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

应用程序标识符：364510 应用项目标题：先进的KNX100治疗阿片类药物戒断：临床前疗效和 毒理学，和一期临床计划。 项目摘要/摘要 Kinoxis Treateutics Pty Ltd是一家总部位于澳大利亚的公司，已从 悉尼大学，包括治疗药物使用障碍的几名候选人。我们有 开发了一种新的小分子铅KNX100，它在临床前动物中显示出巨大的前景 一系列物质使用障碍的模型，包括OUD的模型，具有特别令人印象深刻的效果 减轻小鼠阿片类药物戒断症状的严重程度。KNX100是从一种表型 以脑后叶催产素为靶点的基于片段的药物发现程序衍生化合物的筛选 系统。到目前为止，KNX100在测试中具有良好的药代动力学和安全性。迄今为止，KNX100已经 在两种啮齿动物和两种非人类灵长类动物身上进行了功效信号测试，并进行了测试 跨多个实验室，包括国家药物滥用研究所(NIDA)委托 NIDA药物开发计划下的实验室。 这一供资机会下的拟议活动是推进KNX100在阿片类药物使用方面的开发 精神障碍，具体指征是阿片类药物戒断的治疗。该项目的总体目标 是确定KNX100的安全性和耐受性，以便能够在患者身上开始进行人体疗效测试 需要对阿片类药物戒断进行治疗。这一发展计划长期目标是产生 人类疗效数据支持KNX100作为阿片类药物戒断症状的潜在治疗方法 最终向FDA提交新药申请。 该公司已经制定了一项研究计划，包括UG3阶段和UH3阶段。对于UG3 阶段，该公司计划完成FDA批准所需的所有必要的IND使能研究 在第一阶段临床研究中首次在MAN中使用KNX100。该计划包括对KNX100的额外测试 在阿片类药物戒断的动物模型中；扩大和生产药物物质和药物产品以 支持非临床和临床项目；毒理学项目生成数据以支持阶段 1项研究；以及向FDA提交调查性新药申请。 在成功完成UG3阶段之后，以FDA批准IND的里程碑来衡量 申请在没有临床持有的情况下开始一期研究，该公司随后将进入 UH3阶段通过完成第一阶段临床计划来建立KNX100的安全性和耐受性，当 在人类身上用药。 本NIH/NIDA资金机会公告(RFA-DA-19-002)的目的是 正在提交申请，是为了支持预防和治疗药物的发现和开发 阿片使用障碍(OUD)和过量。KNX100的开发提供了一个机会，可以提供 比目前唯一批准的阿片类药物戒断药物更有效和/或更安全的替代药物， 洛非西定，这一应用将加速朝着这一目标的发展。

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.