zorevunersen (STK-001) / Stoke Therap, Biogen - LARVOL DELTA

Electrophysiological Improvements in Patients with Dravet Syndrome Following Treatment with Zorevunersen, an Investigational Antisense Oligonucleotide (AES 2025) - P1/2 | "Zorevunersen was associated with dose-dependent improvements in the elevated δ-power, a characteristic of DS. Changes in EEG δ-power were associated with seizure reduction and improvement in some relevant clinical domains at 24 weeks after last dose. Although EEG changes were seen as early as 12 weeks after treatment, clinical changes manifested at 24 weeks, indicating that δ-power changes may precede and support potential clinical improvements."

Clinical • Late-breaking abstract • CNS Disorders • Epilepsy • NAV1

Zorevunersen Continues to Demonstrate Potential as a Disease-modifying Therapy in Long-term Open-label Extension Studies of Patients with Dravet Syndrome (AES 2025) - P1/2, P2 | "Patients treated with zorevunersen experienced substantial and durable seizure reductions along with continuing improvements in cognition, behavior and overall functioning despite already receiving the best available ASMs. These findings support the potential of zorevunersen as a disease-modifying therapy and warrant its further evaluation in the ongoing Phase 3 study."

Clinical • CNS Disorders • Epilepsy • Ventriculomegaly • NAV1

Zorevunersen for Dravet Syndrome: Understanding the Safety Profile of CSF Protein Elevations (AES 2025) - P1/2 | "Our data support the hypothesis that albumin penetration through the blood-brain and blood-CSF barriers is the most likely pathophysiologic factor accounting for the transient elevation in CSF protein. These data coincide with reports of CSF alterations triggered by other ASOs requiring intrathecal administration with no new side effects identified. Additionally, the pattern of CSF protein elevation appeared consistent with cumulative dose effect."

Clinical • Late-breaking abstract • CNS Disorders • Epilepsy • Hematological Disorders • Ventriculomegaly

Spectral Electroencephalogram Abnormalities Across Development in Patients with Dravet Syndrome (AES 2025) - P1/2 | "Our findings demonstrate that EEG δ-power is useful in distinguishing between children with DS and neurotypical individuals. Although children with DS showed decreasing δ-power with age, similarly to neurotypical individuals [3], they demonstrated a stable elevation across development (ages 2–18 years). This persistent δ-band abnormality may reflect DS-related pathophysiology, warranting its further exploration as a potential biomarker to assess disease modification induced by novel therapies such as zorevunersen."

Clinical • Late-breaking abstract • CNS Disorders • Epilepsy

Zorevunersen Demonstrates Disease-modifying Potential in Patients with Dravet Syndrome with Increases in Seizure-free Days, Improvements in Quality of Life, and Benefits in Overall Functioning (AES 2025) - P1/2, P2 | "Treatment with zorevunersen resulted in durable seizure reduction, increased seizure-free days, and improvements in QoL and overall functioning in patients with DS. These findings support the potential of zorevunersen as a disease-modifying therapy and are further evaluated in the ongoing Phase 3 study."

Clinical • HEOR • CNS Disorders • Epilepsy • Ventriculomegaly • NAV1

Zorevunersen Demonstrates Substantial Reduction in Seizure Frequency with or Without the Use of Fenfluramine in Patients with Dravet Syndrome (AES 2025) - P1/2, P2 | "Zorevunersen demonstrated substantial and durable seizure reduction and continuing improvements in overall functioning independent of FFA use. These findings support zorevunersen's potential as a disease-modifying therapy and will be further examined in its Phase 3 registration study."

