Development of Novel Small Molecule Therapies for Skeletal Muscle Atrophy

描述（由申请人提供）：骨骼肌萎缩是一个广泛而严重的医学问题。骨骼肌萎缩的常见原因包括骨科损伤、卧床休息、高龄、癌症、心力衰竭、慢性阻塞性肺病、糖尿病、中风、肾衰竭、危重疾病和脊髓损伤。骨骼肌萎缩的影响包括虚弱、活动减少、跌倒、骨折、衰弱、住院和康复时间延长、养老院安置和死亡率增加。尽管骨骼肌萎缩具有广泛的临床影响，但对肌肉萎缩的药物治疗尚不存在，目前的治疗方法（营养和物理康复）往往无效和/或不可行。因此，骨骼肌萎缩代表着一个巨大的未满足的医疗需求和全球市场。Emmyon公司的总体目标是开发一种骨骼肌萎缩的药物治疗方法。在初步研究中，Emmyon在爱荷华大学的创始人发现了一种保密且专有的小分子化合物（化合物a），它可以：1)抑制骨骼肌萎缩，刺激肌肉肥大，增加老鼠的力量和运动能力；2)刺激人类和小鼠培养的骨骼肌管中的蛋白质增加和细胞肥大。基于这项工作，爱荷华大学申请了含有化合物A在预防和治疗骨骼肌萎缩方面的使用权利要求的专利。Emmyon正在就这一知识产权的独家授权进行最后阶段的谈判。从商业化的角度来看，化合物a是一种有吸引力的先导化合物，可以用于预防和治疗人类和伴侣动物的肌肉萎缩。然而，对于药物开发至关重要的物质组成声称是不可能的。因此，为了开发一种治疗骨骼肌萎缩的药物，Emmyon的中心研发目标之一是发现和开发有效的新型化学实体（NCEs），其结构基于化合物a。这些NCEs将实现物质成分的声明，并且可能具有相对于化合物a显著改善的药理学特性。Emmyon将识别具有高商业潜力的有效化合物基新型化学实体（NCEs）。将合成一系列可申请专利的化合物基NCEs，并与化合物A在人骨骼肌管中的应用进行比较。与化合物A相比，具有更高效力和/或功效的NCEs将在小鼠身上测试其减少骨骼肌萎缩的能力。在II期研究中，Emmyon将把最有希望的NCE带入大鼠和狗的药代动力学和毒理学研究，然后进行IND应用。最初的临床研究将面向FDA批准预防和治疗骨科患者的肌肉萎缩。后续研究将面向FDA批准其他导致骨骼肌萎缩的原因，这些原因预计也适用于这些nce。

DESCRIPTION (provided by applicant): Skeletal muscle atrophy is a widespread and serious medical problem. Frequent causes of skeletal muscle atrophy include orthopedic injuries, bed rest, advanced age, cancer, heart failure, COPD, diabetes, stroke, renal failure, critical illness and spinal cord injury. Effects of skeletal muscle atrophy include weakness, reduced activity, falls, fractures, debilitation, prolonged hospitalization and rehabilitation, nursing home placement, and increased mortality. Although skeletal muscle atrophy has broad clinical impact, a pharmacologic therapy for muscle atrophy does not exist, and current therapeutic approaches (nutrition and physical rehabilitation) are often ineffective and/or unfeasible. Thus, skeletal muscle atrophy represents an enormous unmet medical need and market worldwide. The overall goal of Emmyon, Inc. is to develop a pharmacologic therapy for skeletal muscle atrophy. In preliminary studies, Emmyon's founders at the University of Iowa discovered a confidential and proprietary small molecule compound (compound A) that: 1) inhibits skeletal muscle atrophy, stimulates muscle hypertrophy, and increases strength and exercise capacity in mice; and 2) stimulates protein accretion and cellular hypertrophy in cultured skeletal myotubes from humans and mice. Based on this work, the University of Iowa applied for patents containing use claims for compound A in the prevention and treatment of skeletal muscle atrophy. Emmyon is in the final stages of negotiating an exclusive license to this intellectual property. From a commercialization standpoint, compound A is an attractive lead compound for pharmaceuticals that could prevent and treat muscle atrophy in humans and companion animals. However, composition-of-matter claims, which are critical for pharmaceutical development, are not possible. Thus, to develop a pharmaceutical for skeletal muscle atrophy, one of Emmyon's central R&D goals is to discover and develop potent and effective novel chemical entities (NCEs) whose structures are based on compound A. These NCEs will enable composition-of-matter claims, and may possess significantly improved pharmacologic characteristics relative to compound A. In this phase I STTR study, Emmyon will identify potent and effective compound A-based novel chemical entities (NCEs) with high commercial potential as pharmaceuticals. A series of patentable compound A-based NCEs will be synthesized and compared to compound A in human skeletal myotubes. NCEs with increased potency and/or efficacy relative to compound A will then be tested for their capacity to reduce skeletal muscle atrophy in mice. In Phase II studies, Emmyon will carry the most promising NCE forward into pharmacokinetic and toxicology studies in rats and dogs, and then an IND application. The initial clinical study would be geared towards FDA approval for the prevention and treatment of muscle atrophy in orthopedic patients. Subsequent studies would be geared towards FDA approval for other causes of skeletal muscle atrophy, which are also predicted to be amenable to these NCEs.