Ganaxolone - Unveiling the Therapeutic Potential of a Neurosteroid

Overview

Ganaxolone is a neuroactive steroid used in the treatment of seizures that are associated with the deficiency of cyclin-dependent kinase-like 5 (CDKL5) in patients above two years of age. It is the first treatment used specifically for patients with CDKL5 deficiency disorder (CDD) and also for the seizures associated with it. Ganaxolone was first approved by the United States Food and Drug Administration (USFDA) in March 2022 for treating seizures in patients above two years suffering from CDKL5 deficiency disorder. It was assigned as an orphan drug initially and a priority review was performed before it was granted approval.

How Does Ganaxolone Work?

Ganaxolone acts by regulating brain activity; this includes inhibiting the abnormal electrical discharges that cause status epilepticus and seizures and restoring the disrupted balance in the neuronal activity in central nervous system (CNS) disorders. Its anticonvulsant effects are believed to result from the modulation of gamma-aminobutyric acid (GABA) type A receptors in the central nervous system. It has the potential to modulate the synaptic and the extrasynaptic GABA receptors, which makes it unique compared to other antiepileptic drugs.

Available Doses and Dosage Forms:

Ganaxolone is available as an oral suspension, and each contains 110 ml flavored medicine, containing 50 mg/ml (milligram per milliliter) Ganaxolone. It must be taken orally three times a day after food. The dosage recommendations are based on the body weight of the patients, weighing more and less than 28 kg (kilogram). It must be increased based on the tolerability, but not more than every seven days.

The recommended titration schedule (three times a day) for patients below 28 kg includes;

• Days 1 to 7: 6 mg/kg (maximum 18 mg/kg/day).

• Days 8 to 14: 11 mg/kg (maximum 33 mg/kg/day).

• Days 15 to 21: 16 mg/kg (maximum 48 mg/kg/day).

• Days 22 Onwards: 21 mg/kg(maximum 63 mg/kg/day).

The recommended titration schedule (three times a day) for patients with more than 28 kg includes the following;

• Days 1 to 7: 150 mg - 3 ml/dose (maximum 450 mg).

• Days 8 to 14: 300 mg - 6 ml/dose (maximum 900 mg).

• Days 15 to 21: 450 mg - 9 ml/dose (maximum 1350 mg).

• Days 22 Onwards: 600 mg - 12 ml/dose (maximum 1800 mg).

For Patients

What Is CDKL5 Deficiency Disorder?

CDKL5 deficiency disorder, also known as CDD, is characterized by seizures that start during infancy, followed by significant delays in various aspects of development. It usually begins within the third month of life or may even appear in the first week following birth. CDKL5 is associated with generalized tonic-clonic seizures, along with loss of consciousness, convulsions, and muscle rigidity. Tonic seizures are characterized by abnormal muscle contractions, short episodes of muscle jerks, and epileptic spasms. Other features of this condition include;

• Impaired or delayed development and fine motor skills.

• High or broad forehead.

• Small head (microcephaly).

• Widely spaced teeth.

• Large and deep eyes.

• Little or no speech.

• Intellectual disability.

• Scoliosis (side-to-side curvature of the spine).

• Tapered fingers.

• Vision problems.

• Feeding difficulties.

• Bruxism (teeth grinding).

• Disrupted sleep.

• Constipation.

• Gastroesophageal reflux (backflow of food contents into the esophagus).

What Is Ganaxolone?

Ganaxolone is a prescription medicine used in the management of seizures with cyclin-dependent kinase deficiency disorder in patients above two years. It may control seizures or migraine attacks; however, it will not cure the condition. Ganaxolone belongs to a class of medications called anticonvulsants and works by reducing the abnormal excitement in the brain. It has the potential to manage seizures, which are known to be resistant to various other medications. The treatment is initiated and supervised by doctors experienced in treating such medical conditions.

How Effective Is Ganaxolone?

The effectiveness of Ganaxolone in treating seizures associated with CDD in patients above two years was determined by a randomized, double-blind, placebo-controlled study. It included participants, mostly females between two and 19 years of age, with confirmed CDKL5 gene mutations and uncontrolled seizures by at least two treatments. The effect of the drug was evaluated during the 17-week treatment phase, and at the end of the treatment, participants treated with Ganaxolone showed a 31 percent median reduction in seizures compared to a seven percent reduction in participants who received the placebo.

What Is the Dosage of Ganaxolone?

The dose of Ganaxolone varies among patients and is determined by the doctor. It mainly depends on the weight of the individual and the medical condition. The doctor starts the treatment on a low dose and gradually increases it. The drug must be taken exactly as prescribed by the doctor and must not be stopped without the doctor’s consent, as the seizures may worsen. If the symptoms improve, the doctor may gradually decrease the dose.

How Should Ganaxolone Be Taken?

