Development of TNX-1300 (Double Mutant Cocaine Esterase) for the Treatment of Life-Threatening Cocaine Intoxication

项目概要/摘要 在美国，可卡因的娱乐性使用仍然是一个重大的公共健康问题， 关心在2018年，估计有550万人通过娱乐方式自我管理可卡因， 吹入、吸入或注射。这些人中的许多人有可能死于急性 可卡因中毒，一种危及生命的心血管和神经系统疾病， 症状经历。目前的护理标准主要包括支持性急性 针对个别患者表现的具体症状进行护理。增速出现明显 未满足的医疗需求，没有药物治疗被批准用于治疗急性可卡因中毒 护理设置。开发治疗可卡因中毒的根本原因 (i.e.,循环可卡因及其活性代谢物），将使临床医生提供一个潜在的 在急诊护理环境中进行更快、更安全的干预。此外，通过直接去除有毒物质， 从体循环中清除有害物质，这样的治疗可以更有效， 全面解决可卡因中毒的多种医疗风险和后遗症。履行 为了满足这一未满足的需求，Tonix正在开发TNX-1300，一种突变的重组细菌可卡因酯酶 （CocE）已在一项2期临床实验室试验中显示， 在单次静脉给药的2分钟内，全身可卡因水平降低约90%。在这 U01应用程序，Tonix建议通过以下方式推进TNX-1300开发计划 具体目标：1.对出现以下症状的患者进行2期概念验证随机试验： 处于可卡因中毒状态的急诊科站点; 2.优化CMC生产， 用于2期和3期试验的GMP药物产品批次，包括冻干循环; 3.促进 完成监管里程碑，特别是准备和执行 与FDA的第2阶段会议;以及4.一个商业化计划， 开发、目标产品概况测试以及与医生、付款人和 患者，为未来3期的设计提供信息，3期将于2010年全面开发和设计 3这个节目。成功实现本提案中概述的里程碑将 将这种新型治疗方法推进到3期关键试验阶段 新药申请和上市批准所必需的。

PROJECT SUMMARY/ABSTRACT In the United States, recreational cocaine use continues to represent a significant public health concern. In 2018, an estimated 5.5 million people recreationally self-administered cocaine by insufflation, inhalation, or injection. Many of these individuals are at risk of succumbing to acute cocaine intoxication, a condition in which life-threatening cardiovascular and neurological symptoms are experienced. The current standard of care consists primarily of supportive acute care directed at the specific symptoms expressed by individual patients. Despite the significant unmet medical need, no pharmacotherapies are approved for treating cocaine toxicity in the acute care setting. The development of a treatment that addresses the root cause of cocaine intoxication (i.e., circulating cocaine and its active metabolites), would allow clinicians to provide a potentially faster and safer intervention in the acute care setting. Furthermore, by directly removing the toxic offending agent from the systemic circulation, such a treatment could more effectively and comprehensively address the multiple medical risks and sequelae of cocaine intoxication. To fulfill this unmet need, Tonix is developing TNX-1300, a mutant recombinant bacterial cocaine esterase (CocE) that has been shown in a pilot Phase 2 clinical laboratory study to metabolize and reduce by ~90% systemic cocaine levels within 2 minutes of a single intravenous administration. In this U01 application, Tonix proposes to advance the TNX-1300 development program via the following specific aims: 1. conduct a Phase 2 proof-of-concept randomized trial of patients presenting to emergency department sites in a state of cocaine intoxication; 2. optimize CMC production of a GMP drug product batch for use in Phase 2 and 3 trials, including a lyophilization cycle; 3. facilitate completion of regulatory milestones, in particular the preparation and execution of an End of Phase 2 meeting with FDA; and 4. a commercialization program with key opinion leader development, target product profile testing, and market research with physicians, payers and patients, to inform the design of a future Phase 3 that will be fully developed and designed in Year 3 of this program. Successfully achieving the milestones outlined in this proposal would substantially advance this novel treatment approach to the stage of Phase 3 pivotal testing requisite for the New Drug Application and marketing approval.