Drug and energy dose-escalation study of SONALA-001 sonodynamic therapy in the treatment of diffuse intrinsic pontine glioma

SONALA-001声动力疗法治疗弥漫性脑桥胶质瘤的药物和能量剂量递增研究

• 批准号: 10503915
• 负责人: Stuart Marcus
• 金额: $ 47.7万
• 依托单位: SONALASENSE INC
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-20 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10503915
• 关键词: Drug; energy; dose; escalation; study

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; SONALA-001). 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. We also have data that support that ALA SDT is safe and well-tolerated in adult patients with recurrent glioblastoma multiforme, and leads to targeted oxidative stress and accompanying apoptosis in tumor tissue, in the absence of a thermal effect, similar to the animal model results. SONALA-001 is Orphan Drug designated for the treatment of all malignant gliomas and an Investigational New Drug (IND) application was cleared to proceed by the FDA. The goal of this R01 is to execute a Phase 2 clinical trial to provide safety and efficacy data for subsequent trials of ALA SDT in DIPG. As one of three clinical trial sites participating in this trial, the Ivy Brain Tumor Center will enroll 12 DIPG patients in up to 9 cohorts. This trial will be uncontrolled for ethical reasons. First, we will determine blood plasma PK of ALA metabolism and PpIX synthesis as this is the first intravenous (IV) formulation of ALA. Second, we will determine the maximum tolerated dose (MTD) or recommended Phase 2 dose of MRgFUS energy combined with IV ALA. Third, we will determine safety and efficacy of ALA SDT by following patients for up to 12 months. Successful completion of this trial will identify a safe dose 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；SONALA-001）的药物组合。拥有三个独立实验室 证明了 ALA SDT 在动物神经胶质瘤模型中的安全性和有效性，其中动物首先接受给药 使用 ALA 进行治疗，然后使用 MRgFUS 以不会升高脑温度的能量进行治疗。 MRgFUS 激活 原卟啉 IX (PpIX) 是 ALA 的代谢产物，可产生单线态氧，诱导细胞坏死和凋亡 神经胶质瘤的治疗过程类似于光动力疗法。 PpIX 的激活以非侵入性方式引起消退 神经胶质瘤和延长生存期。我们还有数据支持 ALA SDT 在以下情况下是安全且耐受性良好的： 患有复发性多形性胶质母细胞瘤的成年患者，会导致有针对性的氧化应激和伴随的 在没有热效应的情况下，肿瘤组织发生细胞凋亡，与动物模型结果相似。索娜拉-001 是指定用于治疗所有恶性神经胶质瘤的孤儿药，也是一种研究性新药 (IND) FDA 批准该申请继续进行。 R01 的目标是执行 2 期临床试验 为后续 ALA SDT 在 DIPG 中的试验提供安全性和有效性数据。作为三个临床试验中心之一 参与这项试验的 Ivy 脑肿瘤中心将招募最多 9 个队列中的 12 名 DIPG 患者。此次审判将 由于道德原因而不受控制。首先，我们将测定 ALA 代谢和 PpIX 的血浆 PK 合成，因为这是 ALA 的第一个静脉注射 (IV) 制剂。其次，我们将确定最大 MRgFUS 能量联合 IV ALA 的耐受剂量 (MTD) 或推荐的第 2 阶段剂量。第三，我们将 通过跟踪患者长达 12 个月来确定 ALA SDT 的安全性和有效性。顺利完成 该试验将确定进入下一阶段临床开发的安全剂量，其中 DIPG 患者将 每月接受 SDT 治疗，以尝试使用安全的方法最大限度地提高这些患者的生存率 IV 剂量的 ALA 与最佳剂量的 MRgFUS 组合。该开发计划的目标是 获得 FDA 上市批准所需的临床数据，并将该联合疗法商业化 没有治疗选择的 DIPG 患者。 ALA SDT 有潜力成为第一个成功的治疗方法 对于 DIPG，这在医学史上是第一次，DIPG 儿童的父母不仅希望 他们孩子的生命可以延长，而且所使用的联合疗法是非侵入性的，而且也很舒适 具有极其可耐受的副作用。