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

修改项目摘要/摘要部分 该2类商业化准备计划申请的重点是支持与Cenna的肽类候选药物mP8的临床前开发相关的监管提交所需的监管要求。mP8是先前发表的P8的改良稳定版本，正在开发作为治疗阿尔茨海默病（AD）的新型一流肽药物。该申请建立在先前资助的SBIR第2阶段和2B赠款下取得的实质性进展的基础上。目前还没有治愈AD的方法。该疾病的病理学特征包括在脑中形成和积累广泛认为是AD中的主要神经毒性剂的AAE。所有靶向APP产生的治疗尝试都失败了，因为它们直接靶向β-或γ-分泌酶的催化活性，这些酶已知水解APP以外的其他底物，许多具有关键的细胞功能。由于安全性和其他问题，大多数γ-和最近β-分泌酶抑制剂的临床试验已经停止。因此，迫切需要能够抑制总腺苷酸产生而不靶向β-或γ-分泌酶活性的新治疗方法。我们有一种不靶向分泌酶的新技术，该技术已经产生了几种潜在的肽药物候选物，其具有在体外和体内实质性地和特异性地抑制ApoA产生的能力。在本次更新申请中，我们建议完成IND提交所需的mP8临床前研究。拟定的目标是合成大量GLP和GMP级mP8，在猴和大鼠中进行mP8的非GLP剂量范围探索研究，开发和验证GLP生物分析方法，在大鼠和猴中进行IND使能药物安全性毒性研究，并在大鼠和猴中研究IND使能GLP安全性药理学。拟议研究的成功完成将完成向FDA提交IND的主要部分要求，为1期临床试验做准备。

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.