Project Summary Neuronascent (NNI) discovered a unique therapy for Alzheimer’s, NNI-362, that promotes adult- born neurons to replace lost neurons, while protecting from degeneration. In NNI’s completed Phase1a trial, NNI-362 demonstrated safety and significant reduction of brain phosphoTau181. The aim is to follow up the Ph1a with a Phase 2 trial in AD, for which the following 4 specific aims are necessary. 1) NNI requires further GMP manufacture and 2) liquid-gel cap formulation of NNI-362; 3) the long-term (6-months) safety in M/F rats and dogs; and 4) regular IND updates and a meeting with FDA to discuss the Phase 2 clinical plan. This unique drug could be beneficial for AD by limiting phosphoTau pathology and promoting new neurons to reverse disease over a six-month period. In the first aim, Onyx Scientific will scale-up NNI-362 from the 1 kg cGMP method used for Phase 1a, to the >5 kg cGMP required for completion of Phase 2-3. Secondly, NNI-362 clinical product will then be formulated into a liquid-gel capsule prepared at 120 mg/capsule, already shown safe and potentially efficacious in aged subjects. Patheon prepared the formulation used in Phase1a, and determined the practicality of the liquid-gel cap with NNI-362. Thirdly, Charles River will complete a dog and rat (M/F) GLP safety testing for 6-months, as required by FDA for treatment of humans for the same 6-month period. The doses will be the same as the completed 14day/14day washout study in rats at 10, 50 and 150 mg/kg and in dogs at 15, 45 and 210 mg/kg po daily. Charles River has considerable experience in carrying out FDA-approved GLP safety studies. Lastly, regulatory contractors CCS Associates will provide yearly regulatory IND-update filings and will request a FDA meeting to discuss the Phase 2 clinical trial plan for mild to moderate AD patients. With decades of AD drug failures, NNI used human neural cell screen to discover a “neuron generating and neuroprotective” drug. Pre-clinical studies of NNI-362 demonstrated new hippocampal neurons in aging and disease models, and neuroprotection to allow new neuron integration that reversed behavioral deficits. Phase 1a in healthy aged subjects demonstrated safety and indicated that NNI-362, provided significant reduction of AD-progression marker phosphoTau181 after only 16 days of treatment period in human aged subjects. With longer term treatment of AD patients, NNI-362 has the potential to not only slow progression of AD over the short-term, but promote new neurons to fully reverse disease, long-term.