Efficacy, Safety, and Pharmacokinetics of ES-481 in Adult Patients With Essential Tremors

Inclusion Criteria:

• Written and Signed Informed Consent
• Age 18 to 75 years old
• The Subject must have Essential Tremor (ET). ET is defined as at least 1 upperextremity with a tremor score ≥ 1.5 in forward posture, wing beating posture, orfinger-to-nose movement using the Performance subscale of The Essential Tremor RatingAssessment Scale (as per by the Tremor Investigation Group criteria).
• Subject has a diagnosis of essential tremor, as defined by all the following criteria: (a) isolated tremor syndrome consisting of bilateral upper limb action; (b) at leastthree years duration; (c) with or without tremor in other location (e.g., head, voice,or lower limb).
• The Subject must be on stable dose of anti-tremor medication in the four (4) weeksprior to screening and must willing to maintain their current dose for the duration ofthe study.
• The Subject had no prior surgery for tremor.
• The Subject had no botulinum injection for at least six (6) months prior to -screening.
• The Subject does not have a significant imbalance or risk fall.
• The Subject has not previously taken perampanel.

Exclusion Criteria: Subjects will be excluded from 7-day screening period or study enrollment into theTreatment Period 1, if they meet any of the following criteria:

• Unwilling or inability to follow the procedures specified by the protocol
• Pregnancy or breast feeding
• Women of child-bearing potential and men who are unable or unwilling to take adequatecontraceptive precautions, including one of the following:
• Hormonal contraception (birth control pills, injected hormones, or vaginal ring)
• Intrauterine device
• Barrier methods (condom or diaphragm) combined with spermicide
• Surgical sterilization (hysterectomy, tubal ligation, or vasectomy)
• History (within the last year) of illicit drug use or alcohol dependence or a positivescreen for alcohol on the Day 1 visit, or a positive screen for drugs of abuse atScreening or at the Day 1 visit
• Subject is unwilling or unable to refrain from alcohol 24 hours before and duringclinical trial visits, or regular use of alcohol that would preclude abstinence fromalcohol for time periods around visits.
• Subject has a history of substance use disorder consistent with Diagnostic andStatistical Manual of Mental Disorders (DSM)-5 criteria, in the opinion of thePrincipal Investigator,
• Concomitant treatment with more than three drugs to treat essential tremors
• Subject has had recent exposure (14 days prior to Day 1) to tremorgenic drugs.
• Subject has had direct or indirect injury or trauma to the nervous system within 3months before the onset of tremor.
• Subject has a history or clinical evidence of other medical, neurological, orpsychiatric conditions that may explain or cause tremors, including but not limited toParkinson's disease, Huntington's disease, cerebellar disease (includingspinocerebellar ataxias, primary dystonia, Fragile X Tremor/Ataxia syndrome or Familyhistory of Fragile X syndrome, traumatic brain injury, psychogenic tremor, alcohol orbenzodiazepines abuse or withdrawal, multiple sclerosis, polyneuropathy, and endocrinestates such as hyperthyroidism or unstable treatment of hypothyroidism or medication,food, or supplement induced movement disorder (e.g., tremor related to beta agonistsor caffeine), or other medical, neurological or psychiatric condition that may explainor cause tremors.
• Subject has had a previous procedure for the treatment of ET, deep brain stimulation,brain lesioning, or magnetic resonance (MR)-guided procedure, e.g., MR-guided focusedultrasound.
• Subject has historical or clinical evidence of tremor with psychogenic origin (including but not limited to eating disorders, major depression, etc.).
• Subject has history of suicidal behavior within 2 years or is currently at risk forsuicide in the opinion of the investigator.
• Subject has any neurological abnormality other than ET upon neurological exam,including dystonia, ataxia, or any other neurodegenerative disease, including multiplesclerosis.
• Subject has alkaline phosphatase, aspartate aminotransferase (AST), and/or alanineaminotransferase (ALT) level >3.0 x upper limit of normal (ULN) at Screening and/or atPre-dose.
• Subject has serum creatinine >120 μmol/L and/or creatinine clearance <60 mL/min (according to Cockcroft-Gault formula) at Screening.
• Subject has a history of Long QT syndrome and/or QTcF (Fridericia's correction)interval >450 msec (males) or >470 msec (females) per 12-lead ECG done at Screening.
• Subject has a diagnosis of epilepsy or any history of seizure as an adult; headtrauma, stroke, transient ischemic attack within 1 year prior to Screening;unexplained loss of consciousness within 1 year prior to Screening; or any lifetimehistory of asymptomatic or symptomatic orthostatic hypotension (e.g., posturalsyncope)
• Subject has a history of unstable angina, myocardial infarction, chronic heart failure (New York Heart Association Class 3 or 4), or clinically significant conductionabnormalities (e.g., unstable atrial fibrillation) within 1 year prior to screening.
• Subject has any major psychiatric disorder that is uncontrolled (for the past 90 days)that, per the Investigator's judgment, can interfere with any of the study procedures.
• Subject should not have received treatment with another investigational drug within 30days or 5 half-lives (whichever is longer), prior to the screening visit.
• Subject should not have received a vaccine within 60 days prior to study drugadministration, except for vaccines related to Covid-19.
• Subject should not have donated or lost more than 450mL of blood or received atransfusion of any blood or blood products within 90 days prior to screening, ordonated plasma within 7 days prior to admission.
• Subject has a known allergy to ES-481 or its excipients.