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

18-甲氧基冠状病毒盐酸盐（18-

• 批准号: 8448461
• 负责人: Scott M. Freeman
• 金额: $ 366.86万
• 依托单位: SAVANT HWP, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-30 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8448461
• 关键词: Action Potentials; Affect; Alcohols; Amygdaloid structure; Animal Model; Animals; Applications Grants; Attenuated; Behavior; Bone Marrow; Canis familiaris; Cannabis; Cardiac; Cardiovascular system; Cholinergic Receptors; Chromosome abnormality; Clinic; Clinical; Clinical Research; Cocaine; Cocaine Abuse; Contracts; Cues; Data; Development; Disease; Dose; Future; Grant; Hepatocyte; Human; Hydrochloride Salt; In Vitro; Individual; Lead; Lethal Dose 50; Libraries; Liver Microsomes; Manufacturer Name; Manuscripts; Methamphetamine; Microsomes; Modeling; Morphine; Mus; Mutation; Neurons; Neuropharmacology; Neurosciences; Nicotine; Nicotinic Receptors; No-Observed-Adverse-Effect Level; Oryctolagus cuniculus; Pathway interactions; Patients; Peripheral Blood Lymphocyte; Personal Communication; Pharmaceutical Preparations; Pharmacologic Substance; Production; Research; Safety; Self Administration; Societies; Structure of purkinje fibers; Substance-Related Disorders; Time; Toxicology; United States Food and Drug Administration; base; cocaine use; coronardine; cost; dosage; economic cost; improved; in vivo; innovation; micronucleus; novel; receptor; research study; respiratory; safety study; scale up; stability testing; treatment duration

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. PUBLIC HEALTH RELEVANCE: Although this proposal is focused on treating cocaine abuse, because no treatment for cocaine abuse currently exists, an innovative aspect of this proposal is that 18-methoxycoronaridine hydrochloride (18-MC) has the potential to treat multiple forms of Substance-Related Disorders (SRDs). Furthermore, in developing 18-MC for clinical use, we are targeting a receptor mechanism and a neuronal pathway not yet explored in medication development. 18-MC truly represents a "paradigm shift" in the overall approach to treating SRDs. The potential benefit is extraordinary, both in terms of lives saved and economic cost to society.

描述（由申请人提供）：对治疗物质相关疾病（SRDs）的新药的需求至关重要，因为仅在美国，SRDs就对数千万人产生了不利影响。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治疗可卡因、甲基苯丙胺或大麻使用障碍的药物。基于神经药理学和神经科学的最新进展，新药物的开发和批准有可能改善数百万SRDs患者的生活。Savant HWP, Inc.正在开发一种新的口服活性药物，18-甲氧基冠状苯胺盐酸盐（18-MC），一种烟碱胆碱能受体拮抗剂，通过阻断habeno -束间通路和杏仁核基底外侧的烟碱受体，间接调节多巴胺能中脑边缘通路，以治疗SRDs。该拨款提案的目的是开发和扩大18-MC的GMP生产，并完成IND的体外和体内毒理学研究，以支持IND和可卡因使用障碍个体的首次人体（FTIH）研究。目前的数据明确支持正在进行的18-MC治疗SRDs的研究。治疗可卡因使用障碍的药物需求未得到满足，这强调了我们在批准后将18-MC推向临床和FTIH研究的重要性，这些研究在线索诱导药物寻找特别具有挑战性的个体疾病中，如可卡因使用。在研究条件下批量生产小于30g的18-MC的当前数据将用于使GMP合同制造商开发和扩大批量生产高达1.0 Kg的18-MC活性药物成分（API）的GMP生产，用于开发和生产用于未来临床研究的药物产品，ICH稳定性测试和ind - enable体外和体内GLP研究。来自Savant研究的数据将用于使用GMP 18-MC进行IND-enabling GLP研究。GLP的体外研究将包括细菌逆转突变、人外周血淋巴细胞染色体畸变、人肝微粒体p450、兔浦肯野纤维心脏动作电位持续时间和小鼠体内微核，所有这些都将先于更大规模的动物毒理学研究。启用ind的GLP小鼠毒理学研究将包括：7天重复剂量研究；一项为期28天的重复剂量研究，评估低、中、高剂量，以确定NOAEL和中枢神经系统的影响；呼吸安全研究；以及可卡因相互作用的研究。启用ind的GLP犬毒理学研究将包括：剂量发现研究；以低、中、高剂量进行为期7天和28天的研究，以确定NOAEL；可卡因相互作用研究；以及单剂量心血管效应研究。