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Pre-Clinical and Clinical Evaluation of Skeletal Muscle Activator, CK-2017357 for

骨骼肌激活剂的临床前和临床评价，CK-2017357

基本信息

批准号：
8541396
负责人：
AARON C HINKEN
金额：
$ 53.05万
依托单位：
CYTOKINETICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-25 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8541396
关键词：
Acute Aging Antibodies Autoimmune Process Binding Biological Markers Biological Products Blood Cachexia Cholinergic Receptors Chronic Clinical Clinical Protocols Clinical assessments Complex Data Development Disease Dose Double-Blind Method Experimental Autoimmune Myasthenia Gravis Fatigue Frequencies Funding Goals Heart failure Human Immunization In Situ Intermittent Claudication Leg Malignant Neoplasms Measurement Measures Medical Metric Modeling Muscle Muscle Cramp Muscle Fatigue Muscle Fibers Muscle Weakness Muscle function Myasthenia Gravis Nerve Neuromuscular Diseases Oral Pain Passive Transfer Experimental Autoimmune Myasthenia Gravis Patients Performance Peripheral arterial disease Pharmacodynamics Phase Phase I Clinical Trials Phase II Clinical Trials Phase III Clinical Trials Physical Function Randomized Rattus Recovery Rehabilitation therapy Research Research Design Sarcomeres Sentinel Skeletal Muscle Staging Symptoms Testing Therapeutic Time Troponin United States United States National Institutes of Health Weight base coping design drug mechanism food consumption frailty grasp healthy volunteer human study improved muscle strength neuromuscular transmission novel patient population pre-clinical public health relevance receptor research clinical testing response sarcopenia small molecule wasting

项目摘要

DESCRIPTION (provided by applicant): Cytokinetics, Inc. is a clinical-stage biopharmaceutical company focused on the discovery and development of novel small molecule therapeutics that modulate muscle function for the potential treatment of serious diseases and medical conditions. A central effort is to develop novel skeletal muscle activators to treat diseases that result in skeletal muscle weakness and fatigue. The company has developed a direct activator of fast skeletal muscle fibers, CK-2017357. This compound binds to the troponin complex of the sarcomere and sensitizes muscle to nerve stimulation, increasing force development at sub-maximal stimulation. A first time in human (FTIH) study of this compound was initiated in healthy volunteers in the United States in June 2009. Direct activation of the skeletal muscle sarcomere is a unique drug mechanism and has potential applications to a large number of diseases where muscle weakness is a feature; these include serious neuromuscular disorders, rehabilitation recovery, intermittent claudication (cramping pains in the legs caused by peripheral arterial disease), muscle wasting (cachexia) associated with cancer, heart failure or other diseases, and the frailty associated with aging (also known as sarcopenia). The objective of this project is to demonstrate a clinical proof-of-concept in myasthenia gravis (MG), a serious autoimmune neuromuscular disorder caused by auto-antibodies to the acetylcholine receptor of muscle. Preclinical evidence suggests that muscle sensitization with CK-2017357 may directly reduce weakness and fatigue in these patients where neuromuscular transmission is limiting. The specific aims for this project are two-fold: (i) to gather convincing preclinical evidence of efficacy in models of MG by measuring muscle function in a rat model of MG (experimental autoimmune MG model caused by immunization of rats with purified acetylcholine receptor protein) and (ii) to establish proof-of-concept in a Phase 2A trial of patients with MG. Physical performance will be evaluated in MG patients after a single dose or multiple doses. These studies will be enabled by Cytokinetics' FTIH Phase I clinical trial in healthy volunteers. CK-2017357 represents a "first in class" functional activator of skeletal muscle with potentially broad therapeutic application to conditions with muscle weakness. Positive data from a Phase 2A trial in MG would encourage Phase 3 trials in MG and other neuromuscular disorders as well as provide momentum to examine this promising therapeutic strategy in other indications. PUBLIC HEALTH RELEVANCE: We have developed a "first in class" compound, CK-2017357, which can directly increase force in skeletal muscle. The research detailed in this application will provide evidence that CK-2017357 can increase muscle force in the severe neuromuscular disease, myasthenia gravis and help patients cope with the muscle weakness that occurs in this disease.

描述(申请人提供)：细胞动力学公司是一家临床阶段的生物制药公司，专注于发现和开发新型小分子疗法，这些疗法可以调节肌肉功能，用于潜在的严重疾病和医疗条件的治疗。一个主要的努力是开发新的骨骼肌激活剂来治疗导致骨骼肌无力和疲劳的疾病。该公司已经开发出一种快速骨骼肌纤维的直接激活剂CK-2017357。这种化合物与肌节的肌钙蛋白复合体结合，使肌肉对神经刺激敏感，在次最大刺激时增加力量的发展。对这种化合物的首次人体(FTIH)研究于2009年6月在美国健康志愿者中启动。直接激活骨骼肌肌节是一种独特的药物机制，在许多以肌肉无力为特征的疾病中具有潜在的应用；这些疾病包括严重的神经肌肉疾病、康复、间歇性跛行(由外周动脉疾病引起的腿部抽筋疼痛)、与癌症、心力衰竭或其他疾病相关的肌肉萎缩(恶病质)，以及与衰老相关的虚弱(也称为肌萎缩症)。这个项目的目的是证明重症肌无力(MG)的临床概念验证，MG是一种严重的自身免疫性神经肌肉疾病，由肌肉的乙酰胆碱受体自身抗体引起。临床前证据表明，CK-2017357的肌肉敏化可以直接减轻这些神经肌肉传递受限的患者的虚弱和疲劳。该项目的具体目标有两个：(I)通过测量MG(纯化的乙酰胆碱受体蛋白免疫大鼠所致的实验性自身免疫性MG模型)大鼠模型的肌肉功能，收集令人信服的临床前证据，证明MG模型的有效性；(Ii)在MG患者的2A期试验中建立概念验证。MG患者的体能表现将在单剂或多剂后进行评估。这些研究将由细胞动力学公司在健康志愿者身上进行的FTIH I期临床试验实现。CK-2017357代表了一种“一流”的骨骼肌功能激活剂，具有潜在的广泛治疗应用于肌肉无力的条件。MG的2A期试验的积极数据将鼓励MG和其他神经肌肉疾病的3期试验，并为在其他适应症中检验这一有前景的治疗策略提供动力。与公共健康相关：我们已经开发出一种“一流”化合物CK-2017357，它可以直接增加骨骼肌的力量。本申请中详述的研究将提供证据表明，CK-2017357可以增加重症肌无力这一严重神经肌肉疾病的肌力，并帮助患者应对这种疾病中出现的肌肉无力。