Inclusion Criteria:

• Male or female adults ≥ 18 to 18 kg/m^2.
• Diagnosis of DEE that includes Dravet syndrome, Lennox-Gastaut Syndrome, and other DEEs and demonstrates treatment-resistant countable motor seizures with an average of ≥ 4 observed/countable motor seizures per 4-week period during the 12 weeks before screening while on stable ASM treatment based on the subject/caregiver report and investigator’s assessment.
  • Subjects who are characterized as having a DEE but who do not have Dravet syndrome or Lennox-Gastaut Syndrome will have all of the following based on the subject/caregiver history and investigator’s assessment:
    • History of onset of unprovoked seizures at 5 years of age or earlier;
    • History of developmental delay;
    • History of combined focal and generalized seizure types or multiple generalized seizure types;
    • History of slow or disorganized electroencephalogram background;
    • No history of idiopathic generalized seizures;
    • Had an average of ≥ 4 observed countable motor seizures per 4-week period during the 12 weeks before screening while on stable ASM treatment based on the subject/caregiver report and investigator’s assessment.
  • Subjects characterized as having Dravet syndrome must meet all the following:
    • Onset of seizures between 3 and 19 months of age in an otherwise healthy infant;
    • History of seizures that were either generalized tonic-clonic or unilateral clonic or bilateral clonic;
    • Initial development was normal;
    • History of developmental delay;
    • Lack of alternative diagnosis;
    • Had an average of ≥ 4 observed countable motor seizures per 4-week period during the 12 weeks before screening while on stable ASM treatment based on the subject/caregiver report and investigator’s assessment. AND at least 1 of the following:
    • Emergence of another seizure type, including myoclonic, generalized tonic-clonic, tonic, atonic, absence, and/or focal developed after the first seizure type;
    • Prolonged exposure to warm temperatures-induced seizures and/or seizures that were associated with fevers due to illness or vaccines, hot baths, high levels of activity, and sudden temperature changes, and/or seizures were induced by strong natural and/or fluorescent lighting, as well as certain visual patterns;
    • Genetic test results consistent with a diagnosis of Dravet syndrome (pathogenic, likely pathogenic, variant of unknown significance, or inconclusive but unlikely to support an alternative diagnosis).
  • Subjects characterized as having Lennox-Gastaut Syndrome must meet the following:
    • History of tonic seizures or tonic/atonic seizures;
    • More than 1 type of generalized seizure, including but not limited to generalized tonic-clonic, tonic-atonic, atonic, tonic, myoclonic, or drop seizures for ≥ 6 months before screening. Drop seizures are defined as a seizure involving the entire body, trunk, or head that leads to a fall, injury, slumping in a chair, or head hitting the surface, or could have led to a fall or injury, depending on the position of the subject at the time of the attack or spell;
    • A history of seizure before 8 years of age;
    • History of developmental delay;
    • Documentation of previous electroencephalogram reporting diagnostic criteria for Lennox-Gastaut Syndrome (abnormal inter-ictal electroencephalogram background activity accompanied by inter-ictal slow spike-and-wave pattern ≤ 2.5 hertz or inter-ictal generalized paroxysmal fast activity);
    • Had an average of ≥4 observed drop seizures per 4-week period during the 12 weeks before screening while on stable ASM treatment based on the subject/caregiver report and investigator’s assessment.
• Has been taking 1 to 4 ASMs at a stable dose for ≥4 weeks before screening and the subject or subject’s legally acceptable representative is willing to keep the regimen(s) stable throughout the study.
• All medications or interventions for epilepsy (including ketogenic diet and vagus nerve stimulation) must have been stable for 4 weeks before screening and are expected to remain stable throughout the study.
• G-tubes/PEG tubes (where present) should have been placed and been functioning for at least 3 months before screening. Naso-gastric tubes are not allowed.
• Has a reliable caregiver or study partner.
• The subject and/or authorized representative are willing and able to provide a written informed consent or assent form before participation in the study. An assent should be obtained from the subject, if possible. If the subject cannot provide assent (i.e., due to developmental status), the investigator should document why assent was not obtained.
• The subject and/or authorized representative are willing to provide a written consent or assent to allow the investigator and the investigator’s staff to consult with the subject’s medical caregivers and the Medical Monitor during screening and during participation in the study.
• All female subjects must have a negative serum pregnancy (human chorionic gonadotropin) test at screening and a negative urine pregnancy test before randomization. If urine cannot be collected, the results of the serum pregnancy test obtained at screening must be confirmed to be negative by the investigator before randomization.
• A female subject of childbearing potential* who is sexually active with a male partner agrees to use routinely an adequate method of contraception* from signing of informed consent, throughout the duration of the study, and for 30 days after the last dose of study drug.
• A male subject who is sexually active with a female partner of childbearing potential* agrees to use adequate contraception* from the signing of informed consent, throughout the duration of the study, and for 90 days after last dose.
• Subjects and/or subjects’ caregivers agree to not post any subject’s personal medical data related to the study or information related to the study on any website or social media site (e.g., Facebook, Twitter) until the study has been completed.
• The subject, parent, or caregiver is able and willing to comply with completion of the diaries.

