NBI-921352 / Xenon, Neurocrine - LARVOL DELTA

NBI-921352 as Adjunctive Therapy in Adults with Focal Onset Seizures (AES 2025) - P2 | "Although NBI-921352 was not associated with meaningful reductions in FOS frequency in Phase 2 trials, these findings provide valuable data regarding safety and tolerability of adjunctive NBI-921352 in adults with FOS."

Clinical • CNS Disorders • Epilepsy • NAV1

Structure and function of voltage-gated sodium channel Nav1.6: Involvement in the pathological process of neural injury. (PubMed, Neural Regen Res) - "Key findings include the following: (1) Epilepsy studies reveal more than 250 sodium voltage-gated channel alpha subunit 8 mutations with distinct genotype-phenotype correlations, where gain-of-function variants lead to severe epileptic encephalopathies, while loss-of-function variants are associated with generalized epilepsy, highlighting the potential of Nav1.6-selective blockers such as XEN901 and GS967...(4) Amyotrophic lateral sclerosis involves Nav1.6-dependent cortical hyperexcitability preceding motor neuron degeneration, with riluzole showing partial efficacy through sodium current modulation...Future directions emphasize the integration of advanced technologies-such as singlecell multiomics to map neuronal subtype-specific expression patterns, patient-derived organoids for personalized drug testing, and machine learning-assisted drug design-to accelerate translation. Large-scale collaborative efforts will be essential to validate therapeutic candidates and..."

Journal • Alzheimer's Disease • Amyotrophic Lateral Sclerosis • CNS Disorders • Epilepsy • Gene Therapies • Movement Disorders • Multiple Sclerosis • Oncology • Pain • Parkinson's Disease • Vascular Neurology • APP • BACE1 • NAV1 • NFATC1 • SCN8A • TNFA

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

Study to Evaluate NBI-921352 as Adjunctive Therapy in Subjects With SCN8A Developmental and Epileptic Encephalopathy Syndrome (SCN8A-DEE) (clinicaltrials.gov) - P2 | N=8 | Terminated | Sponsor: Neurocrine Biosciences | N=52 ➔ 8 | Active, not recruiting ➔ Terminated; This study was prematurely terminated due to sponsor decision.

Enrollment change • Trial termination • CNS Disorders • Epilepsy • SCN8A

Extension Study to Evaluate How Safe and Tolerable NBI-921352 is as an Adjunctive Therapy for Participants With SCN8A-DEE (clinicaltrials.gov) - P2 | N=8 | Active, not recruiting | Sponsor: Neurocrine Biosciences | Enrolling by invitation ➔ Active, not recruiting | N=52 ➔ 8

Enrollment change • Enrollment closed • CNS Disorders • Epilepsy • SCN8A

Study to Evaluate NBI-921352 as Adjunctive Therapy in Subjects With SCN8A Developmental and Epileptic Encephalopathy Syndrome (SCN8A-DEE) (clinicaltrials.gov) - P2 | N=52 | Active, not recruiting | Sponsor: Neurocrine Biosciences | Recruiting ➔ Active, not recruiting

Enrollment closed • CNS Disorders • Epilepsy • SCN8A

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

Extension Study to Evaluate the Safety and Tolerability of NBI-921352 When Used With Anti-seizure Medications in Adults With Focal Onset Seizures (clinicaltrials.gov) - P2 | N=82 | Terminated | Sponsor: Neurocrine Biosciences | Trial completion date: Dec 2025 ➔ Mar 2024 | Enrolling by invitation ➔ Terminated | Trial primary completion date: Dec 2025 ➔ Mar 2024; The long-term extension study was terminated because the parent study NBI-921352-FOS2021 (NCT05159908) failed to meet its primary endpoint.

