Marina Biotech, Inc. a leading RNAi-based drug discovery and development company announced that it has completed a 9 month toxicology study in non-human primates with its first drug candidate, CEQ508. CEQ508 is currently in a phase I b/II a clinical development programme and is intended for the treatment of Familial Adenomatous Polyposis.

During the study, 18 cynomolgus monkeys were administered daily oral doses of either CEQ508 or control article for 281 days. No test article-related adverse responses were identified in the following parameters: clinical observations, body weights and temperatures, serum chemistry, coagulation, haematology, urinalysis, cytokines and gross pathology.

Additionally, monthly biopsies of colonic mucosa showed no evidence of local immune activation. CEQ508 was recently granted Orphan Drug Designation by the FDA's Office of Orphan Products Development.

“In preparation for an anticipated phase II clinical trial, we initiated the enabling toxicology work early and are pleased to announce the recent completion of this program,” stated Barry Polisky, PhD, chief scientific officer at Marina Biotech, Inc. “Preliminary conclusions identify the No Observed Adverse Effect Level (NOAEL) for long-term daily oral administration of CEQ508 as 1x10(11) colony forming units (cfu)/day. This was the highest dose administered to these animals. We are encouraged by these results which provide important safety data for chronic administration of CEQ508.”

CEQ508 is the first drug candidate in a novel class of therapeutic agents utilizing the transkingdom RNA interference (tkRNAi) platform. CEQ508 comprises attenuated bacteria that are engineered to enter into dysplastic tissue and release a payload of short-hairpin RNA (shRNA), a mediator in the RNAi pathway. The shRNA targets the mRNA of Beta-catenin, which is known to be dysregulated in classical FAP.

CEQ508 is being developed as an orally administered treatment to reduce the levels of Beta-catenin protein in the epithelial cells of the small and large intestine. Upon enrollment, patients will be placed in one of four dose-escalating cohorts. Following completion of the dose escalation phase, the trial plan calls for a stable-dose phase in which additional patients will receive the highest safe dose. CEQ508 will be administered daily in an oral suspension for 28 consecutive days.

CEQ508 is being developed for the treatment of Familial Adenomatous Polyposis (FAP), a hereditary condition that occurs in approximately 1:10,000 persons worldwide. FAP is caused by mutations in the Adenomatous Polyposis Coli (APC) gene. As a result of these mutations, epithelial cells lining the intestinal tract have increased levels of the protein ß-catenin, which in turn, results in uncontrolled cell growth.

Proliferation of the epithelial cells results in the formation of numerous (hundreds to thousands) non-cancerous growths (polyps) throughout the large intestine. By age 35, 95% of individuals with FAP have developed polyps and most will experience adverse effects including increased risk of bleeding and the potential for anaemia. In more severe cases, obstruction of the intestines, abdominal pain, and severe bouts of diarrhoea or constipation can occur.

FAP patients are also at an increased risk of various cancers, the most concerning of which is a nearly 100% occurrence of colon cancer if measures are not taken to prevent the formation of polyps. For many patients, complete colectomy (surgical removal of the entire large intestine), usually performed in the late teenage years or early twenties, is the only viable option for treatment. However, surgical intervention is not curative as the risk of polyps forming in the remaining portions of the intestinal tract and in the small intestine continues after colectomy.

Marina Biotech is a biotechnology company, focused on the development and commercialization of RNA interference -- (RNAi) and RNA-based therapeutics and it currently includes a clinical programme in Familial Adenomatous Polyposis (a precancerous syndrome) and two preclinical programmes -- in hepatocellular carcinoma and bladder cancer.