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

无创声动力疗法治疗弥漫性内源性脑桥胶质瘤的安全性和有效性评价

基本信息

批准号：
10382835
负责人：
Stuart Marcus
金额：
$ 93.9万
依托单位：
SONALASENSE INC
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10382835
关键词：
Address Adult Adverse drug event Age Aminolevulinic Acid Animal Model Animals Apoptosis Area Biological Assay Blood Blood Pressure Blood Volume Blood specimen Body Weight Brain Breathing Bypass Child Childhood Childhood Brain Neoplasm Clinical Clinical Data Clinical Research Clinical Trials Combined Modality Therapy Common Terminology Criteria for Adverse Events Cyclic GMP Data Detection Devices Diagnosis Diffuse intrinsic pontine glioma Disease Dose Dose-Limiting Drug Kinetics Electrocardiogram Enrollment Ethics Evaluation Excision FDA approved Family Leave Fluorescence Focused Ultrasound Formulation Future Glioma Goals Growth Half-Life Heart Rate Hepatotoxicity High Pressure Liquid Chromatography Hospitals Human Intravenous Laboratories Laboratory Study Life Liver Location Magnetic Resonance Imaging Marketing Maximum Tolerated Dose Measurable Medical History Metabolism Methods Minor Modeling Nausea and Vomiting Necrosis Neurosurgeon Operative Surgical Procedures Oral PUVA Photochemotherapy Parents Patients Pharmaceutical Preparations Phase Phase I/II Clinical Trial Plasma Pontine structure Process Prognosis Program Development Radiology Specialty Recommendation Safety Sampling Singlet Oxygen Small Business Innovation Research Grant Speed Stomach Technology Temperature Testing Therapeutic Therapeutic Uses Time Toxic effect Translating Ultrasonic Therapy Urine Visit Visual Aid Work assay development clinical development cohort commercialization design effective therapy experience improved outcome meetings pediatric patients pre-clinical therapy preclinical study programs protoporphyrin IX side effect standard of care tumor tumor progression ultrasound

项目摘要

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.

项目概要弥漫性内源性脑桥胶质瘤 (DIPG) 是一种罕见且致命的儿童脑肿瘤。他们非常脑桥中发现的侵袭性肿瘤，脑桥控制着身体的许多最重要的功能，例如呼吸、血压和心率。目前DIPG尚无有效治疗手段，诊断后中位生存期为 7-11 个月。因此，迫切需要一种有效治疗的方法 DIPG。为了解决这一未满足的需求，SonALAsense 正在开发声动力疗法 (SDT)，这是一种非侵入性疗法药物-设备组合，治疗 DIPG。 SDT 使用 MRI 引导聚焦超声 (MRgFUS) 设备与 5-氨基乙酰丙酸 (ALA) 药物联合使用。三个独立实验室已证明 ALA SDT 在动物神经胶质瘤模型中的安全性和有效性，其中动物首先接受 ALA 给药，然后用 MRgFUS 进行治疗，能量不会升高脑部温度。 MRgFUS 激活原卟啉 IX (PpIX) 是 ALA 的一种代谢产物，在神经胶质瘤中产生单线态氧，诱导坏死和凋亡。过程类似于光动力疗法。 PpIX 的激活非侵入性地导致神经胶质瘤消退并延长生存期。该直接进入第二阶段计划的目标是提供有关该药物的安全性和有效性数据与 10 mg/kg 静脉内 (IV) ALA 一起使用的最佳 MRgFUS 能量剂量用于 ALA SDT 的后续临床试验在 DIPG 中。这将通过执行 3 个目标来实现。在目标 1 中，我们将开发灵敏的检测方法检测少量血液样本中的 ALA 和 PpIX。在目标 2 中，我们将测定血浆静脉给药后 ALA 代谢和 PpIX 合成的药代动力学 (PK)，因为这是第一次静脉给药 ALA 制剂将用于儿童的治疗目的，了解可能的情况很重要儿童和成人受试者之间的 PK 差异。在目标 3 中，我们将确定以下药物的安全性和有效性： ALA SDT 在 DIPG 患者中使用单次静脉注射 ALA，同时使用 3 个递增 MRgFUS 能量剂量组。这将有助于确定 DIPG 患者的最大耐受能量剂量和推荐的阶段 2 剂 MRgFUS 能量与 10 mg/kg IV ALA 组合。本提案的顺利完成将告知药物剂量范围研究。完成这些试验对于进入下一阶段的临床至关重要开发中，DIPG 患者将每月接受 SDT 治疗，以尝试最大化效果使用安全静脉注射剂量的 ALA 与最佳剂量的 MRgFUS 相结合对这些患者的生存有影响。这该开发计划的目标是获得 FDA 营销批准所需的临床数据并将这种联合疗法商业化，用于没有治疗选择的 DIPG 患者。 ALA SDT 具有有可能成为第一个成功治疗 DIPG 的方法，也是医学史上首次为儿童父母提供治疗与 DIPG 一起不仅可以延长孩子的生命，还可以让孩子感到安慰所使用的联合疗法是非侵入性的并且具有极其可耐受的副作用。