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Ganaxolone

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Ganaxolone
Clinical data
Trade namesZtalmy
Other namesGNX; CCD-1042; 3β-Methyl-5α-pregnan-3α-ol-20-one; 3α-Hydroxy-3β-methyl-5α-pregnan-20-one
License data
Routes of
administration		By mouth
Drug classNeurosteroid
ATC code
Legal status
Legal status
Identifiers
  • 1-[(3R,5S,8R,9S,10S,13S,14S,17S)-3-Hydroxy-3,10,13-trimethyl-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthren-17-yl]ethanone
CAS Number
PubChemCID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard(EPA)
ECHA InfoCard100.210.937Edit this at Wikidata
Chemical and physical data
FormulaC22H36O2
Molar mass332.528g·mol−1
3D model (JSmol)
  • CC(=O)[C@H]1CC[C@@H]2[C@@]1(CC[C@H]3[C@H]2CC[C@@H]4[C@@]3(CC[C@@](C4)(C)O)C)C
  • InChI=1S/C22H36O2/c1-14(23)17-7-8-18-16-6-5-15-13-20(2,24)11-12-21(15,3)19(16)9-10-22(17,18)4/h15-19,24H,5-13H2,1-4H3/t15-,16-,17+,18-,19-,20+,21-,22+/m0/s1☒N
  • Key:PGTVWKLGGCQMBR-FLBATMFCSA-N☒N
☒NcheckY(what is this?)(verify)

Ganaxolone,sold under the brand nameZtalmy,is amedicationused to treatseizuresin people withcyclin-dependent kinase-like 5 (CDKL5) deficiency disorder.[1][3]Ganaxolone is a neuroactive steroidgamma-aminobutyric acid (GABA) A receptor positive modulator.[1]

The most common side effects of treatment with ganaxolone includesomnolence(sleepiness), fever, excessive saliva or drooling, and seasonal allergy.[4]

Ganaxolone was approved for medical use in the United States in March 2022,[1][4][5]and in the European Union in July 2023.[2]The USFood and Drug Administration(FDA) considers it to be afirst-in-class medication.[6][7]

Medical uses

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Ganaxolone is indicated for the treatment of seizures associated with cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder.[1][2][8][9]

Pharmacology

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Mechanism of action

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The exact mechanism of action for ganaxolone is unknown; however, results from animal studies suggest that it acts by blocking seizure propagation and elevating seizure thresholds.[10][11]

Ganaxolone is thought to modulate bothsynapticand extrasynapticGABAAreceptorsto normalize over-excitedneurons.[3]Ganaxolone's activation of the extrasynaptic receptor is an additional mechanism that provides stabilizing effects that potentially differentiates it from other drugs that increaseGABAsignaling.[3]

Ganaxolone binds toallostericsites of the GABAAreceptor to modulate and open thechloride ion channel,resulting in ahyperpolarizationof the neuron.[3]This causes an inhibitory effect onneurotransmission,reducing the chance of a successfulaction potential(depolarization) from occurring.[3][10][11]

It is unknown whether ganaxolone possesses significant hormonal activityin vivo,with a 2020 study finding evidence ofin vitrobinding to the membraneprogesterone receptor.[12]

Chemistry

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Ganaxolone is ananalogof theneurosteroidallopregnanolonethat possesses no known hormonal activity and, instead, is thought to primarily function by binding to GABAAreceptors as apositive allosteric modulator.[13]

Other pregnane neurosteroids includealfadolone,alfaxolone,hydroxydione,minaxolone,pregnanolone(eltanolone), andrenanolone,among others.[14]

History

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The FDA approved ganaxolone based on evidence from a single, double-blind, randomized, placebo-controlled study (Study 1, NCT03572933) of 101 participants with cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder who were two years of age and older.[4]The trial was conducted at 36 sites in 8 countries including Australia, France, Israel, Italy, Poland, Russian Federation, the United Kingdom, and the United States.[4]Forty-four (40.7%) of the participants were from US sites.[4]Safety was assessed from a pool of two clinical studies.[4]These include the study of participants with cyclin-dependent kinase-like 5 deficiency disorder and a clinical study that included seven additional participants from a trial of ganaxolone in children and young adults.[4]

