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

点击翻译按钮获取中文摘要

Vivreon Biosciences, LLC 4940 Carroll Canyon Rd., Ste. 110 San Diego, CA 92121 milton@vivreonbiosciences.com NIAID PA-21-259 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) and is triggered by leukocyte receptors for foreign antigens. 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 small molecule lead CRAC channel blocker, VV8220, exhibits physical properties consistent with a gut restricted oral drug candidate, including strong potency and limited systemic exposure upon oral dosing. Here we propose to perform further predevelopment studies with VV8220 to characterize and confirm its suitability as a gut-restricted oral drug candidate for treatment of UC. In Aim 1 (ADME/DMPK studies) we will assess its direct effects on cytochrome P450 family (CYP) enzyme activities and mRNA expression, its cardiovascular liability via an in vitro hERG channel blockade test, its genotoxic potential via an Ames test, and its in vivo pharmacokinetics. In Aim 2 we will evaluate its efficacy in two mouse models. First is the DSS model involving disruption of the intestinal barrier and consequent flora-driven UC. The second involves adoptive transfer of inflammatory naïve T cells into recipient mice lacking suppressive Treg cells that normally control a gut inflammatory response (Adoptive T cell model). The two model results will be assessed by a Disease Activity Index, histopathology and by measurement of the UC inflammatory biomarker myeloperoxidase (MPO) in gut lamina propria. Successful completion of these Aims will position the VV8220 program to advance into IND-enabling studies like advanced toxicology testing, chemistry scale up and dose-range finding with Phase II SBIR and external funding.