Phase 1 Clinical Trial of CMS121, a Novel Therapeutic Candidate for Alzheimer's Disease

摘要 我们的目标是进行CMS121的I期临床试验，CMS121是一种小分子，已在 多种阿尔茨海默病(AD)小鼠模型，为阿尔茨海默病(AD)提供了一种不同的治疗方法 人类阿尔茨海默病的治疗。 目前还没有药物或其他治疗干预措施可以逆转或阻止 阿尔茨海默病(AD)的进展。需要从根本上重新思考临床治疗的方式 AD的候选人被选择和测试，大量的临床试验失败就是例证 潜在的阿尔茨海默病治疗方法。一种有效的AD药物必须对多种疾病表现出强大的疗效 病理过程。一种真正具有长期疗效和立竿见影效果的疾病修改药物 对于数百万受AD影响的人来说，认知方面的好处将是一个巨大的好处。CMS121衍生自 一种不同的AD治疗方法，并且不直接与失败药物的靶点相互作用 候选药物，从而提供了一个全新的AD药物候选药物。 该产品是与索尔克研究所的科学家共同开发的，用于治疗阿尔茨海默氏症 疾病(AD)。母体化合物，从广泛的化合物中鉴定出具有神经保护作用 活性，被修饰以获得一系列具有极好的保护和药理作用的衍生物 特点。这种名为CMS121的衍生物可以预防和逆转一些相关症状 在遗传性和散发性阿尔茨海默病小鼠模型中都存在AD。 对作用机制的研究表明，CMS121影响多种特定的血脂调节剂 合成代谢，导致脂肪酸合成减少，脂质过氧化。两个都是 这些特征在AD大脑中升高，与神经炎症相关的水平增加。 抑制或去除这些脂质合成和新陈代谢的调节剂已被证明是有益的 在阿尔茨海默病小鼠模型中。 目前，支持IND的研究已进入最后阶段。规模化的GMP生产 完整和充足的产品已准备好进行临床试验。该产品已在一种环境下进行了稳定性测试。 各种条件、遗传毒性、吸收、分布、代谢和排泄。最后的毒物学 在老鼠和狗身上进行的药理学研究也接近完成。已经通知了FDA我们的 打算提交IND申请，并已为病毒学公司分配了CMS121的IND编号。呈交 IND的申请计划于2020年第四季度完成。本申请中建议的临床试验是 下一步是评估CMS121作为治疗AD的候选药物。

Abstract Our goal is to conduct a Phase I clinical trial of CMS121, a small molecule that has shown efficacy in multiple mouse models of Alzheimer's Disease (AD) and which affords a different therapeutic approach for treatment of AD in humans. There are currently no drugs or other therapeutic interventions that can reverse or halt the progression of Alzheimer's disease (AD). The need for a fundamental rethinking of the way clinical candidates for AD are chosen and tested is exemplified by the large number of clinical trial failures for potential AD therapeutics. An effective AD drug will have to demonstrate powerful effects against multiple pathological processes. A truly disease-modifying drug with long-term therapeutic benefits and immediate cognitive benefits would be a tremendous benefit to the millions affected by AD. CMS121 was derived from a different approach to an AD therapeutic and does not directly interact with the targets of the failed drug candidates, thereby providing an altogether new AD drug candidate. The product was developed in conjunction with Salk Institute scientists for treatment of Alzheimer's Disease (AD). The parent compound, identified from a broad screen of compounds for neuroprotective activity, was modified to obtain a series of derivatives with vastly superior protective and pharmacologic characteristics. The derivative, CMS121, prevents and reverses a number of the symptoms associated with AD in both genetic and sporadic mouse models of AD. Studies of the mechanism of action show CMS121 affects multiple, specific regulators of lipid synthesis and metabolism, resulting in reduction of fatty acid synthesis and lipid peroxidation. Both of these features are elevated in AD brains with the increased levels associated with neuroinflammation. Inhibition or removal of these regulators of lipid synthesis and metabolism has been shown to be beneficial in mouse models of AD. Currently, the IND-enabling studies are in the final stages. Large scale GMP manufacture has been completed and sufficient product is ready for clinical trial. The product has been tested for stability under a variety of conditions, genotoxicity, absorption, distribution, metabolism and excretion. The last toxicology and pharmacology studies in rats and dogs are nearing completion. The FDA has been notified of our intent to file an IND application and has assigned Virogenics an IND number for CMS121. Submission of the IND application is on target for the fourth quarter 2020. The clinical trial proposed in this application is the next step in evaluating CMS121 as a drug candidate for treatment of AD.