MT-125 for the Therapeutic Treatment of Glioblastoma

项目摘要 一个显著未满足需求的领域是胶质母细胞瘤（GBM）的治疗，胶质母细胞瘤是一种侵袭性的、快速生长的肿瘤。 以及占所有恶性脑肿瘤48%的致命性脑癌。未经治疗，GBM在三年内是致命的 月，并且由于其高复发率和侵入性，目前的护理标准，包括 安全的最大肿瘤切除术，放射治疗和化疗，只延长生存后，最初的 诊断一年。侵袭和增殖，也称为Go和Grow，是GBM的定义表型， 而GBM细胞只做其中一种。然而，阻止入侵刺激增殖，反之亦然， 这意味着理想的治疗需要同时阻断Go和Grow。广泛的遗传 干预已经表明，两种非肌肉肌球蛋白II（NMII）分子马达同时被破坏 （NMIIA和IIB）符合这些标准。然而，这项研究的转化潜力受到了限制， 缺乏临床安全的CNS渗透性NMII小分子抑制剂。经过广泛的药物化学 为了优化安全性和耐受性的选择性，鉴定了MT-125。MT-125是一种耐受性良好的双重 NMIIA和IIB小分子抑制剂具有高度的脑转移，这是有效治疗的要求， GBM治疗。临床前体外和体内研究表明，MT-125阻断Go和Grow表型 延长生存时间由于其独特的作用方式，MT-125还与现有的FDA批准的 治疗，提供了一种潜在的治愈治疗的途径。本提案的总体目标 为MT-125快速进入IND研究做好准备。这将通过几项活动来实现。 I期将重点确认临床可行的体外给药途径的临床前疗效 MT-125与其他现有FDA批准治疗之间的协同作用和体外安全性研究 MT-125的特征分析、预配制研究和示范批次规模放大。过渡到 第二阶段在申请中有详细说明。在II期，将对大多数受试者进行体内疗效试验。 在I期研究中确定的有希望的协同作用组合，以及非GLP给药安全性研究，GLP合成， 以及通过多晶型筛选进行制剂开发。商业化计划详细介绍了GBM市场， 以及Myosin Therapeutics的临床和监管策略，以快速推进MT-125进入临床。

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.