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

项目总结 2018年，美国有100多万人符合甲基苯丙胺(冰毒)使用障碍的资格， 冰毒使用率正在飙升，这在很大程度上是对阿片类药物流行的回应。冰毒使用障碍是一种慢性疾病 目前没有FDA批准的药物的情况。唯一可用的治疗方案是 行为矫正疗法，疗效有限，复发率高(60-60%)就是明证。 90%)。这论证了针对复发诱因的辅助药物疗法来支持禁欲。严谨 我们小组和其他人之前的研究已经证明，由药物使用提醒引发的复发 一种强大的动机影响，作为终身复发的风险因素，无论个人持续多久 弃权。肌球蛋白治疗公司目前正在开发MT-110，作为一种非刺激性、一流的靶向药物 分子马达非肌肉肌球蛋白II(NMII)。BLOBB是第一个NMII变构抑制剂 被发现并因等量抑制心肌肌球蛋白(CMII)而耐受性差。Mt- 110是一种泡泡类似物，具有更好的大脑暴露、效力和对CMII(&gt；100x)的选择性，大大 提高其治疗指数。MT-110目前正在进行IND启用研究，计划进入第一阶段SAD 接近2021年底。它正在被开发为一种支持戒酒的短期给药药物 通过打乱寻求冰毒的动机。此Fast-Track SBIR应用程序的主要目标是 与多个管理部门建立MT-110型S安全配置文件，预计它将使难治性疾病的受试者受益 单次给药治疗或因其他因素复发的患者。MT-110‘S药效的建立 使用多种药物和其他肥皂水的背景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剂量范围发现(DRF)研究以确定测试品的耐受性 (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 心电图的评估将在大鼠身上并行进行，以确保不会对心脏收缩能力产生影响， 与MT-110‘S对NMII的选择性比对CMII的选择性曲线的显著改善一致。里程碑驱动 向第二阶段赠款的过渡始于在大鼠中进行的IND-Enabling GLP安全药理学研究 确定潜在的毒性影响，确定毒性的目标器官，估计MTD和NOAEL，评估 TK，以及重复给药后任何不良反应的可逆性。对重复MT-的评估 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，毒代动力学和 以第二个物种的器官为靶标。而MT-110选择性的提高预计将减少影响 在心输出量方面，长期使用冰毒可能会导致心肌病。因此，我们将建立对 MT-110在冰毒诱导的大鼠心肌病的背景下。最后，MT-110的S药效将在 其他物质使用障碍的背景。MT-110阻断海洛因、可卡因或其他毒品寻找的能力 在迅速升级的多药使用流行中，冰毒使用者的尼古丁将增加治疗选择。

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.