Development of Kv1.3 channel blocker ShK-186 as a therapy for multiple sclerosis

描述(申请人提供)：多发性硬化症(MS)影响大约400,000美国人，并构成一种进行性、致残性疾病，目前的治疗方法不足以治疗。这项应用描述了ShK-186的非临床开发，ShK-186是一种新型的Kv1.3钾通道抑制剂，针对MS中的效应记忆T细胞(TEM)群体，在与自身免疫性疾病相关的组织损伤中发挥着重要作用，已在MS、类风湿性关节炎和1型糖尿病患者的中枢神经系统、滑液和外周血中发现了依赖Kv1.3的自身反应性TEM细胞。ShK-186是由加州大学欧文分校的George Chandy博士(合作者)和他的团队发现的。该药物正由华盛顿州西雅图的Kineta Inc.进行商业开发。ShK-186抑制Kv1.3钾通道功能，抑制Kv1.3钾通道的皮摩尔效应，并减少有丝分裂原刺激的细胞因子的产生、[~3H]-胸腺嘧啶核苷的掺入、细胞运动和由透射电子显微镜细胞与抗原提呈细胞的相互作用。此外，ShK-186及其密切相关的类似物ShK-170已被证明在许多自身免疫动物模型中具有预防和治疗疾病的作用，包括过继传递性实验性自身免疫性脑炎(EAE)、免疫介导的慢性复发性EAE(CR-EAE)和Pristane诱导的关节炎。ShK-186在临床前动物模型中表现出极好的耐受性和安全性，包括在大鼠28天的重复剂量毒性研究中。该药物在受体图谱研究中对Kv1.3表现出极好的特异性，并且没有证据表明心脏毒性，包括在清醒大鼠的心电遥测研究中。本申请将进行：(1)CR-EAE模型的进一步临床前研究，以更好地确定剂量、剂量频率和治疗周期之间的关系对药物疗效的影响；(2)大鼠的GLP耐受性和毒理学研究，以支持向食品和药物管理局提交ShK-186的调查性新药申请；以及(3)准备IND前和IND提交文件。这项为期两年的计划的主要里程碑是向FDA提交了一份IND申请，旨在支持ShK-186的首个人类临床试验。 公共卫生相关性：该项目涉及一种名为ShK-186的药物的开发，用于治疗多发性硬化症和其他自身免疫性疾病。这种药物针对的是一种被称为“效应记忆T细胞”的特定免疫细胞群。

DESCRIPTION (provided by applicant): Multiple sclerosis (MS) affects approximately 400,000 Americans and constitutes a progressive, disabling disease for which current therapies are inadequate. This application describes the nonclinical development of ShK-186, a novel Kv1.3 potassium channel inhibitor that targets the effector memory T cell (TEM) population in MS. TEM cells play a prominent role in the tissue damage associated with autoimmune disease, and autoreactive Kv1.3-dependent TEM cells have been identified in the CNS, synovial fluid, and peripheral blood of MS, rheumatoid arthritis, and type 1 diabetes mellitus patients. ShK-186 was discovered by Dr. George Chandy (co-PI) and his group at the University of California at Irvine. The drug is being developed commercially by KINETA Inc. of Seattle, WA. ShK-186 inhibits Kv1.3 potassium channel function with picomolar potency and reduces mitogen-stimulated cytokine production, [3H]-thymidine incorporation, cell motility, and antigen-presenting cell interaction by TEM cells. In addition, ShK-186 and its closely-related analog, ShK-170 have been shown to prevent and treat disease in a number of autoimmune animal models including adoptive-transfer experimental autoimmune encephalitis (EAE), immunization-mediated, chronic relapsing EAE (CR-EAE), and pristane-induced arthritis. ShK-186 has demonstrated excellent tolerability and safety in preclinical animal models including in a 28-day, repeat dose toxicity study in rat. The drug demonstrates excellent specificity for Kv1.3 in receptor profiling studies, and there is no evidence for cardiac toxicity including in ECG telemetry studies of conscious rats. The present application will undertake: (1) further preclinical studies in the CR-EAE model to better define the relationship between dose, dose frequency, and treatment period on drug efficacy, (2) GLP tolerability and toxicology studies in rat to support an Investigational New Drug application for ShK-186 to the Food and Drug Administration, and (3) preparation of the pre-IND and IND submission documents. The major milestone of this two-year program is the submission to FDA of an IND application intended to support first-in-human clinical trials of ShK-186. PUBLIC HEALTH RELEVANCE: This project involves the development of a drug, ShK-186, to treat multiple sclerosis and other autoimmune diseases. The drug targets a specific population of immune cells termed "effector memory T cells".