R-methadone-TAAP/MPAR: an abuse deterrent methadone prodrug with overdose protection: Pre-Clinical Development and Phase 1 Clinical Trial

R-美沙酮-TAAP/MPAR：具有过量保护功能的防滥用美沙酮前药：临床前开发和 1 期临床试验

• 批准号: 9900195
• 负责人: Lynn Kirkpatrick
• 金额: $ 538.94万
• 依托单位: ENSYSCE BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-30 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9900195
• 关键词: Biological Sciences; Canis familiaris; Cardiac; Cardiotoxicity; Cardiovascular system; Cessation of life; Clinical; Clinical Research; Clinical Trials; Consumption; Cost of Illness; Development; Dose; Drug Kinetics; Drug Prescriptions; Enzymes; Exposure to; Formulation; Goals; Half-Life; Health; Household; Human; In Situ; Ingestion; Methadone; Methods; Molecular; Opiate Addiction; Opioid; Opioid agonist; Oral; Oral Administration; Overdose; Patients; Persons; Pharmaceutical Preparations; Pharmacology Study; Phase; Phase I Clinical Trials; Physiological; Prodrugs; Property; Rattus; Regulation; Reporting; Resistance; Risk; Safety; Schedule; Small Intestines; Societies; Substance Withdrawal Syndrome; Symptoms; System; Toxicokinetics; Translating; Treatment Efficacy; Trypsin; Trypsin Inhibitors; United States; Ventilatory Depression; Weaning; Work; analog; appropriate dose; burden of illness; design; disability; enantiomer; healthy volunteer; improved; inter-individual variation; mu opioid receptors; new technology; novel; novel therapeutics; opioid use disorder; opioid withdrawal; pharmacokinetic characteristic; phase 1 study; pill; pre-clinical; preclinical development; prescription opioid abuse; prevent; programs; response; safety study; side effect; years of life lost

Abstract Prescription opioid abuse and addiction are major burdens to patients and society, resulting in significant costs, illnesses, and deaths. Approximately 3 million persons in the United States and almost 16 million worldwide have a current or past opioid-use disorder (OUD). Because opioid-withdrawal syndromes are caused by rapidly decreasing drug levels after repeated exposure, symptoms can be reduced by administering other opioids to diminish symptoms and then weaning the patient off the new drug. Methadone is useful in the treatment of opioid dependence. As the use of methadone has increased over the past decade, there has also been an increase in the amount of diversion and abuse of the drug. It is much easier to overdose on methadone than other opioid drugs. Furthermore, there has been an alarming increase in methadone related fatalities in patients that have been prescribed the drug The intertwined issues of i) the widespread and increasing abuse of prescription opioids, and ii) the diversion and abuse of methadone and iii) deaths due to the interindividual variation of response to methadone have led us to focus on a producing safer methadone product to reduce overdose in patients suffering from OUD. Ensysce Biosciences has created two complementary, novel technologies that it is applying to methadone. The abuse resistant features of Ensysce Biosciences’ TAAP™ with MPAR™ prodrugs are imparted at the molecular level. Our TAAP™ [Trypsin Activated Abuse Protection] prodrugs are “enzyme-activated” to release clinically effective opioid drugs only when taken orally and exposed to the correct physiologic conditions (i.e., ingested and exposed to trypsin in the small bowel). We have evaluated TAAP™ opioid products in human clinical trials and demonstrated successfully the oral delivery of active opioids with extended release profiles. MPAR™ [multi-pill abuse resistance] involves in situ bio-regulation of opioid delivery from our TAAP™ systems, enabling control over oral multi-dose pharmacokinetic (PK) profiles. MPAR™ oral overdose protection is conferred by the action of a trypsin inhibitor, nafamostat, that is co-formulated with the TAAP™ system. As multiple doses are co-ingested, the trypsin “bio-activation” is progressively inhibited, resulting in a therapeutically effective dose of opioid without the risk of oral overdose. MPARTM protection of our opioid prodrugs has been successfully demonstrated in both rat and dog species, and evaluated in a human Phase 1 trial. The potential benefits to society of a product that resists both oral and parenteral abuse are considerable Methadone, an oral mu-opioid agonist, has a high potential for abuse that can be quite lethal due to its long half-life in an overdose situation usually as a result of respiratory depression. The R-methadone drug product is not available in the US, but it has been reported to have reduced QT-interval prolongation as compared to the S enantiomer. It is envisaged that a R-methadone-TAAP prodrug would demonstrate similar reduced abuse potential as we have shown with other opioid-TAAP products, have reduced cardiac toxicity, and combined with nafamostat, a R-methadone/TAAP/MPAR product could reduce methadone overdose that often results in death. The objective of this proposal is to develop an R-methadone/TAAP/MPARTM drug through Phase 1 clinical studies, to translate our TAAP/MPARTM results into humans, to ultimately reduce the abuse and oral overdose potential of methadone.

