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）发现了一种独特的治疗阿尔茨海默氏症的方法，NNI-362，它可以促进成人- 新生的神经元，以取代失去的神经元，同时防止退化。在NNI完成的 1a期试验，NNI-362证明了安全性和脑磷酸化Tau 181的显著降低。 目的是通过AD的II期试验随访Ph 1a， 目标是必要的。1)NNI需要进一步的GMP生产和2）液体-凝胶帽配方 NNI-362; 3）在M/F大鼠和犬中的长期（6个月）安全性;和4）定期IND更新 并与FDA开会讨论II期临床计划。这种独特的药物可能是 通过限制磷酸化Tau病理学和促进新神经元逆转 疾病在六个月内。 在第一个目标中，Onyx Scientific将从1 kg cGMP方法中放大NNI-362，用于 阶段1a，至完成阶段2-3所需的>5 kg cGMP。其次，NNI-362临床 然后将产品配制成120 mg/胶囊的液体-凝胶胶囊， 在老年受试者中显示出安全性和潜在有效性。Patheon制备了所用制剂 在阶段1a，并确定了实用性的液体凝胶帽与NNI-362。 第三，Charles River将完成为期6个月的犬和大鼠（M/F）GLP安全性试验， FDA要求在相同的6个月期间用于人类治疗。剂量将是 与10、50和150 mg/kg剂量组大鼠和犬中已完成的14天/14天洗脱期研究相同 15、45和210 mg/kg po/天。查尔斯·里弗在执行 FDA批准的GLP安全性研究。最后，监管承包商CCS Associates将提供 年度监管IND更新文件，并将要求FDA召开会议讨论2期 轻度至中度AD患者的临床试验计划。 随着几十年的AD药物失败，NNI使用人类神经细胞筛选发现了一个“神经元 生成和神经保护”药物。NNI-362的临床前研究表明， 衰老和疾病模型中的海马神经元，以及神经保护， 整合，扭转了行为缺陷。在健康老年受试者中进行的1a期研究证实 安全性，并表明NNI-362可显著降低AD进展标志物 在人类老年受试者中，在仅16天的治疗期后，磷酸化Tau 181。长期 在治疗AD患者时，NNI-362不仅有可能减缓AD的进展， 短期的，但促进新的神经元，以充分扭转疾病，长期的。

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.