THERAPY FOR ALCOHOL USE DISORDER

酒精使用障碍的治疗

• 批准号: 10820349
• 负责人: HERBERT H SELTZMAN
• 金额: $ 36.87万
• 依托单位: ARTIAM BIO INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-25 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10820349
• 关键词: Acute; Adverse effects; Affect; Affinity; Age; Agonist; Alcohol consumption; Alcoholism; American; Anhedonia; Anxiety; BALB/cByJ Mouse; Behavior; Behavioral; Behavioral Assay; Binding; Biological Assay; Biotechnology; CNR1 gene; Cannabinoids; Chronic; Clinical; Clinical Trials; Coupled; Darkness; Data; Development; Disease; Dissociation; Dose; Drug Metabolic Detoxication; Eligibility Determination; Emotional; Endocannabinoids; Enzymes; Event; Feeling suicidal; Funding; Future; Generations; Goals; Human; In Vitro; Inbred Strain; Investments; Knowledge; Lead; Licensing; Ligands; Light; Lipids; Mediating; Mental Depression; Modeling; Mus; Naltrexone; North Carolina; Patients; Personal Satisfaction; Persons; Pharmaceutical Preparations; Pharmacotherapy; Phase; Placebo Effect; Privatization; Process; Property; Purines; Rattus; Regimen; Relapse; Research Personnel; Rewards; Risk; Rodent; Role; Route; SR 141716A; Self Administration; Self Stimulation; Signal Induction; Signal Transduction; Small Business Innovation Research Grant; Small Business Technology Transfer Research; Testing; Therapeutic; Toxicology; Universities; addiction; alcohol relapse; alcohol research; alcohol use disorder; antagonist; anxiety-like behavior; behavioral study; cannabinoid receptor; clinical development; conditioned fear; design; drug development; efficacy study; endogenous cannabinoid system; experience; global health; hedonic; in vivo; innovation; lead candidate; meetings; nanomolar; neuropsychiatry; new technology; novel; novel therapeutics; patient subsets; pharmacologic; pre-clinical; preclinical study; preference; preservation; primary endpoint; receptor; rimonabant; success; trend; welfare

Abstract Alcohol use disorder (AUD) is a major global health issue. In the US, AUD affects over 14 million people over the age of 18. While there are three approved drugs for AUD, less than 4% of patients eligible for pharmacotherapy are prescribed a medication – likely due to limited efficacy of currently approved agents. Also, the relapse rate for AUD continues to be exceedingly high. Thus, new therapies are urgently needed for AUD. Both preclinical and clinical evidence suggest that antagonism of the type 1 cannabinoid (CB1) receptor is a promising strategy for AUD. However, first generation CB1 blockers produced adverse psychiatric effects in ~6% of patients making them unsuitable for chronic use. Artiam Bio is developing second generation CB1 blockers that are designed to be efficacious without producing adverse psychiatric effects. Artiam Bio’s approach takes into consideration that intrinsic activity of the CB1 receptor is required for emotional welfare, and that first-generation full inverse agonists/antagonists like SR141716A (rimonabant) completely abrogated this necessary beneficial process. The compounds developed by Artiam, including its lead molecule and backup, are high affinity but low intrinsic efficacy partial inverse agonists that preserve basal activity of the CB1 receptor – thereby reducing the potential of adverse neuropsychiatric events. Supportive evidence comes from rodent studies presented in this application. For this Phase 1 STTR application, Artiam’s team will partner with investigators from University of North Carolina’s Bowles Alcohol Research Center to perform efficacy studies with its lead compound in a rat model of alcohol consumption and relapse. Further, additional behavioral studies are proposed in anxiety-prone mice using a chronic dosing regimen to further de-risk Artiam’s lead compound for clinical development. Successful completion of these studies will pose Artiam’s lead compound, which has good drug-like properties, for clinical development to treat AUD.

抽象的 酒精使用障碍（AUD）是一个重大的全球健康问题。在美国，澳元影响了超过 1400 万人 18 岁。虽然有 3 种批准用于 AUD 的药物，但只有不到 4% 的患者适合接受药物治疗 接受药物治疗——可能是由于目前批准的药物疗效有限。还有复发率 澳元继续处于极高水平。因此，AUD 迫切需要新的疗法。均为临床前 临床证据表明，拮抗 1 型大麻素 (CB1) 受体是一种有前途的策略 澳元。然而，第一代 CB1 阻滞剂对约 6% 的患者产生了不良精神影响 它们不适合长期使用。 Artiam Bio 正在开发第二代 CB1 阻滞剂，旨在 有效且不会产生不良精神影响。 Artiam Bio 的方法考虑到了 CB1 受体的内在活性是情感福利所必需的，并且第一代完全逆 SR141716A（利莫那班）等激动剂/拮抗剂完全废除了这一必要的有益过程。这 Artiam 开发的化合物，包括其先导分子和备用分子，具有高亲和力，但内在特性较低 功效部分反向激动剂，保留 CB1 受体的基础活性 - 从而减少 不良神经精神事件的可能性。支持性证据来自本报告中提出的啮齿动物研究 应用。对于第一阶段 STTR 申请，Artiam 的团队将与伦敦大学的研究人员合作 北卡罗来纳州鲍尔斯酒精研究中心将利用其先导化合物对大鼠进行功效研究 饮酒和复发的模型。此外，还提出了针对焦虑倾向的额外行为研究 小鼠使用长期给药方案进一步降低 Artiam 的先导化合物临床开发的风险。 这些研究的成功完成将使 Artiam 的先导化合物具有良好的药物样特性， 用于治疗 AUD 的临床开发。