Safety and Toxicology Studies of CLT-005 as a Therapeutic for Diabetic Macular Ed

描述(由申请人提供)： 该提案的目的是通过向美国食品和药物管理局(FDA)提交调查性新药申请所需的研究，最终完成STAT3的新型小分子抑制剂CLT-005的开发。在临床和基础科学研究中，已经观察到STAT3通路在视网膜炎症和血管生成疾病中的激活。我们已经证明，在糖尿病动物模型中，CLT-005可以防止STAT3诱导的细胞变化。在玻璃体内给药后，CLT-005降低了视网膜血管的通透性，并降低了许多血管生成和炎症基因和蛋白的表达。此外，CLT-005和基于聚乙二醇库形成的制剂在玻璃体内注射后耐受性良好，对视觉生理没有影响，并产生了良好的体外安全性。该建议的目标是：1)生产足够用于毒性研究和人体临床试验的GMP数量的CLT-005；2)将CLT-005制剂装入无菌灌装瓶并进行稳定性研究；3)完成IND应用的CMC切片准备；4)进行配方CLT-005和未配方CLT-005的药代动力学研究；5)进行配方CLT-005的眼部分布研究；5)进行单剂和多剂量GLP毒理学和毒代动力学研究；6)进行遗传毒理学研究；以及7)进行体外心脏安全药理学研究。这些研究是FDA授权的，以获得启动人体临床试验的批准。对于眼科药物的开发，FDA还要求在两个大型眼科动物模型上进行毒理学研究，如猴子和兔子，这将用于完成上述实验。由于CLT-005对减少视网膜血管渗漏有深远的影响，我们打算寻找治疗糖尿病黄斑水肿的适应症，这种疾病目前还没有FDA批准的药物治疗。我们相信CLT-005对老年性黄斑变性(AMD)和糖尿病视网膜病变(DR)患者也有疗效。随着CLT-005的第二阶段人类临床研究的成功完成，我们打算提交新的IND申请，以研究CLT-005在治疗AMD方面的使用，而CLT-005博士也可能被证明是一种与现有的抗血管内皮生长因子治疗相结合的有效疗法，以减少临床剂量的频率。 公共卫生相关性： 视网膜血管渗漏、炎症或血-视网膜屏障的破坏是糖尿病黄斑水肿(DME)的致病特征，并导致随后的视力丧失。目前，还没有FDA批准的治疗DME的药物。在这个第二阶段的项目中，我们将完成对CLT-005的研究，这是一种新型的小分子疗法，以便向FDA提交调查性新药申请。这些研究包括无菌材料和配方的准备、药代动力学研究的性能，以及FDA规定的、对人体临床试验至关重要的严格毒理学/安全性研究的性能。虽然我们打算寻求DME的初步适应症，但CLT-005很可能也将为患有糖尿病视网膜病变和老年性黄斑变性的患者提供显著的治疗益处。

DESCRIPTION (provided by applicant): The objective of this proposal is to finalize development of CLT-005, a novel small molecule inhibitor of Stat3, through the performance of studies required for the submission of an investigative new drug application with the US Food and Drug Administration (FDA). Activation of the Stat3 pathway in retinal inflammatory and angiogenic diseases has been observed in both clinical and basic science studies. We have demonstrated that CLT-005 prevents Stat3-induced cellular changes in an animal model of diabetes. Following intravitreal administration, CLT-005 reduces retinal vascular permeability, and the expression of numerous angiogenic and inflammatory genes and proteins. Additionally, both CLT-005 and the PEG-based depot-forming formulation were well tolerated following intravitreal injection, had no effect on visual physiology, and produced a favorable in-vitro safety profile. The goal of this proposal is to: 1) Produce GMP amounts of CLT-005 sufficient for toxicity studies and human clinical trials; 2) Perform formulation of CLT-005 into sterile fill vials and conduct stability studies; 3) Complete preparation of the CMC section for the IND application; 4) Perform pharmacokinetic studies of formulated and unformulated CLT-005; 5) Perform ocular distribution studies of formulated CLT-005; 5) Conduct single and multiple dose GLP toxicology and toxicokinetic studies; 6) Perform genetic toxicology studies; and 7) Perform in-vitro cardiac safety pharmacology studies. These studies are mandated by the FDA in order to receive approval for the initiation of human clinical trials. For ocular drug development, the FDA also requires that toxicology studies be performed in two large eye animal models, such as monkeys and rabbits, which will be utilized for completion of the experiments outlined above. As CLT-005 has a profound effect on reducing retinal vascular leakage we intend to seek an indication for treating Diabetic Macular Edema, a disease that currently has no FDA-approved pharmaceutical therapy. We believe that CLT- 005 will also be efficacious in patients suffering from Age-Related Macular Degeneration (AMD) and Diabetic Retinopathy (DR). Following the successful completion of Phase II human clinical studies of CLT-005, we intend to file new IND applications to investigate the use of CLT-005 in treating AMD and DR. CLT-005 could also prove to be an effective combinatorial therapy with existing anti-VEGF treatments to reduce the frequency of clinical dosing. PUBLIC HEALTH RELEVANCE: Retinal vascular leakage, inflammation, or breakdown of the blood-retina barrier are pathogenic features of Diabetic Macular Edema (DME) and cause a subsequent loss of vision. Currently, there are no FDA-approved drug treatments for DME. In this Phase II project, we will finalize studies of CLT-005, a novel small molecule therapeutic, to enable the submission of an investigative new drug application to the FDA. These studies include preparation of sterile materials and formulations, performance of pharmacokinetic studies, and performance of rigorous toxicology/safety studies that are mandated by the FDA and essential for human clinical trials. Although we intend to seek an initial indication for DME, it is likely that CLT-005 will also confer a significant therapeutic benefit to patients suffering from Diabetic Retinopathy and Age-Related Macular Degeneration.