Ganaxolone

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Ganaxolone, sold under the brand name Ztalmy, is a medication used to treat seizures in people with cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder.[2][3] Ganaxolone is a neuroactive steroid gamma-aminobutyric acid (GABA) A receptor positive modulator.[2]

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

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

Medical uses

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

Pharmacology

Mechanism of action

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 both synaptic and extrasynaptic GABAA receptors to normalize over-excited neurons.[3] Ganaxolone's activation of the extrasynaptic receptor is an additional mechanism that provides stabilizing effects that potentially differentiates it from other drugs that increase GABA signaling.[3]

Ganaxolone binds to allosteric sites of the GABAA receptor to modulate and open the chloride ion channel, resulting in a hyperpolarization of the neuron.[3] This causes an inhibitory effect on neurotransmission, reducing the chance of a successful action potential (depolarization) from occurring.[3][10][11]

It is unknown whether ganaxolone possesses significant hormonal activity in vivo, with a 2020 study finding evidence of in vitro binding to the membrane progesterone receptor.[12]

Chemistry

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Ganaxolone is an analog of the neurosteroid allopregnanolone that possesses no known hormonal activity and, instead, is thought to primarily function by binding to GABAA receptors as a positive allosteric modulator.[13]

Other pregnane neurosteroids include alfadolone, alfaxolone, hydroxydione, minaxolone, pregnanolone (eltanolone), and renanolone, among others.[14]

History

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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  14. ↑ <templatestyles src="Citation/styles.css"/>Template:Citation/make link, Masuoka LK, Lappalainen J, "Ganaxolone for use in treating genetic epileptic disorders", issued Script error: No such module "auto date formatter"., assigned to Marinus Pharmaceuticals Inc. Script error: No such module "Check for unknown parameters".

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External links

  • Clinical trial number NCT03572933 for "Study of Adjunctive Ganaxolone Treatment in Children and Young Adults With CDKL5 Deficiency Disorder (Marigold)" at ClinicalTrials.gov

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