Ganaxolone for management of seizures associated with CDKL5 deficiency disorder

STRUCTURE: Ganaxolone is a 3β-methylated synthetic analog of the natural neurosteroid allopregnanolone, a metabolite of progesterone. It is also called 3α-hydroxy-3β-methyl-5α-pregnan-20-one and has a molecular formula C₂₂H₃₆O₂, with a molecular weight of 332.5 g/mol. The 3β-methyl substitution prevents rapid metabolism and thus increases its stability (terminal half-life: 34 h). Ganaxolone is a white crystalline powder that is insoluble in water but soluble in organic solvents.

MECHANISM OF ACTION: γ-Aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the central nervous system. Its principal role is to lower neuronal excitability, mainly via acting on the GABA receptor A subtype (GABA_AR), a ligand-gated ion channel receptor. Upon activation by GABA released from the presynaptic neurons, GABA_AR on the postsynaptic cell selectively allows the influx of negatively charged ions (mainly chloride anion, Cl⁻) into the neurons, resulting in decreased neuronal excitability. GABA_AR has long been implicated in neurological conditions, including seizures; it is the primary target for a number of antiseizure drugs (ASDs). Ganaxolone is a small molecule that has been identified as a positive allosteric modulator for GABA_AR and demonstrated to significantly reduce the frequency of major motor seizures associated with the cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) in clinical trials. The mechanism of action of ganaxolone in the management of seizures is not fully understood; however, its antiseizure action is likely attributed to its potentiation of GABA_AR activation. Ganaxolone is able to augment the activities of both synaptic GABA_AR (containing α, β, and γ subunits) and extrasynaptic GABA_AR (containing α, β, and δ subunits) through a binding site distinct from benzodiazepines or barbiturates (binding sites on GABA_AR are indicated). By contrast, these two groups of conventional ASDs only act on the synaptic GABA_AR. Ganaxolone’s capability of activating GABA_AR on both synaptic and extrasynaptic sites leads to enhanced and persistent suppression of neuronal excitability during seizures. This unique feature differentiates ganaxolone from other GABA-potentiating ASDs, such as benzodiazepines or barbiturates.

NAME:

Ganaxolone; commercially available under the brand name ZTALMY.

DRUG CLASS:

First-in-class positive allosteric modulator that targets both synaptic and extrasynaptic GABA A receptor (GABA_AR).

CLINICAL USE:

Indicated for the treatment of seizures associated with CDKL5 CDD in patients 2 years of age and older. Ganaxolone is administered as an oral suspension three times daily. CDD is a rare genetic disorder (one in 40 000–60 000 newborns) characterized by infantile-onset epilepsy and severe neurodevelopmental delay. It is caused by mutations in the CDKL5 gene, which encodes a protein essential for normal brain functions. Seizures in CDD patients are usually severe and difficult to control.

DEVELOPED BY:

Originally developed by CoCensys Inc. and acquired by Purdue Pharma in 1999. Marinus Pharmaceuticals acquired the compound from Purdue Pharma in 2004.

ADVERSE EFFECTS:

Somnolence, pyrexia, salivary hypersecretion, and seasonal allergy. Avoid concomitant use with strong or moderate CYP3A4 inducers as they will decrease ganaxolone exposure.

TIMELINE:

2018–2021, Phase 3 trials, NCT03572933

March 18, 2022, FDA approval for ZTALMY^® (ganaxolone).

2023–2024, Phase 3 trials, NCT05249556