relutrigine (PRAX-562) / Praxis Precision Medicines - LARVOL DELTA

Praxis Precision Medicines Announces Plans to File an NDA for Relutrigine in SCN2A and SCN8A Developmental and Epileptic Encephalopathies in Early 2026 (GlobeNewswire)

FDA filing • Epilepsy

Preclinical Findings of Relutrigine, a Functional State Sodium Channel Modulator, Point to Anticonvulsant Potential in Dravet Syndrome with Greater Potency than Fenfluramine (AES 2025) - "Preliminary findings in a zebrafish model support relutrigine's anticonvulsant action in Dravet syndrome and the potential for superior efficacy over current standard-of-care. In combination with recent results from the EMBOLD study in SCN2A and SCN8A, these findings emphasize its promising potential to address significant unmet needs across broad DEEs."

Preclinical • CNS Disorders • Developmental Disorders • Epilepsy • SCN8A

Complementary Antisense Oligonucleotide Treatment and Precision Sodium Channel Modulation for Early Onset SCN2A DEE: Emergency Use Cases in a Preterm Infant with Refractory Status Epilepticus (AES 2025) - "Seizure frequency remained stable with ongoing dosing; maintained after tapering phenytoin at 14 months, with no neurodevelopmental worsening. Preliminary first-in-human findings highlight the potential for complementary use of elsunersen and relutrigine for early onset SCN2A DEE, which we hypothesize is due to targeting both the root genetic cause and downstream network hyperexcitability characteristic of this disease."

Clinical • Prematurity • CNS Disorders • Developmental Disorders • Epilepsy

Relutrigine Demonstrates Sustained Seizure Reduction with Continued Exposure on Top of Standard of Care: Results from the EMBOLD Open Label Extension (AES 2025) - P2/3 | "Relutrigine is poised to be a first-line, best-in-class treatment for broad DEEs, demonstrating well-tolerated, robust, short- and sustained long-term improvement in motor seizures alongside marked seizure freedom. A registration-enabling EMBOLD cohort extension is ongoing with topline results anticipated no later than 1H 2026. The EMERALD study is set to initiate globally by mid-2025 in a broader, pan-DEE patient population."

Clinical • CNS Disorders • Epilepsy • SCN8A

Praxis announces accelerated development path for relutrigine in SCN2A and SCN8A DEE patients following positive FDA feedback (GlobeNewswire) - "The FDA agreed that Praxis’ proposed interim analysis, if positive, may serve as the basis of the NDA submission in early 2026. The interim analysis is planned to be conducted in the fourth quarter of 2025....Enrollment for the EMERALD study began in the third quarter of 2025 and is expected to be complete in the second half of 2026, receiving strong interest in the geographies where it is planned. Assuming successful conclusion of the EMBOLD study and subsequent NDA approval, if positive, the EMERALD study would serve as the basis for an sNDA by 2027."

Enrollment status • FDA event • FDA filing • Epilepsy

EMERALD: A Clinical Trial for Participants With DEE to Assess Efficacy, Safety, Tolerability, and PK of Relutrigine (clinicaltrials.gov) - P3 | N=160 | Recruiting | Sponsor: Praxis Precision Medicines | Trial completion date: Feb 2027 ➔ Jul 2027 | Trial primary completion date: Apr 2026 ➔ Jul 2026

Trial completion date • Trial primary completion date • CNS Disorders • Epilepsy

Praxis Precision Medicines Receives FDA Breakthrough Therapy Designation for Relutrigine for the Treatment of Seizures Associated with SCN2A and SCN8A Developmental and Epileptic Encephalopathies (GlobeNewswire) - "Praxis Precision Medicines, Inc...announced that the U.S. Food and Drug Administration (FDA) has granted BTD for relutrigine, a sodium channel functional state modulator for pediatric use for the treatment of patients with SCN2A and SCN8A DEEs...'The EMBOLD cohort 1 study supporting our application enrolled the most severe DEE population ever studied and included patients that failed three treatments on average before joining the study'...The EMBOLD registrational cohort 2 is currently ongoing and continues to enroll, with topline results expected no later than the first half of 2026, followed by a potential NDA filing."

