Preclinical evaluation of an otoprotectant TT002

耳保护剂 TT002 的临床前评估

基本信息

批准号：
10671525
负责人：
Yunlong Huang
金额：
$ 56.58万
依托单位：
TING THERAPEUTICS LLC
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10671525
关键词：
Adult Aftercare Animal Model Animals Anthelmintics Antineoplastic Agents Antioxidants Attenuated Audiology Auditory Auditory Brainstem Responses Authorization documentation Benchmarking Blood Cancer Patient Cancer cell line Cavia Cell Line Cestoda Chemicals Cisplatin Clinical Clinical Treatment Clinical Trials Cochlea Contracts Data Detection Dose Drug Interactions Drug Kinetics Drug Screening Drug usage FDA approved FVB Mouse Food and Drug Administration Drug Approval Freedom Future Germany Glutathione Metabolism Pathway Goals Hair Cells Hearing Protection Human Immunohistochemistry In Vitro International Investigational Drugs Investments Knowledge Labyrinth Legal patent Liquid Chromatography Malignant Neoplasms Malignant neoplasm of testis Measures Morphology Mus New Drug Approvals Observational Study Oral Administration Outcome Patients Performance Perilymph Pharmaceutical Preparations Pharmacodynamics Pharmacologic Substance Phase Procedures Protocols documentation Publishing Quality of life Regimen Research Contracts Rights Rodent Model Safety Small Business Innovation Research Grant Sodium Chloride Testing Therapeutic Therapeutic Index Time Toxic effect Toxicology Treaty United States Food and Drug Administration Western Blotting Work Xenograft Model Zebrafish anticancer activity authority chemotherapy cisplatin induced hearing loss commercial application commercialization design drug testing efficacy study experimental study good laboratory practice guinea pig model healthy volunteer hearing impairment hearing preservation in silico in vitro activity in vivo intraperitoneal manufacture mouse model neoplastic cell novel therapeutics otoacoustic emission otoprotectant ototoxicity pharmacokinetics and pharmacodynamics pharmacologic phase 1 study preclinical development preclinical evaluation preclinical study preclinical trial prevent prevent hearing loss research clinical testing safety and feasibility sodium thiosulfate technological innovation tumor tumor xenograft virtual vitamin metabolism webinar

项目摘要

Project Summary Ting Therapeutics LLC is a pharmaceutical company developing drugs to prevent and treat hearing loss. Cisplatin is one of the most widely used drugs to treat cancers. However, cisplatin therapy causes hearing loss in 40-60% of the patients. To date, no drugs have been approved by the Food and Drug Administration for protection from cisplatin-induced hearing loss (CIHL). Most candidate compounds currently in pre-clinical and clinical trials are related to antioxidants, vitamins, and glutathione metabolism, many of which, such as sodium thiosulfate, interfere with cisplatin’s ability to kill the tumor cells. We have performed unbiased in silico virtual screens for otoprotectants against CIHL and identified 20 FDA-approved drugs including TT002, known as niclosamide, an anthelmintic (gut worm) drug used in humans world-wide for nearly four decades. In vitro: TT002 showed a comparable level of protection against cisplatin damage in a cochlear cell line to kenpaullone, with an IC50 of 0.17 μM, substantially (>10X) lower and better than four other benchmark otoprotectants. Moreover, TT002 did not interfere with cisplatin anti-cancer activity in vitro. In vivo: TT002 attenuates hearing loss in adult mice treated with cisplatin (30 mg/kg once) when delivered intraperitoneally (IP) at 10 mg/kg/day for 4 consecutive days. Interestingly, TT002 also protects against NIHL (100 dB SPL 8-16 kHz for 2 hrs) in adult FVB mice when delivered IP at 10 mg/kg/day for 4 consecutive days. In this SBIR Phase II, we will perform Investigational New Drug-enabling experiments to test TT002’s effect on cisplatin’s tumor killing efficacy in vivo and to conduct efficacy studies to define an optimal dosing regimen and therapeutic index. The long-term goal is for TT002 to become a standard otoprotective drug of cisplatin-based therapies. For this purpose, we will demonstrate TT002’s efficacy in a mouse model of cisplatin ototoxicity that mimics the administration protocol in cancer patients (Aim 1). We will determine pharmacokinetics and pharmacodynamics profiles in blood and perilymph, as well as efficacy, in a guinea pig model for cisplatin-induced hearing loss (Aim 2). This Aim will be performed under contract with an independent and reputable Contract Research Organization, Turner Scientific LLC. Finally, we will test drug-drug interactions in vitro and we will verify, in vivo, that TT002 does not interfere with cisplatin’s anti-cancer activity in mouse model xenografts (Aim 3). By successfully completing these studies, Ting Therapeutics will obtain critical data necessary for the initiation of Investigational New Drug enabling complaint preclinical studies and subsequent clinical trials. Ting Therapeutics has filed a Patent Cooperation Treaty (PCT) for both the US and international rights. The completion of this proposal will allow Ting Therapeutics to initiate conversations with pharmaceutical companies and venture investments for the commercialization of TT002.

项目摘要 Ting Therapeutics LLC是一家制药公司，开发用于预防和治疗听力损失的药物。顺铂是治疗癌症最广泛使用的药物之一。但是，顺铂治疗会导致听力损失在40-60％的患者中。迄今为止，尚未获得食品药品监督管理局的批准防止顺铂诱导的听力损失（CIHL）。目前在临床前的大多数候选化合物临床试验与抗氧化剂，维生素和谷胱甘肽代谢有关，其中许多（例如钠）硫代硫酸盐，干扰顺铂杀死肿瘤细胞的能力。我们在硅虚拟中表演了公正针对CIHL的耳触蛋白的筛选，并确定了20种FDA批准的药物，包括TT002（称为TT002）烟酰胺，一种驱虫（肠蠕虫）药物，在全球范围内使用了近四十年。体外：TT002 在对肯帕隆的耳蜗细胞系中显示出对顺铂损伤的可比保护水平， IC50的0.17μm，大大低（> 10倍），比其他四种基准治疗剂高。而且， TT002在体外不会干扰顺铂抗癌活性。体内：TT002减轻了成人的听力损失腹膜内（IP）以10 mg/kg/天的腹膜内治疗的小鼠（30 mg/kg一次），4 连续几天。有趣的是，TT002还可以在成人FVB中预防NIHL（100 dB SPL 8-16 kHz 2小时）当小鼠以10 mg/kg/天的IP连续4天交付IP时。在SBIR II期中，我们将执行研究新药的实验，以测试TT002对顺铂的肿瘤杀死效果的影响并进行效率研究以定义最佳的给药方案和治疗指数。长期目标是为了使TT002成为基于顺铂的疗法的标准耳效药物。为此，我们将演示TT002的效率在鼠标的鼠标模型中，该模型模仿了管理方案癌症患者（目标1）。我们将确定血液中的药代动力学和药效学特征在豚鼠模型中，以顺铂诱导的听力损失（AIM 2）中，围绕perilymph以及有效。这个目标将是与独立且信誉良好的合同研究组织Turner Scientific合同合同 LLC。最后，我们将在体外测试药物相互作用，并在体内验证TT002不相互作用在小鼠模型Xenographichics中，顺铂的抗癌活性（AIM 3）。通过成功完成这些研究， Ting Therapeutics将获得有关调查新药物的主动性所必需的关键数据投诉临床前研究和随后的临床试验。 Ting Therapeutics已提交专利合作美国和国际权利的条约（PCT）。该提案的完成将允许治疗学与制药公司进行对话，并进行风险投资以商业化 TT002。