Ztalmy (ganaxolone oral) / Marinus, Tenacia Biotech - LARVOL DELTA

Pharmacological characterization of the harmaline mouse model of essential tremor using integrated multimodal biomarker profiling (Neuroscience 2026) - "Across multiple cohorts, we evaluated nine mechanistically distinct compounds: agents used clinically in ET management (propranolol, gabapentin, alprazolam), selective T-type calcium channel inhibitors in clinical development (ulixacaltamide, suvecaltamide), and pharmacological probes targeting ET-relevant pathways (eslicarbazepine, ethanol, caffeine, ganaxolone). T-type calcium channel inhibitors produced the most robust peripheral tremor suppression, with ulixacaltamide and suvecaltamide displaying a distinctive biphasic coherence response that distinguished their mechanistic profile from other compounds.Together, these findings demonstrate that integrated central and peripheral biomarker profiling reveals mechanism-specific pharmacological signatures not captured by single-endpoint approaches. This work establishes a pharmacological reference dataset and translational framework for preclinical drug evaluation in ET."

Preclinical • CNS Disorders • Essential Tremor • Movement Disorders

Cognitive Side Effects of Antiseizure Medications in Adults with Epilepsy: An Update with a Focus on New Therapeutic Agents. (PubMed, CNS Drugs) - "Overall, newer-generation ASMs, including rufinamide, lacosamide, brivaracetam, cannabidiol, fenfluramine, and ganaxolone, demonstrate generally favourable cognitive profiles when used at recommended doses, particularly in monotherapy or rational polytherapy. Eslicarbazepine and cenobamate may be associated with mild, dose-dependent cognitive effects, occurring only at the upper end of the recommended dose range. In contrast, old ASMs and certain second-generation agents, notably topiramate and zonisamide, remain consistently associated with higher cognitive risks...Cognitive dysfunction in epilepsy is multifactorial, reflecting the interaction between disease-related neurobiological mechanisms and treatment effects. Optimal management requires balancing seizure control with cognitive preservation through individualised drug selection, cautious titration, and minimisation of polytherapy to achieve the best functional and quality-of-life outcomes."

Adverse events • Journal • Review • CNS Disorders • Cognitive Disorders • Developmental Disorders • Epilepsy • Mental Retardation

Antiseizure Medications in Development: Novel Mechanisms, Precision Therapy, and the Move Towards Disease Modification. (PubMed, Curr Issues Mol Biol) - "Functional-state-selective sodium channel modulation has emerged as a leading conceptual advance supported by converging mechanistic and early clinical evidence, exemplified by relutrigine (PRAX-562), a preferential persistent-current inhibitor for which a regulatory decision is pending in SCN2A/SCN8A-DEEs, and vormatrigine (PRAX-628), whose large open-label effect was not reproduced in a controlled (blinded) trial...Parallel advances include the selective Kv7 opener azetukalner; the dual-mechanism benchmark cenobamate; cholesterol-24-hydroxylase inhibition (soticlestat); selective serotonergic agonism (bexicaserin); glutamatergic precision agents (radiprodil); subtype-selective GABAA modulators (darigabat, ganaxolone); and gene-directed therapies (zorevunersen, elsunersen)... The pipeline reflects an ongoing shift from broad symptomatic agents toward mechanism-led, genotype-matched, and potentially disease-modifying treatments. This shift is tempered by a persistent..."

Journal • Review • CNS Disorders • Epilepsy • SCN8A

Pharmacokinetics, Safety, and Dosing of Antiseizure Medications in Patients with Renal or Hepatic Impairment. (PubMed, Clin Pharmacokinet) - "Ten newer antiseizure medications (ASMs) approved since 2000 and selected for this review (cenobamate, brivaracetam, eslicarbazepine acetate, lacosamide, perampanel, fenfluramine, ganaxolone, cannabidiol, stiripentol, and rufinamide) have broadened treatment options for drug-resistant epilepsy. Regulatory discrepancies between FDA and EMA labeling were identified for all ten agents, notably divergent hepatic dose caps for perampanel and cenobamate, conflicting renal recommendations for fenfluramine, and discordant guidance for eslicarbazepine acetate in severe renal impairment. These agents exhibit no uniform class effect in organ impairment; prescribing must be governed by agent-specific disposition profiles, organ-function severity, and free-drug monitoring for highly protein-bound agents like perampanel and ganaxolone."

