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， 阿尔茨海默病（AD）的多种小鼠模型，并且其提供了用于治疗阿尔茨海默病的不同治疗方法。 治疗人类AD。 目前还没有药物或其他治疗干预措施可以逆转或停止这种情况。 阿尔茨海默病（AD）的进展。需要从根本上重新思考临床 AD的候选人被选择和测试是例证了大量的临床试验失败， 潜在的AD治疗剂。一种有效的AD药物必须表现出对多种疾病的强大作用， 病理过程。一种真正的疾病修饰药物，具有长期的治疗益处， 认知方面的益处将对数百万受AD影响的人产生巨大的益处。CMS121来源于 一种不同的AD治疗方法，不直接与失败药物的靶点相互作用 候选药物，从而提供全新的AD候选药物。 该产品是与索尔克研究所的科学家合作开发的，用于治疗阿尔茨海默氏症。 疾病（AD）。母体化合物，从广泛的神经保护化合物筛选中鉴定出来， 活性，以获得一系列具有非常优越的上级保护和药理学活性的衍生物。 特色衍生物CMS121可以预防和逆转许多相关症状， 在遗传性和散发性AD小鼠模型中， 作用机制的研究表明，CMS121影响多种特定的脂质调节剂， 合成和代谢，导致脂肪酸合成减少和脂质过氧化。两 这些特征在AD脑中升高，且水平升高与神经炎症相关。 抑制或去除这些脂质合成和代谢的调节剂已被证明是有益的 在AD的小鼠模型中。 目前，国家自主研发扶持研究已进入最后阶段。大规模的GMP生产已 已完成且足够的产品可用于临床试验。该产品已经过稳定性测试， 各种条件、遗传毒性、吸收、分布、代谢和排泄。最后一次毒物检测 在老鼠和狗身上的药理学研究也即将完成。FDA已收到通知， 有意提交IND申请，并已为Virogenics分配了CMS121的IND编号。提交 IND申请将于2020年第四季度完成。本申请中提出的临床试验是 评估CMS 121作为治疗AD的候选药物的下一步。

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.