Development of ITI-333, a μ-opioid Receptor Partial Agonist and 5HT2A and D1 Receptor Antagonist, for the Treatment of Opioid Use Disorders

开发 ITI-333，一种 μ-阿片受体部分激动剂和 5HT2A 和 D1 受体拮抗剂，用于治疗阿片类药物使用障碍

• 批准号: 9841388
• 负责人: SANDRA D COMER
• 金额: $ 291.71万
• 依托单位: INTRA-CELLULAR THERAPIES, INC.
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9841388
• 关键词: Acute; Adverse event; Affinity; Agonist; Animals; Anxiety; Binding; Biological Products; Biotechnology; Brain; Central Nervous System Diseases; Clinical; Clinical Paths; Clinical Research; Clinical Trials; Collaborations; Conduct Clinical Trials; Data; Development; Development Plans; Dopamine; Dopamine D1 Receptor; Dose; Dose-Limiting; Double-Blind Method; Drug Kinetics; Exhibits; Fentanyl; Formulation; Funding; Future; Goals; Grant; HTR2A gene; Heroin; Heroin Users; Human; Image; Individual; Inpatients; Maintenance; Maximum Tolerated Dose; Modeling; Morphine; National Institute of Drug Abuse; Opiate Addiction; Opioid; Opioid Antagonist; Opioid Receptor; Opioid agonist; Outcome; Overdose; Parents; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase; Placebos; Plasma; Positron; Precipitation; Principal Investigator; Regimen; Relapse; Research Personnel; Route; Safety; Serotonin; Serotonin Receptor 5-HT2A; Signal Transduction; Therapeutic; Therapeutic Index; Therapeutic Uses; Toxicology; Withdrawal; associated symptom; base; carfentanil; clinical development; depressive symptoms; design; effective therapy; first-in-human; healthy volunteer; illicit opioid; in vivo; innovation; molecular drug target; mu opioid receptors; novel; opioid abuse; opioid use; opioid use disorder; opioid user; opioid withdrawal; phase 2 study; prescription opioid; prevent; programs; radioligand; receptor; research clinical testing; small molecule; symptom treatment; volunteer

RFA-DA-19-002 Principal Investigator/PD: Vanover, Kimberly E. Project Summary/Abstract Intra-Cellular Therapies Inc (ITI), a clinical-stage biopharmaceutical company, is developing ITI-333, a novel compound with high affinity activity at mu opiate (MOP), 5-HT2A, and D1 receptors. The nonclinical profile of ITI-333 suggests a promising medication, lacking abuse liability, with partial agonist activity at MOP receptors useful for treatment of opiate withdrawal in individuals with Opioid Use Disorders (OUD). ITI is currently completing IND-enabling nonclinical safety, toxicology, pharmacokinetic and manufacturing activities, with the goal of launching Phase 1 human clinical evaluation of ITI-333 in healthy volunteers in Q1 2019. ITI seeks to partner with NIDA in the development of this compound for a novel and safe therapeutic for use in treating OUD, requesting support of clinical development of ITI-333, while committing significant internal funds to a parallel program of non-clinical development and CMC activities in support of the clinical plan. To this end, we submit this application, “Development of ITI-333, a µ-opioid Receptor Partial Agonist and 5HT2A and D1 Receptor Antagonist, for the Treatment of Opioid Use Disorders” to NIDA RFA-DA-19-002, Development of Medications to Prevent and Treat Opioid Use Disorders and Overdose (UG3/UH3). Here, we propose a 2-year UG3 program, including a First-in-Man, single ascending dose (SAD) study (ITI-333-001) to assess the safety, tolerability and pharmacokinetics of ITI-333 in healthy volunteers. The safety, tolerability, and pharmacokinetics of multiple, ascending doses (MAD) of ITI-333 will then be evaluated in a single-center in-patient study (ITI-333-002) with the goal of determining a maximally- tolerated dose (MTD). Both studies will be conducted in collaboration with Clinilabs, a NYC-based CRO. In parallel with the MAD study, we will characterize the in vivo receptor pharmacology of ITI-333 at MOP, 5- HT2A, and D1 receptors in human brain using PET imaging (with Dr. Dean Wong, JHU, ITI-333-003), thereby leveraging our SAD data to clinically validate the mechanism of action of ITI-333 and to inform Phase 2 dose selection. These data will enable us to launch a 3-year UH3 program exploring the human abuse liability (HAL) and functional pharmacology of ITI-333 in collaboration with Dr. Sandra Comer (CUMC), a clinical expert in opioid use and abuse. The HAL study (Phase 2a, ITI-333-004) will characterize the opioid receptor antagonist/partial agonist profile of ITI-333 in humans to explore potential abuse liability in humans. Additional Phase 2 studies will evaluate the in vivo functional pharmacology of ITI-333 in a model of withdrawal precipitation in non-treatment seeking heroin users (ITI-333-005) and in a model of mu-opioid receptor blockade in treatment-seeking heroin users (ITI-333-006). Together, we believe this clinical development plan with inform further development of ITI-333 and the selection of a cogent Phase 3 clinical path toward FDA approval as a medication for the treatment of OUD.