Journal • PK/PD data • Review • CNS Disorders • Epilepsy • Hepatology • Nephrology • Renal Disease

Double-blind, Randomized, Placebo-controlled Trial of Ganaxolone in CDKL5 Deficiency Patients 6 Months to Less Than 2 Years Old (clinicaltrials.gov) - P3 | N=20 | Not yet recruiting | Sponsor: Immedica Pharma AB | Trial completion date: Sep 2028 ➔ Dec 2029 | Trial primary completion date: Sep 2028 ➔ Dec 2029

Trial completion date • Trial primary completion date • CNS Disorders • Epilepsy • Genetic Disorders • Pediatrics • CDKL5

Clinical Trial Evaluating the Effects of Ganaxolone in Children With Autism (clinicaltrials.gov) - P2 | N=66 | Not yet recruiting | Sponsor: Stanford University

New P2 trial • Autism Spectrum Disorder • Genetic Disorders

Allosteric potentiation of GABAA receptor promotes survival and maturation of oligodendroglial cells in vitro via Ca2+/CaMK/AKT signaling pathway. (PubMed, Am J Physiol Cell Physiol) - "β-CCB effects were compared with those by ganaxolone (Gx), a synthetic allopregnanolone analog and unspecific PAM of GABAARs...Additionally, a morphometric analysis showed that both PAMs promoted an increase in cellular complexity commonly associated with cell maturation, increasing the average cell area, number and length of branches per cell, as well as the branch point number. These direct actions on NG2+ cells would explain, at least in part, the positive effects that GABAergic signaling stimulation has on the myelination process in several experimental models, both in vivo and in vivo."

Journal • Preclinical • Solid Tumor

Comprehensive Evaluation of Neurosteroid Monotherapy and Neurosteroid-Midazolam Combination Therapy in Mitigating the Nerve Agent Soman-Induced Chronic Neuropsychiatric Dysfunction, Epileptogenesis, Neuroinflammation and Neurodegeneration in Pediatric Models. (PubMed, Neuropharmacology) - "This study investigated the therapeutic potential of the synthetic neurosteroid ganaxolone (GX) in a pediatric rat model of the nerve agent soman exposure. MRI scans confirmed reduced neuropathological changes in GX-treated animals. Collectively, these findings demonstrate that GX alone or in combination with midazolam offers strong neuroprotective, antiepileptogenic, and anti-inflammatory benefits, highlighting its promise as a robust pediatric anticonvulsant for nerve agent-induced seizures and long-term neurologic dysfunction."

Journal • Monotherapy • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Epilepsy • Inflammation • Mood Disorders • Pediatrics • Psychiatry

Open-State Dynamics and Allosteric Modulation of the α1β3γ2 GABAA Receptor Stabilized by L9'T/S Substitutions. (PubMed, J Chem Inf Model) - "On this open-like background, positive allosteric modulators (diazepam, ganaxolone) primarily tune the residual -2' constriction, whereas the orthosteric antagonist bicuculline drives a time-ordered, bottom-to-top closing sequence (-2' first, followed by 9'/20' and global twist) via an asymmetric collapse of the M2 bundle that approaches closed-state landmarks while sampling desensitized-like coupling of extracellular and transmembrane domains. Two-electrode voltage-clamp recordings confirm spontaneous activity in L9'T-containing receptors, supporting the mutant-stabilized open-like ensembles. Together, these results provide a coherent atomistic framework for gating and allosteric modulation in α1β3γ2 GABAARs and establish a tractable platform for state-selective structure-based design."

