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

• 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
• 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

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（由申请人提供）：Cytokinetics, 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，以潜在治疗严重疾病和医疗状况。一个中心工作是开发新型骨骼肌激活剂来治疗导致骨骼肌无力和疲劳的疾病。该公司开发了快速骨骼肌纤维直接激活剂CK-2017357。这种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，从而增加次最大刺激下的力量发展。该化合物的首次人体 (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，对于许多导致肌肉无力的疾病具有潜在的应用价值。是一个特征；这些包括严重的神经肌肉疾病、康复恢复、间歇性跛行（由外周动脉疾病引起的腿部痉挛性疼痛）、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（也称为肌少症） ）。该项目的目的是证明重症肌无力 (MG) 的临床概念验证，重症肌无力是一种由肌肉乙酰胆碱受体自身抗体引起的严重自身免疫性神经肌肉疾病。临床前证据表明，CK-2017357 的肌肉敏化可能会直接减轻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 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 MG 模型）的肌肉功能，收集 MG 模型疗效的令人信服的临床前证据) 和 (ii) 在 MG 患者的 2A 期试验中建立概念验证。在单次或多次剂量后，将评估 MG 患者的身体表现。这些研究将通过 Cytokinetics 在健康志愿者中进行的 FTIH I 期临床试验来实现。 CK-2017357 代表了一种“一流”的骨骼肌功能激活剂，对于肌无力疾病具有潜在广泛的治疗应用。重症肌无力 2A 期试验的积极数据将鼓励重症肌无力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。 公共健康相关性：我们开发了一种“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，并帮助患者应对这种疾病中出现的肌肉无力。

项目成果

A Double-Blinded, Randomized, Placebo-Controlled Trial to Evaluate Efficacy, Safety, and Tolerability of Single Doses of Tirasemtiv in Patients with Acetylcholine Receptor-Binding Antibody-Positive Myasthenia Gravis.

一项双盲、随机、安慰剂对照试验，旨在评估单剂量 Tirasemtiv 对乙酰胆碱受体结合抗体阳性重症肌无力患者的疗效、安全性和耐受性。

• 发表时间: 2015-04
• 作者: Sanders, Donald B;Rosenfeld, Jeffrey;Dimachkie, Mazen M;Meng, Lisa;Malik, Fady I;Tirasemtiv in Myasthenia Gravis Study Group
• 通讯作者: Tirasemtiv in Myasthenia Gravis Study Group

Obstructive Sleep Apnea and Preclinical Cardiac Damage: Need for U.S. Representative Study Sample

阻塞性睡眠呼吸暂停和临床前心脏损伤：需要美国代表性研究样本

• 发表时间: 2024-09-14
• 作者: Ph.D Monique C. de Waard;S. Frances;Ph.D de Man;M. D. P. J. W. Vermeijden;M. D. Steenvoorde;M. R. Arthur Bouwman;Ph.D Wies Lommen;Ph.D Hieronymus W. H. van Hees;A. LeoM.;M. Heunks;M. Chris Dickhoff;L. Ph.DDonald;M. van der Peet;J. Ph.DArm;R.;R.;M. Girbes;Ph.D Jeff R. Jasper;I. Fady;M. Malik;Ph.D Ger J. M. Stienen;M. Koen J. Hartemink;M. Marinus A. Paul;Ph.D Coen A. C. Ottenheijm
• 通讯作者: Ph.D Coen A. C. Ottenheijm