Advancing KNX100 for the treatment of opioid withdrawal: preclinical efficacy and toxicology, and a phase 1 clinical program.

推进 KNX100 用于治疗阿片类药物戒断：临床前疗效和毒理学，以及 1 期临床计划。

• 批准号: 10571111
• 负责人: Hugh William Alsop
• 金额: $ 214.91万
• 依托单位: KINOXIS THERAPEUTICS PTY LTD
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-30 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10571111
• 关键词: Acceleration; Address; Ames Assay; Animal Model; Brain; Canis familiaris; Certification; Cessation of life; Clinical; Clinical Research; Clinical Trials; Data; Development; Dosage Forms; Dose; Drug Kinetics; Firearms; Formulation; Funding Opportunities; Human; In Vitro; Intellectual Property; Investigation; Investigational New Drug Application; Laboratories; Lead; Licensing; Measures; Micronucleus Tests; Modeling; Mus; National Institute of Drug Abuse; Opiate Addiction; Oral; Outcome; Overdose; Oxytocin; Patients; Pharmaceutical Preparations; Pharmacology; Phase; Phase I Clinical Trials; Phenotype; Phototoxicity; Production; Program Development; Public Health; Rattus; Rehabilitation therapy; Research; Rodent; Rodent Model; Safety; Severities; Signal Transduction; Substance Use Disorder; System; Testing; Therapeutic; Toxic effect; Toxicology; United States National Institutes of Health; Universities; Vehicle crash; Withdrawal; Withdrawal Symptom; acute symptom; animal efficacy; clinical development; comparative; dosage; drug discovery; drug synthesis; efficacy testing; first-in-human; genotoxicity; human subject; in vivo; lead candidate; lofexidine; malignant breast neoplasm; manufacture; nonhuman primate; novel; novel therapeutics; opioid use disorder; opioid withdrawal; pharmacologic; phase 1 study; pre-Investigational New Drug meeting; pre-clinical; preclinical efficacy; prevent; product development; programs; reduce symptoms; safety assessment; safety study; scale up; small molecule; substance use treatment

Application Identifier: 364510 Application Project Title: Advancing KNX100 for the treatment of opioid withdrawal: preclinical efficacy and toxicology, and a phase 1 clinical program. Project Summary/Abstract Kinoxis Therapeutics Pty Ltd is an Australian based company that has licensed intellectual property from the University of Sydney, including several candidates for the treatment of substance use disorders. We have developed a novel small molecule lead, KNX100, which is showing considerable promise in preclinical animal models of a range of substance use disorders, including models of OUD, with particularly impressive efficacy at reducing the severity of opioid withdrawal symptoms in mice. KNX100 was discovered from a phenotypic screen of compounds derived from a fragment-based drug discovery program targeting the brain oxytocin system. KNX100 has a favorable pharmacokinetic and safety profile in testing thus far. To date, KNX100 has undergone testing for efficacy signals in two rodent and two non-human primate species, with testing taking place across multiple laboratories including National Institute on Drug Abuse (NIDA) commissioned laboratories under the NIDA Medications Development Program. The proposed activity under this funding opportunity is to progress the development of KNX100 in opioid use disorder, with the specific indication being treatment of opioid withdrawal. The overall objective of the project is to establish the safety and tolerability of KNX100 to enable human efficacy testing to commence in patients requiring treatment for opioid withdrawal. The long-term objective for this development program is to generate human efficacy data to support KNX100 as a potential treatment for opioid withdrawal symptoms and ultimately enable a New Drug Application to the FDA. The company has developed a research plan which entails both a UG3 Phase and a UH3 Phase. For the UG3 Phase, the company plans to complete all the necessary IND enabling studies required for FDA approval to administer KNX100 in a first in man, Phase 1 clinical study. The program includes additional testing of KNX100 in animal models of opioid withdrawal; scale up and manufacture of drug substance and drug product to support both the non-clinical and clinical programs; a toxicology program to generate data to support the Phase 1 study; and the submission of an Investigational New Drug Application to the FDA. Following the successful completion of the UG3 Phase, measured by the milestone of FDA Clearance of an IND Application to a Commence a Phase 1 Study without a clinical hold, the company would then progress into the UH3 Phase by completing a Phase 1 clinical program to establish the safety and tolerability of KNX100 when dosed in humans. The purpose of this NIH/NIDA Funding Opportunity Announcement (RFA-DA-19-002), for which this application is being submitted, is to support the discovery and development of medications to prevent and treat opioid use disorders (OUD) and overdose. The development of KNX100 offers an opportunity to provide a more efficacious and/or safer alternative to the current only approved medication for opioid withdrawal, lofexidine, and this application will accelerate the development toward this objective.

应用程序标识符：364510 申报项目名称：Advancing KNX 100治疗阿片类戒断：临床前疗效和 毒理学和1期临床项目。 项目总结/摘要 Kinoxis Therapeutics Pty Ltd是一家总部位于澳大利亚的公司， 悉尼大学，包括几个候选人的物质使用障碍的治疗。我们有 开发了一种新的小分子铅，KNX 100，它在临床前动物中显示出相当大的前景 一系列物质使用障碍的模型，包括OUD模型，具有特别令人印象深刻的疗效 减轻小鼠阿片类药物戒断症状的严重程度。KNX 100是从一种表型 筛选来自以脑催产素为靶点的基于片段的药物发现计划的化合物 系统迄今为止，KNX 100在测试中具有良好的药代动力学和安全性特征。到目前为止，KNX 100已经 在两种啮齿动物和两种非人灵长类动物种属中进行了有效性信号检测， 包括国家药物滥用研究所（NIDA）在内的多个实验室 NIDA药物开发计划下的实验室。 本次资助机会下的拟议活动是推进KNX 100在阿片类药物使用中的开发 疾病，具体适应症是阿片类药物戒断治疗。该项目的总体目标 确定KNX 100的安全性和耐受性，以便在患者中开始人体疗效试验 需要阿片类药物戒断治疗该开发计划的长期目标是 支持KNX 100作为阿片类戒断症状潜在治疗的人体疗效数据， 最终向FDA提交新药申请。 该公司已经制定了一项研究计划，其中包括UG 3阶段和UH 3阶段。关于UG 3 在此阶段，该公司计划完成FDA批准所需的所有必要IND支持研究， 在第一次人体I期临床研究中给予KNX 100。该计划包括KNX 100的额外测试 在阿片类药物戒断的动物模型中;原料药和制剂的规模扩大和生产， 支持非临床和临床项目;生成数据以支持阶段的毒理学项目 1项研究;以及向FDA提交研究性新药申请。 成功完成UG 3阶段后，通过IND的FDA批准里程碑进行衡量 申请开始1期研究而不进行临床暂停，然后公司将进入 UH 3期：完成1期临床项目，以确定KNX 100的安全性和耐受性， 在人体内服用 本NIH/NIDA资助机会公告（RFA-DA-19-002）的目的， 申请正在提交，是为了支持药物的发现和开发，以预防和治疗 阿片类药物使用障碍（OUD）和过量。KNX 100的开发提供了一个机会， 更有效和/或更安全的替代目前唯一批准的阿片类戒断药物， 洛非西定，该应用将加速朝着这一目标的发展。