Clinical Trials

Inclusion Criteria:

• Written or oral pediatric assent from the subject if deemed capable of providing assent, and written informed consent from the subject’s parent(s) or legal guardian(s) for subjects < 18 years of age and for subjects ≥ 18 years of age who are not capable of providing consent in accordance with the governing Independent Ethics Committees (IEC)/Institutional Review Boards (IRB) and according to local laws and regulations. Subjects who are ≥ 18 years of age and capable of providing consent should sign an Informed Consent Form (ICF). Informed consent/assent may be done remotely, if allowed and remote consenting procedures are in place.
• Be a male or female 2 to 21 years of age, inclusive.
• Have a diagnosis of SCN8A-DEE supported by both clinical and genetic findings outlined as follows:
• Clinical findings - required:
  • Seizure onset prior to 18 months of age;
  • Developmental delay which may have occurred either prior to or with onset of seizures or after.
• Supportive (not required):
  • Multiple seizure types which include focal seizures (including focal to bilateral tonic-clonic), tonic-clonic seizures, epileptic/infantile spasms, tonic seizures;
  • History or ongoing motor abnormalities including hypotonia, dystonia, choreoathetosis, ataxia, spasticity, hyperekplexia;
  • Episodes of convulsive and nonconvulsive status epilepticus;
  • Beneficial response to sodium channel blockers such as phenytoin, valproate, carbamazepine, lacosamide, lamotrigine, rufinamide, and oxcarbazepine.
• Genetic findings (both required):
  • Pathological gain of function (GOF) mutation in SCN8A defined as either a previously identified GOF mutation or a presumed pathological GOF mutation. Presumed pathological GOF mutations must be either a missense mutation that is not seen in either parent (de novo) OR a mutation which leads to a hyperfunctioning channel in in vitro function tests. Presumed pathological GOF mutations must not be nonsense mutations or other mutations likely to lead to a truncated protein;
  • No other pathogenic mutation in an additional gene that is known to cause epilepsy and is more likely to cause the epilepsy experienced by the subject.  

Genetic findings required for SCN8A-DEE diagnosis may be based on genetic testing performed previously. The genetic mutation in the subject’s SCN8A gene (b[i]) and the absence of other pathogenic mutations that are more likely to cause the epilepsy experienced by the subject (b[ii]) must be confirmed at screening as part of the comprehensive epilepsy panel genotyping.

• Have SCN8A-DEE diagnosis confirmed by the DCP.
• In the 90 days before screening, have a history of on average at least 4 countable motor seizures (defined as GTCS, tonic, atonic or FOS with noticeable motor component) per month.
• Have on average at least 1 countable motor seizure (defined as GTCS, tonic, atonic or FOS with noticeable motor component) per week (4 per 28-day period) and not be seizure-free for more than 20 consecutive days per 28-day period during the baseline period.
• Have at least 4 weeks of reliably and consistently completed baseline seizure diary data.
• Being treated with at least 1 other ASM, but no more than 4 ASMs. Epidiolex®/Epidyolex® will be considered an ASM. The dose should be stable for at least 5 half-lives at screening. Vagus nerve stimulator (VNS) and ketogenic diet are not counted as ASMs.
• Have failed to achieve seizure freedom with at least 2 ASMs.
• The subject, if using a VNS, must have had the VNS placed at least 3 months prior to screening with stable settings for ≥ 30 days before screening; settings must remain stable throughout the duration of the study.
• The subject, if on a ketogenic diet, must have started the ketogenic diet at least 30 days prior to screening; diet must be stable, and continue through the duration of the study.
• Must be using a nocturnal alerting system or practice consistent with standards of care at the time of screening and continue to use this for the duration of the study. Acceptable nocturnal alerting systems or practices include but are not limited to:
  • Parent/caregiver sleeps in the same room as subject;
  • Video- and/or acoustic-based monitoring (e.g., use of baby monitor);
  • Device intended as a seizure alert system (e.g., bracelet devices).
• Must have an adequate rescue medication regimen per the investigator’s judgment in place at the time of screening and for the duration of the study.
• Female subjects of childbearing potential must agree to use contraception consistently from screening until the final study visit or 30 days after the last dose of study treatment, whichever is longer.

A female subject of childbearing potential is defined as a female capable of becoming pregnant, which includes subjects who have had their first menstrual cycle (ie, menarche) and are not surgically sterile (ie, bilateral oophorectomy, hysterectomy or bilateral tubal ligation for at least 3 months prior to screening). A male subject of childbearing potential is defined as a subject who has reached spermarche and has not been vasectomized for at least 3 months prior to screening.

