Long-term toxicology studies for Posiphen; 6 month in rats and 9 months in dogs

Posiphen 的长期毒理学研究；

• 批准号: 10018610
• 负责人: Maria Maccecchini
• 金额: $ 97.54万
• 依托单位: ANNOVIS BIO, INC.
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10018610
• 关键词: Age; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Animals; Applications Grants; Axonal Transport; Behavior monitoring; Blood - brain barrier anatomy; Brain; Canis familiaris; Cerebrospinal Fluid; Clinical; Clinical Pathology; Clinical Research; Cognitive; Data; Disease; Dose; Drug Kinetics; Drug Targeting; Drug usage; Formulation; Gelatin; Human; Impairment; Incidence; Inflammation; Inflammatory; Kinetics; Laboratories; Lead; Learning; Length; Memory; Molecular Weight; Mus; Nerve Degeneration; Neurons; Neurotransmitters; Oral; Organ; Parkinson Disease; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phase; Preparation; Property; Proteins; Quality of life; Rattus; Recovery; Reporting; Research; Rivers; Safety; Stable Isotope Labeling; Tartrates; Testing; Therapeutic; Toxic effect; Toxicokinetics; Toxicology; Transgenic Mice; Translations; Traumatic Brain Injury; aging population; albino rat; alpha synuclein; capsule; cell motility; efficacy study; improved; inhibitor/antagonist; mild cognitive impairment; mouse model; neuron loss; neurotoxic; neurotrophic factor; novel; pre-clinical; preservation; prevent; release factor; safety study; sex; small molecule; tau Proteins

PAR 18-820 Summary Long term toxicology studies for Posiphen®; 6 months in rats and 9 months in dogs Posiphen tartrate is a small molecule of 487.5 molecular weight, with a Log P of 2.22 resulting oral availability and high blood-brain barrier penetrability. It is a translational inhibitor of neurotoxic proteins, APP, tau and α-synuclein. By inhibiting these proteins, posiphen normalizes axonal transport, lowers inflammation and protects nerve cells from dying. This novel mechanism promises stop or slow the course of neurodegeneration and to give people with cognitive difficulties the possibility of living a healthy and independent live way into old age. In order to study this drug in Alzheimer’s and/or Parkinson’s patients we need long term tox studies in animals. We propose to conduct two animal toxicology studies: a 6 month rat study with 1 month recovery and a 9 month dog study with 1 month recovery. During the study the animals will be monitored for behavior and safety and after the study the organs and the brain will be evaluated for toxicological findings. We have already progressed posiphen through 3 human phase I safety studies and ADCS started a pharmacodynamic SILK phase IIa study in mild to moderate AD patients in summer of 2016. The data from the phase IIa together with the data from the proposed animal tox studies will allow us to enter posiphen into a 2 to 3 year pivotal phase II/III study in AD patients to show efficacy. The Alzheimer’s field has been dominated by approaches that prevent the processing to Aβ or remove Aβ in one of its many forms. Posiphen prevents the synthesis of APP and hence of Aβ. Accordingly the Parkinson’s field uses similar approaches to inhibit levels of α-synuclein or LRRK. Again posiphen prevents the synthesis of α-synuclein. By normalizing the levels APP/Aβ, tau/phopho-tau and α- synuclein posiphen prevents the formation of toxic products and prevents death of nerve cells. 1

PAR 18-820 总结 Posiphen®的长期毒理学研究;大鼠6个月和犬9个月 Posiphen酒石酸盐是一种分子量为487.5的小分子，Log P为2.22，导致口服 有效性和高血脑屏障穿透性。它是神经毒性蛋白的翻译抑制剂， APP、tau和α-突触核蛋白。通过抑制这些蛋白质，posiphen使轴突运输正常化， 炎症和保护神经细胞免于死亡。这种新颖的机制有望阻止或减缓 神经退行性疾病的过程，并给有认知困难的人生活的可能性， 健康和独立地生活到老年。 为了研究这种药物在阿尔茨海默氏症和/或帕金森氏症患者，我们需要长期的毒理学研究， 动物我们建议进行两项动物毒理学研究：一项为期6个月的大鼠研究， 恢复期和9个月犬研究（含1个月恢复期）。在研究期间，动物将 监测行为和安全性，并在研究后对器官和大脑进行评估， 毒理学发现。 我们已经通过3项人体I期安全性研究进展了posiphen，ADCS开始了 2016年夏季在轻度至中度AD患者中进行的药效学SILK IIa期研究。 IIa期研究的数据以及拟定的动物毒性研究的数据将使我们能够 将posiphen用于AD患者的2 - 3年关键II/III期研究，以显示其疗效。 阿尔茨海默病领域一直以阻止Aβ加工或去除Aβ的方法为主 Aβ的多种形式之一。Posiphen阻止APP的合成，从而阻止Aβ的合成。相应地 帕金森病领域使用类似的方法来抑制α-突触核蛋白或LRRK的水平。再次posiphen 阻止α-突触核蛋白的合成。通过标准化APP/Aβ、tau/磷酸化tau和α- 突触核蛋白posiphen防止有毒产物的形成并防止神经细胞的死亡。 1