Regulatory Advancement of HXe as a Diagnostic MRI Contrast Agent

描述（由申请人提供）：针对慢性阻塞性肺病（支气管内瓣膜/支架/胶水）和哮喘（支气管内热消融）的新疗法正在开发中。超极化氙 129 (HXe) MRI 是一种评估局部肺结构和功能的无创方法，可能对指导这些局部治疗至关重要。在我们之前的工作中，我们开发了一种创新的氙偏振方法，可提供医学成像所需的升量的高度偏振的氙 129。我们的原型系统部署在弗吉尼亚大学，在那里我们对 64 名患者和健康志愿者进行了 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。这些有希望的结果使我们能够迈向 HXe 商业化的下一步，即进行 2 期临床试验。我们第二阶段的目标是收集阻塞性肺病患者的安全性终点，最终确定 HXe 剂量和 MRI 方法，并通过与现有评估肺功能和微结构的临床方法进行比较来验证 HXe 结果。我们选择了两种最成熟、最有前途的 HXe 技术纳入第二阶段试验：通气和扩散成像。阻塞性肺病（例如慢性阻塞性肺病和哮喘）已被证明具有局部通气异常，这些异常是干预的主要目标。因此，我们的首要目标是验证 HXe MRI 在描绘 COPD 和哮喘患者肺部通气和不通气区域方面的预期用途。在我们的 2a 期试验中，我们将在 10 名健康志愿者和 70 名患有 COPD 和哮喘的患者中比较 HXe 通气 MRI 和 99Tc DTPA 通气闪烁扫描（评估区域肺通气的临床标准）。除了患者安全数据外，我们还将评估 MRI 上的总肺容量和通气肺容量，以及 HXe MRI 和闪烁扫描之间通气量边界的一致性。最近完成的试点研究表明，具有六个 b 值的超极化氦扩散成像可以分别确定腺泡管沿和横向的扩散系数，该系数与肺泡深度和导管直径相关。我们的第二个目标是验证 HXe 扩散 MR 在量化肺气肿肺泡肿大方面的预期用途，肺气肿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，我们将对 18 名计划进行肺移植的 COPD 患者进行体内扩散 HXe MRI，并在摘除肺后在离体肺中重复扫描，从而确定体内和离体 HXe 测量结果是一致的。 HXe 扩散测量验证的最后一步是通过外植肺的组织学将肺泡大小与形态测量进行区域比较。拟议工作的最后部分是将质量提高到第 3 阶段水平，设计第 3 阶段试验草案，与 FDA 召开第 3 阶段前会议，并将 FDA 的意见纳入第 3 阶段方案中。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.