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伤害或疾病引起的重要医学问题，包括Sjögren

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