Participant has at least 1 parent or caregiver ≥ 18 years old who is capable of providing informed consent (signed and dated) and maintaining a daily seizure eDiary for the duration of the study, is able to attend all scheduled study visits and provide feedback regarding the participant’s symptoms and performance as described in the protocol, is able to comply with all study requirements and activities, and agrees not to post any of the participant’s personal medical data or information related to the study on any website or social media site (e.g., Facebook, Instagram, X, YouTube, etc.) until notified that the study is completed.
All females of childbearing potential (CBP; definition of non-pregnant, non-lactating females of non-childbearing potential provided in Section 6.5.1.1) and all males must practice highly effective contraception during the study and be willing and able to comply with the pregnancy prevention requirements set forth in Sections 6.5.1.2 and 6.5.1.3 for the duration of the study and for 14 weeks after their last dose of study drug. In addition, participants should not donate sperm or eggs during the study and for at least 14 weeks (5 half-lives of ION337 in plasma) after their last dose of Study Drug.
Medically stable to complete the study with no significant planned surgical or medical procedures and will tolerate sedation or general anesthesia and other study activities.
Able to complete all study procedures, measurements and visits and caregiver/participant has adequately supportive psychosocial circumstances, in the opinion of the Investigator.
Caregiver can maintain a seizure eDiary for the duration of the study and demonstrates compliance by completing seizure eDiary entries for at least 85% of the Screening period (24 out of the last 28 days).
Males and females age ≥ 2 to ≤ 12 years old at the time of informed consent.
Has a documented diagnosis of DS according to the ILAE criteria and as agreed by the ESCI.
Has confirmation of a pathogenic or likely pathogenic SCN1A variant.
Must be currently receiving ≥ 1 concomitant ASM at a stable dose/regimen for ≥ 4 weeks prior to informed consent. Rescue medications are exempt from the stability requirement and can be administered PRN.
Must have all other interventions for epilepsy (including ketogenic diet or VNS) as well as any other concomitant medications including medications for behavioral management, sleep, and supplements or nutritional support stable for ≥ 4 weeks prior to informed consent. Vagus nerve stimulator implantation must have occurred ≥ 6 months prior to informed consent.
Must have ≥ 4 MMS over 28 consecutive calendar days during the Screening Period. The MMS will be adjudicated by the ESCI. Examples of MMS include (but are not limited to) hemiclonic, generalized tonic-clonic, tonic/atonic with fall, focal to bilateral tonic-clonic, focal with clear motor component. If the participant fails to have ≥ 4 qualifying seizures in the first 28 days, the Screening Period may be extended by an additional 14 days with Sponsor approval.
Female participant of childbearing potential who is pregnant (has positive pregnancy test), or who is lactating at the time of Screening.
Has any significant disease (e.g., gastrointestinal, renal, hepatic, endocrine, respiratory, or cardiovascular system disease) or condition or circumstance, or any finding at Screening that, in the opinion of the Investigator, makes the participant unsuitable for enrollment or that could interfere with the conduct of the study or that would pose an unacceptable risk to the participant in this study.
Has a diagnosis or BP measurements consistent with a diagnosis of hypertension including BP ≥ 95th percentile + 12 mmHg, or ≥ 140/90 mmHg, whichever is lower.
Has had prior treatment with or is currently enrolled in an interventional clinical trial for a gene therapy or for another ASO for the treatment of DS.
Has had treatment with or is currently enrolled in an interventional clinical trial of any other investigational drug, biological agent, or device within 30 days prior to Screening, or 5 half-lives of investigational agent, whichever is longer.
Has history of bleeding diathesis or coagulopathy. Screening values of coagulation parameters including platelet count, INR, PT, and aPTT should be within normal ranges. Coagulation tests may be repeated once at the local laboratory if, in the opinion of the Investigator, values of the initial tests are out of range but not clinically significant. Participants with non-clinically significant and stable out-of-range values may be eligible to enroll in the study at the discretion of the Investigator.
