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

项目摘要 Neuronascent(NNI)发现了一种治疗阿尔茨海默氏症的独特疗法，NNI-362，它可以促进成人- 出生的神经元，以取代丢失的神经元，同时防止退化。在NNI中已完成 1a期试验，NNI-362证明了安全性和显著降低了脑磷脂Tau181。 目的是在Ph1a之后在AD中进行第二阶段试验，以下4项具体 目标是必要的。1)NNI需要进一步的GMP制造和2)液体凝胶帽配方 NNI-362的安全性；3)M/F大鼠和狗的长期(6个月)安全性；4)定期IND更新 以及与FDA的会议，讨论第二阶段临床计划。这种独特的药物可能是 通过限制磷酸化Tau病理和促进新神经元逆转而有益于AD 在六个月的时间内患病。 在第一个目标中，玛瑙科学公司将把NNI-362从用于 阶段1a，至完成阶段2-3所需的5公斤cGMP。其次，NNI-362临床 然后将产品制成液体凝胶胶囊，每粒120毫克，已经 在老年受试者中显示出安全和潜在的有效。帕瑟恩准备了所用的配方 在1a阶段，用NNI-362测定了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(男/女)GLP安全测试，如 FDA要求在同样的6个月内对人类进行治疗。剂量将是 与在10、50和150 mg/kg的大鼠和狗中完成的14天/14天洗脱研究相同 每日剂量分别为15、45和210 mg/kg。查理斯·里弗在执行 FDA批准的GLP安全研究。最后，监管承包商CCS Associates将提供 每年更新监管IND文件，并将要求FDA召开会议讨论第二阶段 轻至中度AD患者的临床试验计划。 在数十年的AD药物失败后，NNI使用人类神经细胞筛查发现了一种 产生和保护神经的“药物”。NNI-362的临床前研究显示了新的 老化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 扭转了行为缺陷的整合。在健康的老年受试者中显示1a期 安全性，并表明NNI-362可显著降低AD进展标志物 磷酸盐Tau181在人类老年受试者仅治疗16天后。具有更长的期限 治疗AD患者，NNI-362不仅有可能减缓AD的进展 短期的，但促进新的神经元完全逆转疾病，长期。

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.