Abstract LB-217: Long term safety observed with CEQ508: An oral RNAi drug targeting β-catenin of GI polyps

Abstract

Abstract Marina Biotech is developing a proprietary drug discovery and delivery platform called transkingdom RNAi (tkRNAi), to develop RNAi-based therapeutics in which non-pathogenic bacteria are engineered to: (1) express short hairpin RNA (shRNA), (2) invade via a specific cell surface receptor and (3) deliver shRNA to the cytoplasm of a targeted cell. CEQ508, an E. coli derivative delivered orally, is the first drug candidate utilizing this approach. CEQ508 expresses a shRNA directed against β-catenin, and has been shown in previous work to significantly reduce β-catenin mRNA levels in vitro and in vivo. In the colorectal cancer cell line, SW480, we observed 90% suppression of β-catenin mRNA. In the non-human primate distal ileum 65% knockdown of β-catenin mRNA was detected. β-catenin is a key oncogene implicated in Colorectal Cancer (CRC) and Familial Adenomatous Polyposis (FAP). FAP is a hereditary disease in which the formation of hundreds of polyps in the gastrointestinal tract ultimately leads to the development of colon cancer. CEQ508 will be tested in a Phase Ib/IIa clinical trial in FAP patients at Massachusetts General Hospital with first patient dosing expected in the first quarter of 2011. CEQ508 was recently granted orphan drug status for the intended treatment of FAP patients by the FDA's Office of Orphan Products Development. In preparation for later pivotal clinical trials, we recently completed a 9 month GLP non-human primate toxicology study assessing the safety of daily, oral chronic administration of CEQ508. In this study, 18 animals were dosed with either CEQ508 or two control articles. No CEQ508-related adverse responses were identified in the following study parameters analyzed: clinical observations, body weights and temperatures, serum chemistry, coagulation, hematology, urinalysis, cytokines and gross pathology. Preliminary conclusions identify the No Observed Adverse Effect Level (NOAEL) for long-term daily oral administration of CEQ508 as 1×1011 colony forming units (cfu)/day. In addition to presenting additional details of long term toxicology study, a clinical update on our Phase Ib/IIa trial will be provided. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-217. doi:10.1158/1538-7445.AM2011-LB-217