Breakthrough therapy • P2 data • Epilepsy

EMERALD: A Clinical Trial for Participants With DEE to Assess Efficacy, Safety, Tolerability, and PK of Relutrigine (clinicaltrials.gov) - P3 | N=160 | Recruiting | Sponsor: Praxis Precision Medicines | Not yet recruiting ➔ Recruiting

Enrollment open • CNS Disorders • Epilepsy

EMERALD: Randomized, Double-Blind Study in Participants With DEE to Assess Efficacy, Safety, Tolerability, and PK of Relutrigine (clinicaltrials.gov) - P3 | N=160 | Not yet recruiting | Sponsor: Praxis Precision Medicines

New P3 trial • CNS Disorders • Epilepsy

Relutrigine (PRAX-562) for Developmental and Epileptic Epilepsies (DEEs) (GlobeNewswire) - "EMBOLD is currently enrolling patients with SCN2A and SCN8A DEEs in the registrational cohort 2, with topline results anticipated in the first half of 2026, followed by a potential NDA filing in 2026...Following recent regulatory interactions, Praxis anticipates initiating the EMERALD study for DEEs by mid-year 2025."

Clinical data • FDA filing • New trial • P2/3 data • CNS Disorders • Epilepsy

EMBOLD: A Clinical Trial of PRAX-562 in Subjects With Developmental and Epileptic Encephalopathies (DEE) (clinicaltrials.gov) - P2/3 | N=100 | Recruiting | Sponsor: Praxis Precision Medicines | Phase classification: P2 ➔ P2/3 | N=20 ➔ 100 | Trial completion date: Jun 2025 ➔ Mar 2027 | Trial primary completion date: Jun 2024 ➔ Mar 2026

Enrollment change • Phase classification • Trial completion date • Trial primary completion date • CNS Disorders • Epilepsy • Pediatrics

Emergency Use Case of Relutrigine, a Next-generation Sodium Channel Functional State Modulator, in an Infant with SCN2A-DEE and Refractory Status Epilepticus (AES 2024) - "Certain pathogenic variants in voltage-gated sodium channel (NaV) genes can increase NaV activity leading to the neuronal hyperexcitability observed in severe DEEs.Tailored for pediatric needs, relutrigine (PRAX-562) is a next-generation sodium channel functional state modulator with demonstrated superior selectivity for disease-state sodium channel hyperexcitability currently in development for DEEs...Here we describe its first emergency use case in an infant with SCN2A-DEE and refractory status epilepticus (SE). An 11-month-old patient with SCN2A-DEE began receiving relutrigine in February 2024 at age 4 months, on a named patient, emergency-use basis following a medical history of refractory seizures with multiple episodes of SE requiring ICU hospital admissions and IV medications to resolve the clinical status.In the 7 days preceding relutrigine treatment initiation, the patient had been in SE on three separate occasions and was receiving clobazam (2 mg/kg/day),..."

Clinical • CNS Disorders • Developmental Disorders • Epilepsy • Mental Retardation • Pediatrics

Persistent sodium currents in neurons: potential mechanisms and pharmacological blockers. (PubMed, Pflugers Arch) - "We provide an overview of the specificity and efficacy of the most widely used INaP blockers: amiodarone, cannabidiol, carbamazepine, cenobamate, eslicarbazepine, ethosuximide, gabapentin, GS967, lacosamide, lamotrigine, lidocaine, NBI-921352, oxcarbazepine, phenytoine, PRAX-562, propofol, ranolazine, riluzole, rufinamide, topiramate, valproaic acid and zonisamide. We conclude that there is strong variance in the pharmacological effects of these drugs, and in the available information. At present, GS967 and riluzole can be regarded bona fide INaP blockers, while phenytoin and lacosamide are blockers that only act on the slowly inactivating component of sodium currents."

