Advancing CAP4196 into in vivo Proof of Concept Translational Studies

将 CAP4196 推进体内概念验证转化研究

• 批准号: 10203992
• 负责人: ALBERT REMACLE
• 金额: $ 64.9万
• 依托单位: PLEX PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10203992
• 关键词: Address; Adopted; Africa; Aging; Anatomy; Area; Back; Bilateral; Biological Availability; Blindness; Canis familiaris; Caring; Cataract; Cataract Extraction; Chemicals; Complex; Control Groups; Corneal edema; Crystalline Lens; Crystallins; Cyclic GMP; Data; Developed Countries; Development; Diabetes Mellitus; Disease; Dose; Drug Kinetics; Endophthalmitis; Enzymes; Eye; Eyedrops; FDA approved; Family; Family suidae; Far East; Formulation; Generations; Goals; Half-Life; Heat shock proteins; Human; Intellectual Property; Intraocular lens implant device; Keratoplasty; Kilogram; Lasers; Lead; Maximum Tolerated Dose; Medical; Modeling; Molecular Chaperones; Naphthalene; New Zealand; Operative Surgical Procedures; Oral; Organ Culture Techniques; Oryctolagus cuniculus; Parkinson Disease; Pathology; Patients; Pharmaceutical Preparations; Pharmacology; Phase; Physiological; Pre-Clinical Model; Prevention; Prodrugs; Proteins; Public Health; Recombinants; Retinal Detachment; Risk Factors; Safety; Series; Small Business Innovation Research Grant; Smoking; Solubility; Source; Time; Topical application; Trauma; Ultraviolet Rays; Uveitis; Visual impairment; World Health Organization; absorption; age related; aged; alpha-Crystallins; analog; aqueous; arm; base; blind; clinical development; cost effective; cost effective intervention; design; disparity reduction; effective therapy; experimental study; gamma-Crystallins; improved; in vivo; innovation; inorganic phosphate; lead candidate; lead optimization; lens; lens capsule; lens transparency; light scattering; low and middle-income countries; member; novel; phase 1 study; preclinical development; prevent; primary endpoint; programs; scaffold; secondary endpoint; small molecule; symptom treatment; tolcapone; translational study

Project Summary Cataract, the clouding of the eye lens is responsible for 51% of world blindness. According to World Health Organization nearly 18 million people are bilaterally blind from cataracts in the world. Cataract is easily treated by surgery and is considered as one of the most cost-effective interventions. Although cataract surgery is generally considered to be safe, there are significant complications: (i) 30-50% of patients in the US having cataract surgery develop opacification of the posterior lens capsule within two years and require laser treatment; (ii) 0.8% have retinal detachments; (iii) 0.6-1.3% are hospitalized for corneal edema or require corneal transplantation and (iv) about 1% are presented with endophthalmitis. In addition, in many remote and poor areas of the developing and under-developed regions of the world, people still remain blind from cataracts, primarily due to lack of access to eye care. As a result of which, cataract related blindness is as high as 50% or more in poor and remote regions of the world compared to only 5% in developed countries. Alpha-crystallin (AC) is one of the three major eye lens crystallins and is a representative member of the small heat shock protein (sHsp) family. AC serves as molecular chaperone, protecting damaged or aged lens proteins and enzymes from aggregation that would otherwise lead to light scattering and cataract formation. It is well established that chaperone-like activity (CLA) of AC is critical for lens transparency and it is hypothesized that maintaining optimal or increasing chaperone activity might aid in the prevention or slowing of cataracts. The rationale of our proposal is based on the observation that small molecule pharmacological agents from natural sources can prevent the loss of CLA of Alpha crystallin A-chain (AAC) and can delay cataract formation in preclinical models. It has been estimated that delaying cataracts formation by 10 years can reduce the vision care expense by 50%. In addition, our preliminary data supports the hypothesis that an FDA approved drug, tolcapone (CAP1160) increases AAC CLA and maintains transparency of the eye lens in organ culture experiments of cataract model. Therefore, the goal of our proposal is to advance the prodrug of CAP1160, CAP4196 through in vivo efficacy and proof of concept studies to develop a cost-effective non-surgical treatment to: (i) delay the need for cataract surgery and (ii) reduce the disparity of cataract-related blindness globally, and the specific aims are: Aim 1a. Design and synthesis of prodrugs of CAP1160, formulation, stability and maximum tolerated dose (MTD). Aim 1b. Establish cGMP manufacturing and formulation of lead candidate prodrug CAP4196. Aim 2a. Ocular pharmacokinetics of CAP4196. Aim 2b. In vivo POC and efficacy of CAP4196 in dogs with age-related cataracts. Aim 3. SAR based hit-to-lead optimization of naphthalene series from ex vivo efficacy through in vivo safety. Project milestone: Successful completion of these aims will enable CAP4196 to be advanced into clinical development.

项目摘要 白内障，眼睛透镜的混浊是造成世界失明的51%的原因。根据世界 世界上有近1800万人因白内障而双目失明。白内障很容易 通过手术治疗，被认为是最具成本效益的干预措施之一。虽然白内障手术 一般认为是安全的，但有显著的并发症：（i）美国30-50%的患者 白内障手术在两年内发展为后透镜囊混浊， 治疗;（ii）0.8%患有视网膜脱离;（iii）0.6-1.3%因角膜水肿住院或需要 角膜移植和（iv）约1%出现眼内炎。此外，在许多偏远地区， 在世界上发展中和欠发达地区的贫困地区，人们仍然因白内障而失明， 主要原因是缺乏眼部护理。因此，与白内障相关的失明率高达50%， 在世界上贫穷和偏远地区，这一比例高于发达国家的5%。晶体蛋白 (AC)是三大眼透镜晶体蛋白之一，是小热休克的代表成员 sHsp蛋白家族。AC作为分子伴侣，保护受损或老化的透镜蛋白， 酶聚集，否则会导致光散射和白内障形成。公 确定AC的分子伴侣样活性（CLA）对于透镜透明度是关键的，并且假设 保持最佳或增加伴侣蛋白活性可能有助于预防或减缓白内障。的 我们的建议的基本原理是基于观察到来自天然的小分子药理学试剂 来源可以防止α晶体蛋白A链（AAC）的CLA丢失，并可以延缓白内障的形成。 临床前模型。据估计，将白内障的形成推迟10年会降低视力。 护理费用50%。此外，我们的初步数据支持这样的假设，即FDA批准的药物， 托卡朋（CAP 1160）增加AAC CLA并在器官培养中保持眼透镜的透明度 白内障模型实验。因此，我们提案的目标是推进CAP 1160的前药， CAP 4196通过体内疗效和概念验证研究开发了一种具有成本效益的非手术 治疗：（i）延迟白内障手术的需要和（ii）减少白内障相关失明的差异 具体目标是：目标1a。CAP 1160前药的设计和合成，制剂， 稳定性和最大耐受剂量（MTD）。目标1b。建立cGMP生产和铅制剂 候选前药CAP 4196。目标2a。CAP 4196的眼部药代动力学。目标2b。体内POC和疗效 CAP 4196在患有年龄相关性白内障的犬中的作用。目标3.基于SAR的萘的命中率优化 从离体有效性到体内安全性的系列。项目里程碑：成功完成这些目标将 使CAP 4196能够进入临床开发阶段。