Completion of Non-clinical long-term GLP safety and GMP manufacture for first-in-class neuron regenerative therapy, NNI-362 Phase 2 POC AD trial

完成用于一流神经元再生治疗的非临床长期 GLP 安全性和 GMP 生产，NNI-362 2 期 POC AD 试验

• 批准号: 10710666
• 负责人: JUDITH A KELLEHER-ANDERSSON
• 金额: $ 210万
• 依托单位: NEURONASCENT, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10710666
• 关键词: Acute; Adult; Aging; Alzheimer' s Disease; Alzheimer' s disease patient; Alzheimer' s disease therapy; Animals; Behavioral; Brain; Canis familiaris; Chronic; Clinical; Cognitive; Contractor; Cyclic GMP; Disease; Disease model; Doctor of Philosophy; Dose; Drug Compounding; Drug Kinetics; Encapsulated; Ensure; FDA approved; Failure; Fasting; Female; Food; Formulation; Gel; Generations; Goals; Grant; Hippocampus; Human; Impaired cognition; Intervention; Kilogram; Length; Lipids; Liquid substance; Measures; Methods; Neurologist; Neurons; Neuroprotective Agents; Oral; Pathology; Patients; Pharmaceutical Preparations; Phase; Phase II Clinical Trials; Placebos; Plasma; Preparation; Rattus; Reporting; Ribosomal Protein S6 Kinase; Safety; Site; Testing; Time; Toxic effect; Toxicokinetics; Translations; Update; Work; aged; aging population; animal safety; aqueous; arm; capsule; clinical development; experience; follow-up; male; manufacture; meetings; neuron regeneration; neuroprotection; patient population; patient stratification; phase II trial; placebo controlled trial; preclinical study; primary endpoint; progression marker; regenerative therapy; safety study; safety testing; scale up; treatment duration; trial planning

Project Summary Neuronascent (NNI) discovered a unique therapy for Alzheimer’s, NNI-362, that promotes adult- born neurons to replace lost neurons, while protecting from degeneration. In NNI’s completed Phase1a trial, NNI-362 demonstrated safety and significant reduction of brain phosphoTau181. The aim is to follow up the Ph1a with a Phase 2 trial in AD, for which the following 4 specific aims are necessary. 1) NNI requires further GMP manufacture and 2) liquid-gel cap formulation of NNI-362; 3) the long-term (6-months) safety in M/F rats and dogs; and 4) regular IND updates and a meeting with FDA to discuss the Phase 2 clinical plan. This unique drug could be beneficial for AD by limiting phosphoTau pathology and promoting new neurons to reverse disease over a six-month period. In the first aim, Onyx Scientific will scale-up NNI-362 from the 1 kg cGMP method used for Phase 1a, to the >5 kg cGMP required for completion of Phase 2-3. Secondly, NNI-362 clinical product will then be formulated into a liquid-gel capsule prepared at 120 mg/capsule, already shown safe and potentially efficacious in aged subjects. Patheon prepared the formulation used in Phase1a, and determined the practicality of the liquid-gel cap with NNI-362. Thirdly, Charles River will complete a dog and rat (M/F) GLP safety testing for 6-months, as required by FDA for treatment of humans for the same 6-month period. The doses will be the same as the completed 14day/14day washout study in rats at 10, 50 and 150 mg/kg and in dogs at 15, 45 and 210 mg/kg po daily. Charles River has considerable experience in carrying out FDA-approved GLP safety studies. Lastly, regulatory contractors CCS Associates will provide yearly regulatory IND-update filings and will request a FDA meeting to discuss the Phase 2 clinical trial plan for mild to moderate AD patients. With decades of AD drug failures, NNI used human neural cell screen to discover a “neuron generating and neuroprotective” drug. Pre-clinical studies of NNI-362 demonstrated new hippocampal neurons in aging and disease models, and neuroprotection to allow new neuron integration that reversed behavioral deficits. Phase 1a in healthy aged subjects demonstrated safety and indicated that NNI-362, provided significant reduction of AD-progression marker phosphoTau181 after only 16 days of treatment period in human aged subjects. With longer term treatment of AD patients, NNI-362 has the potential to not only slow progression of AD over the short-term, but promote new neurons to fully reverse disease, long-term.

项目概要 Neuronascent (NNI) 发现了一种治疗阿尔茨海默病的独特疗法 NNI-362，可促进成人 新生的神经元取代丢失的神经元，同时防止神经元退化。 1a 期试验，NNI-362 证明了安全性并显着降低了脑磷酸化 Tau181。 目的是通过 AD 2 期试验来跟进 1a 期临床试验，其中以下 4 个具体项目 1) NNI 需要进一步的 GMP 生产和 2) 液体凝胶帽配方。 NNI-362 的长期（6 个月）安全性；以及 4）定期 IND 更新； 并与 FDA 召开会议，讨论这种独特药物的 2 期临床计划。 通过限制 phosphTau 病理并促进新神经元逆转，对 AD 有益 疾病超过六个月。 在第一个目标中，Onyx Scientific 将从用于 NNI-362 的 1 kg cGMP 方法中扩大规模 1a 期，达到完成 2-3 期所需的 >5 kg cGMP 其次，NNI-362 临床。 然后将产品配制成 120 毫克/胶囊的液体凝胶胶囊，已 Patheon 制备的配方已被证明对老年受试者安全且可能有效。 在 Phase1a 中，并确定了 NNI-362 液体凝胶帽的实用性。 第三，Charles River将完成为期6个月的狗和老鼠（M/F）GLP安全测试，因为 FDA 要求在相同的 6 个月期间进行人类治疗的剂量将是。 与在 10、50 和 150 mg/kg 剂量的大鼠以及狗中完成的 14 天/14 天清除研究相同 Charles River 在每天口服 15、45 和 210 mg/kg 方面拥有丰富的经验。 最后，监管承包商 CCS Associates 将提供 FDA 批准的 GLP 安全研究。 年度监管 IND 更新备案，并将要求 FDA 召开会议讨论第二阶段 轻度至中度 AD 患者的临床试验计划。 随着数十年 AD 药物的失败，NNI 利用人类神经细胞筛选发现了“神经元” NNI-362的临床前研究证明了新的“生成和神经保护”药物。 衰老和疾病模型中的海马神经元，以及允许新神经元的神经保护 逆转健康老年受试者行为缺陷的整合。 安全性并表明 NNI-362 显着降低了 AD 进展标志物 在人类老年受试者中仅治疗 16 天后，磷酸化 Tau181 的效果就更长。 对于 AD 患者的治疗，NNI-362 不仅有可能减缓 AD 的进展 短期，但长期促进新神经元完全逆转疾病。