Journal • Review • Amyotrophic Lateral Sclerosis • CNS Disorders • Epilepsy • Pain

EMBOLD: A Clinical Trial of PRAX-562 in Subjects With Developmental and Epileptic Encephalopathies (DEE) (clinicaltrials.gov) - P2 | N=20 | Recruiting | Sponsor: Praxis Precision Medicines | Initiation date: Apr 2023 ➔ Aug 2023 | Trial primary completion date: Feb 2025 ➔ Jun 2024

Trial initiation date • Trial primary completion date • CNS Disorders • Epilepsy • Pediatrics

EMBOLD: A Clinical Trial of PRAX-562 in Subjects With Developmental and Epileptic Encephalopathies (DEE) (clinicaltrials.gov) - P2 | N=20 | Recruiting | Sponsor: Praxis Precision Medicines | Trial completion date: Mar 2024 ➔ Jun 2025 | Trial primary completion date: Sep 2023 ➔ Feb 2025

Trial completion date • Trial primary completion date • CNS Disorders • Epilepsy • Pediatrics

EMBOLD: A Clinical Trial of PRAX-562 in Subjects With Developmental and Epileptic Encephalopathies (DEE) (clinicaltrials.gov) - P2 | N=20 | Recruiting | Sponsor: Praxis Precision Medicines

New P2 trial • CNS Disorders • Epilepsy • Pediatrics

Praxis Precision Medicines to Present at the American Academy of Neurology 2023 Annual Meeting (GlobeNewswire) - "Praxis Precision Medicines, Inc....announced that it will deliver presentations on its clinical stage programs at the upcoming American Academy of Neurology (AAN) 2023 Annual Meeting, held April 22-27, 2023 in Boston, Massachusetts....'Also, we expect to dose the first patients in our PRAX-222 EMBRAVE study and PRAX-562 EMBOLD study within the coming weeks and are excited to share data supporting these programs. Finally, we look forward to sharing new in-vivo results for PRAX-628 that highlight this program’s potential to be a best-in-class treatment for focal epilepsy patients'."

Clinical data • Preclinical • CNS Disorders • Epilepsy

PRAX-628: A Novel Sodium Channel Blocker with Greater Potency and Activity Dependence Compared to Standard of Care (AAN 2023) - "This profile differed from CBZ (persistent INa IC50 77,500nM, 30x preference to TB, no UDB observed) and cenobamate (persistent INa IC50 of 71,690nM, 24x preference to TB, UDB 2.3x preference to TB).  The preference for persistent INa exhibited by PRAX-628 was not retained versus activity in the more depolarized VDB assay (0.56x preference to VDB); contrasting with the preferential persistent INa inhibitor PRAX-562 (2.2x preference to VDB). The enhanced activity dependence of PRAX-628 derives from a rapid KON and moderate KOFF. Conclusions PRAX-628 is a next generation NaV blocker with increased potency and activity dependence for peak INa, and greater potency for persistent INa. This profile may translate to efficacy in epilepsy and other indications caused by hyperexcitability, without tolerability issues caused by excessive block of peak INa."

CNS Disorders • Epilepsy

PRAX-562 is a Well-Tolerated, Novel Persistent Sodium Channel Blocker with Broad Anticonvulsant Activity in Multiple DEE Mouse Models (AAN 2023) - "For comparison, carbamazepine and lamotrigine were also assessed in MES and sLMA. Moreover, PRAX-562 markedly improved preclinical tolerability compared to standard-of-care. The profile of PRAX-562 may translate into well-tolerated efficacy in epilepsy and other indications caused by neuronal hyperexcitability."

