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.

P8治疗阿尔茨海默病的临床前研究进展 此次SBIR竞争性IIB期更新申请将继续进行以下药物的临床前开发： Cenna的先导肽候选药物P8用于治疗阿尔茨海默病（AD）。目前还没有治愈 这种疾病该疾病的病理学特征包括在脑中形成和积累 阿托伐他汀是公认的AD的主要神经毒性药物。早期治疗尝试降低总 由于它们直接靶向β-或γ-分泌酶的催化活性， 已知水解APP以外的其他底物的酶，许多具有关键的细胞功能。新 可以抑制总的A β产生而不靶向β-或γ-受体的活性的治疗方法， 因此，分泌酶是非常令人感兴趣。我们有一项新技术，它不针对分泌酶， 这已经产生了一种潜在的肽类药物候选物P8，它具有抑制阿芙林产生的能力 体外和AD的转基因小鼠模型中。P8正在开发作为一种新的肽药物用于治疗 的AD。在本申请中，我们建议在过去两年取得的实质性进展的基础上， II期资金，并继续进行P8的临床前开发。具体而言，我们建议进一步 开发P8作为皮下注射药物的制剂，并进行非GLP研究 研究将提供制剂中P8的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，该测试提供了对安全性的全面评估。 将在APP转基因小鼠中评估P8在制剂中的功效。大量非GLP、GLP 和GMP级的P8也将被合成和表征，用于当前的拟议工作和未来的研究。 IND使能毒理学和I期研究。