RFA-DA-19-002 首席研究员/PD：Vanover，Kimberly E. 项目概要/摘要 Intra-Cellular Therapies Inc (ITI) 是一家临床阶段的生物制药公司，正在开发 ITI-333，这是一种新型药物 对 mu 阿片 (MOP)、5-HT2A 和 D1 受体具有高亲和力活性的化合物。 ITI-333 提出了一种有前途的药物，缺乏滥用倾向，在 MOP 处具有部分激动剂活性 可用于治疗阿片类药物使用障碍（OUD）个体的阿片戒断的受体是。 目前正在完成 IND 支持的非临床安全性、毒理学、药代动力学和制造 活动，目标是在第一季度在健康志愿者中启动 ITI-333 的 1 期人体临床评估 2019. ITI 寻求与 NIDA 合作开发这种化合物，作为一种新型、安全的治疗方法 用于治疗 OUD，请求支持 ITI-333 的临床开发，同时承诺重大 内部资金用于非临床开发和 CMC 活动的并行计划，以支持临床 为此，我们提交了这份申请，“开发一种μ-阿片受体部分”ITI-333。 激动剂以及 5HT2A 和 D1 受体拮抗剂，用于治疗阿片类药物使用障碍”NIDA RFA-DA-19-002，开发预防和治疗阿片类药物使用障碍和过量的药物 (UG3/UH3)，我们提出了一个为期 2 年的 UG3 计划，包括首次人体单次递增剂量。 （SAD）研究（ITI-333-001）评估 ITI-333 在健康人群中的安全性、耐受性和药代动力学 ITI-333 的多次递增剂量 (MAD) 的安全性、耐受性和药代动力学将 然后在单中心住院患者研究（ITI-333-002）中进行评估，目标是确定最大- 这两项研究都将与纽约市的 CRO 合作进行。 与 MAD 研究并行，我们将在 MOP、5- 下表征 ITI-333 的体内受体药理学 使用 PET 成像研究人脑中的 HT2A 和 D1 受体（与 Dean Wong 博士合作，JHU，ITI-333-003），从而 利用我们的 SAD 数据临床验证 ITI-333 的作用机制并为第 2 阶段提供信息 这些数据将使我们能够启动一项为期 3 年的 UH3 计划，探索人类虐待行为。 与 Sandra Comer 博士 (CUMC) 合作研究 ITI-333 的责任 (HAL) 和功能药理学， 阿片类药物使用和滥用方面的临床专家。 HAL 研究（2a 期，ITI-333-004）将描述阿片类药物的特征。 ITI-333 在人类中的受体拮抗剂/部分激动剂概况，以探索人类潜在的滥用倾向。 其他 2 期研究将在模型中评估 ITI-333 的体内功能药理学 未寻求治疗的海洛因使用者 (ITI-333-005) 和 mu-阿片类药物模型中的戒断沉淀 寻求治疗的海洛因使用者的受体阻断 (ITI-333-006) 我们相信这一临床结果。 开发计划，进一步告知 ITI-333 的开发和有效的 3 期临床选择 获得 FDA 批准作为 OUD 治疗药物的途径。