Repurposing of Pyrvinium Pamoate for Familial Adenomatous Polyposis (FAP)

ABSTRACT Individuals with the rare, inherited disorder Familial Adenomatous Polyposis (FAP) develop thousands of precancerous polyps at an early age and ultimately develop colorectal cancer (CRC). The current standard of care for FAP is colectomy. However, unavoidable side-effects of colectomy are debilitating. Furthermore, colectomy does not prevent subsequent development of extra-colonic intestinal tumors, the main cause of death post-colectomy. There are currently no drugs FDA approved for the treatment or chemoprevention of FAP patients. We have demonstrated that pyrvinium can be repurposed as a potent inhibitor of WNT signaling and is efficacious in an animal model of FAP. Oral dosing of pyrvinium pamoate produces negligible systemic exposure and limits the exposure to the gut which reduces the likelihood of toxicity. Submitting these data to the FDA, we were awarded an Orphan Drug Designation to market pyrvinium exclusively for FAP patients. To clarify the steps required to take pyrvinium back into the clinic as a repurposed agent for FAP patients, using a 505(b)(2) regulatory mechanism, we recently had a pre-IND meeting with the FDA. This Phase I/II Fast-Track application is driven by the FDA’s recommendations for a successful Investigational New Drug (IND) application for pyrvinium in the treatment of FAP. The repurposing of pyrvinium for FAP patients, if successful, would represent 1) A major improvement in therapy and in the quality of life, and 2) The successful bench to bedside application of a rationally selected targeted therapy.NARRATIVE Familial Adenomatous Polyposis is an aggressive disease caused by a genetic mutation in the WNT signaling pathway with no effective treatment options. Patients are typically in their teenage years when they develop hundreds of polyps in their colon and subsequently require the removal of their colon. We propose to develop a WNT inhibitor, pyrvinium, under the orphan drug program to treat this disease.