IND Enabling Studies for a Novel Mas Receptor Agonist for Treatment of Cognitive Impairment in Patients at Risk for Alzheimer's Disease Related Dementia

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PROJECT SUMMARY The purpose of this request for an administrative supplement is to cover the increased cost of GMP peptide manufacturing and the increased cost of the in-vivo and in-vitro toxicology studies that will occur in year 2. With regards to manufacturing, since the original submission of this U01 proposal, Polypeptide, our Peptide manufacturing CRO, the cost of a 500gram GMP batch of PNA5 ($970/gram plus stability testing, CMC documentation, and final fill and finish) is now $786,000 vs our original budget of $525,000 for 150 grams ($2500/gram plus stability testing, CMC documentation). This increased batch size is required for our planned extended 21-day repeated dose formal toxicity studies planned in Yr 3 and will also be enough to complete our planned Phase 1a/b studies in humans, thus eliminating the need to produce a second GMP batch for the planned first in human study. The cost difference will be $261,000. This will ultimately save both time and money by not requiring a 2nd GMP batch prior to first-in-human studies batch and a significant $/gram savings. Regarding the 7-day MTD toxicology studies in rat and dog and in vitro assays (hERG, chromosome assay, AMES), we have been able to accelerate the timing of these studies and now plan to have these completed in Year 2. In the original proposal, the original quotes our original vendor (MPI) totaled $452,800. Since then, that vendor was acquired by Charles River and those same studies are now costing $691,456. The cost difference is $238,656. We have included an itemized cost comparison between the original quote and the new quote below. Thus, for Year 2, we are requesting an additional $499,656 in direct costs to cover the increased manufacturing costs and for the increase in-vivo and in-vitro toxicology costs.