References

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  1. ^abcde"Ztalmy- ganaxolone suspension".DailyMed.15 November 2022.Archivedfrom the original on 21 January 2023.Retrieved21 January2023.
  2. ^abc"Ztalmy EPAR".European Medicines Agency.31 July 2023.Archivedfrom the original on 25 August 2023.Retrieved25 August2023.
  3. ^abcdeCarter RB, Wood PL, Wieland S, Hawkinson JE, Belelli D, Lambert JJ, et al. (March 1997). "Characterization of the anticonvulsant properties of ganaxolone (CCD 1042; 3alpha-hydroxy-3beta-methyl-5alpha-pregnan-20-one), a selective, high-affinity, steroid modulator of the gamma-aminobutyric acid(A) receptor".The Journal of Pharmacology and Experimental Therapeutics.280(3): 1284–1295.PMID9067315.
  4. ^abcdefg"Drug Trials Snapshots: Ztalmy".U.S. Food and Drug Administration.18 March 2022.Retrieved9 October2023.Public DomainThis article incorporates text from this source, which is in thepublic domain.
  5. ^Lamb YN (June 2022). "Ganaxolone: First Approval".Drugs.82(8): 933–940.doi:10.1007/s40265-022-01724-0.PMID35596878.
  6. ^"Advancing Health Through Innovation: New Drug Therapy Approvals 2022".U.S.Food and Drug Administration(FDA).10 January 2023.Archivedfrom the original on 21 January 2023.Retrieved22 January2023.Public DomainThis article incorporates text from this source, which is in thepublic domain.
  7. ^New Drug Therapy Approvals 2022(PDF).U.S.Food and Drug Administration(FDA)(Report). January 2024.Archivedfrom the original on 14 January 2024.Retrieved14 January2024.Public DomainThis article incorporates text from this source, which is in thepublic domain.
  8. ^Gould A, Amin S (July 2024). "An overview of ganaxolone as a treatment for seizures associated with cyclin-dependent kinase-like 5 deficiency disorder".Expert Review of Neurotherapeutics:1–7.doi:10.1080/14737175.2024.2385937.PMID39082513.
  9. ^Khan P, Saini S, Hussain S, Majid H, Gupta S, Agarwal N (April 2024). "A systematic review and meta-analysis on efficacy and safety of Ganaxolone in epilepsy".Expert Opinion on Pharmacotherapy.25(5): 621–632.doi:10.1080/14656566.2024.2342413.PMID38606458.
  10. ^abKaminski RM, Livingood MR, Rogawski MA (July 2004). "Allopregnanolone analogs that positively modulate GABA receptors protect against partial seizures induced by 6-Hz electrical stimulation in mice".Epilepsia.45(7): 864–867.doi:10.1111/j.0013-9580.2004.04504.x.PMID15230714.S2CID21974013.
  11. ^abReddy DS, Rogawski MA (May 2010)."Ganaxolone suppression of behavioral and electrographic seizures in the mouse amygdala kindling model".Epilepsy Research.89(2–3): 254–260.doi:10.1016/j.eplepsyres.2010.01.009.PMC2854307.PMID20172694.
  12. ^Thomas P, Pang Y (24 June 2020)."Anti-apoptotic Actions of Allopregnanolone and Ganaxolone Mediated Through Membrane Progesterone Receptors (PAQRs) in Neuronal Cells".Frontiers in Endocrinology.11(417): 417.doi:10.3389/fendo.2020.00417.PMC7331777.PMID32670200.
  13. ^"Ganaxolone".PubChem.U.S. National Center for Biotechnology Information (NCBI), National Library of Medicine (NLM).Archivedfrom the original on 10 December 2022.Retrieved6 August2022.
  14. ^US 20190160078A1,Masuoka LK, Lappalainen J, "Ganaxolone for use in treating genetic epileptic disorders", issued 2019-05-30, assigned to Marinus Pharmaceuticals Inc.
[edit]
  • Clinical trial numberNCT03572933for "Study of Adjunctive Ganaxolone Treatment in Children and Young Adults With CDKL5 Deficiency Disorder (Marigold)" atClinicalTrials.gov
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