Is undergoing treatment with antiplatelet or anticoagulant therapy, including but not limited to clopidogrel, dipyridamole, warfarin, dabigatran, rivaroxaban, and apixaban, ≤ 14 days before a procedure associated with a risk of bleeding (with the exception of aspirin up to 100 mg/day) or anticipated use during the study.
Has known brain or spinal disease that would interfere with the LP procedure or CSF circulation, or presence of other factors that would affect the safety of the LP procedure, including tumors or abnormalities by MRI or computed tomography, subarachnoid hemorrhage, suggestion of raised intracranial pressure on MRI or ophthalmic examination, Chiari malformation, obstructive hydrocephalus, syringomyelia, tethered spinal cord syndrome, or connective tissue disorders such as Ehlers-Danlos syndrome and Marfan syndrome, or including the following:
Platelet count < 100,000/mm3
Suspected spinal epidural abscess as determined by the Investigator
History of intolerance to the LP procedure (e.g., severe headache) as determined by the Investigator
Evidence of infection at the anticipated LP site as determined by the Investigator
Significant lower spinal deformity, prior spinal fusion surgery, or other spinal surgery at the LP site.
Has history of CNS tumors/malignancies, including CNS metastatic disease.
Has any contraindications or unwillingness to undergo an LP.
Has had an LP procedure 30 days or less before the baseline (Day 1) collection visit.
Has history of severe allergic or anaphylactic reactions or other adverse reactions to anesthetics used in this study or known hypersensitivity to any component of the investigational product.
Has active infection requiring systemic antiviral or antimicrobial therapy that will not be completed prior to the Part 1/SAD Week 0 Pre-D1 visit.
Has active infection with human immunodeficiency virus (HIV), hepatitis C or hepatitis B diagnosed by initial serological testing and confirmed with ribonucleic acid (RNA) testing, or prior treatment for hepatitis C. Participants at Screening who test positive by serology, but negative by RNA will be allowed.
Resistance to study procedures to support primary and secondary endpoints, or resistance to cooperate with the Investigator.
Have any other condition, which, in the opinion of the Investigator would make the patient unsuitable for inclusion or could interfere with the patient participating in or completing the study.
Has a pathogenic or likely pathogenic variant in another gene that causes epilepsy including but not limited to: PCDH19, GABRG2, and SCN2A. For known recessive disease, homozygous or compound heterozygous pathogenic (or likely pathogenic) variants are exclusionary.
Has a gain-of function variant in the SCN1A gene including but not limited to:
Thr226Met, Leu263Val, Val422Leu, Thr1174Ser, Trp1204Arg, Pro1345Ser, Gln1489Lys, Phe1499Leu, Arg1575Cys, Val1611Phe, Leu1624Pro, Arg1648Cys, Leu1649Gln, Leu1670Trp, Gly1674Arg, or Asp1866Tyr.
Is currently being treated with an ASM acting primarily as a sodium channel blocker, as maintenance treatment including but not limited to:
phenytoin, carbamazepine, oxcarbazepine, lamotrigine, lacosamide, or rufinamide.
Is currently taking a non-prescription cannabinoid or marijuana product that cannot be safely discontinued at least 4 weeks prior to informed consent. Use of prescription cannabinoids (e.g., Epidiolex) as a maintenance ASM is not exclusionary as long as the dose and dose regimen are stable for ≥ 4 weeks prior to informed consent.
Has experienced seizure freedom for a period of 4 consecutive weeks within the 6-month period prior to informed consent.
Is taking > 4 ASMs with more than 1 instance of convulsive SE that resulted in an emergency department visit or hospitalization in the 4 weeks preceding informed consent.
Has emergence of a new seizure type or reemergence of a past seizure type (seizure types that last occurred more than 12 months before informed consent) prior to dosing or has more than 1 hospitalization for seizures after informed consent prior to dosing.
Has had prior brain surgeries including: corpus callosotomy, implantation of device for deep brain stimulation or any other palliative brain surgery intended to reduce seizure burden.