Regulatory Advancement of HXe as a Diagnostic MRI Contrast Agent

描述（由申请人提供）：正在开发用于COPD（支气管内瓣膜/支架/胶）和哮喘（支气管内热消融）的新疗法。超极化氙-129（HSVN）MRI是一种评估局部肺结构和功能的非侵入性方法，在指导这些局部治疗方面可能至关重要。在我们之前的工作中，我们开发了一种创新的氙偏振方法，可提供医学成像所需的高度偏振氙-129的升数。我们的原型系统部署在UVa，我们在64名患者和健康志愿者中进行了600次实验，并在MR采集策略和图像质量方面取得了重大进展。这些令人鼓舞的结果使我们能够进入HISTORY商业化的下一步，即2期临床试验的性能。我们的第2阶段目标是收集阻塞性肺疾病患者的安全性终点，最终确定Hestival给药和MRI方法，并通过与评估肺功能和微观结构的现有临床方法进行比较来验证Hestival结果。我们选择了两种最成熟和最有前途的HIVER技术纳入2期试验：通气和弥散成像。阻塞性肺疾病如COPD和哮喘已被证明具有通气的局部异常，并且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HSP 70 MRI用于描绘COPD和哮喘患者肺部通气和不通气区域的预期用途。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HIVER通气MRI和99 Tc DTPA通气肺造影（评估局部肺通气的临床标准）。除了患者安全性数据外，我们还将评估MRI上的总肺容量和通气肺容量，以及HALGORITHM MRI和肺动脉造影之间通气容量边界的一致性。最近完成的初步研究表明，超极化氦扩散成像与6个b值可以分别确定扩散系数沿着和横向腺泡导管，这是相关的肺泡深度和管道直径。我们的第二个目的是验证Hulf弥散MR用于量化肺气肿肺泡扩大的预期用途，这是一种目前仅通过组织学评估的基本异常。对于我们的2b期试验，我们将在计划进行肺移植的18名COPD患者中进行体内扩散HSP 70 MRI，并在取出后在离体肺中重复扫描，从而确定体内和离体HSP 70测量结果一致。HPLIFIER扩散测量的验证的最后一步是通过组织学对肺泡大小与肺组织的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3期水平，设计3期试验草案，与FDA举行3期前会议，并将FDA的意见纳入3期方案。拟议工作的完成标志着在实现HALOSE商业化方面取得了重大进展。

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.