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

描述（由申请人提供）：多发性硬化症（MS）影响大约40万美国人，构成一种进行性致残疾病，目前的治疗方法不足以治疗。本申请描述了ShK-186的非临床开发，ShK-186是一种靶向MS中的效应记忆T细胞（TEM）群体的新型Kv1.3钾通道抑制剂。TEM细胞在与自身免疫性疾病相关的组织损伤中起着重要作用，并且已经在MS、类风湿性关节炎和类风湿性关节炎的CNS、滑液和外周血中鉴定出自身反应性Kv1.3依赖性TEM细胞。和1型糖尿病患者。ShK-186是由乔治钱迪博士（合作PI）和他的团队在欧文的加州大学发现的。该药物正在由基内塔Inc.进行商业开发。来自华盛顿州西雅图。ShK-186以皮摩尔效力抑制Kv1.3钾通道功能，并通过TEM细胞减少促分裂原刺激的细胞因子产生、[3 H]-胸苷掺入、细胞运动性和抗原呈递细胞相互作用。此外，ShK-186及其密切相关的类似物ShK-170已被证明可以预防和治疗许多自身免疫动物模型中的疾病，包括过继转移实验性自身免疫性脑炎（EAE）、免疫介导的慢性复发性EAE（CR-EAE）和降植烷诱导的关节炎。ShK-186在临床前动物模型中表现出优异的耐受性和安全性，包括在大鼠28天重复给药毒性研究中。该药物在受体分析研究中表现出对Kv1.3的良好特异性，并且没有心脏毒性的证据，包括在清醒大鼠的ECG遥测研究中。本申请将进行：（1）在CR-EAE模型中进行进一步的临床前研究，以更好地确定剂量、给药频率和治疗期与药物疗效之间的关系，（2）大鼠GLP耐受性和毒理学研究，以支持ShK-186向美国食品药品监督管理局提交的新药研究申请，以及（3）准备pre-IND和IND提交文件。这个为期两年的项目的主要里程碑是向FDA提交IND申请，旨在支持ShK-186的首次人体临床试验。 公共卫生相关性：该项目涉及开发一种药物ShK-186，用于治疗多发性硬化症和其他自身免疫性疾病。该药物靶向称为“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".