IND-Enabling Pre-clinical Development of Modified P8 for the Treatment of Alzheimer's Disease

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Modified Project Summary/Abstract Section The focus of this Type 2 Commercialization Readiness Program application is on the regulatory requirements necessary to support regulatory submissions relating to pre-clinical development of Cenna’s peptide drug candidate mP8. mP8, a modified stabilized version of the previously published P8 is being developed as a new, first-in-class peptide drug for the treatment of Alzheimer’s disease (AD). This application builds on the substantial progress made under the previously funded SBIR Phase 2 and 2B grants. There is currently no cure for AD. The pathological hallmarks of the disease include the formation and accumulation in the brain of Aß, widely recognized to be the major neurotoxic agent in AD. All therapeutic attempts targeting Aß production have failed as they directly targeted the catalytic activities of ß- or γ-secretase, enzymes known to hydrolyze other substrates besides APP, many with critical cellular functions. Most clinical trials of both γ- and more recently ß- secretase inhibitors have been discontinued due to safety and other issues. New therapeutic approaches that can inhibit total Aß production without targeting the activities of the ß- or the γ-secretase are therefore urgently needed. We have a novel technology that does not target the secretases, which has yielded several potential peptide drug candidates with the ability to substantially and specifically inhibit the production of Aß in vitro and in vivo. In this renewal application we propose to complete pre-clinical studies on mP8 necessary for an IND submission. Proposed aims are to get scaled-up quantities of GLP and GMP grade mP8 synthesized, to carry out non-GLP dose-range-finding studies of mP8 in monkeys and rats, to develop and validate bioanalytical methods for GLP, to conduct IND-enabling drug safety toxicity studies in rats and monkeys and to investigate IND-enabling GLP safety pharmacology in rats and monkeys. The successful accomplishment of the proposed studies will complete a major part of the requirements towards submission of an IND to the FDA in preparation for Phase 1 clinical trials.