- |||||||||| Ztalmy (ganaxolone oral) / Marinus, Xcopri (cenobamate) / SK Bio, Angelini Group, Endo
Review, Journal: New GABA-Targeting Therapies for the Treatment of Seizures and Epilepsy: I. Role of GABA as a Modulator of Seizure Activity and Recently Approved Medications Acting on the GABA System. (Pubmed Central) - Sep 15, 2023
We also review the available data for the two most recently approved antiseizure medications that act, at least in part, through GABAergic mechanisms, namely cenobamate and ganaxolone. Differences in the mode of drug discovery, pharmacological profile, pharmacokinetic properties, drug-drug interaction potential, and clinical efficacy and tolerability of these agents are discussed.
- |||||||||| Review, Journal: Pharmacological diversity amongst approved and emerging antiseizure medications for the treatment of developmental and epileptic encephalopathies. (Pubmed Central) - Sep 1, 2023
Rufinamide, fenfluramine, stiripentol, cannabidiol and ganaxolone are antiseizure medications (ASMs) with diverse mechanisms of action that have been approved for treating specific DEEs...Stiripentol is licensed for treating seizures associated with Dravet syndrome in patients taking clobazam and/or valproate...Greater understanding of the causes of DEEs has driven research into the potential use of other novel and repurposed agents. Putative ASMs currently in clinical development for use in DEEs include soticlestat, carisbamate, verapamil, radiprodil, clemizole and lorcaserin.
- |||||||||| Ztalmy (ganaxolone oral) / Marinus
Trial completion date, Trial primary completion date: Open-label Study of Adjunctive GNX Treatment in Children and Adults With TSC-related Epilepsy (clinicaltrials.gov) - Aug 31, 2023
P3, N=169, Enrolling by invitation,
Putative ASMs currently in clinical development for use in DEEs include soticlestat, carisbamate, verapamil, radiprodil, clemizole and lorcaserin. Trial completion date: Dec 2024 --> Jun 2027 | Trial primary completion date: Dec 2024 --> Jun 2027
- |||||||||| Ztalmy (ganaxolone oral) / Marinus
Effect of ganaxolone on behaviours in children with the CDKL5 Deficiency Disorder (South Hall 2, 2nd Floor) - May 29, 2023 - Abstract #EPNS2023EPNS_339;
Non-seizure outcomes can contribute to the success of anti-seizure interventions. Along with better seizure control, children who received ganaxolone had improved behavioural scores in select domains compared to those receiving placebo.
- |||||||||| Ztalmy (ganaxolone oral) / Marinus
Journal: Complex Metabolism of the Novel Neurosteroid, Ganaxolone, in Humans. A Unique Challenge for MIST Assessment. (Pubmed Central) - May 15, 2023
Significance Statement Studies on the metabolism of GNX in humans revealed a complex array of products that circulated in plasma, the two major components of which were formed via an unexpected multi-step pathway. Complete structural characterization of these (disproportionate) human metabolites required extensive in vitro studies, along with contemporary mass spectrometry, NMR spectroscopy, and synthetic chemistry efforts, which served to underscore the limitations of traditional animal studies in predicting major circulating metabolites in man.
- |||||||||| ganaxolone IV / Marinus
Enrollment open, Trial initiation date: Safety and Efficacy Study of IV Ganaxolone as Adjuvant Therapy for Established Status Epilepticus (ESE) (clinicaltrials.gov) - Apr 25, 2023
P2, N=120, Recruiting,
Complete structural characterization of these (disproportionate) human metabolites required extensive in vitro studies, along with contemporary mass spectrometry, NMR spectroscopy, and synthetic chemistry efforts, which served to underscore the limitations of traditional animal studies in predicting major circulating metabolites in man. Not yet recruiting --> Recruiting | Initiation date: Jan 2026 --> Apr 2023
- |||||||||| Ztalmy (ganaxolone oral) / Marinus
Developmental Impacts of Ganaxolone Treatment in the Preterm Born Guinea Pig Cerebellum. (Great Hall 3&4, Foyer Level) - Mar 20, 2023 - Abstract #SRI2023SRI_555;
Ganaxolone was found to increase the myelination in these regions to emulate term born phenotypic levels of myelination. These results indicate that preterm birth causes reductions in MBP staining in the cerebellum which can be restored to a term born phenotype through the neurosteroid therapy Ganaxolone.
