In 2018, over 1 million people in the U.S. qualified as having a methamphetamine (METH) use disorder andrates of METH use are surging, largely in response to the opioid epidemic. METH use disorder is a chroniccondition for which there are currently no FDA-approved medications. The only treatment options available arebehavioral 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. Rigorousprior research from our group and others has established that relapse triggered by reminders of drug use beara powerful motivational influence, serving as a lifelong relapse risk factor, regardless of how long an individualabstains. Myosin Therapeutics is currently developing MT-110 as a non-stimulant, first-in-class drug targetingthe molecular motor nonmuscle myosin II (NMII). Blebbistatin (blebb) was the first NMII allosteric inhibitor to bediscovered 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 greatlyimproves its therapeutic index. MT-110 is currently in IND-enabling studies with a plan to enter a Phase 1 SADtowards the end of 2021. It is being developed as a short-term administration medication to support abstinencethrough a disruption of the motivation to seek METH. A primary goal of this Fast-Track SBIR application is toestablish MT-110's safety profile with multiple administrations, as it is expected to benefit subjects refractory tosingle administration treatment or those that relapse due to another factor. Establishing MT-110's efficacy in thecontext of polydrug use and other SUDs will also expand its therapeutic value. In Phase I of the grant, a repeatdose 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 safetyassessment 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 driventransition to Phase II of the grant initiates with an IND-enabling GLP safety pharmacology study in rats todetermine potential toxic effects, identify target organs of toxicity, estimate the MTD and NOAEL, evaluate theTK, 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 andtarget organs in a second species. While the improved selectivity of MT-110 is expected to reduce the impacton cardiac output, chronic METH use can lead to cardiomyopathy. Therefore, we will establish the tolerability ofMT-110 in the context of METH-induced cardiomyopathy in rats. Finally, MT-110's efficacy will be determined inthe context of other substance use disorders. The ability of MT-110 to disrupt seeking of heroin, cocaine ornicotine in METH users would increase treatment options in a rapidly escalating polydrug use epidemic.
Public Health Relevance Statement: PROJECT NARRATIVE
Rates of methamphetamine (METH) use and accidental overdose deaths are surging and there
are currently no medications for treatment, leaving only abstinence support and various
behavioral modification therapy modalities. Myosin Therapeutics is developing a first-in-class
nonmuscle myosin II (NMII) small molecule inhibitor, MT-110, where preclinical studies indicate
that short-term administration with MT-110 produces a long-lasting, potentially permanent,
disruption of the motivation to seek METH. Expanded safety and tolerability studies proposed in
this Fast-Track SBIR application will expand the IND opened for MT-110 under our NIH funded
Blueprint Neurotherapeutics (BPN) program, ensuring a rapid initiation of a Phase 1 MAD and the
greatest flexibility for design of subsequent proof of concept clinical Phase 2 studies.
Project Terms: Aftercare ; After Care ; After-Treatment ; post treatment ; inhibitor/antagonist ; inhibitor ; Ursidae Family ; Bears ; Ursidae ; bear ; Behavior Therapy ; Behavior Conditioning Therapy ; Behavior Modification ; Behavior Treatment ; Behavioral Conditioning Therapy ; Behavioral Modification ; Behavioral Therapy ; Behavioral Treatment ; Conditioning Therapy ; behavior intervention ; behavioral intervention ; Biology ; Brain ; Brain Nervous System ; Encephalon ; Cardiac Output ; heart output ; Cardiovascular system ; Cardiovascular ; Cardiovascular Body System ; Cardiovascular Organ System ; Heart Vascular ; circulatory system ; Cause of Death ; Cocaine ; Dangerousness ; Heroin ; Diacetylmorphine ; Diamorphine ; Disease ; Disorder ; Canis familiaris ; Canine Species ; Dogs ; Dogs Mammals ; canine ; domestic dog ; Pharmacotherapy ; Drug Therapy ; drug treatment ; Pharmaceutical Preparations ; Drugs ; Medication ; Pharmaceutic Preparations ; drug/agent ; Electrocardiogram ; ECG ; EKG ; Electrocardiography ; Environment ; Epidemic ; Goals ; Grant ; Inpatients ; Laboratories ; Lead ; Pb element ; heavy metal Pb ; heavy metal lead ; Methamphetamine ; Crystal Meth ; Deoxyephedrine ; Desoxyephedrine ; Methylamphetamine ; N-Methylamphetamine ; Motivation ; Myosin ATPase ; Actin-Activated ATPase ; Myosin Adenosine Triphosphatase ; Myosin Adenosinetriphosphatase ; Myosins ; Myosin Type II ; Myosin II ; United States National Institutes of Health ; NIH ; National Institutes of Health ; Nicotine ; Pharmacology ; Plasma ; Blood Plasma ; Plasma Serum ; Reticuloendothelial System, Serum, Plasma ; Prisons ; Rattus ; Common Rat Strains ; Rat ; Rats Mammals ; Rehabilitation therapy ; Medical Rehabilitation ; Rehabilitation ; rehab therapy ; rehabilitative ; rehabilitative therapy ; Relapse ; Research ; Risk Factors ; Rodent ; Rodentia ; Rodents Mammals ; Role ; social role ; Running ; Safety ; Substance Use Disorder ; Technology ; Testing ; Work ; Businesses ; Criminal Justice ; Specialist ; Treatment Cost ; base ; Organ ; improved ; Chronic ; Clinical ; Refractory ; Phase ; Hospital Costs ; Hospitalization cost ; Ensure ; Individual ; Opioid ; Opiates ; Drug usage ; drug use ; analog ; Funding ; Toxicokinetics ; No-Observed-Adverse-Effect Level ; NOAEL ; Therapeutic ; programs ; System ; Infusion ; Infusion procedures ; Molecular Motors ; Toxicities ; Toxic effect ; multidrug use ; poly drug use ; polydrug use ; multiple drug use ; Therapeutic Index ; economic impact ; Modality ; Position ; Positioning Attribute ; Modeling ; response ; drug development ; Myocardial Diseases ; Myocardial Disorder ; Myocardiopathies ; myocardium disease ; myocardium disorder ; Cardiomyopathies ; Adverse effects ; Cardiac Muscle Myosins ; Cardiac Myosins ; nonmuscle myosin ; non-muscle myosin ; blebbistatin ; Pharmaceutical Agent ; Pharmaceuticals ; Pharmacological Substance ; Pharmacologic Substance ; preventing ; prevent ; Address ; Dose ; Data ; Dose-Limiting ; Small Business Innovation Research Grant ; SBIR ; Small Business Innovation Research ; Process ; Cardiac ; Development ; developmental ; pre-clinical ; preclinical ; preclinical study ; pre-clinical study ; cost ; design ; designing ; Outcome ; innovation ; innovate ; innovative ; Impairment ; Abstinence ; drug of abuse ; abused drug ; abused drugs ; drug abused ; drugs abused ; drugs of abuse ; FDA approved ; effective therapy ; effective treatment ; preclinical efficacy ; pre-clinical efficacy ; efficacy testing ; substance use prevention ; prevent substance use ; overdose death ; overdose fatalities ; flexibility ; flexible ; phase 2 study ; phase II study ; methamphetamine use ; METH use ; METH using ; methamphetamine using ; Formulation ; molecular drug target ; molecular pharmacotherapy target ; small molecule inhibitor ; methamphetamine user ; meth user ; relapse risk ; Pharmacology Study ; Pharmacological Study ; efficacy study ; opioid epidemic ; opiate crisis ; opioid crisis ; medication administration ; safety assessment ; COVID-19 pandemic ; COVID crisis ; COVID epidemic ; COVID pandemic ; COVID-19 crisis ; COVID-19 epidemic ; COVID-19 global health crisis ; COVID-19 global pandemic ; COVID-19 health crisis ; COVID-19 public health crisis ; COVID19 crisis ; COVID19 epidemic ; COVID19 global health crisis ; COVID19 global pandemic ; COVID19 health crisis ; COVID19 pandemic ; COVID19 public health crisis ; SARS-CoV-2 epidemic ; SARS-CoV-2 global health crisis ; SARS-CoV-2 global pandemic ; SARS-CoV-2 pandemic ; SARS-CoV2 epidemic ; SARS-CoV2 pandemic ; SARS-coronavirus-2 epidemic ; SARS-coronavirus-2 pandemic ; Severe Acute Respiratory Syndrome CoV 2 epidemic ; Severe Acute Respiratory Syndrome CoV 2 pandemic ; Severe acute respiratory syndrome coronavirus 2 epidemic ; Severe acute respiratory syndrome coronavirus 2 pandemic ; corona virus disease 2019 epidemic ; corona virus disease 2019 pandemic ; coronavirus disease 2019 crisis ; coronavirus disease 2019 epidemic ; coronavirus disease 2019 global health crisis ; coronavirus disease 2019 global pandemic ; coronavirus disease 2019 health crisis ; coronavirus disease 2019 pandemic ; coronavirus disease 2019 public health crisis ; coronavirus disease crisis ; coronavirus disease epidemic ; coronavirus disease pandemic ; severe acute respiratory syndrome coronavirus 2 global health crisis ; severe acute respiratory syndrome coronavirus 2 global pandemic ; cost estimate ; cost estimation ;
