EARLY CLINICAL DEVELOPMENT OF MODIFIED P8 FOR THE TREATMENT OF ALZHEIMER’S DISEASE SUMMARY: The pathological hallmarks of Alzheimer’s disease (AD) include the formation and accumulation in the brain of Aß, widely recognized to be the major neurotoxic agent in AD. Earlier therapeutic attempts at lowering total Aß production all failed as they directly targeted the catalytic activities of ß- or g-secretase, enzymes known to hydrolyze other substrates besides APP, many with critical cellular functions. Most clinical trials of both g- and more recently ß- secretase inhibitors have been discontinued due to safety issues. After years of failures the first new drugs for AD in 20 years, monoclonal antibody (MAb) drugs Aduhelm and Leqembi, were recently approved by the FDA. Both target Aß, but Leqebi is more effective. Although it shows only a modest 27% cognitive improvement in patients, it provides the first definitive evidence that lowering Aß improves cognitive performance. More recently, a third MAb drug Donanamab has shown better cognitive improvement in clinical trials. These drugs represent promising first steps to developing new treatments to slow down and stop AD. Approaches other than MAbs to reduce Aß need to be explored since there are many disadvantages to MAb drugs. These include cost, mode of administration (by IV in the clinic once or twice a month) and safety since all MAbs are known to cause ARIAs (swelling and bleeding in the brain). New therapeutic approaches that can inhibit total Aß production without targeting the activities of the ß- or the g-secretase, that are not monoclonal antibodies, are urgently needed. Cenna’s technology does just that. We have a novel technology that does not target the secretases, which has yielded several peptide drug candidates with the ability to inhibit the production of Aß in vitro and in a transgenic (Tg) mouse model of AD. Our best candidate, modified P8 (mP8), is 8-amino acids in length and can be delivered to the brain by subcutaneous injection. mP8 is being developed as a new, first-in-class, disease-modifying peptide drug for the treatment of AD. IND-enabling GLP ADME, toxicology and safety pharmacology studies on mP8 in rats and monkeys have been completed. In this Direct-to-Phase 2 SBIR application we propose to carry out activities to support a first in human clinical study. The proposed studies include CMC activities to support clinical development of the drug product, to have a pre-IND meeting with the FDA and to submit an IND package and to develop an early clinical program and carry out Phase 1 clinical trials of mP8.