Cequent Pharmaceuticals, a pioneer in the development of novel products to deliver RNAi-based treatments to prevent and treat human disease, has announced that it has filed its first IND (investigational new drug) application with the U.S. Food and Drug Administration (FDA). CEQ508, an orally administered tkRNAi drug candidate, targets beta-catenin, a key oncogene implicated in the formation of colonic polyps and in the progression of polyps to colorectal cancer. Cequent expects to begin the Phase I clinical trial in the FAP (familial adenomatous polyposis) patient population during the first quarter of 2010 at the Fred Hutchinson Cancer Research Center, in Seattle, Washington, part of the Fred Hutchinson/University of Washington Cancer Consortium.
"A first IND filing is obviously a momentous event for a young company like Cequent, and this is also a critical milestone in the development of RNAi therapeutics in general, as our proposed Phase I trial will be the first test of an orally administered RNA interference drug in humans," said Cequent Chief Executive Officer Peter Parker. "In 2006, when RNAi was the subject of the Nobel Prize in Medicine, it was hailed as 'a revolution in biology' - RNAi's discovery created the opportunity to address targets that were previously difficult to treat by effectively deactivating the specific gene or genes implicated in the progression of a disease by "interfering" with messenger RNA. However, success in developing RNAi therapies has been elusive to date because of delivery issues - how do you transport and deposit the molecules triggering RNAi into the target cells and diseased tissues. We believe that our orally administered tkRNAi technology has shown great potential in solving that significant problem."
This Phase I clinical trial, as proposed to the FDA, would be conducted to determine safety and tolerability of CEQ508 at escalating doses in a total of 18 adult FAP patients. A key readout and secondary objective of the proposed trial includes analysis of biomarker (beta-catenin) expression changes in the gastrointestinal tract of patients determined from biopsy samples taken prior to taking the drug, and following a daily, 28-day dosing regimen. The principal investigator (PI) of this clinical trial will be Gideon Steinbach, M.D., Ph.D., associate professor of medicine at the University of Washington and the PI of a number of earlier FAP studies. The Cancer Consortium maintains a registry of FAP patients and is also one of 40 National Cancer Institute-designated comprehensive cancer centers nationwide.
In preclinical testing with non-human primates, tkRNAi therapeutic candidates have demonstrated potent silencing of the beta-catenin, a protein known to accumulate and lead to the proliferation of polyps in affected patients. During preclinical testing, CEQ508 demonstrated an encouraging safety profile when administered as a daily oral therapeutic.
FAP is a rare inherited gastrointestinal disease that causes hundreds to thousands of precancerous polyps to form in the colon. Approximately 35,000 people in the U.S. carry the genetic mutation inherent to the disease. Today, without prophylactic removal of the colon, people with FAP almost inevitably develop cancer, and there is no generally accepted pharmacological treatment available. FAP has been designated as an orphan disease under the U.S. Orphan Drug Act, which provides various incentives for sponsors to encourage development of products for rare diseases. Phase I studies of novel therapeutics for such rare, underserved diseases are often allowed to enroll patients as opposed to healthy volunteers, potentially accelerating the timeline to develop approved products.
Commenting on Cequent's progression as a company, Mr. Parker said, "We also continue to make important progress with our tkRNAi inflammatory bowel disease (IBD) program, for which this CEQ508 trial serves as a regulatory and safety pathbreaker. Cequent is moving ahead with preclinical development of tkRNAi products targeting immunological genes implicated in the pathology of IBD."
Mr. Parker continued, "We have now entered a new phase in the company's lifecycle; we have transitioned away from research to focus on our clinical programs, much of which we will pursue with contract resources. As such, we have promoted Alison Silva to the new position of vice president of drug development, overseeing all clinical development and regulatory affairs for the company. Co-inventor of the tkRNAi technology, Johannes Fruehauf, M.D., will support the upcoming clinical trial through a consultancy arrangement as vice president of medical affairs."