SPN-817 Phase 2, Double-Blind, Placebo-Controlled Study in Adults with Focal Onset Seizures

Prior treatment

• Has a diagnosis of cannabis use disorder (per DSM-5) within 6 months before Screening and has a positive urine drug screen (UDS) for cannabis at Screening. a. At the discretion of the Sponsor, recreational use of cannabis (3 times a week) is allowed and should be kept consistent during the study. Participants must agree to refrain from are using cannabis 48 hours prior to the study visits. b. Cannabis (including cannabidiol [CBD] products) prescribed for a medical condition or used as an ASM is allowed if taken at a stable regimen for at least 28 days prior to Screening. Newly prescribed cannabis treatment and/or a change to the existing regimen is prohibited. When applicable, participants should show proof of their prescription for medical cannabis.
• Positive UDS at Screening. Participants who test positive for specific medications (benzodiazepines, amphetamines, etc.) must show proof of the prescription and should not be excluded due to a positive UDS
• Chronic concomitant therapy with non-ASMs that are cholinergic or anticholinergic. Eligibility for participants who are taking anticholinergic drugs on an as needed basis during the study should be discussed with the Medical Monitor (MM) and/or Sponsor
• Currently taking or within the 3 days prior to first dose of SM has taken epigallocatechin gallate (EGCG) or consumed foods or drinks containing EGCG (including all green, white, or oolong teas and all black teas or food containing >100 grams of carob powder). The aforementioned teas/foods containing EGCG cannot be consumed at any time from 3 days before the first dose of SM through the last dose of SM. Herbal teas without EGCG may be consumed during the study
• Participation in any clinical investigational drug or device study within 4 weeks or 5 half-lives of the clinical investigational drug, whichever is longer, prior to Visit 1
• Has known hypersensitivity (eg, anaphylaxis) to ondansetron or any of the components of the formulation, or receiving concomitant apomorphine
• Donation of 50 to 499 mL of blood within 30 days prior to screening or >499 mL within 56 days prior to screening. Following screening and throughout the study (Visit 1 to EOS), participants should not donate blood; or
• Prior diagnosis of combined focal and generalized epilepsy syndrome as evidenced by severe developmental delay and multiple seizure types and confirmed by electroencephalography (EEG) (eg, Lennox-Gastaut syndrome). Participants should also be excluded in case of nondiagnostic information
• History of status epilepticus within 6 months prior to screening
• Change in ASM regimen within 28 days prior to screening. No changes in ASMs are allowed throughout the study (Visit 1 through EOS or ET)
• Vagus nerve stimulation, deep brain stimulation, responsive neurostimulator system, or other neurostimulation for epilepsy device implanted or activated within 1 year prior to screening; or epilepsy surgery within 1 year prior to screening. Stimulation parameters for devices must have been stable for at least 3 months prior to Screening. Battery change for any epilepsy devices will be allowed; however, stimulation parameters must remain stable during the duration of the study

Other illness

• Any condition that may impact the ability of a participant to follow study procedures or the safety of a participant based on what is known about the pharmacology/toxicology profile of SPN-817
• Pre-existing medical condition (including an existing progressive or degenerative neurological disorder including brain tumor, active encephalitis, active meningitis, or abscess) or medications that, in the opinion of the Investigator, could interfere with the suitability of the participant for involvement in the study
• History of or evidence of current significant psychiatric disturbance (eg, schizophrenia, schizoaffective, or bipolar disorder) that would preclude meaningful participation in the study
• History within the past 6 months or evidence of current alcohol and/or substance use disorder as defined by the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5)
• Positive result for human immunodeficiency virus (HIV), hepatitis B, or hepatitis C (HCV) at screening unless: • HIV positive: subjects must have a HIV Confirmation Test. If the confirmatory test is positive, the subject is eligible if on chronic suppressive antiviral medication with an undetectable viral load; • HBsAg positive: subjects should be tested for Hep B core antibodies to detect acute or chronic infection (ineligible). Subjects whose results indicate immunity (either by natural infection or vaccination) with no active infection are eligible; and/or • HCV positive: subjects must have undetectable HCV RNA to be eligible.
• History of >2 allergic reactions to an ASM or 1 serious hypersensitivity reaction to an ASM
• History of or current nonepileptic events that could be confused by the participant and/or study staff as epileptic seizures
• History of uncountable seizures, such as seizures that happen in a cluster that are too rapid to be counted individually

