Development of a first-in-class nonmuscle myosin II inhibitor to prevent substance use disorder relapse

开发一流的非肌肉肌球蛋白 II 抑制剂以预防药物滥用障碍复发

• 批准号: 10757807
• 负责人: Erica J Young
• 金额: $ 44.09万
• 依托单位: MYOSIN THERAPEUTICS INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10757807
• 关键词: Abstinence; Accidents; Address; Administrative Supplement; Adverse effects; Aftercare; Award; Behavior; Behavior Therapy; Biological Assay; Biology; Brain; Businesses; COVID-19 pandemic; Canis familiaris; Cardiac; Cardiac Myosins; Cardiac Output; Cardiomyopathies; Cause of Death; Chronic; Clinic; Clinical; Cocaine; Criminal Justice; Dangerousness; Development; Dose; Dose Limiting; Drug usage; Electrocardiogram; Ensure; Environment; Epidemic; FDA approved; Funding; Goals; Grant; Heroin; Hospital Costs; Individual; Inpatients; Laboratories; Left; Methamphetamine; Methamphetamine use disorder; Modality; Molecular Motors; Motivation; Myosin ATPase; Myosin Type II; Nicotine; No-Observed-Adverse-Effect Level; Opioid; Organ; Parents; Persons; Pharmaceutical Preparations; Pharmacology Study; Pharmacotherapy; Phase; Phase I Clinical Trials; Prisons; Process; Qualifying; Rattus; Refractory; Rehabilitation therapy; Relapse; Research; Risk Factors; Role; Running; Safety; Small Business Innovation Research Grant; Specialist; Substance Use Disorder; System; Technology; Testing; Therapeutic; Therapeutic Index; Toxic effect; Toxicokinetics; Treatment Cost; United States National Institutes of Health; Vertebral column; analog; blebbistatin; cost; cost estimate; density; design; drug development; economic impact; effective therapy; efficacy study; flexibility; improved; inhibitor; innovation; medication administration; methamphetamine use; methamphetamine user; molecular drug target; multiple drug use; non-muscle myosin; opioid epidemic; overdose death; phase 2 study; pre-Investigational New Drug meeting; preclinical efficacy; preclinical study; prevent; programs; relapse risk; response; safety assessment; safety study; small molecule inhibitor; substance use prevention

PROJECT SUMMARY In 2018, over 1 million people in the U.S. qualified as having a methamphetamine (METH) use disorder and rates of METH use are surging, largely in response to the opioid epidemic. METH use disorder is a chronic condition for which there are currently no FDA-approved medications. The only treatment options available are behavioral modification therapies, which have limited efficacy, as evidenced by the high rate of relapse (60- 90%). This argues for an adjunct pharmacotherapy targeting relapse triggers to support abstinence. Rigorous prior research from our group and others has established that relapse triggered by reminders of drug use bear a powerful motivational influence, serving as a lifelong relapse risk factor, regardless of how long an individual abstains. Myosin Therapeutics is currently developing MT-110 as a non-stimulant, first-in-class drug targeting the molecular motor nonmuscle myosin II (NMII). Blebbistatin (blebb) was the first NMII allosteric inhibitor to be discovered and suffers from poor tolerability due to equipotent inhibition of cardiac muscle myosin (CMII). MT- 110 is a blebb analog with improved brain exposure, potency, and selectivity for CMII (>100x) which greatly improves its therapeutic index. MT-110 is currently in IND-enabling studies with a plan to enter a Phase 1 SAD towards the end of 2021. It is being developed as a short-term administration medication to support abstinence through a disruption of the motivation to seek METH. A primary goal of this Fast-Track SBIR application is to establish MT-110’s safety profile with multiple administrations, as it is expected to benefit subjects refractory to single administration treatment or those that relapse due to another factor. Establishing MT-110’s efficacy in the context of polydrug use and other SUDs will also expand its therapeutic value. In Phase I of the grant, a repeat dose non-GLP dose range finding (DRF) study in rats is planned to determine the tolerability of the test article (MT-110) and to identify potential dose limiting toxicities, toxicokinetics and target organs. A cardiac safety assessment with electrocardiography will be run in parallel in rat to ensure no effects on cardiac contractility, consistent with the dramatic improvement in MT-110’s selectivity profile for NMII over CMII. Milestone driven transition to Phase II of the grant initiates with an IND-enabling GLP safety pharmacology study in rats to determine potential toxic effects, identify target organs of toxicity, estimate the MTD and NOAEL, evaluate the TK, and reversibility of any adverse effects following repeated dose administrations. Assessment of repeat MT- 110 dosing in a non-GLP DRF study in dogs will establish potential dose limiting toxicities, toxicokinetics and target organs in a second species. While the improved selectivity of MT-110 is expected to reduce the impact on cardiac output, chronic METH use can lead to cardiomyopathy. Therefore, we will establish the tolerability of MT-110 in the context of METH-induced cardiomyopathy in rats. Additionally, in this Administrative Supplement application, we seek funding to perform expanded safety and tolerability studies, as they could not be foreseen because the application was submitted and funded prior to the pre-IND meeting. To directly address the guidance Myosin received, we are proposing to perform GLP and non-GLP behavior assays and spine density analysis. Importantly, these studies will help to ensure a strong IND package and MT-110’s continued momentum to the clinic. Finally, MT-110’s efficacy will be determined in the context of other substance use disorders. The ability of MT-110 to disrupt seeking of heroin, cocaine or nicotine in METH users would increase treatment options in a rapidly escalating polydrug use epidemic.

