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

使用 P2X7 受体拮抗剂 AZD9056 局部和全身给药治疗干燥综合征患者唾液腺功能障碍的 I/IIa 期临床试验

• 批准号: 10487866
• 负责人: Arjan Vissink
• 金额: $ 20.23万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-08 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10487866
• 关键词: Acinar Cell; Affect; Ageusia; Agonist; Agreement; American; Artificial Saliva; Autoimmune Diseases; Bacterial Infections; Biochemical; Biological Assay; Biopsy; Budgets; Case Report Form; Cell Surface Receptors; Cells; Chemicals; Chronic; Clinical; Clinical Data; Clinical Protocols; Clinical Research; Clinical Trials; Data; Dental caries; Development; Diagnostic Imaging; Digestive System Disorders; Disease; Dose; Duct (organ) structure; Enrollment; Ensure; Esthesia; European; Fibrosis; Functional disorder; Gases; Goals; Human; Hydration status; Image; Immune; Infiltration; Inflammation; Inflammatory; Informed Consent; Injury; Intellectual Property; Investigation; Lymphocyte; Manuals; Maximum Tolerated Dose; Medical; Medicine; Microbubbles; Missouri; Monitor; Morphology; Mus; Muscarinic Acetylcholine Receptor; Nucleotides; Pamphlets; Parotid Gland; Pathogenesis; Patients; Pharmacy facility; Phase; Principal Investigator; Production; Property; Protocols documentation; Publishing; Quality of life; Receptor Signaling; Regulation; Research; Research Personnel; Residual state; Safety; Saliva; Salivary Gland Diseases; Salivary Gland Tissue; Salivary Glands; Salivary duct structure; Sampling; Serum; Services; Sialadenitis; Signal Pathway; Sjogren' s Syndrome; Speech; Standardization; Statistical Data Interpretation; Therapeutic Intervention; Training; Translating; Treatment Efficacy; Woman; Work; Xerostomia; adjudication; antagonist; cell injury; clinical efficacy; cohort; contrast enhanced; data management; dosage; extracellular; injured; mouse model; novel therapeutics; operation; pharmacokinetics and pharmacodynamics; pre-clinical; programs; receptor; saliva diagnostic; saliva secretion; sample fixation; screening; therapeutically effective; tissue degeneration; treatment group; ultrasound; yeast infection

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.

唾液腺功能障碍是由损伤或疾病（包括干燥综合症）引起的严重医学问题 综合征（SS），一种慢性炎症性自身免疫性疾病，其特征是唾液分泌不足和淋巴细胞增多 唾液腺浸润（即唾液腺炎）。唾液腺分泌不足的治疗方法有限，被认为是无效的。 因此，开发有效的 SS 治疗方法对于慢性唾液腺炎来说至关重要。 局部在唾液腺中促进免疫细胞的积累、组织变性和腺体纤维化， 加剧了 SS 发病机制和唾液分泌不足。首席研究员已发表的初步数据。 实验室表明，受损细胞局部释放细胞质核苷酸警报素（例如 ATP）会激活 P2X7 受体 (P2X7R) 信号通路促进 SS 小鼠模型唾液分泌不足和唾液腺炎， 而 P2X7R 拮抗作用使唾液分泌正常化并减少唾液腺炎。 研究人员已确定唾液内窥镜检查是治疗 SS 相关唾液分泌不足的一种有前途的疗法，其中 通过内窥镜冲洗唾液腺导管以扩张闭塞，将我们的（前）临床发现转化为临床结果。 为了有效的治疗干预，我们建议使用超声造影和唾液内镜检查（CEUSS） 用充气微泡溶解导管闭塞并结合局部和全身应用 P2X7R 拮抗剂 AZD9056（从 Phoenicis 获得），在一项预期的 U01 I/IIa 期人类临床试验中 这种方法将为SS患者减少唾液腺炎并增强唾液分泌提供前所未有的效果。 减轻 SS 患者负担的可能性，同时实现术中诊断唾液腺 预期的 U01 I/IIa 期试验将评估安全性和最大疗效。 AZD9056首次的耐受剂量、药代动力学和药效学特性以及临床疗效 对原发性 SS 患者进行剂量递增和队列扩展试验 该试验将确定是否可以。 SS 患者导管内和全身 AZD9056 联合给药可抑制细胞机制 使用临床生物样本研究潜在的 SS。 R34 具体目标 1：制定 SS 患者 SG 导管内和全身 AZD9056 的监管计划。 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给药 AZD9056。 R34 具体目标 3：制定 SS 患者生物样本的方案，以确定 AZD9056 对 SS 患者 SG 功能障碍的机制。

项目成果

The minimally important difference for the Xerostomia Inventory among Sjögren's disease patients.

干燥病患者口干症清单的最小重要差异。

• DOI: 10.1111/odi.14841
• 发表时间: 2023
• 期刊: Oral diseases
• 影响因子: 3.8
• 作者: Assy,Zainab;Thomson,WilliamMurray;Brand,HenkS;Cha,Seunghee;Susam,MerveM;Weisman,GaryA;Vissink,Arjan;Bikker,FlorisJ;Jager,DerkHendrikJan
• 通讯作者: Jager,DerkHendrikJan