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

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

Ganaxolone Reverses the Effect of Amyloid β-Induced Neurotoxicity by Regulating the Liver X Receptor Expression in APP Transfected SH-SY5Y Cells and Murine Model of Alzheimer's Disease. (PubMed, J Neurochem) - "Taken together, these novel results highlight the central role of LXR in mediating Aβ-induced toxicity and provide preclinical evidence for ganaxolone as a potential agent to reduce toxicity in an LXR-dependent manner. This may serve as a promising treatment strategy to slow or prevent neurodegeneration in AD patients."

IO biomarker • Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Inflammation • ABCA1 • APOE • BCL2 • CASP3 • IL1B • TNFA

Update on neonatal and infantile onset epilepsies. (PubMed, Curr Opin Pediatr) - "The integration of genetic and molecular advancements is transforming the management of neonatal and infantile epilepsies, fostering precision-driven care. Continued research and innovation are essential to refine these strategies, optimize patient outcomes, and establish new standards of care."

Journal • CNS Disorders • Epilepsy

Effect of two novel GABAA receptor positive allosteric modulators on neuropathic and inflammatory pain in mice. (PubMed, Neuropharmacology) - "This study tested the antinociceptive properties of two novel NAS PAMs, ganaxolone and zuranolone, in segmental spinal nerve ligation (SNL)-induced neuropathic pain and complete Freund's adjuvant (CFA)-induced inflammation pain models. Furthermore, the PAMs alleviated SNL-induced mechanical allodynia synergistically with diazepam or GABAA receptor activator muscimol at inactive doses, consistent with the non-competitive activity and distinct binding sites from benzodiazepines. In summary, our findings suggest that NASs may not only acutely modulate GABA receptor activity but also induce sustained metabotropic effects on GABAA receptors and thus exert long-lasting antinociceptive effects."

Journal • Preclinical • Inflammation • Neuralgia • Pain

From barbiturates to ganaxolone: The importance of chirality in drug development and in understanding the actions of old and new antiseizure medications. (PubMed, Pharmacol Ther) - "Out of 37 antiseizure medications (ASMs) currently in the market, 17 are chiral molecules and an additional one (oxcarbazepine) is a prodrug of the chiral compound licarbazepine. Of the 17 chiral ASMs, six (ethosuximide, fenfluramine, methsuximide, mephobarbital, stiripentol and vigabatrin) are marketed as racemates, and the remainder are licensed as enantiomerically pure medicines...We identified a number of critical knowledge gaps that are relevant to the use of chiral drugs in epilepsy, including a remarkable lack of published information on the comparative pharmacokinetics, toxicity and antiseizure activity of the enantiomers of most racemic ASMs. The importance of chirality aspects in understanding the clinical actions of racemic ASMs is discussed, together with the rationale for the development of enantiomerically pure follow-up compounds with potentially improved efficacy, safety and commercial viability."

Journal • Review • CNS Disorders • Epilepsy

Update on Antiseizure Medications 2025. (PubMed, Continuum (Minneap Minn)) - "Since the most recent version of this article was published, one new antiseizure medication, ganaxolone, has been approved by the US Food and Drug Administration (FDA), and the indications of some approved medications were expanded...These agents include lamotrigine, oxcarbazepine, levetiracetam, topiramate, zonisamide, and lacosamide...Lacosamide, pregabalin, and eslicarbazepine have undergone successful trials of conversion to monotherapy for focal epilepsy...Knowledge of antiseizure medication pharmacokinetics, efficacy, and tolerability profiles facilitates the choice of appropriate antiseizure medication therapy for patients with epilepsy. Rational antiseizure medication combinations should avoid antiseizure medications with unfavorable pharmacokinetic interactions or pharmacodynamic interactions related to mechanism of action."

Journal • Review • CNS Disorders • Epilepsy

Antiseizure Medications: Advancements, Challenges, and Prospects in Drug Development. (PubMed, Curr Neuropharmacol) - "Here we describe the conventional and unique mechanisms of action of ASMs, focusing on everolimus, cannabidiol, cenobamate, fenfluramine, and ganaxolone, the five most recently marketed ASMs. The review also discusses the development of new potential ASMs, including modifying existing ASMs to improve efficacy and tolerability. Furthermore, we expound on the modulation of γ- aminobutyric acid type A receptor (GABAAR) as a strategy for the treatment of epilepsy and the identification of a GABAAR agonist, isoguvacine, as a potential ASM."