Journal

Ganaxolone, an approved therapy for CDKL5-Deficiency Disorder, is an inhibitor of PTP1B. (PubMed, J Biol Chem) - "We observed that ganaxalone was able to inhibit PTP1B activity both in an in vitro assay of enzyme activity and in different cell models, with similar potency to known inhibitors of PTP1B, including MSI-1436, which has a similar chemical structure. In these cells, inhibition of PTP1B not only brought BDNF signaling to levels similar to those of wild-type cells, but also restored cellular morphology. Our results suggest that, like in Rett syndrome, targeting PTP1B may be a beneficial therapeutic strategy for CDD."

Journal • CNS Disorders • Developmental Disorders • Epilepsy • Genetic Disorders • Mental Retardation • Movement Disorders • CDKL5 • PTPN1

Prevalence, Treatment Patterns, and Healthcare Resource Utilization Among Patients with CDKL5 Deficiency Disorder: Retrospective Analysis of US Claims Data (AAN 2026) - "Levetiracetam (34%), clobazam (33%), and clonazepam (30%) were the most common seizure-related drugs utilized. Increase in uptake post diagnosis was seen for ganaxolone (23%), fenfluramine (5%), and cenobamate (4%)...Conclusions This real-world retrospective analysis reports prevalence for patients with CDD for the first time in a large, claims-based population. Comorbidities and HCRU burden are significant for patients with CDD."

HEOR • Retrospective data • Cerebral Palsy • CNS Disorders • Developmental Disorders • Epilepsy • Genetic Disorders • Movement Disorders • CDKL5

The role of neuroactive steroids in psychiatric and neurological disorders: Neurobiology and therapeutic perspectives. (PubMed, Neurosci Biobehav Rev) - "This review synthesizes current evidence on how neurosteroids (and, more broadly, neuroactive steroids) contribute to the endogenous regulation of neural excitability, affective reactivity, and immune signaling, and explores how their dysregulation may represent a shared mechanism of vulnerability across diverse brain disorders. Finally, we highlight emerging therapeutic opportunities, underscored by recent advances such as zuranolone and ganaxolone, and discuss future challenges in optimizing delivery, enhancing receptor specificity, and refining clinical trial design to establish neurosteroid-based interventions as a versatile platform for treating and preventing complex neuropsychiatric disease."

Journal • Review • Autism Spectrum Disorder • Bipolar Disorder • CNS Disorders • Depression • Epilepsy • Genetic Disorders • Mental Retardation • Mood Disorders • Movement Disorders • Multiple Sclerosis • Post-traumatic Stress Disorder • Psychiatry • Schizophrenia • Tic Disorders • Tourette Syndrome

Ganaxolone as a promising therapeutic agent for Alzheimer's disease: signaling pathways and mechanistic insights-a narrative review. (PubMed, Inflammopharmacology) - No abstract available

Journal • Review • Alzheimer's Disease • CNS Disorders • Inflammation

Open-State Dynamics and Allosteric Modulation of the α1β3γ2 GABAA Receptor Stabilized by L9'T/S Substitutions. (PubMed, bioRxiv) - "On this open-like background, PAMs (diazepam, ganaxolone) primarily tune the residual -2' constriction, whereas bicuculline (orthosteric antagonist) drives a time-ordered, bottom-to-top closing sequence (-2' first, then 9'/20', then twist) via an asymmetric collapse of the M2 bundle that approaches closed-state landmarks while sampling desensitized-like ECD-TMD coupling. Two-electrode voltage clamp confirms spontaneous activity in L9'T-containing receptors, supporting the mutant-stabilized open-like ensembles. These results provide a coherent atomistic framework for gating and allosteric modulation in α1β3γ2 GABAARs and establish a tractable, ligand-responsive platform for state-selective structure-based design."

