Authors :
Presenting Author: Silvana Frizzo, MD – Praxis Precision Medicines
brian spar, BS – Praxis Precision Medicines; Kelley dalby, MEd – Praxis Precision Medicines; Dharit Patel, MBBS, MPH – Praxis Precision Medicines; Henry Jacotin, MD – Praxis Precision Medicines; Marcio souza, PharmD, MBA – Praxis Precision Medicines; Steven Petrou, PhD – Praxis Precision Medicines
Rationale:
Early onset SCN2A developmental and epileptic encephalopathy (SCN2A-DEE) is a rare, severe, and life-threatening condition caused by gain-of-function (GoF) variants in the SCN2A gene encoding the voltage-gated sodium channel Na
V1.2. With no approved therapy specifically for treatment of affected patients, current standard-of-care for seizure treatment includes polypharmacy with antiseizure medications in addition to medications for other devastating comorbidities.
In addition to their limited efficacy and significant adverse event profiles, current treatments do not address the profound developmental impairments and outcomes beyond seizure symptomatology in SCN2A-DEE, implicating an urgent need for new therapeutic approaches.
Preclinical evidence suggests selective reduction in SCN2A function via human mRNA-targeting antisense oligonucleotides (ASOs) has the potential to achieve more widespread seizure freedom and potentially improve developmental outcomes following disease onset by addressing the underlying genetic cause of disease. PRAX-222 is an ASO designed to down-regulate NaV1.2 expression currently in development for early onset SCN2A GoF DEE.
The EMBRAVE study (NCT05737784) is a first-in-human clinical trial designed to investigate the safety and efficacy of PRAX-222 in pediatric participants with early-onset SCN2A-DEE.
Methods:
EMBRAVE is a seamless trial designed to explore the safety, tolerability, pharmacokinetics (PK), and efficacy of ascending doses of PRAX-222 in eligible male and female participants aged two to eighteen years, inclusive, with an early onset SCN2A-DEE diagnosis. The trial will be conducted in four parts: the preliminary safety Part 1 (open label, n=4), dose-escalation Part A (double-blind), confirmatory Part B (double-blind), followed by an open-label extension in Part C. In Part 1, participants will receive PRAX-222 intrathecally at ≥ 4-week intervals for up to 13 weeks. Interim analysis of safety, tolerability and PK data will be conducted after participants receive a minimum of two doses and have had a minimum of two weeks monitoring. Trial continuation to Parts A, B and C in the US will be subject to FDA review and approval.
Results:
Part 1 will assess the incidence and severity of treatment-emergent adverse events with preliminary efficacy and safety also assessed after four doses. Enrollment is ongoing with Part 1 results expected in the second half of 2023.
Conclusions:
PRAX-222 has potential to be the first disease-modifying treatment for early onset SCN2A GoF DEE. The EMBRAVE trial is intended to identify and confirm a safe and efficacious PRAX-222 dose for seizure control, with Part 1 designed to assess preliminary safety and inform subsequent dose escalation and trial continuation.
Funding:
Praxis Precision Medicines