Ganaxolone, sold under the brand name Ztalmy, is a

medication Medication (also called medicament, medicine, pharmaceutical drug, medicinal product, medicinal drug or simply drug) is a drug used to medical diagnosis, diagnose, cure, treat, or preventive medicine, prevent disease. Drug therapy (pharmaco ...

used to treat

seizure A seizure is a sudden, brief disruption of brain activity caused by abnormal, excessive, or synchronous neuronal firing. Depending on the regions of the brain involved, seizures can lead to changes in movement, sensation, behavior, awareness, o ...

s in people with cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder. Ganaxolone is a neuroactive steroid gamma-aminobutyric acid (GABA) A receptor positive modulator. The most common side effects of treatment with ganaxolone include

somnolence Somnolence (alternatively sleepiness or drowsiness) is a state of strong desire for sleep, or sleeping for unusually long periods (compare hypersomnia). It has distinct meanings and causes. It can refer to the usual state preceding falling aslee ...

(sleepiness), fever, excessive saliva or drooling, and seasonal allergy. Ganaxolone was approved for medical use in the United States in March 2022, and in the European Union in July 2023. The US

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...

(FDA) considers it to be a

first-in-class medication A first-in-class medication is a prototype drug that uses a "new and unique mechanism of action" to treat a particular medical condition. While the Food and Drug Administration's Center for Drug Evaluation and Research tracks first-in-class medic ...

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 GABA_A receptors to normalize over-excited

neuron A neuron (American English), neurone (British English), or nerve cell, is an membrane potential#Cell excitability, excitable cell (biology), cell that fires electric signals called action potentials across a neural network (biology), neural net ...

s. 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 GABA (gamma-aminobutyric acid, γ-aminobutyric acid) is the chief inhibitory neurotransmitter in the developmentally mature mammalian central nervous system. Its principal role is reducing neuronal excitability throughout the nervous system. GA ...

signaling. Ganaxolone binds to

allosteric In the fields of biochemistry and pharmacology an allosteric regulator (or allosteric modulator) is a substance that binds to a site on an enzyme or receptor distinct from the active site, resulting in a conformational change that alters the p ...

sites of the GABA_A receptor to modulate and open the chloride ion channel, resulting in a hyperpolarization of the neuron. This causes an inhibitory effect on

neurotransmission Neurotransmission (Latin: ''transmissio'' "passage, crossing" from ''transmittere'' "send, let through") is the process by which signaling molecules called neurotransmitters are released by the axon terminal of a neuron (the presynaptic neuron ...

, reducing the chance of a successful

action potential An action potential (also known as a nerve impulse or "spike" when in a neuron) is a series of quick changes in voltage across a cell membrane. An action potential occurs when the membrane potential of a specific Cell (biology), cell rapidly ri ...

(

depolarization In biology, depolarization or hypopolarization is a change within a cell (biology), cell, during which the cell undergoes a shift in electric charge distribution, resulting in less negative charge inside the cell compared to the outside. Depolar ...

) from occurring. It is unknown whether ganaxolone possesses significant hormonal activity

in vivo Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, an ...

, with a 2020 study finding evidence of

in vitro ''In vitro'' (meaning ''in glass'', or ''in the glass'') Research, studies are performed with Cell (biology), cells or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in ...

binding to the membrane

progesterone receptor The progesterone receptor (PR), also known as NR3C3 or nuclear receptor subfamily 3, group C, member 3, is a protein found inside cells. It is activated by the steroid hormone progesterone. In humans, PR is encoded by a single ''PGR'' gene resi ...

Chemistry

Ganaxolone is an analog of the

neurosteroid Neurosteroids, also known as neuroactive steroids, are endogenous or exogenous steroids that rapidly alter neuronal excitability through interaction with ligand-gated ion channels and other cell surface receptors. The term ''neurosteroid'' was coi ...

allopregnanolone Allopregnanolone is a natural product, naturally occurring neurosteroid which is made in the body from the hormone progesterone. As a medication, allopregnanolone is referred to as brexanolone, sold under the brand name Zulresso, and used to t ...

that possesses no known hormonal activity and, instead, is thought to primarily function by binding to GABA_A receptors as a positive allosteric modulator. Other pregnane neurosteroids include

alfadolone Alfadolone ( INN), or alphadolone is a neuroactive steroid and general anesthetic. Along with alfaxolone, as alfadolone acetate, it is one of the components of the anesthetic drug mixture althesin. Chemistry See also * Ganaxolone * Hydr ...

, alfaxolone,

hydroxydione Hydroxydione, as hydroxydione sodium succinate (, , ) (brand names Viadril, Predion, and Presuren), also known as 21-Hydroxy-5β-pregnane-3,20-dione, is a neuroactive steroid which was formerly used as a general anesthetic, but was discontinued d ...

, minaxolone, pregnanolone (eltanolone), and

renanolone Renanolone (International Nonproprietary Name, INN), or 11-ketopregnanolone, also known as 5β-pregnan-3α-ol-11,20-dione, is a synthetic compound, synthetic neuroactive steroid which is described as a general anesthetic but was never introduced ...

, 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

External links

* {{Portal bar , Medicine Sterols Anticonvulsants GABAA receptor positive allosteric modulators Ketones Neurosteroids Pregnanes Sedatives Orphan drugs