MT-125 for the Therapeutic Treatment of Glioblastoma

项目总结 一个重要的未得到满足的领域是胶质母细胞瘤(GBM)的治疗，这是一种侵袭性的、快速增长的 和致命性脑癌，占所有恶性脑瘤的48%。如果不治疗，GBM在三年内就会致命 由于其高复发率和侵袭性，目前的护理标准包括 安全的最大限度肿瘤切除、放射治疗和化疗，仅延长初次治疗后的生存时间 诊断时间为一年。侵袭和增殖，也被称为Go和Growth，是GBM的定义表型， 而基底膜细胞只做其中的一种。然而，阻止入侵会刺激增殖，反之亦然， 这意味着理想的治疗方法需要同时阻止GO和生长。广泛的遗传 干预措施表明，两个非肌肉肌球蛋白II(NMII)分子马达同时中断 (NMIIA和IIB)符合这些标准。然而，这项研究的翻译潜力受到了 缺乏临床上安全的、中枢神经系统穿透性的NMII小分子抑制剂。在广泛的药物化学之后 为了优化安全性和耐受性的选择性，确定了MT-125。MT-125是一款耐受性很好的双 小分子抑制剂NMIIA和IIB具有高度的脑外透性，需要有效的 GBM治疗。临床前体外和体内研究表明MT-125抑制GO和GH表型 并延长生存时间。由于其独特的作用模式，MT-125还可以与FDA批准的现有产品协同工作 治疗，提供了一条通往潜在根治疗法的道路。当前提案的首要目标是 是为MT-125做好准备，以便快速进入支持IND的研究。这将通过几项活动来实现。 第一阶段将集中于通过临床可行的体外给药途径来确认临床前的疗效。 MT-125与FDA批准的其他现有治疗之间的协同作用和体外安全性研究 MT-125的性能分析、配方前研究和批量放大演示。过渡到的量化里程碑 第二阶段在申请表中有详细说明。在第二阶段，将对最多的 在第一阶段确定的有希望的增效组合，以及非GLP给药安全性研究，GLP合成， 以及通过多晶型筛选开发的配方。商业化计划详细说明了GBM市场， 以及肌球蛋白治疗公司将MT-125快速推向临床的临床和调控策略。

PROJECT SUMMARY An area of significant unmet need is the treatment of glioblastoma (GBM), an aggressive, fast-growing and lethal brain cancer that represents 48% of all malignant brain tumors. Untreated, GBM is fatal within three months, and due to its high rate of recurrence and invasive nature, the current standard of care, consisting of safe maximal tumor resection, radiation therapy and chemotherapy, only extends survival following initial diagnosis to one year. Invasion and proliferation, also known as Go and Grow, are defining phenotypes of GBM, and GBM cells do only one or the other. However, blocking invasion stimulates proliferation and vice versa, implying that an ideal therapeutic needs to block both Go and Grow simultaneously. Extensive genetic interventions have shown that simultaneous disruption of two non-muscle myosin II (NMII) molecular motors (NMIIA and IIB) meet these criteria. However, the translational potential of this research has been limited by the lack of a clinically safe, CNS-penetrant NMII small molecule inhibitor. Following extensive medicinal chemistry efforts to optimize selectivity for safety and tolerability, MT-125 was identified. MT-125 is a well-tolerated, dual small molecule inhibitor of NMIIA and IIB with a high degree of brain penetrance, a requirement for an effective GBM therapeutic. Preclinical in vitro and in vivo studies show that MT-125 blocks the Go and Grow phenotypes and extends survival. Due to its unique mode of action, MT-125 also synergizes with existing FDA-approved treatments, presenting a path to a potentially curative treatment. The overarching goal of the current proposal is to ready MT-125 for rapid entry into IND-enabling studies. This will be achieved through several activities. Phase I will focus on confirmation of preclinical efficacy with a clinically viable route of administration, in vitro studies of synergy between MT-125 and additional existing FDA-approved treatments, and in vitro safety profiling, pre-formulation studies and demo batch scale-up of MT-125. Quantitative milestones for transition to Phase II are detailed in the application. In Phase II, in vivo efficacy testing will be performed on the most promising synergy combinations identified in Phase I, as well as a non-GLP dosing safety study, GLP synthesis, and formulations development with polymorph screening. The Commercialization Plan details the GBM market, as well as Myosin Therapeutics’ clinical and regulatory strategy for rapid advancement of MT-125 to the clinic.