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

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

A Phase 1 Trial Evaluating the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of PRAX-562 in Healthy Volunteers (AES 2022) - "Part B evaluated the effects of oxcarbazepine (OXC) in combination with 120mg PRAX-562 (QD) vs. OXC alone over 28 days. A total of 48 participants were enrolled (Part A, n=18 PRAX-562, n=12 placebo; Part B, n=14 0XC+PRAX-562, n=4 OXC+placebo). PRAX-562 exposure resulted in concentrations that exceeded the EC50 in the mouse maximal electroshock seizure (MES) model by 13-fold (based on Day 28 mean concentration), and was unaltered with OXC coadministration. PRAX-562 did not appear to alter the PK of OXC or its primary metabolite."

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

PRAX-562 Is a Well-tolerated, Novel Persistent Sodium Channel Blocker with Broad Anticonvulsant Activity in Multiple DEE Mouse Models (AES 2022) - "The effects of carbamazepine (CBZ) and lamotrigine (LTG) were also assessed using MES (3-30 mg/kg and 1-10 mg/kg, respectively) and sLMA (30-96 mg/kg and 20-63.4 mg/kg, respectively). PRAX-562 exhibited robust anticonvulsant activity in multiple mouse models of non-NaV DEE indicating broad protection regardless of the underlying genetic cause. Moreover, PRAX-562 exhibited markedly improved preclinical tolerability compared to standard of care NaV blockers, potentially due to its preference for persistent INa. The profile of PRAX-562 may translate into well-tolerated efficacy in epilepsy as well as other indications caused by neuronal hyperexcitability."

Preclinical • CNS Disorders • Epilepsy • SCN8A

Praxis Precision Medicines to Advance PRAX-562 Phase 2 Study in Pediatric Patients with Developmental and Epileptic Encephalopathies (GlobeNewswire) - "Praxis Precision Medicines, Inc...announced plans to initiate the PRAX-562 Phase 2 EMBOLD study for the treatment of pediatric patients with developmental and epileptic encephalopathies (DEEs), following U.S. Food and Drug Administration (FDA) authorization to proceed with the study as proposed by Praxis, up to the planned maximum dose of 1.0 mg/kg/day. The EMBOLD Study is expected to initiate in the U.S in the first quarter of 2023, with two distinct cohorts in early-onset SCN2A-DEE and SCN8A-DEE patients. Topline results for both cohorts are expected in the second half of 2023....Approximately 20 participants will be enrolled in a total of 2 distinct cohorts (n≈10 for SCN2A-DEE and n≈10 for SCN8A-DEE)."

New P2 trial • CNS Disorders • Epilepsy

Praxis Precision Medicines Provides Updates on Clinical Stage Pediatric Epilepsy Programs (GlobeNewswire) - "Praxis Precision Medicines, Inc...announced the plan to start the PRAX-222 EMBRAVE clinical study for the treatment of pediatric patients with early-seizure-onset SCN2A developmental and epileptic encephalopathy (DEE), after the U.S. Food and Drug Administration (FDA) cleared the Investigational New Drug (IND) application for the initial dose cohort. Following collection of the safety and efficacy data from the first cohort of patients in the EMBRAVE study, the data will be evaluated and submitted to the FDA to seek authorization for further dose escalation....Topline results for the PRAX-562 Phase 2 study for the treatment of pediatric patients with SCN2A and SCN8A DEEs are expected in 2023."

New P2 trial • New trial • P2 data • CNS Disorders • Epilepsy

Praxis Precision Medicines Provides Corporate Update and Reports Second Quarter 2022 Financial Results (GlobeNewswire) - "Praxis plans to initiate a PRAX-562 Phase 2, placebo-controlled trial for treatment of developmental epileptic encephalopathies (DEEs) in pediatric patients in the second half of 2022....Topline results are expected in mid-2023....The Company submitted the required data in July 2022 and expects to start its first-in-patient study with PRAX-222 in the second half of 2022."

New trial • P2 data • CNS Disorders • Epilepsy

Praxis Precision Medicines Showcases Largest Targeted Epilepsy Portfolio in Industry at 2022 Epilepsy Day - "Updates from Praxis’ three most advanced epilepsy programs, each of which is expected to be clinical stage by year-end 2022: PRAX-222: Investigational New Drug (IND) submitted to the U.S. Food and Drug Administration (FDA) proposing a seamless study design for SCN2A patients with early-onset seizures; PRAX-562:...A Phase 2 clinical study in cohorts of children with SCN2A epilepsy, SCN8A epilepsy, and Tuberous Sclerosis Complex (TSC) is expected to initiate in 2H2022; PRAX-628: Expected initiation of a Phase 1 study in the fourth quarter of 2022 and a Phase 2 study in focal epilepsy in 2023; A review of the significant progress in Praxis’ early-stage epilepsy pipeline, including plans to declare antisense oligonucleotide (ASO) candidates for PRAX-080 for PCDH19 and PRAX-090 for SYNGAP1 in 2023."

New P1 trial • New P2 trial • CNS Disorders • Epilepsy

The novel persistent sodium current inhibitor PRAX-562 has potent anticonvulsant activity with improved protective index relative to standard of care sodium channel blockers. (PubMed, Epilepsia) - "PRAX-562 demonstrated robust preclinical anticonvulsant activity similar to CBZ but improved compared to LTG. PRAX-562 exhibited significantly improved preclinical tolerability compared with standard Na blockers (CBZ and LTG), potentially due to the preference for persistent I . Preferential targeting of persistent I may represent a differentiated therapeutic option for diseases of hyperexcitability, where standard Na blockers have demonstrated efficacy but poor tolerability."

Journal • CNS Disorders • Epilepsy • SCN8A

Praxis Precision Medicines Announces Publication of Preclinical Data Highlighting Differentiated and Potent Antiepileptic Activity of PRAX-562 (GlobeNewswire) - "The Company expects to initiate a Phase 2 trial of PRAX-562 for DEEs in the first half of 2022 and anticipates reporting topline Auditory Steady-State Response (ASSR) biomarker data in the first half of 2022. PRAX-562 has received Orphan Drug and Rare Pediatric Disease Designations from the Food and Drug Administration, and Orphan Designation from the European Medicines Agency for the treatment of SCN2A-DEE and SCN8A-DEE."

New P2 trial • P2 data • CNS Disorders • Epilepsy