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

描述（由申请人提供）： 本提案的目的是通过向美国食品药品监督管理局（FDA）提交研究性新药申请所需的研究，最终完成CLT-005（一种新型Stat 3小分子抑制剂）的开发。在临床和基础科学研究中都观察到了视网膜炎症和血管生成疾病中Stat 3通路的激活。我们已经证明，CLT-005可以预防糖尿病动物模型中Stat 3诱导的细胞变化。玻璃体内给药后，CLT-005降低视网膜血管通透性，以及许多血管生成和炎症基因和蛋白质的表达。此外，CLT-005和基于PEG的储库形成制剂在玻璃体内注射后耐受良好，对视觉生理学没有影响，并且产生有利的体外安全性特征。本提案的目标是：1）生产足以用于毒性研究和人体临床试验的CLT-005的GMP量; 2）将CLT-005配制成无菌灌装小瓶并进行稳定性研究; 3）完成IND申请的CMC部分准备工作; 4）对配制和未配制的CLT-005进行药代动力学研究; 5）进行配制的CLT-005的眼部分布研究; 5）进行单剂量和多剂量GLP毒理学和毒代动力学研究; 6）进行遗传毒理学研究;和7）进行体外心脏安全药理学研究。这些研究由FDA授权，以便获得启动人体临床试验的批准。对于眼部药物开发，FDA还要求在两种大眼睛动物模型中进行毒理学研究，例如猴子和兔子，这些动物模型将用于完成上述实验。由于CLT-005对减少视网膜血管渗漏具有深远的影响，我们打算寻求治疗糖尿病黄斑水肿的适应症，糖尿病黄斑水肿是一种目前没有FDA批准的药物治疗的疾病。我们相信CLT- 005在患有视网膜相关黄斑变性（AMD）和糖尿病视网膜病变（DR）的患者中也将是有效的。在成功完成CLT-005的II期人类临床研究之后，我们打算提交新的IND申请以研究CLT-005在治疗AMD和DR中的用途。CLT-005也可以被证明是与现有抗VEGF治疗有效的组合疗法，以减少临床给药的频率。

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.