SB1AG087756

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, there is an urgent need to develop therapeutics that can slow disease progression.

Alongside accumulation of improperly aggregated proteins such as amyloidβ (Aβ), 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.

Vivreon Biosciences

TO ENCOURAGE BIOMEDICAL, SOCIAL, AND BEHAVIORAL RESEARCH AND RESEARCH TRAINING DIRECTED TOWARD GREATER UNDERSTANDING OF THE AGING PROCESS AND THE DISEASES, SPECIAL PROBLEMS, AND NEEDS OF PEOPLE AS THEY AGE. THE NATIONAL INSTITUTE ON AGING HAS ESTABLISHED PROGRAMS TO PURSUE THESE GOALS. THE DIVISION OF AGING BIOLOGY EMPHASIZES UNDERSTANDING THE BASIC BIOLOGICAL PROCESSES OF AGING. THE DIVISION OF GERIATRICS AND CLINICAL GERONTOLOGY SUPPORTS RESEARCH TO IMPROVE THE ABILITIES OF HEALTH CARE PRACTITIONERS TO RESPOND TO THE DISEASES AND OTHER CLINICAL PROBLEMS OF OLDER PEOPLE. THE DIVISION OF BEHAVIORAL AND SOCIAL RESEARCH SUPPORTS RESEARCH THAT WILL LEAD TO GREATER UNDERSTANDING OF THE SOCIAL, CULTURAL, ECONOMIC AND PSYCHOLOGICAL FACTORS THAT AFFECT BOTH THE PROCESS OF GROWING OLD AND THE PLACE OF OLDER PEOPLE IN SOCIETY. THE DIVISION OF NEUROSCIENCE FOSTERS RESEARCH CONCERNED WITH THE AGE-RELATED CHANGES IN THE NERVOUS SYSTEM AS WELL AS THE RELATED SENSORY, PERCEPTUAL, AND COGNITIVE PROCESSES ASSOCIATED WITH AGING AND HAS A SPECIAL EMPHASIS ON ALZHEIMER'S DISEASE. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.866 - Aging Research

National Institute on Aging (NIA) [HHS - NIH]

California United States

State-Wide

SBIR/STTR Commercialization Readiness Pilot (CRP) Program Technical Assistance and Late Stage Development (SB1, Clinical Trial Not Allowed) (PAR-23-219)