• Highly effective methods of contraception are required for female subjects of childbearing potential:
  • Intrauterine device (IUD) or intrauterine hormone-releasing system (IUS);
  • Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (which may be oral, intravaginal, or transdermal) initiated and used in accordance with medical direction for at least 3 months prior to screening;
  • Progestogen-only hormonal contraception associated with inhibition of ovulation, which may be oral, injected, or implanted initiated and used in accordance with medical direction for at least 3 months prior to screening;
  • Bilateral tubal ligation;
  • Total abstinence from sexual intercourse (periodic abstinence is not acceptable);
  • Sexual partner(s) who had been vasectomized at least 3 months prior to screening with medically confirmed successful procedure;

Male subjects must agree to use effective barrier contraception consistently from screening until 30 days after the last dose of study treatment. The acceptable method of contraception for male subjects is condom with spermicide (cream, spray, foam, gel, suppository, or polymer film).

• Have a body weight of at least 10 kg.
• Be able to carry out all the appropriate assessments and take the study treatment with the help of the parent/caregiver in the opinion of the investigator.
• Te subject’s parent/caregiver is able to accurately identify seizure types, especially countable motor seizures (defined as GTCS, tonic, atonic or FOS with noticeable motor component) and is able to complete seizure diary.

Exclusion Criteria:

• Have previously been enrolled in this study and received blinded treatment.
• Have participated in an interventional clinical trial <30 days prior to screening.
• Have symptoms that would be more consistent with another epilepsy disorder such as Dravet syndrome (e.g., fever-induced episodes of status epilepticus, frequent myoclonic seizures, worsening on sodium channel blockers).
• Are currently receiving cannabinoids or medical marijuana except Epidiolex/Epidyolex, unless approved by the Sponsor.
• Are currently taking systemic steroids (excluding inhaled medication for asthma treatments) such as adrenocorticotropin hormone (ACTH), high dose prednisolone for epileptic spasms.
• If subject has received these medications in the past, must be off these medications for at least 3 months prior to the screening visit and these drugs may not be initiated during the duration of the study. Intermittent steroids to treat nonepilepsy related diseases (such as allergies or dermatological conditions) are not exclusionary.
• Are taking strong CYP3A4 inhibitor (e.g., ketoconazole, erythromycin, ritonavir) or inducer (e.g., rifabutin, rifampin, St. John's Wort) other than concurrent ASMs.
• Have a history of severe drug allergy or hypersensitivity to NBI-921352 or its excipients.
• Have a previous exposure to NBI-921352.
• Have any other disorder for which the treatment takes priority over treatment of SCN8A-DEE or is likely to interfere with study treatment or impair treatment compliance.
• Have a history of moderate or severe head trauma or other neurological disorders or systemic medical diseases that are, in the investigator’s opinion, likely to affect nervous system functioning.
• Have a clinically significant medical condition or chronic disease (including history of neurological, hepatic, renal, cardiovascular, gastrointestinal, significant malabsorption, hematologic, pulmonary, psychiatric, or endocrine disease) that in the opinion of the investigator would preclude the subject from participating in and completing the study or that could confound interpretation of study outcome.
• Are taking or have received disallowed concomitant medication or it is anticipated that the subject will require treatment with at least one of the disallowed concomitant medications during the study.
• Have clinically significant abnormal vital signs at the screening visit as determined by the investigator.
• Have one or more clinical laboratory test values outside the reference range, based on blood samples taken at the screening visit, that are of potential risk to the subject’s safety as determined by the investigator, or have at the screening visit:
  • A serum creatine value > 1.5 times the upper limit of the reference range;
  • A total bilirubin value > 1.5 times the upper limit of the reference range;
  • A serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) value > 2.5 times the upper limit of the reference range. For subjects on valproate, ALT or AST values up to 3 times the upper limit of the reference range are acceptable, if these values have remained stable over the past 3 months based on investigator judgement.
• Have, at the screening visit, an ECG finding of a corrected QT interval using Fridericia’s formula (QTcF) > 450 msec or presence of any significant cardiac abnormality.
• The subject or subject’s parent/caregiver, in the investigator’s opinion, is unlikely to comply with the protocol, including the requirement to travel to the study sites for study visits, or is unsuitable for any reason.
• Have attempted suicide within the last year or are at significant risk of suicide (either in the opinion of the investigator or defined as a “yes” to suicidal ideation questions 4 or 5 or “yes” to suicidal behavior on the C-SSRS within the past 12-months).
• Females who are pregnant or currently breastfeeding.
• Have a history of a positive hepatitis A virus immunoglobulin M (HAV-IgM), hepatitis B surface antigen (HBsAg), or human immunodeficiency virus antibody (HIV-Ab) test results at screening. Subject with positive hepatitis C antibody (HCV-Ab) and confirmatory positive polymerase chain reaction (PCR) reflex test results at screening will be allowed to participate in the study provided that the subject is asymptomatic as assessed by the investigator and does not have exclusionary liver function test abnormalities (ALT, AST, and total bilirubin).
• Have ingested grapefruit juice or grapefruit products within a 7-day period before Day -1.