards a TERM2-R47H genotype-targeted initial efficacy clinical trial design. Success for VV8325 here will attract external funding support for advancement of this promising therapy.

Public Health Relevance Statement:
Vivreon Biosciences, LLC 4940 Carroll Canyon Rd., Ste. 110 San Diego, CA 92121 milton@vivreonbiosciences.com Vivreon Biosciences - NIA PAS-19-316 Preclinical Characterization of CRAC Channel Inhibitors for the Treatment of Alzheimer's Disease Project Narrative Alzheimer's Disease (AD) is currently treated with therapies that address disease symptoms without altering the root cause mechanisms or course of the disease. This project will advance Vivreon Biosciences' lead drug candidate for reduction of neurotoxic inflammation that contributes to the rate and extent of progression of AD. A successfully completed project will lead to private funding that will allow Vivreon to carry the drug candidate forward through clinical trials and market it as a true disease modifying therapy for AD.

Project Terms:
Alleles; Allelomorphs; 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; Amyloid; Amyloid Substance; Animals; inhibitor; Biological Sciences; Biologic Sciences; Bioscience; Life Sciences; Brain; Brain Nervous System; Encephalon; capsule; Capsules; Cell Death; necrocytosis; Cell membrane; Cytoplasmic Membrane; Plasma Membrane; plasmalemma; Chemistry; Clinical Trials; Disease; Disorder; Dosage Forms; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Investigational Drugs; Investigational New Drugs; Equilibrium; balance; balance function; Gene Expression; Genetic Markers; genetic biomarker; Genotype; Goals; Grant; Human; Modern Man; In Vitro; Inflammation; Investments; Lead; Pb element; heavy metal Pb; heavy metal lead; Mission; Persons; Neuron Degeneration; neural degeneration; neurodegeneration; neurodegenerative; neurological degeneration; neuronal degeneration; Nerve Degeneration; Patients; Phagocytic Cell; amebocyte; Phagocytes; Pharmacokinetics; Drug Kinetics; Privatization; Production; Program Development; Research; Risk; Risk Management; Rodentia; Rodents Mammals; Rodent; Signal Pathway; Cell Communication and Signaling; Cell Signaling; Intracellular Communication and Signaling; Signal Transduction Systems; Signaling; biological signal transduction; Signal Transduction; Synaptic; synapse; Synapses; Tablets; Target Populations; Testing; Toxicology; United States Food and Drug Administration; Food and Drug Administration; USFDA; Amyloid beta-Protein; Alzheimer beta-Protein; Alzheimer's Amyloid beta-Protein; Alzheimer's amyloid; Amyloid Alzheimer's Dementia Amyloid Protein; Amyloid Beta-Peptide; Amyloid Protein A4; Amyloid ß; Amyloid ß-Peptide; Amyloid ß-Protein; Aß; a beta peptide; abeta; amyloid beta; amyloid-b protein; beta amyloid fibril; soluble amyloid precursor protein; Measures; Health Care Costs; Health Costs; Healthcare Costs; promoter; promotor; Investigational New Drug Application; Chronic; Clinical; Phase; Variant; Variation; Biochemical; Microglia; Hortega cell; gitter cell; mesoglia; microglial cell; microgliocyte; perivascular glial cell; Disease Progression; root; Plant Roots; Funding; Therapeutic; Genetic; infectious organism; Infectious Agent; Inflammatory; Cognitive Disturbance; Cognitive Impairment; Cognitive decline; Cognitive function abnormal; Disturbance in cognition; cognitive dysfunction; cognitive loss; Impaired cognition; programs; Event; Oral; Treatment Period; treatment days; treatment duration; Dementia rating scale; Clinical dementia rating scale; Viral; mutant; Receptor Protein; receptor; success; cohort; Animal Models and Related Studies; model of animal; model organism; Animal Model; attenuation; PLCγ2; phospholipase C gamma2; PLCgamma2; novel; validation studies; drug metabolism; Maximal Tolerated Dose; Maximally Tolerated Dose; Maximum Tolerated Dose; Modeling; Property; response; drug development; Pharmaceutical Agent; Pharmaceuticals; Pharmacological Substance; Pharmacologic Substance; preventing; prevent; small molecule; Address; Dose; Symptoms; Data; Sum; in vivo; Clinical Trials Design; Small Business Innovation Research Grant; SBIR; Small Business Innovation Research; Process; Development; developmental; Pathway interactions; pathway; pre-clinical; preclinical; 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; protein aggregation; insoluble aggregate; protein aggregate; Population; neurotoxic; Alzheimer's disease risk; Alzheimer risk factor; alzheimer risk; Alzheimer's disease model; AD model; alzheimer model; induced pluripotent stem cell; iPS; iPSC; iPSCs; inducible pluripotent stem cell; therapeutic development; therapeutic agent development; patient population; candidate marker; candidate biomarker; safety testing; efficacy testing; drug candidate; candidate validation; Regimen; Drug Targeting; trial design; Alzheimer's disease pathology; AD pathology; Alzheimer's pathology; TREM2 gene; TREM2; Triggering Receptor Expressed on Myeloid Cells 2; efficacy study; in vivo evaluation; in vivo testing; first-in-human; first in man; Alzheimer's disease related dementia; AD related dementia; ADRD; Alzheimer related dementia; side effect; infection risk; pharmacokinetics and pharmacodynamics; PK/PD; Alzheimer's disease therapeutic; Alzheimer's therapeutic; Alzheimer's disease therapy; Alzheimer's therapy; Alzheimer's disease patient; Alzheimer's patient; efficacy clinical trial; reparative process