Praxis Submits NDAs for Ulixacaltamide in Essential Tremor and Relutrigine in SCN2A/SCN8A Developmental Epileptic Encephalopathies

In recent news, Praxis Precision Medicines announced that it submitted new drug applications (NDAs) to the FDA for ulixacaltamide for essential tremor (ET) and relutrigine for SCN2A- and SCN8A-related developmental epileptic encephalopathies (DEEs).¹ The FDA has yet to assign PDUFA dates for each of the respective agents.¹

Both submissions stem from programs targeting neurologic disorders with substantial unmet need. ET remains inadequately managed despite available symptomatic therapies,² while SCN2A- and SCN8A-related DEEs are rare genetic epilepsies frequently characterized by early-onset, treatment-refractory seizures and developmental impairment.³

“After a landmark fourth quarter, filled with a breadth of clinical and regulatory advancements across our portfolio, we started 2026 with two NDA submissions for ulixacaltamide and relutrigine. Pending their expected positive reviews, we will be positioned to transition into a commercial company,” Marcio Souza, MD, president and chief executive officer, said in a statement.¹ “The other two programs in the clinic, vormatrigine and elsunersen, will both have topline results in the first half of 2026, keeping us on track for additional NDA submissions in the next two years. Together, these four assets have a revenue potential of over $20 billion.”

Ulixacaltamide in Essential Tremor

The NDA submission for ulixacaltamide is based on results from the phase 3 Essential3 program (NCT06087276), previously reported in October 2025 and summarized in the company’s February 2026 corporate update.^1,4 For context, Essential3 consisted of 2 concurrently enrolled, decentralized studies conducted across the United States.

Study 1 was a 12-week, randomized, double-blind, placebo-controlled parallel-group trial that enrolled 473 adults with ET, using change in Modified Activities of Daily Living 11 (mADL11) score at Week 8 as the primary outcome. All told, patients receiving ulixacaltamide demonstrated a mean 4.3-point improvement on this scale compared with a 1.7-point improvement in the placebo group (P < .0001).^1,4 Improvements were reported to be sustained throughout the dosing period, and key secondary endpoints—including rate of disease improvement, Patient Global Impression of Change (PGI-C), and Clinical Global Impression of Severity (CGI-S)—were also statistically significant.

Study 2 used a randomized-withdrawal design. After 8 weeks of open-label ulixacaltamide, responders (defined as ≥3-point improvement in mADL11) were randomized to continue treatment or switch to placebo. During the 4-week withdrawal phase, 55% of patients continuing ulixacaltamide maintained response compared with 33% of those switched to placebo (P = .0369).^1,4 The first key secondary endpoint achieved statistical significance, whereas PGI-C and CGI-S favored treatment numerically but did not meet significance thresholds.

In terms of safety, ulixacaltamide was generally well tolerated over 12 weeks. The most common treatment-emergent adverse events (≥10%) included constipation, dizziness, euphoric mood, brain fog, headache, paraesthesia, and insomnia.¹ Discontinuations due to adverse events occurred in approximately 27% to 28% of treated participants across studies.

In prior remarks accompanying the phase 3 results, co–lead investigator Salima Brillman, MD, stated that the findings showed “clinically meaningful improvements in tremor control and daily function for adults with ET,” reflecting the functional focus of the mADL11 endpoint.

ET affects millions of individuals in the United States and is primarily treated with repurposed agents such as propranolol and primidone, both of which were not originally developed for ET and may provide incomplete symptom control.² If approved, ulixacaltamide would represent the first medication specifically developed and submitted for approval for ET.

Relutrigine in SCN2A and SCN8A Developmental Epileptic Encephalopathies

Praxis also announced submission of an NDA for relutrigine in SCN2A- and SCN8A-related DEEs.¹ These conditions arise from pathogenic variants in genes encoding voltage-gated sodium channel subunits, contributing to neuronal hyperexcitability and severe early-onset epilepsy.³

The NDA is supported by data from the EMBOLD registrational cohort, previously presented at the 2025 American Epilepsy Society meeting.¹ Detailed peer-reviewed efficacy and safety results have not yet been published. According to the February 2026 update, the submission is based on efficacy observed in that cohort.

EMBOLD was a randomized, double-blind, placebo-controlled study with an open-label extension that tested relutrigine in children with SCN2A-DEE or SCN8A-DEE. In the study, Cohorts 1 (n = 16) and 2 (n = 53) were randomized 1:1 to receive once-daily relutrigine for 16 weeks or relutrigine for 12 weeks followed by 4 weeks of blinded placebo, with Cohort 1 starting at 0.5 mg/kg/day (optional increase to 1.0 mg/kg/day) and Cohort 2 maintained at 1.0 mg/kg/day, administered orally or via G/J tube.

In the study, relutrigine demonstrated placebo-adjusted seizure reduction of 46% at 16 weeks in the first cohort (P = .0354) and 53% reduction (P <.0002) in the confirmatory, registration cohort. Overall, the treatment produced rapid and substantial early seizure reduction, with effects that were sustained and progressively deepened over time, demonstrating consistent responses across cohorts. It was also associated with meaningful functional improvement, including a 66% increase in motor seizure-free days and strong clinician- and caregiver-reported global outcomes.⁵

Additional data from EMBOLD revealed that relutrigine treatment led to broad, clinically meaningful improvements across behavior, function, and overall status. More specifically, clinician and caregiver scales showed placebo-adjusted gains exceeding 25% within a single 28-day period. These benefits included marked behavioral improvement, enhanced alertness and communication, and consistent reductions in seizure severity and intensity.

In terms of safety, there were no drug-related serious adverse events (AEs) and treatment-related AEs were predominantly mild and moderate. Of note, investigators recorded no clinically significant safety findings in vital signs, clinical laboratory results, physical exams, and ECGs.

Relutrigine is described as a sodium channel modulator designed to target hyperexcitable sodium channel states. SCN2A- and SCN8A-related DEEs are often resistant to multiple antiseizure medications, and management frequently involves polytherapy with variable effectiveness.³ To date, the agent has received Breakthrough Therapy and Orphan Drug designations from the FDA.

REFERENCES
1. Praxis Precision Medicines Inc. Praxis provides corporate update and reports fourth quarter and full-year 2025 financial results; announces NDA submissions for ulixacaltamide and relutrigine. Press release. February 19, 2026. https://www.globenewswire.com/news-release/2026/02/19/XXXXXXX
2. Louis ED. Essential tremor. Lancet Neurol. 2014;13(10):1023-1034. https://doi.org/10.1016/S1474-4422(14)70140-2
3. Scheffer IE, Berkovic S, Capovilla G, et al. ILAE classification of the epilepsies: Position paper of the ILAE Commission. Epilepsia. 2017;58(4):512-521. https://doi.org/10.1111/epi.13709
4. ClinicalTrials.gov. A Study to Evaluate Ulixacaltamide in Participants With Essential Tremor (Essential3). NCT06087276. https://clinicaltrials.gov/study/NCT06087276.
5. Kamireddy S, Frizzo S, Spar B, et al. Relutrigine Demonstrates Disease-Modifying Impact in DEEs: Results from the EMBOLD Study. Presented at: 2026 AES Annual Meeting; December 5-9; Atlanta, GA.