Breakthrough Therapy Designation Granted to Relutrigine for SCN2A and SCN8A Developmental and Epileptic Encephalopathies

Marcio Souza, MD, PhD

Praxis Precision Medicines recently announced the FDA’s decision to grant breakthrough therapy designation to its investigational agent relutrigine as a potential therapy for SCN2A and SCN8A developmental and epileptic encephalopathies, 2 rare forms of epilepsy. The company’s phase 2 EMBOLD study is on track for topline data readout in the first half of 2026, with a new drug application (NDA) expected to follow.

Relutrigine, previously known as PRAX-562, is a first-in-class small molecule with a mechanism of precision sodium channel modulation that is consistent with superior selectivity for disease-state NaV channel hyperexcitability. Prior to this new designation, the agent has received orphan drug designation and rare pediatric disease designation by the FDA for the treatment of SCN2A-DEE, SCN8A-DEE, and Dravet syndrome.

SCN2A-DEE has an estimated prevalence of around 1-3 per 100,000 individuals and is considered one of the most common single-gene causes of epilepsy with onset in the first few months of life. SCN8A-DEE, a bit less common, accounts for roughly 1-2% of DEEs overall, and is more commonly associated with de novo gain-of-function variants, leading to severe, early-onset epilepsy. Currently, there are no FDA-approved drugs specifically indicated for SCNA2-DEE or SCN8A-DEE.

"This BTD represents a significant milestone for our relutrigine program and further validates its potential," Marcio Souza, MD, PhD, president and chief executive officer at Praxis Precision Medicines, said in a statement.¹ "We are excited that this BTD, in addition to the Rare Pediatric Disease Designation in SCN2A and SCN8A DEEs, further supports expedited development of relutrigine."

The decision to grant breakthrough therapy designation was based on positive findings from cohort 1 of the phase 2 EMBOLD study, as well as 11-month data from the open-label extension portion of the trial. In the double-blind study, treatment with the investigational agent led to a 46% placebo-adjusted reduction in monthly motor seizure frequency over the 16-week treatment period, as well as a 30% attenuation in seizure freedom.

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EMBOLD, a multicenter, double-blind, placebo-controlled study, featured 16 patients aged 2-18 who were randomly assigned either relutrigine QD for 16 weeks or relutrigine QD for 12 weeks or matching placebo for 4 weeks. In the trial, relutrigine was considered well tolerated, with mostly mild to moderate adverse events (AEs), no drug-related serious AEs, no dose reductions, and more than 50% of patients reached 1 mg/kg/day. Additional data on caregiver and clinician scales revealed patient improvements in disruptive behavior (caregiver: 29%; clinician: 23%), communication (43%; 31%), seizure severity and intensity (71%; 62%), and alertness (57%; 69%).^2,3

Ongoing data from the open-label extension, shared in a virtual investor event earlier this year, showed that at month 11, approximately 90% seizure reduction was observed in patients treated with relutrigine. In addition, investigators observed sustained and continuous improvement in seizure-free periods, with a mean of 67 days without seizures compared with 3 days in the baseline period. Above all, the therapy continued to show a safety profile that was consistent with previous observations, with no dose reductions noted.

Souza added, "We continue to execute on the registrational EMBOLD cohort 2 study and expect to share the topline results no later than the first half of 2026. In addition to this exciting update for the SCN2A and SCN8A population, we are looking forward to results from the EMERALD study which has recently been initiated for DEE patients, regardless of etiology.”¹

EMERALD, a phase 3 study, will further test how safe and effective relutrigine is in reducing seizures in patients with DEEs. The study, a registrational, placebo-controlled trial, includes a 16-week treatment period, with an optional 48-week open-label extension. Patients are expected to be between 1-18 years old, have a diagnosis of either SCN2A-DEE or SCN8A-DEE, and have at least 8 motor seizures in the 4 weeks prior to screening.

REFERENCES
1. Praxis Precision Medicines Receives FDA Breakthrough Therapy Designation for Relutrigine for the Treatment of Seizures Associated with SCN2A and SCN8A Developmental and Epileptic Encephalopathies. June 17, 2025. Accessed June 17, 2025. https://www.globenewswire.com/news-release/2025/07/17/3117145/0/en/Praxis-Precision-Medicines-Receives-FDA-Breakthrough-Therapy-Designation-for-Relutrigine-for-the-Treatment-of-Seizures-Associated-with-SCN2A-and-SCN8A-Developmental-and-Epileptic-E.html
2. Frizzo S, Spar B, Dalby K, et al. Relutrigine demonstrates robust seizure reduction and seizure freedom in Dees: results from the EMBOLD study. Presented at: 2024 AES Annual Meeting; December 6-10; Los Angeles, CA. ABSTRACT 1.528
3. Praxis Precision Medicines announces positive topline results from the EMBOLD study in SCN2A and 8A developmental epilepsies, highlighting the disease-modifying potential of relutrigine. News release. Praxis Precision Medicines. September 3, 2024. Accessed July 17, 2025. https://www.globenewswire.com/news-release/2024/09/03/2939566/0/en/Praxis-Precision-Medicines-announces-positive-topline-results-from-the-EMBOLD-study-in-SCN2A-and-8A-developmental-epilepsies-highlighting-the-disease-modifying-potential-of-relutri.html