Progressing the Pre-clinical development of P8 for Alzheimer's Disease

推进 P8 治疗阿尔茨海默病的临床前开发

• 批准号: 9467211
• 负责人: NAZNEEN N DEWJI
• 金额: $ 75万
• 依托单位: CENNA BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9467211
• 关键词: Abeta synthesis; Affect; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid beta-Protein; Animals; Brain; Cell physiology; Disease; Dose; Drug Kinetics; Elderly; Enzymes; Evaluation; Formulation; Funding; Future; Goals; In Vitro; Injectable; Lead; Maximum Tolerated Dose; Movement; Neurodegenerative Disorders; Pathologic; Pharmaceutical Preparations; Pharmacotherapy; Phase; Population; Safety; Small Business Innovation Research Grant; Testing; Therapeutic; Time; Toxicokinetics; Toxicology; Transgenic Mice; Work; drug candidate; gamma secretase; in vivo; interest; neurotoxic; new technology; novel; novel therapeutic intervention; peptide drug; phase 1 study; preclinical development; secretase; subcutaneous

Progressing the Preclinical Development of P8 for Alzheimer's disease This SBIR competitive Phase IIB renewal application is to continue with the preclinical development of Cenna's lead peptide drug candidate, P8, to treat Alzheimer's disease (AD). There is currently no cure for the disease. 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. Earlier therapeutic attempts at lowering total Aß production were unsatisfactory 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. New therapeutic approaches that can inhibit total Aß production without targeting the activities of the ß- or the γ- secretase are therefore of great interest. We have a novel technology that does not target the secretases, which has yielded a potential peptide drug candidate, P8, with the ability to inhibit the production of Aß in vitro and in a transgenic mouse model of AD. P8 is being developed as a new peptide drug for the treatment of AD. In this application we propose to build upon the substantial progress made in the last two years of Phase II funding and to continue with the preclinical development of P8. Specifically, we propose to further develop the formulation of P8 as a subcutaneous injectable drug and carry out investigative non-GLP studies that will provide a toxicological and toxicokinetic assessment of P8 in formulation in order to facilitate its movement into GLP regulatory toxicological testing, which provides a full assessment of the safety profile. Efficacy of P8 in formulation will be assessed in APP transgenic mice. Larger quantities of non-GLP, GLP and GMP grades of P8 will also be synthesized and characterized for the current proposed work and future IND-enabling toxicology and Phase 1 studies.

推进 P8 治疗阿尔茨海默病的临床前开发 该 SBIR 竞争性 IIB 期更新申请将继续进行临床前开发 Cenna 的主要候选肽药物 P8 用于治疗阿尔茨海默氏病 (AD) 目前尚无治愈方法。 该疾病的病理特征包括在大脑中的形成和积累。 Aß，被广泛认为是 AD 中主要的神经毒剂，早期尝试降低总神经毒性。 Aß 的生产并不令人满意，因为它们直接针对 ß- 或 γ-分泌酶的催化活性， 已知可水解除 APP 外的其他底物，其中许多底物具有关键的细胞功能。 可以抑制总 Aß 产生而不针对 ß- 或 γ- 活性的治疗方法 因此，我们有一种不针对分泌酶的新技术， 产生了一种潜在的候选肽药物 P8，能够抑制 Aß 的产生 P8 正在体外和在 AD 转基因小鼠模型中被开发为一种用于治疗的新肽药物。 在本申请中，我们建议以过去两年取得的实质性进展为基础。 具体而言，我们建议进一步开展第二阶段资金并继续进行 P8 的临床前开发。 开发P8皮下注射药物剂型并开展非GLP研究 研究将对制剂中的 P8 进行毒理学和毒代动力学评估，以促进 其进入 GLP 监管毒理学测试，提供对安全性的全面评估。 将在 APP 转基因小鼠中评估制剂中 P8 的功效。 P8 的 GMP 等级也将针对当前拟议的工作和未来进行综合和表征 支持 IND 的毒理学和 1 期研究。