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

项目总结 申请行政补充的目的是为了弥补GMP多肽增加的成本 将在第二年进行的体内和体外毒理学研究的制造和增加的成本。 关于制造，自从这份U01提案最初提交以来，我们的多肽 制造CRO，500克GMP批次的PNA5的成本(970美元/克加上稳定性测试，CMC 文档，以及最终填充和完成)现在是786,000美元，而我们最初的预算是525,000美元150克 (每克2500美元，外加稳定性测试、CMC文档)。此增加的批次大小是我们计划的 延长的21天重复剂量的正式毒性研究计划在第三年进行，也将足以完成我们的 计划中的1a/b阶段人体研究，从而消除了为 这是人类研究中的第一个计划。成本差额将为261,000美元。这最终将节省时间和 在人类第一批研究之前，不需要第二批GMP，从而节省了大量资金，每克节省了大量美元。 关于为期7天的大鼠和狗的MTD毒理学研究和体外试验(HERG，染色体试验， ，我们已经能够加快这些研究的时间，现在计划在#年完成这些研究 第二年。在最初的提案中，原始报价为我们的原始供应商(MPI)总计452,800美元。从那时起， 供应商被Charles River收购，这些研究现在花费了691,456美元。成本差异 是238,656美元。我们已经包括了原始报价和新报价之间的分项成本比较 下面。因此，在第二年，我们要求增加499,656美元的直接费用，以弥补增加的费用 制造成本以及体内和体外毒理学成本的增加。

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.