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伤害或疾病引起的重大医学问题，包括Sjögren 综合征(SS)，一种慢性炎症性自身免疫性疾病，以淋巴细胞减少和淋巴细胞减少为特征 唾液腺的浸润性病变(即涎腺炎)。肝功能低下的治疗是有限的，并被认为是 不够充分。因此，开发有效的SS治疗方法是至关重要的。在慢性涎腺炎中，警报器产生 唾液腺局部促进免疫细胞堆积，组织变性和腺体纤维化， 加重SS的发病和肺功能减退。来自首席调查员的公布和初步数据 实验室表明，从受损细胞中局部释放胞质核苷酸警报蛋白，如ATP，可以激活 2X7受体(P2X7R)信号通路在SS小鼠模型中促进淋巴功能减退和涎腺炎的作用 而P2X7R拮抗剂可使唾液分泌正常化，减少涎腺炎。联席会议以前的工作-- 研究人员已确定涎腺内窥镜检查是治疗SS相关性腺功能减退的一种有前途的治疗方法，其中 唾液腺导管在内窥镜下冲洗以扩张闭塞。将我们(临床前期)的发现转化为 有效的治疗干预，我们建议使用对比增强超声和唾液内窥镜(CEUSS) 充气微泡溶解胆管闭塞结合局部全身应用 P2X7R拮抗剂AZD9056(从Phoenicis获得)，在预期的人类U01 I/IIa期临床试验中 减少SS患者的涎腺炎，提高唾液产量。这种方法将提供前所未有的 减轻SS患者负担的可能性，同时实现术中唾液腺诊断 治疗效果的影像和证据。预期的U01阶段I/IIa试验将最大限度地评估安全性 AZD9056的耐受量、药代动力学、药效学特性及临床疗效 原发SS患者的剂量递增和队列扩展试验。审判将决定是否 AZD9056导管内联合全身给药抑制SS患者的细胞机制 在SS基础上使用临床生物样品。 R34具体目标1：为SS患者SGS的导管内和全身AZD9056制定调控计划。 R34具体目标2：制定临床方案、预算和跨国临床数据管理计划 SS患者全身和导管内联合应用AZD9056。 R34特定目标3：建立SS患者生物检疫方案，以确定AZD9056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.