Journal • CNS Disorders • Epilepsy • Psychiatry

Ganaxolone: A Review in Epileptic Seizures Associated with Cyclin-Dependent Kinase-Like 5 Deficiency Disorder. (PubMed, Paediatr Drugs) - "While somnolence and sedation are related to the dose of ganaxolone, they appear early in treatment and may decrease with continued therapy. Thus, although current evidence is somewhat limited, adjunctive ganaxolone could be a valuable therapeutic option for patients aged 2-17 years with epileptic seizures associated with CDD."

Journal • Review • Anesthesia • CNS Disorders • Epilepsy • Genetic Disorders

Immedica to Acquire Biopharmaceutical Company Marinus Pharmaceuticals, Inc. (Businesswire) - "Immedica Pharma AB...and Marinus Pharmaceuticals, Inc...announced that they have entered into an agreement and plan of merger under which Immedica has agreed to acquire Marinus, by means of a tender offer and subsequent merger....Adds global rights to ZTALMY, a commercial-stage rare neurology medicine approved by FDA, the European Commission (EC), the UK Medicines and Healthcare products Regulatory Agency (MHRA) and the National Medicines Product Administration (NMPA) in China with potential for further approvals worldwide. Accelerates Immedica’s growth into the North American market, providing an immediate revenue-generating rare disease product and an experienced commercial team upon closing of the transaction....Transaction is expected to close in Q1 2025."

M&A • CNS Disorders

Neurosteroid Protection of Nerve Agent-Induced Long-term Seizures and Neurological Dysfunction in a Pediatric Rat Model (AES 2024) - "Ganaxolone was administered 40 minutes post-GD exposure, standalone, or with standard anticonvulsant midazolam. These results demonstrate the neuroprotective effect of the neurosteroid GX in the GD exposure model, which has implications for mitigating epileptic seizures and long-term neuropsychiatric dysfunction associated with nerve agent exposure."

Preclinical • CNS Disorders • Cognitive Disorders • Epilepsy • Mood Disorders • Pediatrics • Psychiatry • CDKN1A

Long-term Safety and Efficacy of Ganaxolone for the Treatment of Seizures Associated with Tuberous Sclerosis Complex During the Extension Phase of an Open-Label Phase 2 Study (AES 2024) - P2 | "Ganaxolone demonstrated sustained reductions in TSC-associated seizure frequency out to two years in a subgroup of refractory patients. Ganaxolone was generally well-tolerated with a safety profile consistent with previous clinical studies. A Phase 3, placebo-controlled study of ganaxolone for the treatment of seizures associated with TSC is ongoing."

Clinical • P2 data • CNS Disorders • Developmental Disorders • Epilepsy • Genetic Disorders • Oncology • Skin Cancer

Ganaxolone In Patients With CDKL5 Deficiency Disorder Under Age 2: A Single-Center Experience (AES 2024) - "Ganaxolone was well tolerated, safe and provided seizure reduction in our case series of children with CDD under the age of 2 years. Some of the patients entered honeymoon after initiating treatment with ganaxolone, nevertheless the reason for honeymoon in patients with CDD is not well understood. Early genetic diagnosis allows for early initiation of the medication."

Clinical • CNS Disorders • Epilepsy • Genetic Disorders • CDKL5

A Phase I, Single Dose Study of Ganaxolone Pharmacokinetics in Adult Subjects with Normal and Impaired Hepatic Function (AES 2024) - "Exposure to ganaxolone increased with severity of hepatic impairment. Dose adjustment is required in patients with severe hepatic impairment."

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

Long-term Neuroprotective Effects of Neurosteroid Therapy Following Acute Soman Exposure-induced Status Epilepticus in Pediatric Rats (AES 2024) - "This study evaluated the efficacy of the neurosteroid ganaxolone (GX) in combating the long-term neuropathological impairments caused by acute pediatric GD intoxication and status epilepticus. Postnatal day 21 male rats (P21) were subjected to GD and treated with GX in addition to midazolam at 40 minutes post-exposure... These results demonstrate the long-term neuroprotective effects of GX in mitigating neurologic dysfunction, neurodegeneration, and neuroinflammation in pediatric GD model."