- |||||||||| Ztalmy (ganaxolone oral) / Marinus
Clinical, P2 data, Journal: Phase 2, placebo-controlled clinical study of oral ganaxolone in PCDH19-clustering epilepsy. (Pubmed Central) - Mar 14, 2023
P2
Ganaxolone was generally well tolerated and led to a greater reduction in the frequency of PCDH19-clustering seizures compared to placebo; however, the trend did not reach statistical significance. Novel trial designs are likely needed to evaluate the effectiveness of antiseizure treatments for PCDH19-clustering epilepsy.
- |||||||||| Review, Journal: Novel antidepressant drugs: Beyond monoamine targets. (Pubmed Central) - Feb 27, 2023
The renaissance of psychedelic drugs and the emergence of preliminary positive clinical trial results with psilocybin, Ayahuasca, 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), and lysergic acid diethylamide (LSD) may pave the way towards establishing this class of drugs as effective therapies for MDD, TRD and other neuropsychiatric disorders. Going beyond the monoamine targets appears to be an effective strategy to develop novel antidepressant drugs with superior efficacy, safety, and tolerability for the improved treatment of MDD and TRD.
- |||||||||| Ztalmy (ganaxolone oral) / Marinus
Journal: Ganaxolone: A New Treatment for CDKL5 Deficiency Disorder. (Pubmed Central) - Nov 26, 2022
Quantitative electroencephalography (qEEG) measures, bispectral index (BIS), modified observers' assessment of alertness and sedation (MOAA/S), plasma concentrations, and safety data were collected. No abstract available
- |||||||||| Ztalmy (ganaxolone oral) / Marinus
Journal: Ganaxolone versus phenobarbital for neonatal seizure management. (Pubmed Central) - Nov 19, 2022
Ganaxolone provided better seizure control than phenobarbital in this perinatal asphyxia model and was neuroprotective for the newborn brain, affording a new therapeutic opportunity for treatment of neonatal seizures. ANN NEUROL 2022;92:1066-1079.
- |||||||||| progesterone / Generic mfg.
Review, Journal: Many or too many progesterone membrane receptors? Clinical implications. (Pubmed Central) - Nov 18, 2022
CT1812 (Elayta™) is also being tested for the treatment of Alzheimer's disease (AD) in Phase 2 clinical trials, targeting the P4 receptor membrane component 1 (PGRMC1)/S2R complex. In this Review, we highlight emerging knowledge on the mechanisms of nongenomically initiated actions of P4 and its derivatives.
- |||||||||| Ztalmy (ganaxolone oral) / Marinus
Trial completion, Trial completion date: Adjunctive Ganaxolone Treatment (Part A) in TSC Followed by Long-term Treatment (Part B) (clinicaltrials.gov) - Oct 31, 2022
P2, N=24, Completed,
Trial completion date: Oct 2023 --> Dec 2024 | Initiation date: Apr 2022 --> May 2023 | Trial primary completion date: Oct 2023 --> Dec 2024 Active, not recruiting --> Completed | Trial completion date: Dec 2021 --> Aug 2022
- |||||||||| Ztalmy (ganaxolone oral) / Marinus
Journal: Ganaxolone. (Pubmed Central) - Oct 25, 2022
Active, not recruiting --> Completed | Trial completion date: Dec 2021 --> Aug 2022 No abstract available
- |||||||||| ganaxolone IV / Marinus
Trial completion date, Trial primary completion date: RAISE: Randomized Therapy In Status Epilepticus (clinicaltrials.gov) - Oct 21, 2022
P3, N=124, Recruiting,
No abstract available Trial completion date: Mar 2022 --> Oct 2023 | Trial primary completion date: Jan 2022 --> Oct 2023
- |||||||||| Zulresso (brexanolone) / Sage Therapeutics, Ztalmy (ganaxolone oral) / Marinus, zuranolone (SAGE-217) / Sage Therapeutics, Shionogi, Biogen
Journal: Neuroactive steroids - new possibilities in the treatment of postpartum depression. (Pubmed Central) - Oct 16, 2022
In the case of severe depression, the patient is switched to pharmacological treatment, with sertraline being the most commonly used for this diagnosis...In addition to the registered brexanolone, another steroidal drug, zuranolone, is available in the third phase of the clinical trial...Another synthetic analogue of neuroactive allopregnanolone, known as ganaxolone, did not show a significant reduction in depressive symptoms in the second phase of the clinical trial compared to placebo. Nevertheless, it has great therapeutic potential in the treatment of various types of epilepsy.