Clinical • CNS Disorders • Epilepsy • NAV1

The zorevunersen story: insights from the development of the first potential disease-modifying medicine for Dravet syndrome (ESGCT 2024) - No abstract available

CNS Disorders • Epilepsy

SWALLOWTAIL: An Open-Label Extension Study of STK-001 for Patients With Dravet Syndrome (clinicaltrials.gov) - P2 | N=60 | Active, not recruiting | Sponsor: Stoke Therapeutics, Inc | Enrolling by invitation ➔ Active, not recruiting | Trial completion date: Mar 2027 ➔ Mar 2029 | Trial primary completion date: Feb 2026 ➔ Mar 2029

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

Voltage-gated sodium channels in the nervous system: Molecular physiology to therapeutic interventions. (PubMed, Neural Regen Res) - "It analyzes two major categories of conventional sodium channel blockers and their applications: antiepileptic drugs (such as carbamazepine, lamotrigine, and phenytoin) and antiarrhythmic drugs (such as lidocaine, flecainide, and quinidine)...Additionally, this review evaluates gabapentin, cannabidiol, and calcium channel blockers with different mechanisms of action...This review also highlights advances in gene therapy for specific diseases, such as STK-001, which promotes effective splicing of the SCN1A gene, and ETX101, which utilizes adeno-associated virus 9 vectors to deliver engineered transcription factors...Furthermore, this review summarizes some innovative therapeutic agents in clinical trials, including PRAX-222 (for SCN2A gain-of-function mutation-related epilepsy), which has received Food and Drug Administration orphan drug designation, and the selective Nav1.6 inhibitor NBI-921352 (for SCN8A-related epilepsy). Collectively, this review comprehensively..."

Journal • Autism Spectrum Disorder • CNS Disorders • Epilepsy • Gene Therapies • Genetic Disorders • Migraine • Ophthalmology • Pain • NAV1 • SCN8A

Biogen and Stoke Therapeutics Announce Presentation of Data from Studies of Zorevunersen, an Investigational Medicine for Dravet syndrome, at the 16th European Paediatric Neurology Society (EPNS) Congress (Biogen Press Release) - "A mixed-effects model for repeated measures (MMRM) analysis was used to evaluate the potential effects of the Phase 3 zorevunersen dosing regimen on patient cognition and behavior at Week 68. The model was developed using clinical data from patients in the Phase 1/2a ADMIRAL study and the LONGWING OLE study. An analysis of patients who received a total cumulative dose consistent with the Phase 3 EMPEROR regimen of two loading doses of 70mg followed by two maintenance doses of 45mg, showed improvements in cognition and behavior. The analysis was performed to inform the design of the Phase 3 EMPEROR study. Baseline covariates for patients followed in the BUTTERFLY natural history study were matched to the selected ADMIRAL patient population. Improvements in patients treated with zorevunersen contrasted with findings from BUTTERFLY."

Clinical data • Epilepsy

A Double-blind Study Evaluating the Efficacy, Safety, and Tolerability of Zorevunersen in Patients With Dravet Syndrome (clinicaltrials.gov) - P3 | N=150 | Recruiting | Sponsor: Stoke Therapeutics, Inc | Not yet recruiting ➔ Recruiting

Enrollment open • CNS Disorders • Epilepsy

Current and Emerging Precision Therapies for Developmental and Epileptic Encephalopathies. (PubMed, Pediatr Neurol) - "Targeted approaches for channelopathies include antisense oligonucleotides and gene therapies, such as zorevunersen and ETX101 for SCN1A-related Dravet syndrome, alongside novel small molecules for other ion channel disorders. Advances in targeting neurotransmitter receptor dysfunctions, including γ-aminobutyric acid and glutamate receptor variants, highlight the use of modulators such as gaboxadol, radiprodil, and l-serine, alongside emerging gene therapies...Future directions focus on addressing the challenges in developing and implementing gene-based therapies, integrating systems biology, leveraging artificial intelligence for data analysis, and fostering collaboration among stakeholders. The rapidly advancing field of precision therapeutics for DEEs holds promise to improve outcomes through tailored, equitable, and patient-centered care."

Journal • Review • CNS Disorders • Developmental Disorders • Epilepsy • Gene Therapies • Metabolic Disorders • Movement Disorders • XBP1

Stoke Therapeutics Reports Fourth Quarter and Full Year 2024 Financial Results and Provides Business Updates (Businesswire) - "Phase 3 EMPEROR study of zorevunersen, a first-in-class potential disease-modifying medicine for Dravet syndrome, on track to initiate in 2Q 2025."

