Predevelopment of VV8321, a Novel CRAC Channel Therapeutic for the Treatment of Osteoarthritis - Vivreon Biosciences, LLC
4940 Carroll Canyon Rd., Ste. 110
San Diego, CA 92121
milton@vivreonbiosciences.com
NIAMS PA-20-260
Project Summary
Osteoarthritis (OA) is a progressive arthritic condition and the most common form of painful and disabling
arthritis, affecting over 10% of adults over 60 years of age. Destruction of joint cartilage and bone occurs with
significant chronic inflammation of the synovium tissue that normally nourishes and supports the joint. There is
no available Disease Modifying Osteoarthritis Drug (DMOAD), and the need is great. Joint destructive synovitis
is driven largely by inflammatory and destructive innate immune cell responses to signals from damaged tissues
and senescent joint cells. An ideal therapeutic to control synovitis and modify OA progression would be safe and
able to reduce damaging macrophage overactivity in the synovium while maintaining the repair activities of
beneficial macrophage activation. The Ca2+ Release Activated Ca2+ Channel (CRAC), the topic of this SBIR
Phase I project, is supported as a drug target by genetic evidence of a causative role for CRAC pathway
components and by upregulation of the CRAC channel protein in OA tissues. The CRAC channel is activated by
multiple proinflammatory receptors on macrophages, and signaling events downstream of CRAC activation drive
a multiplicity of biochemical and gene expression events driven by NF-B and NFAT promoters typical of chronic
inflammation.
Vivreon Biosciences seeks to control synovitis and reduce OA-associated morbidity by advancing a lead CRAC
blocker compound, VV8321, into the drug development pipeline. We propose that VV8321 exhibits properties
that make it suitable for intra-articular injection and the likelihood of a prolonged retention in the joint to provide
sustained inhibition of synovial macrophage inflammation. In this project we will further characterize VV8321 to
advance it into a full drug development program appropriate for external funding support. In Aim 1 we will perform
in vitro assays to characterize VV8321 ADME behaviors, cytochrome P450 enzyme family liabilities (CYP mRNA
induction), cytotoxicity screening, cardiovascular hERG channel liability and genotoxic liabilities (Ames test). Aim
1 will also investigate the joint and plasma pharmacokinetic behavior of VV8321 upon intra-articular injection into
rat knees. In Aim 2 VV8321 efficacy will be tested in two rat models of OA – a destabilization of the medial
meniscus model and a chemical induction model (monosodium iodoacetate injection into the knee joint).
Successful completion of the program will position Vivreon to advance VV8321 into a full drug development
program with sufficient documentation to attract additional Phase II and external funding support.
