Phase 1/2 Open‑Label Single and Multiple Ascending Dose Study of Intrathecal ION337 Assessing Safety, Tolerability, PK and PD in Patients with Dravet Syndrome

The primary objective is to assess the safety and tolerability of intrathecally administered ION337 in patients with Dravet Syndrome, providing essential data on the risk profile of a central nervous system‑directed therapy in this severe epileptic encephalopathy. Secondary objectives include: (1) characterization of the pharmacokinetics of ION337 in cerebrospinal fluid and plasma to define exposure parameters; and (2) evaluation of the effect of ION337 on seizure frequency to explore potential therapeutic benefit.

The trial enrolled 20 participants diagnosed with Dravet Syndrome, encompassing both male and female children aged ≥ 2 to ≤ 12 years. Candidates were selected on the basis of a documented diagnosis according to ILAE criteria, confirmation of a pathogenic or likely pathogenic SCN1A variant, and the requirement to be on at least one stable antiseizure medication regimen for a minimum of four weeks prior to consent. Additional stabilization criteria included a consistent ketogenic diet or vagus nerve stimulator placement (≥ 6 months prior) and unchanged use of concomitant therapies for behavior, sleep, or nutritional support during the same period. The population was defined as patients, representing a vulnerable group, and all participants were required to have an authorized representative capable of providing informed consent and attending scheduled visits.

The study is a Phase 1‑2, open-label, single and ascending dose investigation of the intrathecally‑administered investigational product ION337 in participants with Dravet Syndrome. The primary objective is to assess safety and tolerability, while secondary objectives include pharmacokinetic and pharmacodynamic profiling and evaluation of changes in major motor seizure frequency. The protocol comprises two parts: a single‑ascending‑dose (SAD) segment followed by a multiple‑ascending‑dose (MAD) segment. Participants will undergo a screening visit to confirm diagnosis, pathogenic SCN1A variant, seizure count, and stability of concomitant anti‑seizure and supportive therapies. A baseline visit will collect pre‑dose safety laboratories, vital signs, ECG, physical/neurological examination, and C‑SSRS assessments. Subsequent dosing visits will administer ION337 intrathecally, with dose escalation according to the SAD or MAD schedule, and will include post‑dose PK sampling (CSF trough, plasma Cmax, AUC, and half‑life). Follow‑up visits will be scheduled at predefined intervals to monitor adverse events, repeat safety assessments, and obtain additional PK/PD data. The trial concludes with an end‑of‑study visit that repeats all safety and efficacy evaluations. Participant involvement extends from the screening encounter through the end‑of‑study visit, encompassing the full duration of the assigned study part. Early termination may occur if a participant experiences a treatment‑emergent serious adverse event, clinically significant laboratory or ECG abnormality, loss of stable concomitant therapy, or withdrawal of consent.

The investigational product, ION337, is supplied as a sterile injection for Dravet syndrome patients and is administered via the intrathecal route. The formulation is presented in a single-use vial intended for intrathecal injection. Dosing follows a single‑ascending dose (SAD) and multiple‑ascending dose (MAD) schedule, with each cohort receiving a predetermined dose level based on safety and pharmacokinetic assessments. The exact dose amount and volume are defined in the protocol and are adjusted for body weight or surface area as required. Administration occurs under aseptic conditions by qualified personnel, with each dose delivered at intervals specified for the SAD or MAD phases.

No active comparator or placebo is employed in this open‑label study; participants receive only the investigational medication alongside their usual standard‑of‑care therapies for seizure management, which are continued unchanged throughout the trial. Concomitant antiepileptic drugs are permitted, and their use is documented to assess potential drug‑drug interactions.

Compliance with the dosing regimen is monitored through direct observation of each intrathecal injection, documentation of infusion parameters, and verification of study drug accountability. Pharmacokinetic and pharmacodynamic sampling is performed at predetermined time points post‑dose to evaluate systemic exposure and biological effect. Safety monitoring includes regular clinical assessments, laboratory evaluations, and adverse event reporting in accordance with the study protocol.

Efficacy will be evaluated by determining the percent change from baseline in the 28‑day normalized major motor seizure frequency for each participant. The assessment will be performed for subjects receiving single ascending doses (SAD) as well as those receiving multiple ascending doses (MAD) of the investigational product.