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

基本信息

批准号：
10682482
负责人：
Erica J Young
金额：
$ 120.83万
依托单位：
MYOSIN THERAPEUTICS INC.
依托单位国家：
美国
项目类别：
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/10682482
关键词：
Abstinence Accidents Address Adverse effects Aftercare Behavior Therapy Biology Brain Businesses COVID-19 pandemic Canis familiaris Cardiac Cardiac Myosins Cardiac Output Cardiomyopathies Cardiovascular system Cause of Death Chronic Clinical Cocaine Criminal Justice Dangerousness Data Development Dose Dose Limiting Drug usage Echocardiography Electrocardiogram Ensure Environment Epidemic FDA approved Formulation Funding Goals Grant Heroin Hospital Costs Impairment Individual Infusion procedures Inpatients Laboratories Methamphetamine Methamphetamine use disorder Modality Modeling Molecular Motors Motivation Myosin ATPase Myosin Type II Nicotine No-Observed-Adverse-Effect Level Opioid Organ Outcome Persons Pharmaceutical Preparations Pharmacologic Substance Pharmacology Pharmacology Study Pharmacotherapy Phase Plasma Positioning Attribute Prisons Process Qualifying Rattus Refractory Rehabilitation therapy Relapse Research Risk Factors Rodent 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 Work analog blebbistatin cost cost estimate design drug development drug of abuse economic impact effective therapy efficacy study efficacy testing 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-clinical preclinical efficacy preclinical study prevent programs relapse risk response safety assessment small molecule inhibitor substance use prevention

项目摘要

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. 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.

项目概要 2018 年，美国有超过 100 万人患有甲基苯丙胺 (METH) 使用障碍，并且冰毒的使用率正在飙升，主要是为了应对阿片类药物的流行。冰毒使用障碍是一种慢性病目前尚无 FDA 批准的药物可治疗该病症。唯一可用的治疗选择是行为矫正疗法的疗效有限，高复发率就证明了这一点（60- 90%）。这主张采用针对复发触发因素的辅助药物疗法来支持戒酒。严格的我们小组和其他人的先前研究已经证实，吸毒提醒会引发复发强大的动机影响力，作为终生复发的风险因素，无论个体持续多久弃权。 Myosin Therapeutics 目前正在开发 MT-110 作为一种非刺激性、一流的靶向药物分子运动非肌肉肌球蛋白 II (NMII)。布雷他汀 (blebb) 是第一个上市的 NMII 变构抑制剂由于心肌肌球蛋白 (CMII) 的等价抑制，发现并遭受较差的耐受性。公吨- 110 是一种 blebb 类似物，具有改善的大脑暴露、效力和 CMII 选择性 (>100x)，这大大提高了提高其治疗指数。 MT-110目前正在进行 IND 支持研究，计划进入 1 期 SAD 到 2021 年底。它正在被开发为一种短期给药药物，以支持戒酒通过破坏寻求冰毒的动机。此快速通道 SBIR 应用程序的主要目标是通过多次给药建立 MT-110 的安全性，因为它有望使难治性受试者受益单次给药治疗或因其他因素而复发的治疗。确定 MT-110 的功效多种药物的使用和其他 SUD 的背景也将扩大其治疗价值。在资助的第一阶段，重复计划在大鼠中进行非 GLP 剂量范围发现 (DRF) 研究以确定受试物的耐受性 (MT-110) 并确定潜在的剂量限制毒性、毒代动力学和靶器官。心脏安全心电图评估将在大鼠中并行进行，以确保对心肌收缩力没有影响，这与 MT-110 对 NMII 的选择性相对于 CMII 的显着改进是一致的。里程碑驱动过渡到第二阶段的资助始于在大鼠中开展一项支持 IND 的 GLP 安全药理学研究，以确定潜在的毒性作用，确定毒性靶器官，估计 MTD 和 NOAEL，评估 TK 以及重复剂量给药后任何不良反应的可逆性。重复 MT 的评估 110 在狗身上进行的非 GLP DRF 研究中的剂量将确定潜在的剂量限制毒性、毒代动力学和第二个物种的目标器官。虽然 MT-110 改进的选择性有望减少影响对心输出量的影响，长期使用冰毒可导致心肌病。因此，我们将建立耐受性 MT-110 在 METH 诱导的大鼠心肌病中的作用。最后，MT-110的功效将在以下时间确定：其他物质使用障碍的背景。 MT-110 能够阻止海洛因、可卡因或冰毒使用者中的尼古丁将在迅速升级的多种药物使用流行病中增加治疗选择。