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

项目摘要 2018年，美国有超过100万人被认定患有甲基苯丙胺（METH）使用障碍， 甲基苯丙胺的使用率正在飙升，主要是为了应对阿片类药物的流行。METH使用障碍是一种慢性 目前没有FDA批准的药物。唯一可用的治疗方案是 行为矫正疗法的疗效有限，复发率高（60- 90%）。这就需要一种针对复发触发因素的辅助药物治疗来支持禁欲。严格 我们小组和其他人先前的研究已经确定，由吸毒的提醒引发的复发， 一个强大的动机影响，作为一个终身复发的风险因素，无论多久，一个人 弃权。肌球蛋白治疗公司目前正在开发MT-110作为一种非兴奋剂，一流的药物靶向 分子马达非肌肉肌球蛋白II（NMII）。Blebbistatin（blebb）是第一个被发现的NMII变构抑制剂。 由于心肌肌球蛋白（CMII）的等效抑制，发现并患有不良耐受性。MT- 110是一种blebb类似物，具有改善的脑暴露、效力和对CMII的选择性（> 100倍）， 提高其治疗指数。MT-110目前正处于IND使能研究中，计划进入1期SAD 到2021年底。它正在开发作为一种短期管理药物，以支持禁欲 通过破坏寻找冰毒的动机。此快速通道SBIR应用程序的主要目标是 确定MT-110多次给药的安全性特征，因为预期它将使难治性受试者受益， 单次给药治疗或因其他因素复发者。确定MT-110在 多药使用和其他SUD的背景也将扩大其治疗价值。在赠款的第一阶段， 计划在大鼠中进行剂量非GLP剂量范围探索（DRF）研究，以确定供试品的耐受性 （MT-110），并确定潜在的剂量限制性毒性、毒代动力学和靶器官。心脏安全 在大鼠中平行进行心电图评估以确保对心脏收缩力没有影响， 这与MT-110对匪II的选择性概况相对于CMII的显著改善一致。里程碑驱动 过渡到II期的补助金开始与IND使GLP安全药理学研究的大鼠， 确定潜在毒性作用，确定毒性靶器官，估计MTD和NOAEL，评价 TK和重复给药后任何不良反应的可逆性。重复MT的评估- 在狗的非GLP DRF研究中的110给药将建立潜在的剂量限制性毒性、毒代动力学和 第二个物种的目标器官虽然MT-110的改进的选择性预计将减少影响， 在心输出量方面，长期使用METH可导致心肌病。因此，我们将确定 MT-110在大鼠中引起的心肌病的背景下。此外，在本行政补充文件中， 申请，我们寻求资金进行扩大的安全性和耐受性研究，因为他们无法预见 因为申请是在IND前会议之前提交和资助的。直接针对指导意见 收到肌球蛋白后，我们建议进行GLP和非GLP行为试验和棘密度分析。 重要的是，这些研究将有助于确保一个强大的IND包装和MT-110的持续势头， 诊所最后，MT-110的疗效将在其他物质使用障碍的情况下确定。的能力 的MT-110，以扰乱寻求海洛因，可卡因或尼古丁在METH用户将增加治疗选择， 一种快速升级的多种毒品使用流行病。

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.