Preclinical • CNS Disorders • Epilepsy • Inflammation • Pediatrics • CDKN1A

Effect of Ganaxolone in Patients with Features of Lennox-gastaut Syndrome: Post-hoc Analysis from a Clinical Trial in CDKL5 Deficiency Disorder (AES 2024) - "Patients with CDD meeting the defined LGS criteria demonstrated greater decreases in seizure frequency with ganaxolone compared to placebo and similar to those not meeting LGS criteria. Safety and tolerability were comparable between groups. Although there are limitations in diagnostic confirmation, the results suggest that ganaxolone could be safe and effective in treating patients with LGS."

Clinical • Retrospective data • CNS Disorders • Developmental Disorders • Epilepsy • Genetic Disorders • Psychiatry

Case Report: Good outcome in Adult Patient with Super-refractory Status Epilepticus treated with Multimodal Therapy and Emergency Use Ganaxolone (AES 2024) - "We describe a patient with SRSE who achieved a good outcome by hospital discharge despite early poor prognostic indicators. Multidisciplinary coordination and early aggressive management of SRSE through multimodal therapy - including antiseizure medications, immunotherapy, and eIND ganaxolone – was incorporated throughout his clinical course and may have supported SE control and patient recovery."

Case report • Clinical • IO biomarker • Aesthetic Medicine • Anesthesia • CNS Disorders • Epilepsy • Immunology

Neuroactive Steroids Induce Sex Specific Effects on Intracellular Signaling via Activation of Membrane Progesterone Receptors (AES 2024) - "Recent FDA approval of the synthetic NAS Ganaxolone to arrest refractory seizures in cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder and of Brexanolone to treat postpartum depression has increased interest in NAS as novel therapeutic treatments. Collectively, these results highlight the first evidence that mPRδ and mPRε display divergent signaling via Gq and Gs, respectively, and that mPR activation leads to a sex-specific effect on intracellular signaling in the brain. Additionally, the high potency of NAS for mPRs is at concentrations similar to endogenous ALLO in the brain and is below demonstrated plasma levels of FDA approved NAS treatments. Therefore, this work emphasizes the importance of understanding mPR signaling in the brain and the ability of mPRs to modulate neuronal inhibition to better develop future novel therapies."

Breast Cancer • CNS Disorders • Depression • Epilepsy • Genetic Disorders • Hormone Receptor Breast Cancer • Oncology • Postpartum Depression • Psychiatry • Solid Tumor • Triple Negative Breast Cancer • PGR

A Study of Ganaxolone in Seizures Associated With Tuberous Sclerosis Complex: A Randomized, Double-Blind, Placebo-Controlled Phase 3 Study (TrustTSC) (AES 2024) - P3 | "This global, placebo-controlled trial is designed to generate rigorous clinical evidence on the safety and efficacy of ganaxolone for the treatment of seizures associated with TSC."

Clinical • P3 data • CNS Disorders • Developmental Disorders • Epilepsy • Genetic Disorders • Oncology • Skin Cancer • TSC1 • TSC2

Neurosteroid replacement approaches for improving outcomes after compromised pregnancies and preterm birth. (PubMed, Front Neuroendocrinol) - "Postnatal treatment with the allopregnanolone analogue ganaxolone improves myelination and reduces hyperactive behaviour. TSPO ligands such as emapunil have been shown to improve oligodendrocyte maturation. These findings support the use of allopregnanolone supplementation approaches after pregnancy compromises to improve outcome."

Journal • Review • Behavior Disorders • CNS Disorders • Psychiatry • Solid Tumor

LPM682000012, a Synthetic Neuroactive Steroid That Ameliorates Epileptic Seizures by Downregulating the Serpina3n/NF-κB Signaling Pathway. (PubMed, Molecules) - "The dose-dependent sedative effects of LPM682000012 and Ganaxolone in normal rats were evaluated, which revealed that they both dose-dependently alleviated acute epileptic seizure in the pentylenetetrazol (PTZ)-mediated seizure model...In summary, this report demonstrated that the novel neurosteroid GABAA PAM LPM682000012 activated the synaptic and extra-synaptic GABAA receptors and alleviated KA-induced neuronal loss and synaptic remodeling, potentially by down-regulating the Serpina3n/NF-κB signaling pathways. The results provide evidence that LPM682000012 is a potential anti-seizure pharmacotherapy candidate for epilepsy and warrants further research."

Journal • CNS Disorders • Epilepsy • SERPINA3