Trial status • CNS Disorders • Epilepsy

A Double-blind Study Evaluating the Efficacy, Safety, and Tolerability of Zorevunersen in Patients with Dravet Syndrome (clinicaltrials.gov) - P3 | N=150 | Not yet recruiting | Sponsor: Stoke Therapeutics, Inc

New P3 trial • CNS Disorders • Epilepsy

Biogen and Stoke Therapeutics Enter into Collaboration to Develop and Commercialize Zorevunersen for the Treatment of Dravet Syndrome, a Rare Genetic Epilepsy Associated with Refractory Seizures and Neurodevelopmental Impairments (GlobeNewswire) - "Biogen...and Stoke Therapeutics...announced a collaboration for the development and commercialization of zorevunersen, a potential first-in-class disease modifying medicine in development for the treatment of Dravet syndrome, in all territories outside the United States, Canada, and Mexico. Zorevunersen is an investigational antisense oligonucleotide (ASO) that targets the SCN1A gene, the underlying cause of most cases of Dravet syndrome. Stoke recently announced plans to initiate a global Phase 3 registrational study of zorevunersen (EMPEROR) following successful alignment with regulatory agencies in the United States, Europe, and Japan. The study is on track to initiate in the second quarter of 2025, with a pivotal data readout expected in the second half of 2027, which is anticipated to support global regulatory filings."

Licensing / partnership • New P3 trial • CNS Disorders • Epilepsy

Stoke Therapeutics to Host Webcast to Discuss Successful Global Regulatory Alignment for a Phase 3 Study of Zorevunersen as Potentially the First Disease Modifying Medicine for Dravet Syndrome (Businesswire) - "Stoke Therapeutics...today announced that its management team will host a webcast and conference call for investors and analysts to discuss successful alignment with global regulatory agencies related to a Phase 3 study of zorevunersen as potentially the first disease-modifying medicine for the treatment of Dravet syndrome."

Clinical • CNS Disorders

Stoke Therapeutics Announces Alignment with Global Regulatory Agencies and Plans to Initiate a Phase 3 Study of Zorevunersen as Potentially the First Disease-Modifying Medicine for the Treatment of Dravet Syndrome (Businesswire) - "Stoke Therapeutics, Inc...announced alignment with global regulatory agencies on the design of the Company’s Phase 3 EMPEROR study of zorevunersen as potentially the first disease-modifying medicine for the treatment of Dravet syndrome. Following successful interactions with the FDA, EMA and PMDA, the Company has finalized its EMPEROR Phase 3 study protocol. The proposed study will evaluate two loading doses of 70mg followed by two maintenance doses of 45mg over 52-weeks compared to sham in children and adolescents ages 2 to <18 with Dravet syndrome. The primary endpoint will be reduction in major motor seizure frequency. Key secondary endpoints will include improvements in cognition and behavior as measured primarily by Vineland-3. The Company plans to initiate the Phase 3 study in mid-2025."

Clinical protocol • New P3 trial • CNS Disorders • Epilepsy

Spectral EEG Analysis Demonstrates Decreased Slow-wave Activity in Patients with Dravet Syndrome (DS) After Treatment with STK-001, an Antisense Oligonucleotide (ASO) (AES 2024) - P1/2 | "Our study demonstrates that spectral EEG analysis can reliably capture treatment effects on the CNS, in DS patients following STK-001 ASO administration. This is indicated by decreased slow-wave activity compared to baseline, (reduced power in the Delta, Theta and Alpha bands) that are more pronounced at higher STK-001 ASO dose levels. Moreover, these changes persisted for many months post-treatment, suggesting a sustained effect of STK-001."

Clinical • CNS Disorders • Epilepsy • NAV1

Zorevunersen (STK-001) Demonstrates Potential for Disease Modification Including Reductions in Seizures and Improvements in Cognition and Behavior in Children and Adolescents with Dravet Syndrome (DS) (AES 2024) - P1/2 | "Patients were highly refractory to available treatments with 85% taking ≥3 and 54% taking ≥4 concomitant anti-seizure medications, including 49% taking fenfluramine. STK-001 benefit-risk profile appears favorable in single and multiple doses up to 70mg/dose, supporting continued development as the first potential disease-modifying medicine to treat DS. The fact that these effects are on top of the best available anti-seizure medicines support the highly differentiated mechanism of action for STK-001. We are currently planning a global registrational study of STK-001 in patients with DS."

