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

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

Recent Advances in the Management of Seizures in Children. (PubMed, Paediatr Drugs) - "In the past decade, new ASMs have been approved for specific childhood-onset epilepsy syndromes, notably cannabidiol for Lennox-Gastaut syndrome (LGS), Dravet syndrome (DS) and tuberous sclerosis complex (TSC); fenfluramine for LGS and DS; everolimus for TSC; and ganaxolone for cyclin-dependent kinase-like deficiency disorder. In parallel with these developments, accumulating research in the areas of genetic testing, including genetic and related therapies designed to correct or compensate for underlying genetic causes of seizures, suggests that these technologies may have the potential to transform epilepsy treatment in the future. This review summarises major recent developments and current research in the treatment of epilepsy in children."

Journal • Review • CNS Disorders • Epilepsy • Pediatrics

Ganaxolone in Epilepsy: Insights into a Neurosteroid-Based Therapy. (PubMed, Epilepsy Res) - "Beyond epilepsy, GNX's modulation of GABAergic signaling suggests potential applications in neuropsychiatric conditions. Its favorable safety profile further supports its therapeutic value."

Journal • Review • CNS Disorders • Epilepsy • Genetic Disorders • Mental Retardation • Psychiatry

Open-label Study of Adjunctive GNX Treatment in Children and Adults With TSC-related Epilepsy (clinicaltrials.gov) - P3 | N=117 | Terminated | Sponsor: Marinus Pharmaceuticals | Trial completion date: Jun 2027 ➔ Apr 2025 | Enrolling by invitation ➔ Terminated | Trial primary completion date: Jun 2027 ➔ Apr 2025; Sponsor's decision

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

Peripartum Depression Pharmacotherapies Targeting GABA-Glutamate Neurotransmission. (PubMed, J Clin Med) - "Search criteria targeted randomized clinical trials investigating GABA-A-positive allosteric modulators (brexanolone, zuranolone, and ganaxolone) and NMDA receptor antagonists (ketamine and esketamine) in PPD patients. These glutamate-GABA pathway modulators represent novel therapeutic alternatives with rapid onset profiles. Further investigation and research are needed to optimize dosing protocols and patient selection criteria and to establish long-term efficacy before PPD treatment guidelines can be drafted."

Clinical • Journal • Review • CNS Disorders • Depression • Mood Disorders • Postpartum Depression • Psychiatry

Perampanel, Brivaracetam, Cenobamate, Stiripentol, and Ganaxolone in Lennox-Gastaut Syndrome: A Comprehensive Narrative Review. (PubMed, J Clin Med) - "Background: Lennox-Gastaut syndrome (LGS) is a severe childhood-onset developmental and epileptic encephalopathy characterized by treatment-resistant seizures and significant morbidity. Perampanel offers the most extensive evidence base, cenobamate demonstrates exceptional efficacy potential, while brivaracetam provides an alternative for levetiracetam-intolerant patients. Further controlled studies are needed to define optimal treatment algorithms."

Journal • Review • CNS Disorders • Epilepsy

Tough to treat: What we know about managing PCDH19-related epilepsy - Systematic review. (PubMed, Seizure) - "Treatment remains challenging due to clinical heterogeneity and limited high-quality data. Early, individualized, multimodal approaches appear most beneficial. There is a need for genotype-informed, multicenter trials and standardized outcome measures to guide evidence-based care."

Journal • Review • Alzheimer's Disease • Autism Spectrum Disorder • CNS Disorders • Cognitive Disorders • Developmental Disorders • Epilepsy • Genetic Disorders • CDH23 • PCDH

Antiseizure medications in CDKL5 encephalopathy- systematic review. (PubMed, Seizure) - "Because low number of patients studied worldwide, information on treatment options and outcomes is limited. Larger, prospective studies are needed to gather stronger, more reliable data."

Journal • Review • CNS Disorders • Epilepsy • Genetic Disorders • Movement Disorders

Novel Medication Ganaxolone for Seizure Disorders. (PubMed, Discoveries (Craiova)) - "The results of these trials suggest that ganaxolone may be effective in reducing seizure frequency in patients with various types of epilepsy, including CDKL5 deficiency disorder, Lennox-Gastaut syndrome, and Protocadherin 19. However, further studies are needed to determine its safety and efficacy in a larger patient population."

Journal • Review • CNS Disorders • Epilepsy • Genetic Disorders • Pain • CDH23 • PCDH

The Emerging Role of Neurosteroids: Novel Drugs Brexanalone Sepranolone Zuranolone and Ganaxolone in Mood and Neurological Disorders (APA 2025) - "Description This review investigates the potential of neurosteroids, including brexanolone, zuranolone, sepranolone, and ganaxalone, as therapeutic agents for a range of mood and neurological disorders. Their modulation of the GABA system emerges as a central mechanism of action, emphasizing the importance of GABAergic signaling in these conditions. The path forward entails continued investigation and clinical trials to fully unlock the potential of neurosteroids, offering hope for enhanced treatments in these challenging clinical domains."

