IND-enabling Studies and GMP Scale-up of 18-Methoxycoronaridine hydrochloride(18-

描述(由申请人提供)：需要治疗物质相关疾病(SRDS)的新药是至关重要的，因为仅在美国就有数千万人受到SRD的不利影响。目前，美国食品和药物管理局批准的治疗SRDS的药物都不是最佳的。此外，目前还没有批准用于可卡因、甲基苯丙胺或大麻使用障碍的药物。根据神经药理学和神经科学的最新进展开发和批准新药有可能改善数百万SRDS患者的生活。Savant HWP，Inc.正在开发一种新型的口服活性药物18-甲氧基冠醚盐酸盐(18-MC)，这是一种尼古丁胆碱能受体拮抗剂，通过阻断缰核-脚间通路和基底外侧杏仁核中的尼古丁受体间接调节多巴胺能中脑边缘通路，以治疗SRDS。这项赠款提案的目的是开发和扩大18-MC的GMP生产，并完成启用IND的体外和体内毒理学研究，以支持IND和首次在人类(FTIH)中对可卡因使用障碍患者的研究。目前的数据清楚地支持正在进行的18-MC治疗SRDS的开发。治疗可卡因使用障碍的药物需求尚未得到满足，这突显了我们的赠款后战略的重要性，即将18-MC转移到临床和FTIH研究中，这些研究针对患有线索诱导的药物寻找特别具有挑战性的障碍的个人，例如可卡因的使用。在研究条件下，18-MC批量生产的最新数据将被用来使GMP合同制造商能够开发和扩大最多1.0公斤批次的18-MC活性药物成分(API)的GMP生产，用于开发和制造用于未来临床研究、ICH稳定性测试和体外和体内GLP研究的药物产品。来自Savant研究的数据将被用来为使用GMP 18-MC的IND-Enabling GLP研究提供信息。GLP的体外研究将包括细菌反向突变、人外周血淋巴细胞染色体畸变、使用人肝微粒体的P450以及在兔浦肯野纤维和体内小鼠微核中的心脏动作电位持续时间，所有这些都将在更大规模的动物毒理学研究之前进行。IND-Enable GLP小鼠毒理学研究将包括：7天重复剂量研究；28天重复剂量研究，评估低、中、高剂量以确定NOAEL和CNS的影响；呼吸安全性研究；以及可卡因相互作用研究。IND-Enabling GLP狗的毒理学研究将包括：剂量发现研究；7天和28天的低、中、高剂量研究以确定NOAEL；可卡因相互作用研究；以及单剂量心血管影响研究。

DESCRIPTION (provided by applicant): The need for new medications to treat Substance-Related Disorders (SRDs) is critical since SRDs adversely affect tens of millions of people in the U.S. alone. Currently, no medication approved by the Food and Drug Administration for the treatment of SRDs is optimal. Also, there are no medications approved for cocaine, methamphetamine or cannabis use disorders. The development and approval of new medications based upon recent advances in neuropharmacology and neuroscience has the potential to improve the lives of millions suffering with SRDs. Savant HWP, Inc. is developing a novel, orally active medication, 18-methoxycoronaridine hydrochloride (18-MC), an ¿3¿4nicotinic cholinergic receptor antagonist that indirectly modulates the dopaminergic mesolimbic pathway via blockade of ¿3¿4nicotinic receptors in the habenulo-interpeduncular pathway and the basolateral amygdala, to treat SRDs. The purpose of this grant proposal is to develop and scale-up GMP production of 18-MC and to complete IND-enabling in vitro and in vivo toxicology studies in support of an IND and First Time In Human (FTIH) studies in individuals with cocaine use disorders. Current data clearly support the ongoing development of 18-MC for the treatment of SRDs. The unmet need for medications to treat cocaine use disorders underscores the importance of our post-grant strategy to move 18-MC into the clinic and FTIH studies in individuals with disorders where cue-induced drug seeking is particularly challenging, such as cocaine use. Current data from the production of 18-MC in batches of less than 30g under research conditions will be used to enable a GMP contract manufacturer to develop and scale-up GMP manufacturing of up to 1.0 Kg batches of 18-MC active pharmaceutical ingredient (API) for use in the development and manufacture of drug product for future clinical studies, ICH stability testing and IND-enabling in vitro and in vivo GLP studies. Data from Savant's research studies will be used to inform IND-enabling GLP studies using GMP 18-MC. GLP in vitro studies will include bacterial reverse mutation, chromosome aberration in human peripheral blood lymphocytes, p450 using human liver microsomes and cardiac action potential duration in rabbit Purkinje fibers and in vivo mouse micronucleus, all of which will precede larger scale animal toxicology studies. IND-enabling GLP murine toxicology studies will include: a 7-day repeat dose study; a 28-day repeat dose study evaluating low, intermediate and high doses to identify the NOAEL and CNS effects; a respiratory safety study; and a cocaine interaction study. IND-enabling GLP dog toxicology studies will include: a dose finding study; 7- and 28-day studies with low, intermediate and high doses to identify the NOAEL; a cocaine interaction study; and a single dose cardiovascular effects study.