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

慢性肺移植物功能障碍（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，没有治疗 预防CLAD或BOS的药物。治疗仅限于支持性策略， 成功率一旦CLAD发展。ARINA-1，一种抗坏血酸雾化治疗的专利配方 (ASC)设计用于患者出现BOS前体（称为BOS-0 p）时，而不是等到 发展成潜在的不可恢复的病理。当患者出现BOS-0 p时， 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。这引发了一个炎症和感染的循环， 肺功能最终导致移植物排斥和衰竭ASC对一线气道防御至关重要， 在肺移植后患者的气道中显著耗尽。因此，ARINA-1的机制 治疗方法很简单：ARINA-1直接将ASC输送到肺部，恢复了抗ASC的第一道防线。 炎症和感染。在临床前研究中，我们证明了ARINA-1既激活CFTR介导的 离子转运和粘液转运，降低粘液粘度和炎症，并抑制细菌生长。 在三名严重肺部疾病患者中进行的初步研究证明了ARINA-1的安全性和初步疗效。 功效在稳定的肺移植患者中进行的一项成功的1期研究证实了ARINA-1的安全性，并提示 FDA允许在BOS-0 p患者中进行NDA支持的2期临床试验。这项建议的目的是 旨在推进ARINA-1获得FDA批准用于BOS-0 p肺移植患者， 目前没有治疗方法。在本次直接进入II期申报中，我们将进行NDA启用多中心 严格评估ARINA-1在BOS-0 p中的疗效的临床试验。这些目标的成功实现将 导致FDA批准的第一种用于BOS-0 p肺移植患者的治疗的NDA申请，以防止 进展为CLAD和移植物衰竭。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-0 p发展为CLAD之前治疗BOS-0 p的治疗选择，不仅增加了 生存期，而且在延长生存期的生活质量。

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.