Regulatory Advancement of HXe as a Diagnostic MRI Contrast Agent

描述(由申请人提供)：COPD(支气管内瓣膜/支架/胶水)和哮喘(支气管内热消融术)的新疗法正在开发中。超极化氙气-129(HXE)MRI是一种无创性的评估局部肺结构和功能的方法，可能对指导这些区域治疗至关重要。在我们之前的工作中，我们开发了一种创新的氙极化方法，提供了医学成像所需的少量高极化氙气-129。我们的原型系统部署在弗吉尼亚大学，在患者和健康志愿者身上进行了600次实验，在MR获取策略和图像质量方面取得了显着进展。这些有希望的结果使我们能够进入HXE商业化的下一步，即第二阶段临床试验的表现。我们第二阶段的目标是收集阻塞性肺疾病患者的安全终点，最终确定HXE剂量和MRI方法，并通过与现有临床方法比较来验证HXE结果，以评估肺功能和微结构。我们选择了两种最成熟和最有前景的HXE技术用于第二阶段试验：通风和扩散成像。阻塞性肺疾病，如慢性阻塞性肺病和哮喘，已被证明存在区域性的换气异常，这些异常是干预的主要目标。因此，我们的第一个目标是验证HXE MRI在COPD和哮喘患者中描绘肺的通风和非通风区域的预期用途。在我们的2a期试验中，我们将在10名健康志愿者和70名COPD和哮喘患者中比较HXE通气机MRI和99TcDTPA通气机核素(评估局部肺通气量的临床标准)。除了患者安全数据外，我们还将在MRI上评估总肺容量和通气量，以及HXE MRI和核素扫描的通气量边界的一致性。最近完成的初步研究表明，具有六个b值的超极化氦扩散成像可以分别确定沿腺泡导管和横向到腺泡导管的扩散系数，这与肺泡深度和导管直径有关。我们的第二个目标是验证HXE弥散磁共振用于量化肺气肿的肺泡扩大的预期用途，这是一种基本的异常，目前仅通过组织学进行评估。在我们的2b期试验中，我们将对18名计划进行肺移植的COPD患者进行体内扩散HXE磁共振成像，并在摘除肺后在体外重复扫描，从而确定体内和体外HXE测量是一致的。验证HXE弥散测量的最后一步是通过移植肺的组织学对肺泡大小和形态测量进行区域性比较。拟议工作的最后一部分是将质量提高到第三阶段水平，设计第三阶段试验草案，与FDA会面举行第三阶段前会议，并将FDA的意见纳入第三阶段方案。拟议工作的完成代表着HXE商业化的重大进展。

DESCRIPTION (provided by applicant): New therapies are in development for COPD (endobronchial valves/stents/glue) and asthma (endobronchial thermal ablation). Hyperpolarized xenon-129 (HXe) MRI, a noninvasive method to assess regional lung structure and function, may prove critical in the guidance of these regional treatments. In our prior work we developed an innovative approach to xenon polarization that provides the liter quantities of highly polarized xenon-129 as required for medical imaging. Our prototype system was deployed at UVa where we performed 600 experiments in 64 patient and healthy volunteers and made significant advances in MR acquisition strategies and image quality. These promising results enable us to move to the next step in the commercialization of HXe, the performance of a Phase 2 clinical trial. Our goals for Phase 2 are to collect safety endpoints in patients with obstructive lung diseases, finalize the HXe dosing and MRI methods, and validate the HXe results by comparing with the existing clinical methods for assessing lung function and microstructure. We selected the two most mature and promising HXe techniques for inclusion in the Phase 2 trial: ventilation and diffusion imaging. Obstructive lung diseases such as COPD and asthma have been shown to have regional abnormalities of ventilation and these abnormalities are prime targets for intervention. Thus our first aim is to validate HXe MRI for the intended use of delineating ventilated and unventilated regions of the lung in COPD and asthma patients. For our Phase 2a trial we will compare HXe ventilation MRI and 99Tc DTPA ventilation scintigraphy (a clinical standard for assessing regional lung ventilation) in 10 healthy volunteers and 70 patients with COPD and asthma. In addition to the patient safety data, we will assess total lung volume and ventilated lung volume on MRI, and the congruence of ventilated volume boundaries between HXe MRI and scintigraphy. Recently completed pilot studies show that hyperpolarized helium diffusion imaging with six b-values can separately determine diffusion coefficients along and transverse to acinar ducts, which are related to alveolar depth and duct diameter. Our second aim is to validate HXe diffusion MR for the intended use of quantifying alveolar enlargement in emphysema, a fundamental abnormality that currently is assessed only by histology. For our Phase 2b trial we will perform diffusion HXe MRI in vivo in 18 COPD patients scheduled for lung transplant, and repeat the scan in the ex vivo lung after it is removed, thereby establishing that in vivo and ex vivo HXe measurements are concordant. The final step in the validation of the HXe diffusion measurement is to regionally compare alveolar size with morphometric measurements via histology from the explanted lung. The final portion of the proposed work is to raise quality to Phase 3 level, design a draft Phase 3 trial, meet with the FDA for a pre-Phase 3 meeting, and incorporate the FDA input into the Phase 3 protocol. The completion of the proposed work represents a significant advancement towards commercialization of HXe.