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

Study to Evaluate NBI-921352 as Adjunctive Therapy in Subjects With SCN8A Developmental and Epileptic Encephalopathy Syndrome (SCN8A-DEE) (clinicaltrials.gov) - P2 | N=52 | Recruiting | Sponsor: Neurocrine Biosciences | Trial completion date: Feb 2024 ➔ Dec 2025 | Trial primary completion date: Jan 2024 ➔ Dec 2025

Trial completion date • Trial primary completion date • CNS Disorders • Epilepsy • SCN8A

A Study to Investigate How Effective, Safe and Tolerable the Drug NBI-921352 is When Used With Anti-seizure Medications in Adults With Focal Onset Seizures (clinicaltrials.gov) - P2 | N=101 | Completed | Sponsor: Neurocrine Biosciences | Active, not recruiting ➔ Completed

Trial completion • CNS Disorders • Epilepsy

A Study to Investigate How Effective, Safe and Tolerable the Drug NBI-921352 is When Used With Anti-seizure Medications in Adults With Focal Onset Seizures (clinicaltrials.gov) - P2 | N=100 | Active, not recruiting | Sponsor: Neurocrine Biosciences | Recruiting ➔ Active, not recruiting

Enrollment closed • CNS Disorders • Epilepsy

NEUROCRINE BIOSCIENCES INC Management's Discussion and Analysis of Financial Condition and Results of Operations (form 10-K) (Market Screener) - "For 2022 compared to 2021, the increase in early stage expenses primarily reflected continued investment in our Phase II programs for NBI-921352 in epilepsy..."

Commercial • CNS Disorders • Epilepsy

A Study to Investigate How Effective, Safe and Tolerable the Drug NBI-921352 is When Used With Anti-seizure Medications in Adults With Focal Onset Seizures (clinicaltrials.gov) - P2 | N=100 | Recruiting | Sponsor: Neurocrine Biosciences | Trial completion date: May 2023 ➔ Aug 2023 | Trial primary completion date: Feb 2023 ➔ Aug 2023

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

Xenon Pharmaceuticals Outlines Key Milestone Opportunities for 2023 (GlobeNewswire) - '"In addition, our partners at Neurocrine expect to have a clinical read-out from their Phase 2 study in adult patients with focal onset seizures in the second half of this year'....A Phase 3 randomized, double-blind, placebo-controlled, parallel group, multicenter clinical trial, called EPIK, is ongoing to evaluate the efficacy, safety, and tolerability of XEN496 administered as adjunctive treatment in approximately 40 pediatric patients aged one month to less than six years with KCNQ2-DEE. Xenon anticipates that the EPIK study will be completed in 2024....Neurocrine Biosciences is conducting a Phase 2 clinical trial evaluating NBI-921352 in adult patients with focal onset seizures, with data expected in the second half of this year."

P2 data • Trial completion date • CNS Disorders • Epilepsy

Extension Study to Evaluate the Safety and Tolerability of NBI-921352 When Used With Anti-seizure Medications in Adults With Focal Onset Seizures (clinicaltrials.gov) - P2 | N=100 | Enrolling by invitation | Sponsor: Neurocrine Biosciences | Not yet recruiting ➔ Enrolling by invitation

Enrollment open • CNS Disorders • Epilepsy

Xenon Pharmaceuticals Reports Third Quarter 2022 Financial Results and Provides Corporate Update (Yahoo Finance) - "Strong financial position of approximately $752 million to fully support XEN1101 Phase 3 program development and expected cash runway into 2026...Based on current patient enrollment rates, Xenon now anticipates that the EPIK study will be completed in 2024....Neurocrine Biosciences is conducting a Phase 2 clinical trial evaluating NBI-921352 in adult patients with focal onset seizures, with data expected in 2023....Research and development expenses for the quarter ended September 30, 2022 were $29.4 million, compared to $18.9 million for the same period in 2021. The increase of $10.5 million was primarily attributable to increased expenses related our XEN1101 program..."

Commercial • P2 data • Trial completion date • CNS Disorders • Epilepsy

Neurocrine Biosciences Reports Third Quarter 2022 Financial Results and Raises 2022 INGREZZA Sales Guidance (PRNewswire) - "Expected Future Pipeline Milestones and Key Activities...NBI-921352 (Selective NaV1.6 Channel Blocker); Focal Onset Seizure in Adults; Phase 2 Data in 2023."

