Efficacy and Safety Evaluation of Elsunersen in Pediatric Patients with Early-Onset SCN2A Developmental and Epileptic Encephalopathy
- Trial ID
- 2024-515598-82-00
- Protocol
- PRAX-222-311
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this clinical trial is to assess the **efficacy** of elsunersen on seizure frequency in pediatric participants with early-onset SCN2A developmental and epileptic encephalopathy (SCN2A-DEE). This objective is clinically relevant as it aims to determine the potential of elsunersen to reduce seizure frequency, which is a critical aspect of managing SCN2A-DEE, a severe neurological disorder characterized by frequent and debilitating seizures.
Secondary objectives include:
- Assessing secondary efficacy outcomes of elsunersen during the treatment period in participants with early-onset SCN2A-DEE.
- Evaluating the safety and tolerability of elsunersen during the treatment period.
- Characterizing the pharmacokinetics of elsunersen in the same population.
- Exploring long-term safety and tolerability during the extension period.
- Exploring long-term efficacy outcomes of elsunersen during the extension period.
- Assessing exploratory efficacy outcomes during the extension period.
Participants
The clinical trial involves a total of **30 participants** diagnosed with **Voltage-gated sodium channel type II alpha subunit (SCN2A) developmental and epileptic encephalopathy (DEE)**. The study population includes both male and female subjects, ranging in age from 0 (with a gestational age of at least 37 weeks +1 day) to 18 years. Participants were selected based on specific criteria, including the onset of seizures prior to 3 months of age and a documented Gain of Function SCN2A variant confirmed through genetic testing. The trial population is characterized by a seizure frequency of four or more countable motor seizures refractory to current treatment per 28-day during the Baseline Observation Period. Participants are required to have a stable regimen of any antiepileptic drugs or non-pharmacological interventions, such as a ketogenic diet or vagus nerve stimulation, for at least one month prior to screening. The study includes a vulnerable population, and all participants or their legal guardians have provided informed consent. Key health parameters, such as an estimated glomerular filtration rate (eGFR) of ≥ 60 mL/min/1.73 m² and specific liver function test values, are also considered in the selection process.
Plans and Procedures
The clinical trial is designed to evaluate the **efficacy** and safety of the investigational product, PRAX-222, in pediatric participants with early-onset **Voltage-gated sodium channel type II alpha subunit (SCN2A) developmental and epileptic encephalopathy (DEE)**. This is a randomized, multi-center, double-blind, sham-procedure-controlled trial. The trial will assess the primary endpoint of median percent change in monthly motor seizure frequency from baseline to treatment after 24 weeks. Secondary endpoints include responder rate, changes in motor seizure-free days, and various clinical and caregiver global impression scores, among others. The trial is expected to conclude by April 2027, with recruitment starting in April 2025.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, seizure frequency, and genetic testing results. The trial includes a baseline observation period, followed by treatment and extension periods. Follow-up visits will be conducted to monitor safety, efficacy, and pharmacokinetics of the treatment. The end-of-study visit will conclude the participant's involvement, which is expected to last up to 48 weeks, depending on individual response and adherence to the protocol.
Participant involvement may be terminated early if they experience significant adverse events, fail to comply with study procedures, or if the investigator deems it necessary for the participant's safety. The investigational product, PRAX-222, is administered via intrathecal injection, with a maximum daily dose of 1 mg and a total dose not exceeding 12 mg over the treatment period. The trial is not classified as low intervention and is conducted under the auspices of Praxis Precision Medicines Inc., with the product being an orphan drug designated for this rare condition.
Treatment
The clinical trial involves the administration of **PRAX-222**, an experimental medication developed by Praxis Precision Medicines Inc. This investigational product is a **solution for injection** and is classified as a synthetic antisense oligonucleotide. The active substance in PRAX-222 is a complex nucleic acid sequence: 5'-MOEMC-(SP)-MOEMC-(P)-MOEA-(P)-MOEMC-(P)-MOEG-(P)-MOEA-(P)-DMC-(SP)-DA-(SP)-DT-(SP)-DA-(SP)-DT-(SP)-DT-(SP)-DT-(SP)-DT-(SP)-DT-(SP)-DMC-(SP)-MOET-(P)-MOEA-(SP)-MOEMC-(SP)-MOEA 3'. The pharmaceutical form of PRAX-222 is a solution intended for **intrathecal use**, which involves administration directly into the spinal canal. The dosing regimen for PRAX-222 specifies a maximum daily dose of 1 mg, with a total maximum dose of 12 mg over a treatment period of up to 48 weeks.
In this trial, PRAX-222 is compared against a sham procedure, serving as the control treatment. The sham procedure is designed to mimic the administration process of the experimental drug without delivering the active substance, thereby maintaining the double-blind nature of the study. This control is essential for evaluating the efficacy and safety of PRAX-222 in reducing seizure frequency in pediatric participants with early-onset SCN2A developmental and epileptic encephalopathy (SCN2A-DEE). Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the protocol and to accurately assess the outcomes of the treatment.
Efficacy
The efficacy of the investigational product, elsunersen, in the treatment of early-onset SCN2A **Developmental and Epileptic Encephalopathy** (SCN2A-DEE) will be assessed through a series of predefined endpoints. The primary endpoint is the median percent change in monthly (28 days) motor seizure frequency from baseline to treatment after 24 weeks. Secondary endpoints include the responder rate, defined as a ≥50% reduction in monthly seizure frequency from baseline compared to treatment after 24 weeks, and changes in motor seizure-free days from baseline during both the Treatment and Extension Periods.
