Vivreon Biosciences, LLC 4940 Carroll Canyon Rd., Ste. 110 San Diego, CA 92121 milton@vivreonbiosciences.com NIA PAS-19-316 Project Summary 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 Aβ 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 t...