Preclinical • CNS Disorders • Epilepsy

PRAX-562-101: A Phase 1 Trial Evaluating the Safety, Tolerability, Pharmacokinetics and Food Effect of PRAX-562 in Healthy Volunteers (AAN 2023) - "90mg in the fed state resulted in a slight increase in Cmax (9%), delay in tmax (4 vs. 2.5h), and modest increase in AUC (14%) vs. the fasted state. Conclusions PRAX-562 was well tolerated in healthy participants at single doses up to 150mg (fasted) in Part A, at multiple doses up to 120mg QD for 14 days (fasted) in Part B, and at a single dose of 90mg in fed and fasted states in Part C. Our findings suggest that PRAX-562 can be administered without regard for food."

Clinical • P1 data • PK/PD data

PRAX-562-102: A Phase 1 Trial Evaluating the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of PRAX-562 in Healthy Volunteers (AAN 2023) - "Part B evaluated oxcarbazepine (OXC) in combination with 120mg PRAX-562 (QD) over 28 days vs. OXC alone. Most AEs including SAEs in Part B were considered due to coadministration of projected supratherapeutic doses of PRAX-562 with OXC. Our PK and tolerability findings are consistent with a wide therapeutic window for PRAX-562, while PD findings indicate qEEG may be a sensitive translational biomarker of sodium channel blockade."

Clinical • P1 data • PK/PD data • CNS Disorders • Epilepsy

Praxis Precision Medicines Provides Corporate Update and Reports Fourth Quarter and Full Year 2022 Financial Results (GlobeNewswire) - "Topline results expected for each of three clinical-stage epilepsy programs in 2023 – PRAX-222 first-in-patient EMBRAVE Study safety data mid-2023, PRAX-628 first-in-human Phase 1 data mid-2023, PRAX-562 Phase 2 EMBOLD Study results in 2H23."

P1 data • P2 data • CNS Disorders • Epilepsy

Praxis Precision Medicines to Present at the American Epilepsy Society 2022 Annual Meeting (GlobeNewswire) - "Praxis Precision Medicines, Inc...announced that it will deliver presentations on its epilepsy programs at the American Epilepsy Society (AES) 2022 Annual Meeting, held December 2-6, 2022 in Nashville, Tennessee....'It’s an incredibly exciting time for Praxis and our epilepsy portfolio, with first-in-patient studies for PRAX-222 and PRAX-562 and a first-in-human study for PRAX-628 expected to start shortly'....Together with pharmacokinetic findings demonstrating a 13-fold increase in concentrations compared to preclinical maximal electroshock seizure effects, our results are consistent with earlier work suggesting a wide therapeutic window for PRAX-562."

New trial • P1 data • Preclinical • CNS Disorders • Epilepsy

A phase 1 Trial Evaluating the Safety, Tolerability, Pharmacokinetics and Food Effect of PRAX-562 in Healthy Volunteers (AES 2022) - "PRAX-562 was well tolerated in healthy participants at single doses up to 150 mg (fasted) in Part A, at multiple doses of up to 120 mg QD for 14 days (fasted) in Part B, and at a single dose of 90 mg in the fed and fasted states in Part C. Our findings further suggest that PRAX-562 can be administered without regard for food."

Clinical • P1 data • PK/PD data • CNS Disorders • Developmental Disorders • Epilepsy • Mental Retardation • Pain

PRAX-628: A Novel Sodium Channel Blocker with Greater Potency and Activity Dependence Compared to Standard of Care (AES 2022) - "This profile was different than that of CBZ (persistent INa IC50 of 77,500nM, 30x preference to TB, no UDB observed) and cenobamate (persistent INa IC50 of 71,690nM, 24x preference to TB, UDB 2.3x preference to TB)...The preference for persistent INa exhibited by PRAX-628 was not retained when compared to activity in the more depolarized VDB assay (0.56x preference to VDB); contrasting with the preferential persistent INa inhibitor PRAX-562 (2.2x preference to VDB)... PRAX-628 is a next generation NaV blocker with increased potency and activity dependence for peak INa as well as greater potency for persistent INa. The profile of PRAX-628 may translate to efficacy in epilepsy, and other indications caused by neuronal hyperexcitability, without tolerability issues caused by excessive tonic block of peak INa."

CNS Disorders • Epilepsy • SCN8A