Preclinical Characterization of CRAC Channel Inhibitors for the Treatment of Alzheimer's Disease

Vivreon Biosciences, LLC 4940 Carroll Canyon Rd., Ste. 110 San Diego, CA 92121 milton@vivreonbiosciences.com Vivreon Biosciences Technical Assistance and Late-Stage Development, PAR-23-219, NOT-AG-23-048, AG061995 Preclinical Characterization of CRAC Channel Inhibitors for the Treatment of Alzheimer's Disease Project Summary Delaying onset of Alzheimer’s Disease (AD) by 5 years would reduce US healthcare costs by one third, however, and there is an urgent need to develop therapeutics that can slow disease progression. Alongside accumulation of improperly aggregated proteins such as amyloidb (Ab), synapse loss is also driven by neurotoxic inflammation of activated brain microglia. 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 and slow disease progression. The Ca2+ Release-Activated Ca2+ (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. Indeed, the CRAC channel, is supported as a drug target for AD therapy by genome-wide association study (GWAS) evidence. Vivreon’s long-term goal is to develop a novel CRAC channel therapeutic to delay cognitive decline in persons with AD by targeting microglia. AD risk genes TREM2 and PLCγ2 function in the same microglial Ca2+ signaling pathway and TREM2 mutant microglia have exacerbated CRAC signaling. We hypothesize that Aβ and cell death-associated biomolecules like ADP drive sustained Ca2+ signaling by microglial CRAC channels, resulting in AD pathology. Vivreon CRAC channel modulators selectively inhibit neurotoxic microglial inflammation while promoting beneficial phagocytic and survival functions without dampening the beneficial immune response to a viral challenge. Vivreon is currently conducting pre-development/candidate validation studies as part of grant AG061995. We now seek supplemental funding to advance our lead brain-penetrant CRAC-modulating compound, VV8325, into Investigational New Drug (IND)-enabling studies. Specifically, Vivreon seeks CRP supplemental funding to accomplish the 3 following: · Chemistry, Manufacturing, and Control (CMC) activities · IND-enabling Good Laboratory Practice (GLP) toxicity, safety pharmacology, and genotoxicity · Technical assistance towards IND filing These specific aims are complementary to, and will run concurrently with, the ongoing Phase 2 SBIR. CMC studies will entail process and analytical R&D, method quantification, production of a 500 g batch and polymorph and stability studies. GLP studies will include genetic toxicology, general toxicology, and safety pharmacology. We will develop our IP and regulatory strategy in partnership with a development consultant, and assemble the documentation needed in Standard for Exchange of Nonclinical Data (SEND) dataset to support IND filing. Completion of grant milestones will generate the data necessary to de-risk our novel AD therapeutic program and attract third-party investment to fund first-in-human (FIH) studies.