Inclusion Criteria - Randomization:

• Investigator completion of the Seizure Identification and Diagnostic Review Form (SIF/DRF) and submission to The Epilepsy Study Consortium for their review and approval before randomization of otherwise eligible subjects.
• Approved for study inclusion by The Epilepsy Study Consortium.
• Had a stable baseline with ≥ 4 observed countable motor seizures during the 28-day Baseline period, with a minimum of 2 in the first 14 days and 2 in the second 14 days and was not seizure-free for more than 21 consecutive days during the 28-day Baseline period.
• The subject, parent, or caregiver has been compliant with diary completion during the Baseline period, in the opinion of the investigator (i.e., at least 80% compliant but not more than 5 total days missing).
• The subject, parent, or caregiver responsible for study drug administration demonstrates an understanding of how to administer study drug correctly.

Exclusion Criteria:

• Has been admitted to a medical facility for treatment of status epilepticus requiring mechanical respiration within 3 months before screening.
• Current or prior idiopathic generalized seizures.
• Has had a vagus nerve stimulator implanted within 6 months before screening, and/or settings have been changed within 1 month before screening and/or anticipated to change during the study.
• Is on a ketogenic diet that has been started within 6 months before the Screening Visit, has been changed within 1 month of the Screening Visit, or is anticipated to change during the study.
• Subjects with Dravet syndrome who have used ASMs that principally target voltage-gated sodium channels (phenytoin, fosphenytoin, carbamazepine, oxcarbazepine, eslicarbazepine, lamotrigine, lacosamide, and rufinamide) as well as vigabatrin and tiagabine, within the last month (30 days) before screening.
• Current use of felbamate, unless the subject is on a stable dose of felbamate ≥6 months before screening with stable liver function and hematology laboratory tests.
• Current use of topiramate, unless the subject is on a stable dose of topiramate ≥6 months before screening with stable weight.
• Use of fenfluramine within 30 days of screening, failure to control seizures while on fenfluramine, or intolerance to fenfluramine.
• Use of lorcaserin within 30 days of screening, failure to control seizures while on lorcaserin, or intolerance to lorcaserin.
• Considered at risk of suicidal behavior based on the C‑SSRS. A subject should be excluded, and a risk assessment should be done by a qualified mental health professional if the subject has had suicidal intent (Ideation items 4 or 5) in the last 6 months before randomization, or suicidal behaviors or attempts in the past year. If the subject is unable to complete the C-SSRS due to developmental status, an authorized representative may not complete the C-SSRS. The investigator may also use clinical judgment to assess the subject’s status and ability for completion, which must then be documented in the source document.
• PHQ-9 score of >9 or a positive response to Question 9. If the subject is unable to complete the PHQ-9 due to developmental status, an authorized representative may not complete the PHQ-9. The investigator may also use clinical judgment to assess the subject’s status and ability for completion, which must then be documented in the source document.
• Current or recent history of moderate or severe depression, anorexia nervosa, or bulimia per the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, within the prior year.
• Positive for human immunodeficiency virus (HIV), hepatitis B, or hepatitis C infections. Note that subjects who have been vaccinated against hepatitis B (hepatitis B surface antibody-positive) who are negative for other markers of prior hepatitis B infection (e.g., negative for hepatitis B core antibody) are eligible. Also note that subjects who are positive for hepatitis C antibody are eligible as long as they have a negative hepatitis C viral load by quantitative polymerase chain reaction.
• Use of cannabidiol must have been stable for 30 days before the Screening Visit, and use is not anticipated to change during the study.
• Has a positive result on the urine drug screen, except tetrahydrocannabinol for subjects taking cannabidiol or Epidiolex, and excluding other controlled medications taken as prescribed.
• Unstable, clinically significant neurologic (other than the disease being studied), psychiatric, cardiovascular, pulmonary, hepatic, renal, metabolic, gastrointestinal, urologic, immunologic, hematopoietic, or endocrine disease or other abnormality which may impact the ability of the subject to participate or potentially confound the study results.
• Has pulmonary arterial hypertension, current or history of cardiovascular or cerebrovascular disease, such as cardiac valvulopathy, myocardial infarction, or stroke.
• Is pregnant, breast-feeding, or intending to become pregnant before, during, or within 30 days after participating in this study; or intending to donate ova during such time period. If male, the subject intends to donate sperm during the course of this study or within 90 days after the last dose of study drug.
• Has a known hypersensitivity to any component of LP352 formulation.
• Unwilling to abstain from donation of blood during and within 2 weeks after the study.
• Travel plans during the treatment and follow-up periods that would preclude clinic visits.
• Has been part of a clinical study involving another investigational drug in the 30 days prior to screening or within 5 half-lives of the other investigational drug prior to screening, whichever is longer, or the subject is currently receiving an investigational drug.

Eligibility last updated 4/6/22. Questions regarding updates should be directed to the study team contact.