In this Competing Continuation of our STTR Phase II grant, we propose to build upon the considerable progress made during the previous two funding cycles in our effort to develop a new family of phosphatidylcholine (PC)-associated nonsteroidal anti-inflammatory drugs (NSAIDs). During this period we have continued to develop our lead compounds, ibuprofen-PC and aspirin-PC, in which we chemically associate the NSAIDs with soy PC, and have demonstrated that these formulations have reduced GI toxicity while maintaining or enhancing the drugs therapeutic activity in rodent model systems. Based upon this evidence, and that provided by our Contract Research Organization (Synergos, Inc.) and manufacturer (Cardinal Health), the FDA has issued an IND for the ibuprofen-PC and has approved an accelerated 505(b)(2) regulatory path for bioequivalence, which was supported by human pharmacokinetic data in Phase I/II and III trials on healthy subjects, together with a Phase II trial in which osteoarthritic (OA) patients were placed on either ibuprofen or ibuprofen-PC for a 6 week study period, to provide information on the GI safety and therapeutic activity of the test drugs. As described in the revised application, these clinical studies, that were funded by the small business and a R03 grant from NIH, demonstrated that ibuprofen-PC had similar bioavailability and therapeutic activity to ibuprofen, but was significantly less injurious to the gastroduodenal mucosa of OA patients most susceptible to NSAID-induced GI side effects, those who were >55 years of age. In this revised grant application, we propose to continue this promising line of investigation, and perform a 12 week endoscopic trial in OA patients, which should provide confirmatory evidence on the GI safety and anti- inflammatory/analgesic activity of ibuprofen-PC. We also propose a series of laboratory experiments in which we will be working closely with our project team at Cardinal Health to optimize the current ibuprofen-PC formulation, so that it can meet FDA's manufacturing guidelines, and to further develop a new method of preparing PC-NSAIDs, which appears to result in obtaining a purified ibuprofen-PC complex, as an oil. This purified ibuprofen-PC possesses superior GI safety and therapeutic activity in rodent model systems and we also propose in this grant to evaluate its bioavailability in healthy human subjects under a modified IND, to obtain accelerated regulatory approval for this product. We also propose to file an IND for aspirin-PC and propose pharmacokinetic studies in healthy subjects to determine if it is bioequivalent to aspirin, which would allow us to pursue a 505(b)(2) regulatory pathway. Lastly, we propose a series of preclinical and pilot clinical studies to confirm preliminary evidence that aspirin-PC is far less toxic than aspirin when co-administered to animals with Celebrex. The successful completion of the above studies will allow us to file an NDA on one or both formulations of ibuprofen-PC and aspirin-PC, initially for bioequivalence, and ultimately for enhanced GI safety and therapeutic activity. Accomplishing these milestones should place us in a very competitive position to attract a corporate partner to facilitate the commercialization of both ibuprofen- PC and aspirin-PC, and perhaps the entire PC-NSAID franchise, making this novel class of drugs available to the public, that is in great need for a safe and effective NSAID. Nonsteroidal anti-inflammatory drugs (NSAIDs) are highly consumed by Americans, especially older members of our population suffering from osteoarthritis (OA), due to their potent anti- inflammatory and analgesic actions. However, the use of NSAIDs is limited by their serious side effect of inducing gastrointestinal (GI) ulceration and bleeding in susceptible individuals, being responsible for 103,000 hospitalizations and 16,500 deaths a year. The technology to be developed in this grant proposal relates to prevention of NSAID-induced GI ulceration and bleeding by chemical association of NSAIDs with the surface-active lipid, phosphatidylcholine (PC). Development of PC-associated NSAIDs will provide drugs that can be more safely used by millions with OA for relief of pain and inflammation, and for other potential uses like prevention of cancer and Alzheimer's disease.