- |||||||||| Differential network activity of benzodiazepines and neuroactive steroids observed with cortical EEG in rat. (SDCC Halls B-H) - Oct 10, 2022 - Abstract #Neuroscience2022NEUROSCIENCE_4742;
Increased θ-band power was observed clinically with zuranolone (Antonoudiou 2022), whereas reduced θ-band power was reported in humans with lorazepam (Gilles 2002)...All compounds increased β-band power. The differential effects on θ-band power in rat EEG recordings between NAS GABAAR PAMs and the other GABAergic compounds tested may reflect the differential modulation of GABAAR subpopulations, since only the NAS GABAAR PAMs in this study modulate both γ and δ subunit-containing GABAARs.
- |||||||||| Journal: Current and future pharmacotherapy options for drug-resistant epilepsy. (Pubmed Central) - Sep 30, 2022
For specific epilepsy syndromes, XEN 496 is under Phase III development for potassium voltage-gated channel subfamily Q member 2 developmental and epileptic encephalopathy (KCNQ2-DEE), carisbamate is under Phase III development for LGS and Ganaxolone under Phase III development for TSC. Finally, in preclinical models several molecular targets including inhibition of glycolysis, neuroinflammation and sodium channel inhibition have been identified in animal models although further data in animal and later human studies are needed.
- |||||||||| Diacomit (stiripentol) / Biocodex, Meiji Seika, Ztalmy (ganaxolone oral) / Marinus
Review, Journal: Adjuvant Treatment for Protocadherin 19 (PCDH19) Syndrome. (Pubmed Central) - Aug 26, 2022
A ketogenic diet has been studied to treat several refractory epilepsies, including PCDH19; it has promising results as effective adjuvant therapy in the resolution of status epilepticus, suggesting it could be used as part of the treatment in early childhood. Stiripentol was given as adjuvant therapy in a patient with PCDH19 epilepsy resulting in the most extended period of seizure-free episodes, but more studies must be performed to assess its efficacy.
- |||||||||| Ztalmy (ganaxolone oral) / Marinus
Review, Journal: Epilepsy and cognitive impairment in childhood and adolescence: A Mini review. (Pubmed Central) - Jul 9, 2022
In addition to conventional antiseizure medications (ASMs), ketogenic diet, hormone therapy and epilepsy surgery play an important role especially in cases of drug resistance. This review aims to provide a comprehensive overview of the mainfactors influencing cognition in children and adolescents with epilepsy and the main therapeutic options available for the epilepsies associated with intellectual disability.
- |||||||||| Ztalmy (ganaxolone oral) / Marinus
Review, Journal: Ganaxolone: First Approval. (Pubmed Central) - Jun 23, 2022
Oral ganaxolone is also currently undergoing phase III evaluation in the treatment of tuberous sclerosis complex-related epilepsy, while an intravenous formulation of ganaxolone is being evaluated in refractory status epilepticus. This article summarizes the milestones in the development of ganaxolone leading to this first approval for seizures associated with CDD.
- |||||||||| Review, Journal: GABAkines - Advances in the discovery, development, and commercialization of positive allosteric modulators of GABA receptors. (Pubmed Central) - May 19, 2022
Traditional GABAkines like diazepam have safety and tolerability concerns that include sedation, motor-impairment, respiratory depression, tolerance and dependence...The compounds that are presently being developed and commercialized include several neuroactive steroids (an allopregnanolone formulation (brexanolone), an allopregnanolone prodrug (LYT-300), Sage-324, zuranolone, and ganaxolone), the α2/3-preferring GABAkine, KRM-II-81, and the α2/3/5-preferring GABAkine PF-06372865 (darigabat)...Medicinal chemistry efforts are also ongoing to identify novel and improved GABAkines. The data document gaps in our understanding of the molecular pharmacology of GABAkines that drive differential pharmacological profiles, but emphasize advancements in the ability to successfully utilize GABA receptor potentiation for therapeutic gain in neurology and psychiatry.
- |||||||||| Ztalmy (ganaxolone oral) / Marinus
Journal: Examining Neurosteroid-Analogue Therapy in the Preterm Neonate For Promoting Hippocampal Neurodevelopment. (Pubmed Central) - May 7, 2022
We found that of the three doses, only the highest dose of ganaxolone (2.5 mg/kg) impaired key indicators of physical health and wellbeing over extended periods of time. Whilst it may be too early to see improvements in markers of neurodevelopment, further long-term study utilising the lower doses are warranted to assess functional outcomes at ages when preterm birth associated behavioural disorders are observed.
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