Phase I/IIa Clinical Trial Using Localized and Systemic Delivery of the P2X7 Receptor Antagonist AZD9056 for the Treatment of Salivary Gland Dysfunction in Sjögren's Syndrome Patients

唾液腺功能障碍是由损伤或疾病（包括干燥综合征）引起的重要医学问题 综合征（SS）是一种慢性炎症性自身免疫性疾病，其特征是唾液分泌减少和淋巴细胞增多。 唾液腺的浸润（即，涎腺炎）。唾液过少的治疗是有限的， 不足因此，开发有效的SS治疗方法至关重要。在慢性涎腺炎中， 局部在唾液腺中促进免疫细胞的积累、组织变性和腺纤维化， 加重SS发病机制和唾液分泌不足。主要研究者的已发表和初步数据 实验室表明，从受损细胞中局部释放胞质核苷酸警报素，如ATP，激活 P2 X7受体（P2 X7 R）信号通路促进SS小鼠模型中的唾液分泌不足和涎腺炎， 而P2 X7 R拮抗作用使唾液产生正常化并减少涎腺炎。联合国以前的工作- 研究者已经确定唾液腺内窥镜检查是SS相关唾液过少的一种有前景的治疗方法，其中 通过内窥镜冲洗唾液腺导管以扩张闭塞。将我们的（预）临床发现转化为 有效的治疗干预，我们建议使用对比增强超声和涎腺内窥镜（CEUSS） 用充气微泡溶解导管闭塞，结合局部和全身应用 P2 X7 R拮抗剂AZD 9056（获自Phoenixel）在预期的U 01 I/IIa期临床试验中， SS患者减少涎腺炎，增强唾液分泌。这种方法将提供前所未有的 可能减轻SS患者的负担，同时实现术中诊断唾液腺 成像和疗效证据。预期的U 01 I/IIa期试验将评估安全性，最大限度 AZD 9056的耐受剂量、药代动力学和药效学特性以及临床疗效 在原发性SS患者中进行的剂量递增和队列扩展试验。审判将决定 在SS患者中，导管内和全身给药AZD 9056联合抑制细胞机制 使用临床生物样本的潜在SS。 R34具体目标1：制定SS患者SG中导管内和全身AZD 9056的监管计划。 R34具体目标2：制定临床方案、预算和多国临床数据管理计划， SS患者中全身和导管内AZD 9056联合给药。 R34具体目标3：制定SS患者生物标本的方案，以确定AZD 9056对 SS患者SG功能障碍的机制。

Salivary gland dysfunction is a significant medical problem caused by injury or disease, including Sjögren’s Syndrome (SS), a chronic inflammatory autoimmune disease characterized by hyposalivation and lymphocytic infiltration of salivary glands (i.e., sialadenitis). Treatments for hyposalivation are limited and deemed to be inadequate. Thus, development of effective SS treatments is essential. In chronic sialadenitis, alarmins produced locally in salivary glands promote accumulation of immune cells, tissue degeneration and glandular fibrosis that exacerbate SS pathogenesis and hyposalivation. Published and preliminary data from the Principal Investigator’s lab show that localized release of cytoplasmic nucleotide alarmins, such as ATP, from damaged cells activates the P2X7 receptor (P2X7R) signaling pathway to promote hyposalivation and sialadenitis in SS mouse models, whereas P2X7R antagonism normalizes saliva production and reduces sialadenitis. Previous work of the Co- Investigators has established sialendoscopy as a promising therapy for SS-associated hyposalivation, in which salivary gland ducts are endoscopically irrigated to dilate occlusions. To translate our (pre)clinical findings into an effective therapeutic intervention, we propose to use contrast-enhanced ultrasound and sialendoscopy (CEUSS) with gas-filled microbubbles to dissolve ductal occlusions combined with local and systemic application of the P2X7R antagonist AZD9056 (obtained from Phoenicis), in an anticipated U01 phase I/IIa clinical trial with human SS patients to reduce sialadenitis and enhance saliva production. This approach will offer unprecedented possibilities to reduce the burden to patients with SS, while achieving intra-operative diagnostic salivary gland imaging and evidence of therapeutic efficacy. The anticipated U01 phase I/IIa trial will assess safety, maximum tolerated dose, pharmacokinetic and pharmacodynamic properties and clinical efficacy of AZD9056 in the first dose-escalation and cohort-expansion trial with primary SS patients. The trial will determine whether the combination of intraductal and systemic AZD9056 administration in SS patients inhibits cellular mechanisms underlying SS using clinical biospecimens. R34 Specific Aim 1: Develop regulatory plan for intraductal and systemic AZD9056 in SGs of SS patients. R34 Specific Aim 2: Develop clinical protocol, budget and multinational clinical data management plan for systemic and intraductal AZD9056 co-administration in SS patients. R34 Specific Aim 3: Develop protocols for SS patient biospecimens to determine effects of AZD9056 on mechanisms of SG dysfunction in SS patients.