Journal • CNS Disorders • Depression • Epilepsy • Mood Disorders • Psychiatry

Molecular mechanisms of neurosteroids in temporal lobe epilepsy: current insights and therapeutic perspectives. (PubMed, Mol Biol Rep) - "Neurosteroids (NSs) are endogenous progesterone derivatives that act as natural allosteric modulators of GABAA ​receptors, exerting distinct effects from conventional receptor agonists...Accumulating evidence indicates that NSs, including Allopregnanolone, brexanolone, and ganaxolone, may exert neuroprotective and anti-epileptogenic effects through both direct GABAergic modulation and indirect regulation of mTORC1, AMPK, and BDNF signaling pathways, as well as autophagy activation...This review synthesizes current knowledge on the mechanistic roles of NSs in TLE, highlighting their potential as adjuvant therapies alongside antiepileptic drugs. Further translational studies are warranted to clarify optimal dosing strategies, identify patient subgroups most likely to benefit, and develop targeted NS analogues for refractory TLE management."

Journal • Review • CNS Disorders • Epilepsy • Inflammation

Felbamate and Ganaxolone for Improving Outcome in Pediatric Febrile Infection-Related Epilepsy Syndrome (FIRES) (AES 2025) - "1) Felbamate was trialed during acute phase of illness and continued as maintenance regimen 2) Ganaxalone was trialed off label for two severe cases of FIRES. Both medication trials correlated with lower mortality, decreased ICU duration compared to data described in prior NORSE/FIRES literature, and exhibit no recurrence of seizures to date. This institutional experience suggests that utilizing Ganaxalone and Felbamate during acute hospitalization and continuing outpatient may facilitate improved outcomes as defined by seizure control, mortality, and relatively shorter ICU duration."

Clinical • Late-breaking abstract • CNS Disorders • Epilepsy • Immunology • Infectious Disease • Pediatrics • IL2 • IL6

Evaluation of Pharmacological Treatments for Infantile Spasms: A Review of ClinicalTrials.gov (AES 2025) - "Key elements extracted included therapeutic agents, study design, primary endpoints, and reported efficacy and safety outcomes. The included trials assessed a range of pharmacologic agents, spanning both established therapies (ACTH, vigabatrin, prednisolone) and investigational compounds (cannabidiol, ganaxolone, TAK-935, tricaprilin, pyridoxine, lithium carbonate). This review highlights the diversity of pharmacologic interventions under investigation for IS and reinforces the role of both established and emerging therapies. While completed trials provide valuable insight into evolving treatment strategies, important gaps remain—particularly the lack of patient-level outcomes and long-term neurodevelopmental data. Future research should focus on stratified study designs, biomarker-informed approaches, and extended follow-up to optimize treatment selection and improve clinical outcomes in this high-risk pediatric population."

Clinical • Review • CNS Disorders • Epilepsy • Gastrointestinal Disorder

A Phase I, Single Dose Study of Ganaxolone Pharmacokinetics in Adult Subjects with Normal and Impaired Hepatic Function (AES 2025) - "Exposure to ganaxolone increased with severity of hepatic impairment. Dose adjustment is required only in patients with severe hepatic impairment. The safety profile in adult subjects with normal and impaired hepatic function following a single oral dose of ganaxolone was acceptable"

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

Neurosteroid Treatment Mitigates Persistent Neuroinflammation and Neuronal Damage in a Pediatric Model of Nerve Agent Exposure and Status Epilepticus (AES 2025) - "This study tested the effectiveness of the synthetic neurosteroid ganaxolone (GX) on the long-term consequences of soman exposure and status epilepticus in pediatric rats. Pediatric rats at postnatal day 28 (P28) were exposed to soman and SE and were treated with GX 40 minutes after exposure. Control group received midazolam alone... The findings confirm the long-term neuroprotective effects of GX in mitigating neuroinflammation and neurodegeneration in a pediatric model of soman-induced SE."

Clinical • CNS Disorders • Epilepsy • Inflammation • Pediatrics • GFAP

A Modified Titration Regimen of Ganaxolone In the Treatment of Rare Seizure Disorders Optimizes Tolerability (AES 2025) - P2, P3 | "The modified titration schedule is characterized by a progressively increased dose of ganaxolone over 5 weeks to the same target dose as stated in the current prescribing information. Adjusting the ganaxolone titration schedule minimized the occurrence of somnolence-related adverse events experienced by patients in the TrustTSC study. This modified titration schedule has the potential to improve ganaxolone tolerability with respect to the somnolence-related adverse events that have been associated with premature therapy discontinuation and/or interruption while not impacting ganaxolone exposure levels that have been shown effective in CDD patients."

