Predevelopment of VV8220, a Gut-selective CRAC Channel Therapeutic for Ulcerative Colitis

Vivreon Biosciences, LLC 4940 Carroll Canyon Rd., Ste. 110 San Diego, CA 92121 milton@vivreonbiosciences.com NIAID PA-23-230 Project Summary Ulcerative colitis (UC) is the most common form of inflammatory bowel disease affecting up to one in 5,000 individuals. The pathologic inflammation occurs in the inner lining of the colon and rectum due to an inappropriate response of resident leukocytes to normally tolerated bacteria and other pro-inflammatory material in the gut. This results in potentially life-threatening ulcerative lesions and significant disruption to quality of life. Currently indicated small molecule and biologic drugs are not effective in all patients, or many patients become unresponsive to therapies over time, and additional treatment options are needed. One promising and novel therapeutic approach to controlling UC is to restrict anti-inflammatory drug action to the inner lining of the gut where the local inflammatory response is most extreme, thereby simultaneously limiting systemic anti- inflammatory side effects of the drug. An orally available drug with such gut-restricted properties would be acting similarly to topical agents applied to the skin to control autoimmune inflammation of the skin. The leukocyte Ca2+ release activated Ca2+ (CRAC) channel is operative on gut monocytes and T cells (primary cellular drivers of UC), is triggered by leukocyte receptors for foreign antigens, and the CRAC pathway regulates many pro- inflammatory genes in these cells through activation of NFAT and NF-B transcriptional activity. These attributes make the CRAC channel a suitable target for development of a gut-restricted small molecule drug. Vivreon’s candidate therapeutic CRAC channel blocker exhibits physical properties consistent with a gut restricted oral drug candidate, including strong potency and limited systemic exposure upon oral dosing. Vivreon seeks NIAID Phase 2 funding for investigational new drug (IND)-enabling good laboratory practice (GLP) toxicity, safety, and genotoxicity studies. Specifically, NCI funding will go towards two-species GLP 28-day toxicity studies, GLP safety pharmacology and genetic toxicology, GLP pharmacological respiratory safety assessment, and GLP cardiovascular telemetry. Activities in this proposal will run in parallel with chemistry manufacturing and controls (CMC) processes. Completion of these studies will support and be written up in an IND application, with the final milestone being IND submission to the US Food and Drug Administration (FDA).