项目摘要 2018年，美国有超过100万人有资格患有甲基苯丙胺（甲基苯丙胺）使用障碍和 甲基苯丙胺的使用率在很大程度上响应阿片类药物流行。甲基甲基化障碍是慢性 目前没有FDA批准的药物的状况。可用的唯一治疗选择是 效率有限的行为修饰疗法，这是由高救济率所证明的（60-- 90％）。这是针对继电器触发因素支持禁欲的辅助药物治疗的论点。严格的 我们小组和其他人的事先研究确定，该中继提醒毒品使用熊触发 强大的动机影响 戒烟。肌球蛋白疗法目前正在开发MT-1110作为一种非刺激，一流的药物靶向 分子运动非肌肉肌球蛋白II（NMII）。布利比斯汀（BLEBB）是第一个NMII变构抑制剂 由于对心肌肌球蛋白（CMII）的抑制作用而发现并遭受耐受性差。公吨- 110是一个BLEBB类似物，具有改善的脑暴露，效力和CMII（> 100x）的选择性 改善其治疗指数。 MT-1110目前正在进行一项计划，并计划进入第1阶段的SAD 截至2021年底。它正在作为短期管理药物开发以支持禁欲 通过破坏寻求甲基苯丙胺的动机。此快速轨道SBIR应用程序的主要目标是 建立MT-1110的安全性以及多个管理部门的安全性 单个给药治疗或因其他因素引起的继电器。建立MT-11的效率 Polydrug使用和其他SUD的上下文也将扩大其治疗价值。在赠款的第一阶段，重复 计划在大鼠中进行剂量非GLP剂量范围研究（DRF）研究以确定测试文章的耐受性 （MT-1110）并确定潜在的剂量限制毒性，毒性和靶器官。心脏安全 对心电图的评估将在大鼠中并行进行，以确保对心脏收缩性没有影响， 与CMII相对于MT-110的NMII选择性概况的显着提高。里程碑式驱动器 过渡到赠款的第二阶段启动，通过在大鼠的GLP安全药理学研究中启动 确定潜在的毒性作用，确定毒性目标器官，估计MTD和NOAEL，评估 TK，以及重复剂量管理后的任何不良反应的可逆性。评估重复MT- 110在狗的非GLP DRF研究中的剂量将建立潜在的剂量限制毒性，毒理学和 第二种物种中的目标器官。尽管MT-1110的选择性提高有望减少影响 在心输出量上，慢性甲基甲基苯丙胺的使用会导致心肌病。因此，我们将确定 MT-1110在大鼠甲基诱导的心肌病的背景下。此外，在此行政补充中 应用程序，我们寻求资金来进行扩展的安全性和耐受性研究，因为无法预见它们 因为该申请是在录取前会议之前提交和资助的。直接解决指导 肌球蛋白收到，我们提议执行GLP和非GLP行为分析和脊柱密度分析。 重要的是，这些研究将有助于确保强大的IND包和MT-11的持续势头 诊所。最后，MT-1110的效率将在其他物质使用障碍的背景下确定。能力 在MT-110中断寻求海洛因，可卡因或甲基苯丙胺用户中的尼古丁将增加治疗方案 快速升级的多毒使用流行病。