Clinical • CNS Disorders • Developmental Disorders • Epilepsy • Mental Retardation • NAV1

Patients with Dravet Syndrome in Open-label Extension Studies of Zorevunersen (STK-001) Have Durable Reductions in Seizure Frequency and Clinically Meaningful Improvements in Cognition and Behavior (AES 2024) - P2 | "In summary, clinically meaningful improvements in multiple measures of cognition and behavior over 12 months were observed as well as a consistency across caregiver and clinician assessments of improvements. Overall, the data from patients treated with 30mg or 45mg of STK-001 every 4 months support plans for maintenance dosing as part of a pivotal study regimen. STK-001 has the potential to be the first disease-modifying medicine addressing the underlying pathogenic mechanism of DS."

Clinical • CNS Disorders • Developmental Disorders • Epilepsy • Mental Retardation • NAV1

Zorevunersen (STK-001) Demonstrates Potential for Disease Modification Including Reductions in Seizures and Improvements in Cognition and Behavior in Children and Adolescents with Dravet Syndrome (DS) (AES 2024) - No abstract available

Clinical • CNS Disorders • Epilepsy

Progress report on new medications for seizures and epilepsy: A summary of the 17th Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XVII). II. Drugs in more advanced clinical development. (PubMed, Epilepsia) - "These investigational treatments include azetukalner (XEN1101), a potent, KV7.2/7.3-specific potassium channel opener in development for the treatment of focal seizures, generalized tonic-clonic seizures, and major depressive disorder; bexicaserin (LP352), a selective 5-HT2C receptor superagonist in development for the treatment of seizures associated with developmental and epileptic encephalopathies; radiprodil, a selective negative allosteric modulator of NR2B subunit-containing N-methyl-D-aspartate glutamate receptors, in development for the treatment of seizures and behavior manifestations associated with disorders caused by gain-of-function mutations in the GRIN1, -2A, -2B, or -2D genes; soticlestat (TAK-935), a selective inhibitor of cholesterol 24-hydroxylase in development for the treatment of seizures associated with Dravet syndrome and Lennox-Gastaut syndrome; and STK-001, an antisense oligonucleotide designed to upregulate Nav1.1 protein expression and improve..."

Journal • Metastases • CNS Disorders • Depression • Epilepsy • Major Depressive Disorder • Mood Disorders • Psychiatry • NAV1

An Open-Label Study to Investigate the Safety of Single and Multiple Ascending Doses in Children and Adolescents With Dravet Syndrome (clinicaltrials.gov) - P1/2 | N=62 | Completed | Sponsor: Stoke Therapeutics, Inc | Active, not recruiting ➔ Completed | Trial completion date: May 2025 ➔ Apr 2024 | Trial primary completion date: Sep 2024 ➔ Dec 2023

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

Utilization of a Pharmacokinetic (PK) Model for STK-001 in Patients with Dravet Syndrome (DS) to Support the Selection of Dosing Regimens in Clinic (AES 2023) - "The PK model developed with NHP data along with published data for animal to human scaling was leveraged to predict dosing regimens with adequate safety margins and that would lead to pharmacologically active levels in brain tissues in patients with DS. The model will be further validated or adjusted using data from ongoing Phase 1/2 and OLE studies in patients with DS receiving STK-001."

Clinical • PK/PD data • Ataxia • CNS Disorders • Developmental Disorders • Epilepsy • Mental Retardation • Movement Disorders • Pediatrics

SWALLOWTAIL and LONGWING: Open-Label Extension (OLE) Studies for Children and Adolescents with Dravet Syndrome (DS) Who Previously Participated in a Study of Antisense Oligonucleotide (ASO) STK-001 (AES 2023) - P1/2, P2 | "Data support continued STK-001 development as the first potential disease-modifying approach to treat DS. SWALLOWTAIL and LONGWING will inform on the long-term safety and tolerability of repeat administration and will help inform future STK-001 clinical studies."

Clinical • Ataxia • CNS Disorders • Developmental Disorders • Epilepsy • Mental Retardation • Movement Disorders