Alzheimer's Disease • CNS Disorders • Depression • Epilepsy • Major Depressive Disorder • Mood Disorders • Postpartum Depression • Post-traumatic Stress Disorder • Psychiatry

Therapeutic Potential of Enzymes, Neurosteroids, and Synthetic Steroids in Neurodegenerative Disorders: A Critical Review. (PubMed, J Steroid Biochem Mol Biol) - "Endogenous steroids synthesized in the central nervous system, such as pregnenolone (PREG), dehydroepiandrosterone (DHEA), progesterone (PROG), and allopregnanolone (ALLO), have been identified as potential therapeutic agents for neurodegenerative diseases...Moreover, Brexanolone and Ganaxolone are synthetic steroids approved for the treatment of postpartum depression and epilepsy, respectively...This comprehensive review discusses the therapeutic effects of enzymes, neurosteroids, and synthetic steroids in different neurodegenerative diseases, particularly AD, PD, ALS, and MS. Potential challenges in the therapeutic use of neurosteroids, such as the limited bioavailability and off-target effects of synthetic steroids, are also discussed, and an up-to-date and comprehensive review of the impact of these steroids on neurodegenerative disorders is presented."

Journal • Review • Alzheimer's Disease • Amyotrophic Lateral Sclerosis • CNS Disorders • Depression • Epilepsy • Inflammation • Metabolic Disorders • Movement Disorders • Parkinson's Disease • Postpartum Depression • Psychiatry • TARDBP

Neurosteroid mitigation of developmental neurological dysfunction, long-term epileptic biomarkers, chronic neuroinflammation, and neurodegeneration in a pediatric rat model of organophosphate exposure. (PubMed, J Pharmacol Exp Ther) - "This study explores the potential of ganaxolone, a synthetic neurosteroid, to mitigate the neurodevelopmental consequences of OP exposure. Our findings reveal that ganaxolone provides significant neuroprotection in a pediatric model of OP intoxication, reducing long-term seizures, ictal biomarkers, neurodegeneration, neuroinflammation, and associated neurological dysfunctions, offering a promising therapeutic avenue for pediatric victims of OP exposure."

Journal • Preclinical • CNS Disorders • Cognitive Disorders • Depression • Developmental Disorders • Epilepsy • Inflammation • Mood Disorders • Pediatrics • Psychiatry

A multicenter, prospective, observational post-marketing study on the safety and efficacy of Ganaxolone oral suspension for the treatment of seizures in Chinese patients aged 2 years and older with cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) (ChiCTR) - P4 | N=12 | Not yet recruiting | Sponsor: children's hospital of fudan university; children's hospital of fudan university

New P4 trial • CNS Disorders • Epilepsy • Genetic Disorders

Exploring potential key genes and disease mechanisms in Εarly-onset genetic epilepsy via integrated bioinformatics analysis. (PubMed, Neurobiol Dis) - "Enrichment analysis showed that among significant pathways were nicotine addiction, GABAergic synapse, synaptic vesicle cycle, regulation of membrane potential, cholinergic synapse, dopaminergic synapse, and morphine addiction. Clustering analysis of the PPI network via MCODE showed significant functional modules, indicating also other pathways such as N-Glycan biosynthesis and protein N-linked glycosylation, retrograde endocannabinoid signaling, mTOR signaling and aminoacyl-tRNA biosynthesis. Drug-gene interaction analysis identified a number of drugs as potential medications for EOE, among which the non-FDA approved drugs azetukalner (under clinical development), indiplon and ICA-105665 and the FDA approved drugs retigabine, ganaxolone and methohexital."

Journal • CNS Disorders • Epilepsy • Nicotine Addiction • Psychiatry • SCN8A • XBP1

New Directions in Neurosteroid Therapeutics in Neuropsychiatry. (PubMed, Neurosci Biobehav Rev) - "In recent years three neuroactive steroids (NAS), brexanolone (allopregnanolone, AlloP), ganaxolone and zuranolone, have been approved for the treatment of neuropsychiatric illnesses including postpartum depression and seizures in a neurodevelopmental syndrome. In this review, we explore GABAergic and other cellular effects of pregnane steroids including novel molecules that have potential therapeutic importance. This work discusses the complex chemical nature of NAS and what is being learned at cellular, molecular, synaptic and brain network levels about key sites of action including GABAARs and other targets."

Journal • Review • CNS Disorders • Depression • Epilepsy • Inflammation • Major Depressive Disorder • Mental Retardation • Postpartum Depression • Psychiatry