Ganaxolone is available as an oral suspension and must be taken orally three times a day along with food. It must be taken at almost the same time daily, and instructions given on the label must be followed. The bottle adapter and measuring syringe provided with the suspension must be used to measure each dose. The suspension must be shaken well for about one minute to allow the medication to mix evenly. The bottle must be then placed in an upright position for one minute before use to allow any foam to settle. Ganaxolone must be taken exactly as prescribed, and the dosage must not be altered.

What Are Some of the Important Instructions About Ganaxolone?

• Ganaxolone helps to control seizures or migraines but will not completely cure the condition. The medicine must be continued even if the patient feels well.

• Ganaxolone is initiated with a low dose and gradually increased, but not more than once every week. It must not be stopped without consent from the doctor, as it may worsen the seizures.

• The doctor can probably decrease the dose gradually if the frequency of seizures is controlled.

• Ganaxolone can make the patient drowsy; hence, driving or operating heavy machinery must be avoided.

• Alcoholic beverages must be avoided while taking Ganaxolone as it can worsen the side effects.

• Ganazolone may affect mental health status, so the doctor must be informed if the patient experiences impulsive or dangerous behavior, anxiety, difficulty in sleeping, depression, mood abnormalities, suicidal thoughts, etc., during the course of treatment.

• Ganaxolone is a controlled substance and must not be used for any condition other than prescribed, and must not be taken by others even if they have similar symptoms, as it can harm them.

What Must the Patient Inform the Doctor Before Taking Ganaxolone?

• Patients must inform the healthcare provider if they are allergic to Ganaxolone or its ingredients or any other medicines.

• Female patients must inform the doctor if they are pregnant or planning to become pregnant or lactating before taking Ganaxolone.

• Patients must inform the healthcare provider if they are taking any other medications, vitamin or herbal supplements, or over-the-counter medicines before taking Ganaxolone.

• Patients must inform the doctor if they are currently drunk, have ever consumed large amounts of alcoholic beverages, or have previously experienced mood disorders, depression, or suicidal thoughts.

What Are the Side Effects of Ganaxolone?

Ganaxolone can cause serious side effects, which include;

• Suicidal thoughts or actions.

• Increases or worsens depression or anxiety.

• Restlessness.

• Sleepiness.

• Irritability.

• Behavior or mood changes.

• Aggressiveness.

• Panic attacks.

• Trouble sleeping.

• Seasonal allergy.

• Fever, cough, sore throat, and runny nose (flu-like symptoms).

• Excessive saliva or drooling.

• Difficulty walking.

Dietary Considerations: There are no specific dietary considerations to be followed while taking Ganaxolone unless advised by the healthcare provider.

Missed Dose: The missed dose of Ganaxolone must be taken as soon as remembered, but if it is time for the next dose, the missed dose can be skipped, and the regular dosing schedule must be continued. A double dose must not be taken to cover up for a missed one.

Overdose: There is limited information regarding the overdose of Ganaxolone, but in case of an overdose, the patient must be closely monitored, and standard supportive care must be provided. A certified poison control center, a hospital, or a healthcare provider must be contacted immediately for the necessary management of the patient.

Storage:

• Ganaxolone must be stored between 59°F to 86°F (15°C to 30°C) in its original bottle in an upright position.

• The child-resistant cap must be tightly closed.

• It must be used within 30 days of first opening the bottle, and any unused medicine must be discarded after 30 days.

• Keep Ganaxolone and all medicines out of the reach of children.

For Doctors

Indications of Ganaxolone:

Ganaxolone is indicated in the treatment of seizures associated with CDKL5 deficiency disorder (CDD) in patients above two years of age.

Dose:

Ganaxolone is available as an oral suspension and must be taken three times daily along with food. The dose of Ganaxolone and the duration of treatment are determined by the doctor based on the patient's weight and medical condition. The dose is increased based on the tolerability of the patient and not more frequently than every seven days.

Dosing Considerations:

The recommended doses must be titrated gradually depending on the patient’s tolerance and to achieve the expected clinical response, and any patient not tolerating the dose can be maintained at a low dose for additional days before initiating the next dose. The total daily dose must be administered in three equal doses throughout the day. If it is not tolerated by the patient, the dose may be adjusted for symptomatic management, provided the total daily dose is administered.

What Are the Pharmacological Aspects of Ganaxolone?

Mechanism of Action: The exact mechanism exerted by Ganaxalone and its therapeutic effect in treating seizures associated with CDKL5 deficiency disorder is not known. However, the neuroactive steroids present in the drug called the epalons act as positive allosteric modulators of both synaptic and extrasynaptic gamma-aminobutyric acid (GABA) receptors, thus enhancing the GABAergic inhibitory effect on neurotransmission.

Pharmacokinetics:

• Absorption: After an oral administration of Ganaxolone, the time taken to achieve maximum concentration is around two to three hours. On administration of Ganaxolone with a high-fat meal, the maximum serum concentration was increased by threefold, and the area under the curve (AUC) was increased by twofold when compared to the administration of the drug under fasting conditions.

• Distribution: Approximately 99 percent of Ganaxolone is bound to serum proteins.