Lab values

• Clinical laboratory abnormalities within 2 months prior to screening considered of clinical significance by the Investigator
• Clinically significant cardiologic abnormalities at screening, including history of congenital prolonged QT syndrome and congestive heart failure; Abnormal ECG that is, in the opinion of the Investigator, clinically significant including: a. QT corrected for HR using Fridericia’s method (QTcF) >450 ms for males and >470 ms for females; b. Second or third-degree atrioventricular block; or c. Any rhythm, other than sinus rhythm, that is interpreted by the Investigator to be clinically significant. One repeat ECG assessment is allowed per Investigator discretion.
• Has abnormal renal function as demonstrated by estimated glomerular filtration rate (eGFR) of <60 mL/min according to the eGFR Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation at screening
• Only has seizures that are difficult to count; for example, seizures that are not clinically observable

Other

• Has taken huperzine A within the past 6 months
• Any suicidal behavior or suicidal ideation related to item 4 (active suicidal ideation with some intent to act, without specific plan) or item 5 (active suicidal ideation with specific plan and intent) based on the C-SSRS assessment in the 1 year before screening; a suicide attempt in the last 2 years before screening; or more than 1 lifetime suicide attempt
• Planning to become pregnant or impregnate partner, not using an acceptable method of birth control (defined in Inclusion Criteria #12 and #13), pregnant, and/or nursing
• Clinically significant vital sign abnormalities per Investigator discretion at screening
• Any other reason which, in the opinion of the Investigator, would prevent the participant from taking part in the study.

• Diagnosis of treatment-resistant focal epilepsy as adjudicated by the Epilepsy Study Consortium, Inc (ESCI)
• At least 4 clinically observable focal onset seizures accepted by the ESCI prior to the first dose of SM (during the days of baseline Seizure eDiary data collection) and no more than a consecutive 21-day period that was seizure free. To be eligible for the study, participants must comply with the eDiary on at least 90% of the days of baseline data collection
• Good general health in the judgment of the Investigator based upon medical history, physical exam, standard 12-lead ECG, vital signs, and clinical laboratory evaluations obtained during the Screening Period
• Nonpregnant females of childbearing potential (FOCP): • who are exclusively in a same-sex relationship are eligible to participate without any contraception; • if sexually active with a male partner who is biologically capable of having children, must agree to use one of the following acceptable birth control methods after signing the ICF, throughout the study, and for 30 days following the last dose of SM; o simultaneous use of male condom and intrauterine contraceptive device (IUCD) placed at least 4 weeks prior to first dose of SM; o simultaneous use of male condom and diaphragm with or without spermicide; o simultaneous use of male condom with or without spermicide; or o established hormonal contraceptive (started at least 4 weeks prior to first dose of SM). Females are considered not to be of childbearing potential if they are either postmenopausal (amenorrhea for at least 2 years and serum follicle-stimulating hormone [FSH] level >40 IU/L) or permanently sterilized (eg, bilateral tubal ligation, bilateral oophorectomy, etc.) for 6 months minimum prior to screening. All FOCP must have a negative serum pregnancy test result before administration of SM.
• Male participants: • who have been surgically sterilized (6 months minimum) prior to the screening visit are eligible to participate without any contraception; • who are biologically capable of having children and have female partners of childbearing potential must use one or more methods of contraception as stated in Inclusion Criterion #12 (IC #12) which must be used from the time of signing the ICF until 90 days after the last dose of SM. All male participants must refrain from donating any sperm from the date of first administration of SM until 90 days after the last dose of SM.
• Failed to achieve sustained seizure freedom after ≥2 tolerated, appropriately chosen, and adequately dosed ASM drug schedules
• Adults aged 18 to ≤ 70 years at screening
• Able to read, understand, and sign the Informed Consent Form (ICF). If the participant is unable to provide informed consent, a Legally Authorized Representative (LAR) may complete the ICF
• Able to keep accurate Seizure eDiaries (with the aid of a caregiver as needed)
• Has a body mass index (BMI) between 18.0 and 40.0 kg/m2
• Able to swallow capsules whole without crushing, chewing, or cutting
• Willing to adhere to all study procedures (including patient-reported outcomes and cognitive assessments) and able to attend study visits within the specified time windows
• Treatment with a stable dose of 1 to 4 current ASMs for ≥28 days prior to screening. If following a diet plan along with the ASM, the participant should have been on a stable diet plan for at least 1 month prior to Visit 1. The diet plan should be maintained throughout the duration of the study