摘要 处方阿片类药物滥用和成瘾是患者和社会的主要负担，导致巨大的成本，疾病， 和死亡在美国大约有300万人，全世界大约有1600万人现在或过去有一个 阿片类药物使用障碍（OUD）。因为阿片类药物戒断综合征是由药物浓度在 反复暴露，症状可以通过给予其他阿片类药物来减轻症状，然后断奶， 患者服用新药。美沙酮可用于治疗阿片类药物依赖。随着美沙酮使用量的增加 在过去十年中，这种药物的转移和滥用数量也有所增加。要容易得多 服用美沙酮比服用其他阿片类药物要多。此外，与美沙酮有关的 已开药患者的死亡率 这些相互交织的问题是：一）处方类阿片滥用的普遍和日益增加，二）药物的转移和滥用， 美沙酮和iii）由于美沙酮反应的个体间差异而导致的死亡导致我们关注生产 更安全的美沙酮产品，以减少OUD患者的过量服用。Ensysce Biosciences创建了两个 它正在应用于美沙酮的互补的、新的技术。Ensysce Biosciences的抗滥用功能 TAAP™与MPAR™前药在分子水平上被赋予。 我们的TAAP™ [胰蛋白酶激活滥用保护]前药是“酶激活”释放临床有效的阿片类药物 药物仅在口服并暴露于正确的生理条件下（即，摄入并接触胰蛋白酶， 小肠）。我们已经在人体临床试验中评估了TAAP™阿片类药物产品，并成功证明了口服 具有延长释放曲线的活性阿片样物质的递送。 MPAR™ [多药丸滥用抗性]涉及从我们的TAAP™系统中对阿片类药物递送的原位生物调节， 控制口服多剂量药代动力学（PK）曲线。MPAR™口服过量保护是通过以下作用实现的： 胰蛋白酶抑制剂萘莫司他，其与TAAP™系统共同配制。由于同时摄入多剂，胰蛋白酶 “生物活化”被逐渐抑制，导致治疗有效剂量的阿片样物质，而没有口服给药的风险。 服药过量我们的阿片类前药的MPAR TM保护作用已在大鼠和犬种属中成功证明， 在人类1期试验中进行了评估。抗口服和胃肠外滥用的产品对社会的潜在益处 是相当大 美沙酮是一种口服μ-阿片类激动剂，由于其在体内的半衰期长，因此具有很高的滥用可能性， 过量的情况通常是由于呼吸抑制。R-美沙酮药物产品在美国不可用， 但据报道，与S对映体相比，它具有减少的QT间期延长。据设想， R-美沙酮-TAAP前药将显示出与我们用其他阿片类药物-TAAP所显示的类似的降低滥用潜力 产品，具有降低的心脏毒性，并且与萘莫司他组合，R-美沙酮/TAAP/MPAR产品可以降低 美沙酮过量通常会导致死亡 本提案的目的是通过1期临床研究开发R-美沙酮/TAAP/MPAR TM药物， 将我们的TAAP/MPAR TM结果转化为人类，以最终减少美沙酮的滥用和口服过量的可能性。