P2 data • CNS Disorders • Epilepsy

Progress report on new antiepileptic drugs: A summary of the Sixteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XVI): I. Drugs in preclinical and early clinical development. (PubMed, Epilepsia) - "This progress report summarizes preclinical and, when available, phase 1 clinical data on five different investigational compounds in preclinical or early clinical development, namely GAO-3-02, GRT-X, NBI-921352 (formerly XEN901), OV329, and XEN496 (a pediatric granular formulation of retigabine/ezogabine). Overall, the data presented in this report illustrate novel strategies for developing antiseizure medications, including an interest in novel molecular targets, and a trend to pursue potential new treatments for rare and previously neglected severe epilepsy syndromes."

Journal • Preclinical • CNS Disorders • Epilepsy • Pediatrics

Extension Study to Evaluate the Safety and Tolerability of NBI-921352 When Used With Anti-seizure Medications in Adults With Focal Onset Seizures (clinicaltrials.gov) - P2 | N=100 | Not yet recruiting | Sponsor: Neurocrine Biosciences

New P2 trial • CNS Disorders • Epilepsy

Extension Study to Evaluate How Safe and Tolerable NBI-921352 is as an Adjunctive Therapy for Subjects With SCN8A-DEE (clinicaltrials.gov) - P2 | N=52 | Enrolling by invitation | Sponsor: Neurocrine Biosciences | Not yet recruiting ➔ Enrolling by invitation

Enrollment open • CNS Disorders • Epilepsy

NBI-921352, a first-in-class, Na1.6 selective, sodium channel inhibitor that prevents seizures in Scn8a gain-of-function mice, and wild-type mice and rats. (PubMed, Elife) - "NBI-921352 was effective in preventing seizures at lower brain and plasma concentrations than commonly prescribed sodium channel inhibitor anti-seizure medicines (ASMs) carbamazepine, phenytoin, and lacosamide. NBI-921352 was well tolerated at higher multiples of the effective plasma and brain concentrations than those ASMs. NBI-921352 is entering phase II proof-of-concept trials for the treatment of SCN8A-developmental epileptic encephalopathy (SCN8A-DEE) and adult focal-onset seizures."

Journal • Preclinical • CNS Disorders • Epilepsy • SCN8A

Xenon Pharmaceuticals Reports 2021 Financial Results and Provides Corporate Update (Yahoo Finance) - "Xenon anticipates participating in an 'end-of-Phase 2' meeting with the U.S. Food and Drug Administration (FDA) in the second quarter of this year to support the initiation of its Phase 3 XEN1101 clinical program in adult patients with focal epilepsy, estimated in the second half of the year...These U.S. patents are expected to expire in 2040 and 2039, respectively, absent any extensions of patent term...XEN496...Xenon anticipates that the EPIK study will be completed in the first half of 2023...Neurocrine Biosciences is conducting a Phase 2 clinical trial evaluating NBI-921352 in adult patients with focal onset seizures, with data expected in 2023."

New P3 trial • P2 data • Patent • Trial completion date • CNS Disorders • Epilepsy

Study to Evaluate NBI-921352 as Adjunctive Therapy in Subjects With SCN8A Developmental and Epileptic Encephalopathy Syndrome (SCN8A-DEE) (clinicaltrials.gov) - P2 | N=52 | Recruiting | Sponsor: Neurocrine Biosciences | Trial primary completion date: Oct 2023 ➔ Jan 2024

Trial primary completion date • CNS Disorders • Epilepsy • SCN8A

Extension Study to Evaluate How Safe and Tolerable NBI-921352 is as an Adjunctive Therapy for Subjects With SCN8A-DEE. (clinicaltrials.gov) - P2 | N=52 | Not yet recruiting | Sponsor: Neurocrine Biosciences

New P2 trial • CNS Disorders • Epilepsy

Extension Study to Evaluate how safe and tolerable the drug NBI-921352 is when used as Adjunctive Therapy in Subjects With SCN8A Developmental and Epileptic Encephalopathy Syndrome (SCN8A-DEE). (clinicaltrialsregister.eu) - P2 | N=52 | Sponsor: Neurocrine Biosciences, Inc.

New P2 trial • CNS Disorders • Epilepsy