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

开发 TNX-1300（双突变可卡因酯酶）用于治疗危及生命的可卡因中毒

• 批准号: 10668212
• 负责人: GREGORY M SULLIVAN
• 金额: $ 201.92万
• 依托单位: TONIX PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10668212
• 关键词: Accident and Emergency department; Acute; Address; Applications Grants; Behavioral Symptoms; Biological Assay; Blood; Butyrylcholinesterase; Cardiovascular system; Circulation; Clinical; Clinical Research; Cocaine; Cocaine Abuse; Coupled; Development; Diagnosis; Dose; Emergency Care; Enzymes; Fermentation; Freeze Drying; Future; Goals; Health; Health care facility; Individual; Inhalation; Injections; Insufflation; Intervention; Intoxication; Investigational Drugs; Investigational New Drug Application; Laboratory Study; Life; Market Research; Marketing; Measures; Medical; Nature; Neurologic; Neurologic Symptoms; Outcome; Output; Patients; Persons; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacotherapy; Phase; Physicians; Plasma; Positioning Attribute; Preparation; Prevalence; Process; Production; Program Development; Public Health; Publications; Recombinants; Recreation; Risk; Running; Safety; Serious Adverse Event; Single-Blind Study; Site; Supportive care; Symptoms; Temperature; Testing; Therapeutic; Therapeutic Agents; Toxic effect; United States; United States Food and Drug Administration; acute care; associated symptom; cocaethylene; cocaine esterase; cocaine self-administration; cocaine use; commercialization; cost; design; efficacy evaluation; emergency settings; experience; first-in-human; healthy volunteer; human study; individual patient; innovation; insight; intravenous administration; intravenous injection; manufacturing process; meetings; mutant; norcocaine; novel; novel therapeutics; open label; phase 2 study; phase 3 study; programs; randomized trial; standard of care; thermostability

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.

项目摘要/摘要 在美国，娱乐性可卡因的使用继续代表着重大的公共健康 担忧。到2018年，估计有550万人娱乐性地自我管理可卡因 雾化、吸入或注射这些人中的许多人都有死于急性呼吸道疾病的危险 可卡因中毒，一种危及生命的心血管和神经疾病 症状是有经验的。目前的护理标准主要包括支持性急性护理 针对个别患者表现出的特定症状的护理。尽管重要的是 未得到满足的医疗需求，没有药物疗法被批准用于治疗急性 护理环境。解决可卡因中毒的根本原因的治疗方法的发展 (即循环中的可卡因及其活性代谢物)，将使临床医生能够提供潜在的 在急性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 来自体循环的有害物质，这样的治疗可以更有效和 综合治理可卡因中毒的多重医疗风险和后遗症。履行 这一未得到满足的需求，Tonix正在开发一种突变型重组细菌可卡因酯酶TNX-1300 (COCE)已在试验性第二阶段临床实验室研究中显示可代谢和减少 在一次静脉注射后2分钟内，全身可卡因水平降低了~90%。在这 U01申请，Tonix建议通过以下方式推进TNX-1300开发计划 具体目标：1.进行第二阶段概念验证随机试验 处于可卡因中毒状态的急诊科现场；2.优化CMC生产 GMP药品批次，用于第二阶段和第三阶段试验，包括冻干周期；3.促进 完成管理里程碑，特别是编制和执行结束 与FDA的第二阶段会议；以及4.与主要意见领袖的商业化计划 开发、目标产品配置文件测试以及与医生、付款人和 患者，告知未来第三阶段的设计，该阶段将在年内完全开发和设计 这一计划的3个。成功实现本提案中概述的里程碑将 将这一新的治疗方法大幅推进到第三阶段关键测试阶段 新药申请和上市审批所必需的。