Evaluation of the safety and efficacy of non-invasive sonodynamic therapy for diffuse intrinsic pontine glioma

项目总结 弥漫性桥脑胶质瘤(DIPG)是一种少见且致命的儿童脑肿瘤。他们是非常 在脑桥发现的侵袭性肿瘤，它控制着身体的许多最重要的功能，如 呼吸、血压和心率。目前还没有有效的治疗DIPG的方法， 中位生存期为确诊后7~11个月。因此，非常需要一种有效治疗的方法 DIPG。为了解决这一未得到满足的需求，SonALAsense正在开发声动力疗法(SDT)，一种非侵入性的 药物-装置结合，治疗DIPG。SDT使用MRI引导的聚焦超声(MRgFUS)设备 与一种名为5-氨基乙酰丙酸(ALA)的药物联合使用。三个独立的实验室已经证明 ALA-SDT在动物脑胶质瘤模型中的安全性和有效性 然后在不会提高大脑温度的能量下进行MRgFUS治疗。MRgFUS活化的原卟啉 丙氨酸的代谢产物IX(PpIX)产生单线态氧，诱导脑胶质瘤细胞的坏死和凋亡。 过程类似于光动力疗法。PpIX的非侵入性激活导致胶质瘤的消退 以及延长存活期。这一直接到第二阶段计划的目标是提供关于 静脉注射10 mg/kg丙氨酸用于ALA SDT后续临床试验的最佳MRgFUS能量剂量 在DIPG。这将通过执行3个目标来实现。在目标1中，我们将开发灵敏的分析方法 目的：检测微量血样中的ALA和PPIX。在目标2中，我们将测定血浆 丙氨酸代谢和PpIX合成的药物动力学(PK) ALA的配方将用于儿童的治疗目的，了解可能的 儿童PK与成人PK的差异。在目标3中，我们将确定 DIPG患者使用单一剂量ALA的ALA SDT，同时使用3个递增的MRgFUS能量剂量队列。 这将有助于确定DIPG患者的最大耐受能量剂量和推荐阶段 2剂量MRgFUS能量加10 mg/kg丙氨酸静脉注射。成功完成这项提案将 通知药物剂量范围研究。这些试验的完成对于进入下一阶段的临床至关重要。 发展，DIPG患者将每月接受SDT治疗，试图最大化效果 使用安全的静脉注射ALA和最佳剂量的MRgFUS对这些患者的存活率的影响。这个 该开发计划的目标是获得FDA上市批准所需的临床数据，并 对于没有治疗选择的DIPG患者，将这种联合疗法商业化。ALA SDT拥有 有可能成为DIPG的第一个成功的治疗方法，也是医学史上第一次有孩子的父母 有了DIPG，他们不仅有希望延长孩子的生命，而且还会感到安慰， 使用的联合疗法是非侵入性的，并且副作用极易耐受。

PROJECT SUMMARY Diffuse Intrinsic Pontine Gliomas (DIPG) are rare and deadly pediatric brain tumors. They are extremely aggressive tumors that are found in the pons, which controls many of the body's most vital functions such as breathing, blood pressure, and heart rate. There is no currently effective means of treatment for DIPG, and the median survival is 7-11 months after diagnosis. Thus, there is significant need for a method to effectively treat DIPG. To address this unmet need, SonALAsense is developing sonodynamic therapy (SDT), a non-invasive drug-device combination, to treat DIPG. SDT uses an MRI-Guided Focused Ultrasound (MRgFUS) device in combination with a drug called 5-aminolevulinic acid (ALA). Three independent laboratories have demonstrated the safety and efficacy of ALA SDT in animal glioma models where the animals were dosed first with ALA and then treated with MRgFUS at energies that do not raise brain temperature. MRgFUS activated Protoporphyrin IX (PpIX), a metabolite of ALA, created singlet oxygen that induced necrosis and apoptosis in the glioma in a process similar to photodynamic therapy. Activation of PpIX non-invasively caused regression of the gliomas and extended survival. The goal of this Direct to Phase II program is to provide safety and efficacy data on the best MRgFUS energy doses to use with 10 mg/kg intravenous (IV) ALA for subsequent clinical trials of ALA SDT in DIPG. This will be accomplished through the execution of 3 Aims. In Aim 1, we will develop sensitive assays to detect ALA and PpIX in small blood sample volumes. In Aim 2, we will determine blood plasma pharmacokinetics (PK) of ALA metabolism and PpIX synthesis following IV dosing as this is the first time an IV formulation of ALA will be used for therapeutic purposes in children, and it is important to understand possible differences in PK between pediatric and adult subjects. In Aim 3, we will determine the safety and efficacy of ALA SDT in DIPG patients using a single IV dose of ALA while using 3 ascending MRgFUS energy dose cohorts. This will help determine both the maximum tolerated energy dose in DIPG patients and the recommended Phase 2 dose of MRgFUS energy in combination with 10 mg/kg IV ALA. Successful completion of this proposal will inform a drug dose ranging study. Completion of these trials are critical to proceed to the next stage of clinical development, in which DIPG patients will receive SDT therapy on a monthly basis to attempt to maximize effects on survival of these patients using a safe IV dose of ALA in combination with an optimal dose of MRgFUS. The goal of this development program is to obtain the clinical data necessary for FDA marketing approval and to commercialize this combination therapy for DIPG patients who have no therapeutic options. ALA SDT has the potential to be the first successful treatment for DIPG and for the first time in medical history parents of children with DIPG would not only have hope that the life of their child could be extended, but also the comfort that the combination therapy used is noninvasive and has extremely tolerable side effects.