Phase 2 Clinical Trial Evaluating a Novel Therapy in Patients who are Post-lung Transplant

慢性肺移植功能障碍(Clad)是肺移植受者死亡的主要原因。 移植一年，包括闭塞性细支气管炎综合征(BOS)。目前，还没有治疗方法 可提供防止包衣或BOS的代理。治疗仅限于支持性策略，具有低和可变 一旦穿上衣服，成功率就会提高。Arina-1，抗坏血酸雾化疗法的专利配方 (ASC)被设计为在患者发展为BOS-0p的前体时使用，而不是等到它 进展到可能无法恢复的病理状态。当患者发生BOS-0P时，物理化学 通常维持肺部健康的屏障受损，使肺部更容易受到刺激物的影响。 和环境中的细菌。这会引发炎症和感染的循环，从而导致 肺功能，最终导致移植物排斥反应和衰竭。ASC对一线呼吸道防御至关重要，而且 肺移植后患者的呼吸道明显耗尽。因此，Arina-1的作用机制 治疗很简单：Arina-1将Asc直接输送到肺中，恢复了对 炎症和感染。在临床前研究中，我们证明了Arina-1既激活了cftr介导的 离子运输和粘液运输，降低粘液粘度和炎症，并抑制细菌生长。 对三名严重肺部疾病患者的初步研究表明Arina-1是安全的和初步的 功效。在稳定的肺移植患者中进行的一项成功的一期研究证实了Arina-1的安全性，并提示 FDA允许在BOS-0P患者中进行NDA启用的第二阶段临床试验。这项提议的目的是 旨在推动ARINA-1获得FDA批准，用于患有BOS-0P的肺移植患者，对他们来说 都不是目前的疗法。在这份直接提交到第二阶段的报告中，我们将进行支持NDA的多中心 严格评估ARINA-1在BOS-0P中疗效的临床试验。这些目标的成功实现将 结果FDA批准了首个针对肺移植患者使用BOS-0P的疗法的NDA申请，以防止 进展为包层和移植物失败。ARINA-1的批准将改善肺移植护理的临床实践， 通过为医生提供在BOS-0P进展为包膜之前治疗它的治疗选择，不仅增加了 生存，还要延长生存期间的生活质量。

Chronic lung allograft dysfunction (CLAD) is the primary cause of mortality in lung transplant recipients beyond one year of transplant and includes bronchiolitis obliterans syndrome (BOS). Currently, there are no therapeutic agents available to prevent CLAD or BOS. Treatments are limited to supportive strategies with low and variable success rates once CLAD develops. ARINA-1, a patented formulation for a nebulized therapy of ascorbic acid (ASC), is designed to use when patients develop precursors to BOS, known as BOS-0p, rather than wait until it progresses to potentially unrecoverable pathology. As a patient develops BOS-0p, the physical and chemical barriers that typically maintain pulmonary health are compromised, making the lung more susceptible to irritants and bacteria in the environment. This initiates a cycle of inflammation and infection that leads to decreased pulmonary function and, ultimately, graft rejection and failure. ASC is critical to first-line airway defenses and is significantly depleted in the airway of patients who are post lung transplant. Thus, the mechanism of ARINA-1 therapy is simple: ARINA-1 delivers ASC directly to the lung, which restores the first lines of defense against inflammation and infection. In preclinical studies, we demonstrate that ARINA-1 both activates CFTR-mediated ion transport and mucus transport, decreases mucus viscosity and inflammation, and inhibits bacterial growth. Pilot studies in three patients with severe pulmonary disease demonstrate ARINA-1 safety and preliminary efficacy. A successful Phase 1 study in stable lung transplant patients confirmed ARINA-1 safety and prompted the FDA to permit an NDA-enabling Phase 2 clinical trial in patients with BOS-0p. The Aims of this proposal are designed to advance ARINA-1 to FDA approval for use in lung transplant patients with BOS-0p, for whom there are no current therapies. In this Direct-to-Phase II submission, we will conduct the NDA-enabling multi-center clinical trial to rigorously evaluate ARINA-1 efficacy in BOS-0p. The successful completion of these Aims will result in NDA filing for the first FDA-approved therapy for lung transplant patients with BOS-0p to prevent the progression to CLAD and graft failure. ARINA-1 approval will improve clinical practice for lung transplant care, by offering physicians a therapeutic option for treating BOS-0p before it progresses to CLAD, increasing not only survival, but also quality of life during the prolonged survival.