• Metabolism: Ganaxolone is metabolized by the following enzymes: CYP2B6, CYP3A4/5, CYP2D6, and CYP2C19.

• Elimination: The terminal half-life of Ganaxolone is around 34 hours.

• Excretion: After an administration of a single oral dose of 300 mg of Ganaxolone to healthy male participants, 55 percent of the drug was recovered in feces, and 18 percent was recovered in urine.

Pharmacodynamics:

No relevant information is available on the pharmacodynamic effects of Ganaxolone, but similar to other neurosteroids, Ganaxolone lacks classical hormonal activity. However, it exerts its effects directly through the modulation of GABA receptors. Like other antiepileptic drugs, Ganaxolone is associated with significant sedation and somnolence.

Adverse Effects of Ganaxolone:

The adverse effects of Ganaxolone include;

• Somnolence.

• Pyrexia.

• Increased salivary secretion.

• Sedation.

• Upper respiratory tract infections.

• Nasal congestion.

• Influenza.

• Bronchitis.

• Behavioral changes.

• Lack of appetite.

• Suicidal thoughts.

• Lack of concentration.

• Irritability.

• Diarrhea.

• Muscle and joint pain.

Warnings and Precautions:

• Ganaxolone can cause sedation and somnolence that may appear early during the treatment and is usually dose-related. Hence, healthcare professionals must monitor the patients and advise them not to drive or operate machinery until they have gained sufficient experience in the treatment with Ganaxolone. Intake of opioids, antidepressants, or alcohol consumption can also potentiate sedation and somnolence during the treatment.

• Antiepileptic drugs, including Ganaxolone, can cause suicidal thoughts, depression, or mood changes in patients; hence, the patients must be regularly monitored, and the emergence of any such symptoms may be related to the illness that is under treatment.

• Similar to other anti-epileptic drugs, Ganaxolone must be gradually withdrawn due to its high risk of frequent seizures and status epilepticus. Rapid discontinuation of the drug may be considered in cases of withdrawal due to serious adverse events.

• Ganaxolone can cause drug dependence or can be abused; hence, the patients must be frequently monitored.

Drug Interactions of Ganaxolone

The following drugs may interact with Ganaxolone, and hence, an alternative must be advised;

• Carbamazepine.

• Butabarbital.

• Enzalutamide.

• Mobocertinib.

• Phenobarbital.

• Phenytoin.

• Primidone.

• St.John’s wort.

• Rifampin.

• Secobarbital, etc.

Clinical Studies:

The effectiveness of Ganaxolone in the management of seizures associated with CDD in patients above two years was determined by a single, randomized, double-blind, placebo-controlled study. Patients in Study I had molecular confirmation of mutation in the CDKL5 gene, had a minimum of 16 major motor seizures per 28 days prior to screening, and seizures that were inadequately controlled by two previous treatment regimens. Patients were randomized to receive either Ganaxolone or placebo in a 1:1 ratio. After a 21-day titration period, patients below 28 kg received a maintenance dose of 21 mg/kg three times a day, and patients above 28 kg received a maintenance dose of 600 mg three times a day. Patients treated with Ganaxolone showed a significant reduction in the major motor seizures in 28-day frequency compared to the patients receiving placebo.

Nonclinical Toxicology:

• Carcinogenesis: Carcinogenicity studies have not been conducted with Ganaxolone.

• Mutagenicity: Ganaxolone was known to be negative for genotoxicity in the in vitro Ames test, mouse lymphoma tests, and in vivo rat bone marrow micronucleus assays. It was found that oxy-dihydro Ganaxolone, which is the major circulating human metabolite, was negative for mutagenicity in the in vitro Ames assay. However, it was positive for an in vitro mammalian chromosomal aberration test in peripheral lymphocytes of humans.

• Fertility: After an oral administration of Ganaxolone to male and female rats, no significant effects were observed on fertility, spermatogenesis, embryonic development, etc. The maximum dose tested was 40 mg/kg/day, with plasma exposures less than the maximum recommended human dose, which is around 1800 mg.

Specific Considerations

• Pregnancy: There is no information available regarding the use of Ganaxolone in pregnant women.

• Lactation: There is no information available regarding the use of Ganaxolone in lactating women. Hence, potential benefits must be weighed against the potential risks before using this medication.

• Pediatric Use: Appropriate studies have not been conducted to study the effects of Ganaxolone in patients below two years of age; hence, safety and efficacy have not been established.

• Geriatric Use: As CDD is usually a disease seen in children and young adults, appropriate studies have not been conducted in the geriatric population to study the effects of Ganaxolone.

• Hepatic Impairment: The effect of hepatic impairment on the pharmacokinetics of Ganaxolone has not been evaluated. However, as Ganaxolone undergoes clearance through the hepatic route, hepatic impairment may increase the exposure of Ganaxolone. Therefore, patients with hepatic disorders must be frequently monitored, and a reduced dose of Ganaxolone must be recommended.