Additional secondary endpoints involve the Clinical Global Impression-Severity (CGI-S) and Clinical Global Impression-Improvement (CGI-I) subdomain scores, which will be evaluated at baseline and compared to each postdose time point. Caregiver Global Impression-Severity (CgGI-S) and Caregiver Global Impression-Improvement (CgGI-I) subdomain scores will also be assessed. Sleep assessment scores, incidence and severity of treatment-emergent adverse events (TEAEs), and changes in physical and neurological examinations, vital sign measurements, clinical laboratory results, and electrocardiogram (ECG) parameters will be monitored throughout the Treatment and Extension Periods.
Pharmacokinetic parameters, including plasma and cerebrospinal fluid (CSF) concentrations of elsunersen, will be measured. Changes in the antiepileptic drug (ASM) regimen, dose, and number of ASMs compared to baseline will be evaluated during the Extension Period only. These efficacy parameters will be collected and analyzed at specified time points to determine the therapeutic impact of elsunersen on the target population.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Participant, or parent/legal guardian, is willing to sign an informed consent document indicating that he/she understands the purpose of the clinical trial; understands, and can perform, complete, and comply with all the procedures and assessments that are required during the clinical trial; and is willing to participate in the clinical trial.
- Has a confirmed SCN2A variant based on genetic testing.
- Has onset of seizures prior to 3 months of age.
- Is between the ages of 0 (with a gestational age of at least 37 weeks +1 day) to ≤18 years at Screening.
- Seizure frequency of 4 or more countable motor seizures refractory to current treatment per 28-day during the Baseline Observation Period. Note: Countable motor seizures are defined as tonic seizures (bilateral; with or without fall or risk of fall); clonic seizures (bilateral); tonic-clonic seizures; atonic seizures (with fall or risk of fall) and atonic seizures (without fall or risk of fall); focal to bilateral tonic-clonic; focal or focal seizures with observable motor symptoms (including unilateral tonic or unilateral clonic).
- If prescribed any ASM or non-pharmacological intervention (including ketogenic diet and vagus nerve stimulation ) for the treatment of epilepsy or other symptoms of early-onset SCN2A-DEE (auxiliary medicinal products) is on a stable dose, settings, or parameters for 1 month prior to Screening (not to include weight-based dose changes of medications).
- Has been reviewed by the ERC prior to enrollment, including documentation of early onset SCN2A clinical phenotype , disease etiology, MRI results, and seizure frequency
- Seizure diary completion must occur on ≥80% days in the Screening/Observation
- Has a serum total bilirubin value <1.5× the ULN or a serum ALT or AST value <3×ULN.
- Has an eGFR ≥ 60 mL/min/1.73 m², calculated using the Schwartz formula (updated bedside version).
Exclusion Criteria
- At screening, has any significant ongoing disease, disorder, laboratory abnormalities, environmental factor, or any ongoing or history of any psychiatric, medical, or surgical condition that, in the judgment of the investigator in consultation with the medical monitor and/or sponsor’s designee, might jeopardize the participant’s safety or interfere with the absorption, distribution, metabolism, or excretion of elsunersen; impact the clinical trial scientific objectives, or interfere with participation in the clinical trial.
- Has any clinically significant or known pathogenic genetic variant other than in the SCN2A gene, or a genetic variant that may explain or contribute to the participant’s epilepsy and/or developmental disorder, in the opinion of the investigator or confirmed by the ERC.
- Has any other/additional etiology for epilepsy and/or DEE (e.g. encephalomalacia, etc) in the opinion of the investigator or confirmed by the ERC.
- Has bone, spine (eg, kyphosis, scoliosis), bleeding, or other disorder (including, but not limited to, intolerance to anesthesia, if applicable) that might expose the participant to risk of injury or unsuccessful lumbar puncture.
- Is unwilling or unable to discontinue medications that might increase the risk of bleeding (eg, heparin, low molecular weight heparin, platelet inhibitors) during the clinical trial (as defined in Section 6.4.1 of the protocol).
- Is required to take any excluded medication or is anticipated to require treatment with at least 1 excluded medication during the clinical trial (as defined in the relevant section of the protocol).
- Has laboratory test results at Screening outside the normal ranges for platelet count, prothrombin time (PT)/ partial thromboplastin time (PTT)/ international normalized ratio (INR), or renal function (serum creatinine [sCr] and urine protein [Uprot]), that are clinically meaningful as judged by the investigator.
- Has received any experimental or investigational drug, device, or other therapy within 30 days or 5 half-lives (whichever is longer) prior to Screening, including any prior use of gene therapy. Note: This restriction does not apply to participants from PRAX 222-111 clinical trial or to patients currently receiving elsunersen through Expanded or Emergency Access, who may enroll directly into the Extension Period.
- Has a known hypersensitivity to any component of the formulation of elsunersen.
- Is currently pregnant or breastfeeding or is planning to become pregnant during the clinical trial or within the timeframe specified in Section 5.5.3 of the protocol.
- Has any abnormal findings on brain MRI that may be contributing to the participant’s epilepsy, would put the participant at increased risk of ASO therapy (including but not limited to hydrocephalus), or any other finding that may be considered clinically significant as judged by the PI or ERC. Note: If a brain MRI has not been performed within 6 months of screening, the participant will need to have a brain MRI without gadolinium as part of Screening to assess ventricle size.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Germany | Recruiting | 30 Apr 2025 | 10 |
 Italy | Recruiting | 30 Apr 2025 | 15 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
PRAX-222 | Test | SOLUTION FOR INJECTION | INTRATHECAL USE | 1 | 48 | PRD9804966 |