Anesthesia • CNS Disorders • Epilepsy

Neurosteroid Protection of Nerve Agent-induced Epileptogenesis and Neurological Comorbidities in Pediatric Rat Model of Status Epilepticus (AES 2025) - "This study evaluated the efficacy of the synthetic neurosteroid ganaxolone (GX) in combating the persistent behavioral deficits, epileptogenic markers, and neuropathological damage induced by the nerve agent soman (GD) in pediatric rats. Postnatal day 21 rats were exposed to GD and were treated with GX at 40-minutes post-exposure... These findings demonstrate the protective efficacy of GX in reducing epileptogenesis and mitigating comorbidities, and neurodegeneration associated with GD exposure, which confirms the potential of neurosteroid treatment for pediatric SE."

Preclinical • CNS Disorders • Depression • Epilepsy • Mood Disorders • Pediatrics • Psychiatry

Neurosteroid Mitigation of Long-term Neuropsychiatric Outcomes in Pediatric Nerve Agent Neurotoxicity (AES 2025) - "In this study, we investigated the long-term developmental impact of pediatric exposure to the nerve agent soman (GD) and the use of the synthetic neurosteroid ganaxolone (GX) as a potential neurotherapeutic intervention. Pediatric rats (P28) were exposed to GD via SC injection and treated 40 minutes after exposure with either midazolam (MDZ) alone, MDZ+ GX, or GX alone. This pediatric model replicates the long-term developmental and cognitive dysfunction associated with nerve agent exposure, while neurosteroid intervention demonstrated significant neuroprotection against these sequelae."

Clinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Depression • Developmental Disorders • Pediatrics • Psychiatry

SIG | Neuropharmacology: Use of Anti-seizure Medications in the Era of AI and Precision Medicine (AES 2025) - "Overview There have been several new anti-seizure medications (ASM) FDA-approved for treatment of epilepsy in the last 5-6 years (for example: Stiripentol, Fenfluramine, Ganaxolone, Cenobamate). The 2025 Neuropharmacology SIG addresses the mechanisms of action of these new medications, use of EMR-integrated AI to guide the use of ASMs in different clinical scenarios, detection of drug-drug interactions, and use of ASMs in epilepsy treatment from a precision medicine approach. Following the presentations, a moderated panel discussion addresses questions from the audience.Learning Objectives Following participation in this activity, participants will be able to: • Identify mechanisms of action and clinical indications of newly FDA-approved anti-seizure medications • Understand advantages and challenges of AI models for identifying drug-drug interactions in epilepsy, enhancing patient safety and treatment efficacy • Describe use of anti-seizure medications from a precision..."

CNS Disorders • Epilepsy

Ganaxolone, an approved therapy for CDKL5-Deficiency Disorder, is an inhibitor of PTP1B. (PubMed, bioRxiv) - "We observed that ganaxalone was able to inhibit PTP1B activity both in an in vitro assay of enzyme activity and in different cell models, in a comparable way to known inhibitors of PTP1B, including MSI-1436, which has a similar chemical structure. Finally, loss of CDKL5 function resulted in increased levels of PTP1B. Our results suggest that, like in Rett syndrome, targeting PTP1B may be a beneficial therapeutic strategy for CDD."

Journal • CNS Disorders • Developmental Disorders • Epilepsy • Genetic Disorders • Mental Retardation • Movement Disorders • CDKL5 • PTPN1

Double-blind, Randomized, Placebo-controlled Trial of Ganaxolone in CDKL5 Deficiency Patients 6 Months to Less Than 2 Years Old (clinicaltrials.gov) - P3 | N=20 | Not yet recruiting | Sponsor: Marinus Pharmaceuticals | Trial completion date: Mar 2027 ➔ Sep 2028 | Trial primary completion date: Dec 2026 ➔ Sep 2028

Trial completion date • Trial primary completion date • CNS Disorders • Epilepsy • Genetic Disorders • Pediatrics • CDKL5