Perform non-GLP and GLP TOX/TK studies, and file a novel drug IND with the FDA for advanced pancreatic cancer patient clinical trials

Abstract/Summary The goals of this SBIR Phase I grant are: (1) to use the clinically compatible FL118 product to perform the non- good laboratory practice (GLP) and GLP toxicology (TOX) and toxicokinetics (TK) studies; and (2) to author and file the FL118 Investigational New Drug (IND) application with the FDA for first-in-human FL118 phase 1 clinical trials in patients with advanced pancreatic ductal adenocarcinoma (PDAC). The reason to use PDAC as FL118’s first indication in clinical trials is that (i) FL118 targets the oncoprotein DDX5 and shows high efficacy to eliminate PDAC with low toxicity; (ii) PDAC is a difficult-to-treat cancer with a 5-year survival rate of ~11% and is ≤ 3% in advanced PDAC patients; (iii) PDAC is expected to become the second greatest cause of cancer death by 2030; and (iv) currently there is no effective treatment. Therefore, there is an unmet clinical need for PDAC patients. We discovered FL118 via high throughput screening, followed by in vitro-and-in vivo hit-to-lead analyses. FL118 is water-insoluble, which has prevented its development. Together with our partners, we have now resolved the FL118 water-insoluble issues. FL118 has a unique chemical structure of “10,11-methylenedioxy” and possesses distinct mechanisms of action (MOA) from camptothecin (CPT) and its clinically used analogues (e.g., irinotecan and topotecan). Our studies indicated that FL118 inhibits multiple oncogenic proteins (e.g., survivin, Mcl-1, XIAP, cIAP2, MdmX, c-Myc) and key DNA damage repair regulators (e.g., ERCC6) by directly targeting the upstream master oncogenic regulator DDX5. Unlike clinically used CPTs, FL118 is not a substrate of multi-efflux proteins, ABCG2/BCRP and MDR1/Pgp, and can bypass their drug resistance. Furthermore, cancer stem cells (CSC) are known to play a critical role in treatment resistance. Accordingly, FL118 inhibits both CSC markers (ABCG2, ALDH1A1, Oct4) and invasive CSC spread. FL118 has demonstrated the capability to eliminate PDAC patient- derived xenograft (PDX) tumors and inhibit PDAC metastasis, while showing low toxicity in murine and canine animal models. FL118 is orally available, highly stable chemically, accumulates and resides in tumors, and is rapidly cleared from the bloodstream circulation (favorable pharmacokinetics - PK). Canget, along with its partner Roswell Park, successfully held the first pre-IND meeting (No: PIND 133477) with the FDA in 2017. Following the IND guideline and the pre-IND outline recommended by the FDA, we have completed the major components of IND-Enabling Studies and CMC (Chemistry, Manufacturing, and Control) work. FL118 has passed numerous hurdles, and the results obtained to date from the IND-Enabling Studies and other preclinical studies strongly support FL118 first-in-human clinical trials with PDAC patients. The Specific Aim of this SBIR Phase I project is to file the FL118 IND with the FDA after performing the non- GLP TOX/MTD and GLP TOX/TK studies using the clinically compatible FL118 product. Test of Feasibility: FDA accepts our IND application and allows for FL118 clinical trials to commence. Upon completion of this project, we will have the FL118 IND in place for qualifying FL118 first-in-human clinical trials.