Ganaxolone

Medical uses

Ganaxolone is indicated for the treatment of seizures associated with cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder.

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.

Ganaxolone is thought to modulate both synaptic and extrasynaptic GABAA receptors to normalize over-excited neurons. 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.

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

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.

Chemistry

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.

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

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. 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. Forty-four (40.7%) of the participants were from US sites. Safety was assessed from a pool of two clinical studies. 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.

References

References

1. (15 November 2022). "Ztalmy- ganaxolone suspension".
2. (31 July 2023). "Ztalmy EPAR".
3. (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.
4. (June 2022). "Ganaxolone: First Approval". Drugs.
5. (10 January 2023). "Advancing Health Through Innovation: New Drug Therapy Approvals 2022".
6. (January 2024). "New Drug Therapy Approvals 2022".
7. (July 2024). "An overview of ganaxolone as a treatment for seizures associated with cyclin-dependent kinase-like 5 deficiency disorder". Expert Review of Neurotherapeutics.
8. (April 2024). "A systematic review and meta-analysis on efficacy and safety of Ganaxolone in epilepsy". Expert Opinion on Pharmacotherapy.
9. (July 2004). "Allopregnanolone analogs that positively modulate GABA receptors protect against partial seizures induced by 6-Hz electrical stimulation in mice". Epilepsia.
10. (May 2010). "Ganaxolone suppression of behavioral and electrographic seizures in the mouse amygdala kindling model". Epilepsy Research.
11. (Jun 24, 2020). "Anti-apoptotic Actions of Allopregnanolone and Ganaxolone Mediated Through Membrane Progesterone Receptors (PAQRs) in Neuronal Cells". Frontiers in Endocrinology.
12. "Ganaxolone". U.S. National Center for Biotechnology Information (NCBI), National Library of Medicine (NLM).
13. "Ganaxolone for use in treating genetic epileptic disorders".
14. (18 March 2022). "Drug Trials Snapshots: Ztalmy".