Development of a first-in-class nonmuscle myosin II inhibitor to prevent substance use disorder relapse

开发一流的非肌肉肌球蛋白 II 抑制剂以预防药物滥用障碍复发

• 批准号: 10757807
• 负责人: Erica J Young
• 金额: $ 44.09万
• 依托单位: MYOSIN THERAPEUTICS INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10757807
• 关键词: Abstinence; Accidents; Address; Administrative Supplement; Adverse effects; Aftercare; Award; Behavior; Behavior Therapy; Biological Assay; Biology; Brain; Businesses; COVID-19 pandemic; Canis familiaris; Cardiac; Cardiac Myosins; Cardiac Output; Cardiomyopathies; Cause of Death; Chronic; Clinic; Clinical; Cocaine; Criminal Justice; Dangerousness; Development; Dose; Dose Limiting; Drug usage; Electrocardiogram; Ensure; Environment; Epidemic; FDA approved; Funding; Goals; Grant; Heroin; Hospital Costs; Individual; Inpatients; Laboratories; Left; Methamphetamine; Methamphetamine use disorder; Modality; Molecular Motors; Motivation; Myosin ATPase; Myosin Type II; Nicotine; No-Observed-Adverse-Effect Level; Opioid; Organ; Parents; Persons; Pharmaceutical Preparations; Pharmacology Study; Pharmacotherapy; Phase; Phase I Clinical Trials; Prisons; Process; Qualifying; Rattus; Refractory; Rehabilitation therapy; Relapse; Research; Risk Factors; Role; Running; Safety; Small Business Innovation Research Grant; Specialist; Substance Use Disorder; System; Technology; Testing; Therapeutic; Therapeutic Index; Toxic effect; Toxicokinetics; Treatment Cost; United States National Institutes of Health; Vertebral column; analog; blebbistatin; cost; cost estimate; density; design; drug development; economic impact; effective therapy; efficacy study; flexibility; improved; inhibitor; innovation; medication administration; methamphetamine use; methamphetamine user; molecular drug target; multiple drug use; non-muscle myosin; opioid epidemic; overdose death; phase 2 study; pre-Investigational New Drug meeting; preclinical efficacy; preclinical study; prevent; programs; relapse risk; response; safety assessment; safety study; small molecule inhibitor; substance use prevention

PROJECT SUMMARY In 2018, over 1 million people in the U.S. qualified as having a methamphetamine (METH) use disorder and rates of METH use are surging, largely in response to the opioid epidemic. METH use disorder is a chronic condition for which there are currently no FDA-approved medications. The only treatment options available are behavioral modification therapies, which have limited efficacy, as evidenced by the high rate of relapse (60- 90%). This argues for an adjunct pharmacotherapy targeting relapse triggers to support abstinence. Rigorous prior research from our group and others has established that relapse triggered by reminders of drug use bear a powerful motivational influence, serving as a lifelong relapse risk factor, regardless of how long an individual abstains. Myosin Therapeutics is currently developing MT-110 as a non-stimulant, first-in-class drug targeting the molecular motor nonmuscle myosin II (NMII). Blebbistatin (blebb) was the first NMII allosteric inhibitor to be discovered and suffers from poor tolerability due to equipotent inhibition of cardiac muscle myosin (CMII). MT- 110 is a blebb analog with improved brain exposure, potency, and selectivity for CMII (>100x) which greatly improves its therapeutic index. MT-110 is currently in IND-enabling studies with a plan to enter a Phase 1 SAD towards the end of 2021. It is being developed as a short-term administration medication to support abstinence through a disruption of the motivation to seek METH. A primary goal of this Fast-Track SBIR application is to establish MT-110’s safety profile with multiple administrations, as it is expected to benefit subjects refractory to single administration treatment or those that relapse due to another factor. Establishing MT-110’s efficacy in the context of polydrug use and other SUDs will also expand its therapeutic value. In Phase I of the grant, a repeat dose non-GLP dose range finding (DRF) study in rats is planned to determine the tolerability of the test article (MT-110) and to identify potential dose limiting toxicities, toxicokinetics and target organs. A cardiac safety assessment with electrocardiography will be run in parallel in rat to ensure no effects on cardiac contractility, consistent with the dramatic improvement in MT-110’s selectivity profile for NMII over CMII. Milestone driven transition to Phase II of the grant initiates with an IND-enabling GLP safety pharmacology study in rats to determine potential toxic effects, identify target organs of toxicity, estimate the MTD and NOAEL, evaluate the TK, and reversibility of any adverse effects following repeated dose administrations. Assessment of repeat MT- 110 dosing in a non-GLP DRF study in dogs will establish potential dose limiting toxicities, toxicokinetics and target organs in a second species. While the improved selectivity of MT-110 is expected to reduce the impact on cardiac output, chronic METH use can lead to cardiomyopathy. Therefore, we will establish the tolerability of MT-110 in the context of METH-induced cardiomyopathy in rats. Additionally, in this Administrative Supplement application, we seek funding to perform expanded safety and tolerability studies, as they could not be foreseen because the application was submitted and funded prior to the pre-IND meeting. To directly address the guidance Myosin received, we are proposing to perform GLP and non-GLP behavior assays and spine density analysis. Importantly, these studies will help to ensure a strong IND package and MT-110’s continued momentum to the clinic. Finally, MT-110’s efficacy will be determined in the context of other substance use disorders. The ability of MT-110 to disrupt seeking of heroin, cocaine or nicotine in METH users would increase treatment options in a rapidly escalating polydrug use epidemic.

项目总结