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

描述（由申请人提供）：Cytokerase，Inc.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，调节肌肉功能，用于治疗严重疾病和医疗状况。一个中心的努力是开发新的骨骼肌激活剂，以治疗导致骨骼肌无力和疲劳的疾病。该公司开发了一种快速骨骼肌纤维直接激活剂CK-2017357。该化合物与肌节的肌钙蛋白复合物结合，使肌肉对神经刺激敏感，增加次最大刺激时的力量发展。2009年6月，在美国健康志愿者中开始了该化合物的首次人体（FTIH）研究。骨骼肌肌节的直接激活是一种独特的药物机制，并对肌无力为特征的大量疾病具有潜在的应用;这些包括严重的神经肌肉疾病、康复恢复、间歇性跛行（外周动脉疾病引起的腿部痉挛性疼痛），肌肉萎缩与癌症、心力衰竭或其他疾病相关的恶病质（cachexia），以及与衰老相关的虚弱（也称为肌肉减少症（sarcopenia））。本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，由肌肉乙酰胆碱受体的自身抗体引起。临床前证据表明，CK-2017357的肌肉致敏作用可直接减轻这些神经肌肉传递受限患者的虚弱和疲劳。该项目的具体目标有两个方面：（i）通过测量MG大鼠模型（用纯化的乙酰胆碱受体蛋白免疫大鼠引起的实验性自身免疫性MG模型）的肌肉功能，收集MG模型有效性的令人信服的临床前证据;（ii）在MG患者的2A期试验中建立概念验证。将在MG患者中评价单次给药或多次给药后的体能。这些研究将通过Cytokerase在健康志愿者中进行的FTIH I期临床试验来实现。CK-2017357代表了骨骼肌的“一流”功能激活剂，具有潜在的广泛治疗应用，可用于肌无力疾病。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查这种有前途的治疗策略提供动力。 公共卫生相关性：我们开发了一种“同类第一”的化合物CK-2017357，它可以直接增加骨骼肌的力量。本申请中详细描述的研究将提供证据证明CK-2017357可以增加严重神经肌肉疾病重症肌无力的肌肉力量，并帮助患者科普这种疾病中发生的肌肉无力。

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.