Phosphosulindac for dry eye

磷舒林治疗干眼症

• 批准号: 9907964
• 负责人: Basil Rigas
• 金额: $ 37.71万
• 依托单位: APIS THERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9907964
• 关键词: Absence of pain sensation; Address; Affect; Analgesics; Anti-Inflammatory Agents; Antigen-Presenting Cells; Antiinflammatory Effect; Artificial Tears; Binding Proteins; Biodistribution; Blindness; Blood Circulation; CD4 Positive T Lymphocytes; Categories; Cauterize; Characteristics; Chronic; Clinical; Complement; Concanavalin A; Cornea; Cyclosporine; Data; Development; Diagnosis; Diagnostic; Dose; Drug Kinetics; Etiology; Excision; Eye diseases; Eyedrops; Film; Formulation; Functional disorder; Gelatinase B; Goals; Goblet Cells; Gold; Homeostasis; Human; In Vitro; Inflammation; Inflammatory; Injections; Innate Immune Response; Interferon Type II; Interleukin-1 beta; Interleukin-17; Investigational Drugs; Lacrimal gland structure; Lactoferrin; Lead; Lectin; Medical; Metabolic; Modeling; Molecular Target; Mucins; Narcotics; Nerve Endings; Neuropathy; New Agents; Operative Surgical Procedures; Oryctolagus cuniculus; Osmolar Concentration; Pathogenesis; Patients; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phase; Plasma Proteins; Prevalence; Price; Production; Protocols documentation; Rose Bengal; Safety; Signs and Symptoms; Stains; Stress; Subgroup; Sulindac; Symptoms; T-Lymphocyte; Testing; Time; Toxic effect; Toxicology; Validation; Work; adaptive immune response; analytical method; aqueous; base; conjunctiva; corneal epithelium; cost; cytokine; evaporation; eye dryness; human disease; improved; lead optimization; meibomian gland; melting; novel; ocular pain; ocular surface; optimal treatments; phase 1 study; phase 2 study; posterior eyeball chamber; preclinical development; preclinical evaluation; scale up; side effect; small molecule; sulfated glycoprotein 2

ABSTRACT The treatment of dry eye disease (DED) has been hampered by weak agents, significant side effects and high cost. The pathophysiological hallmark of DED that unifies its diverse etiologies is inflammation of the ocular surface that accounts for its clinical manifestations. The optimal treatment of DED must provide strong efficacy; topical analgesia; safety; convenient dosing; and low cost. None of the available treatments for DED meets these criteria. Phosphosulindac (PS) is a proprietary compound. We developed novel robust rabbit models of DED encompassing its main pathophysiological subgroups (evaporative, aqueous deficient and mixed). PS showed remarkable efficacy against DED; excellent safety; practically instantaneous topical analgesia; superiority in terms of efficacy over cyclosporine and lifitegrast, the two currently available drugs for the treatment of DED; and has projected low cost Additional preliminary data include the IND-enabling development of a scaled-up synthesis of PS; and development and validation of all the required analytical methods. We have also identified molecular targets of PS; and developed several formulations for PS encompassing the main physicochemical categories. Our goal is to develop PS as an efficacious drug for DED. In this Fast Track application, we propose the following studies: Phase I studies: Aim#1: Study the effect of PS in an evaporative model of DED, complementing our results with the aqueous deficient and mixed models. Aim #2: Develop the lead formulation of PS. Phase II studies: Aim #3: Optimize the lead formulation from aim #2. Aim #4: Study the in vitro metabolic stability and plasma protein binding of PS. Aim #5: Perform toxicity studies of PS. And Aim # 6: Prepare the IND protocol and package for the FDA. The proposed work, if successful, will contribute greatly towards a successful treatment of DED, a prevalent human disease, which represents an unmet medical need.

抽象的 干眼病 (DED) 的治疗一直受到弱药物、显着副作用的阻碍 效果好，成本高。 DED 的病理生理学特征统一了其多种病因 是导致其临床表现的眼表面炎症。最优的 DED 的治疗必须具有强大的疗效；局部镇痛；安全;给药方便；和 低成本。现有的 DED 治疗方法均不符合这些标准。 Phosphosulindac (PS) 是一种专有化合物。我们开发了新型强健兔 DED 模型涵盖其主要病理生理学亚组（蒸发、房水 缺乏和混合）。 PS对DED表现出显着的功效；卓越的安全性；几乎 瞬时局部镇痛；功效优于环孢素和利菲格斯特， 目前可用于治疗 DED 的两种药物；并预计成本低廉 初步数据包括 PS 放大合成的 IND 开发；和 开发和验证所有必需的分析方法。我们还确定了 PS的分子靶标；并开发了多种 PS 配方，涵盖主要 物理化学类别。 我们的目标是将 PS 开发为治疗 DED 的有效药物。在此快速通道应用程序中， 我们建议进行以下研究： 第一阶段研究：目标#1：研究 PS 在 DED 蒸发模型中的影响， 用缺水模型和混合模型补充我们的结果。目标#2：开发 PS 的主要配方。 II 期研究：目标#3：优化目标#2 的先导制剂。目标#4：研究 PS 的体外代谢稳定性和血浆蛋白结合。目标#5：进行毒性研究 附言。目标#6：为 FDA 准备 IND 协议和包装。 拟议的工作如果成功，将大大有助于成功治疗 DED 是一种流行的人类疾病，代表着未得到满足的医疗需求。