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）影响了大约40万美国人，是一种进行性致残疾病，目前的治疗方法尚不充分。该申请描述了ShK-186的非临床开发，ShK-186是一种新型Kv1.3钾通道抑制剂，靶向MS中的效应记忆T细胞（TEM）群体。TEM细胞在与自身免疫性疾病相关的组织损伤中发挥着重要作用，并且在MS、类风湿关节炎和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博士和他的团队发现的。这种药物正在由华盛顿州西雅图的KINETA公司进行商业开发。ShK-186以皮摩尔效抑制Kv1.3钾通道功能，减少TEM细胞的有丝分裂原刺激的细胞因子产生、[3H]-胸苷结合、细胞运动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已在许多自身免疫性动物模型中被证明可以预防和治疗疾病，包括过继性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）和前列腺素诱导的关节炎。ShK-186在临床前动物模型中表现出良好的耐受性和安全性，包括在28天的大鼠重复给药毒性研究中。在受体谱研究中，该药物对Kv1.3表现出极好的特异性，并且在有意识大鼠的心电图遥测研究中，没有证据表明其具有心脏毒性。目前的申请将进行：(1)进一步的CR-EAE模型临床前研究，以更好地确定剂量、剂量频率和治疗周期对药物疗效的关系；(2)大鼠GLP耐受性和毒理学研究，以支持ShK-186向美国食品和药物管理局申请新药；(3)准备IND前和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。

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".