Ganaxolone Shown to Reduce Seizure Frequency

Orrin Devinsky, MD

An open-label study of ganaxolone (3α-hydroxy-3β-methyl-5α-pregnan-20-one) has shown that the therapy is capable of reducing the frequency of seizures and increasing the number of seizure-free days in young patients.

The drug is intended for the treatment of patients with Lennox-Gastaut syndrome (LGS), a form of childhood-onset epilepsy that accounts for between 2% and 5% of all childhood cases of epilepsy. The cumulative prevalence is 2.6 in 10,000 cases, but despite its rarity, the condition is debilitating and is associated with multiple seizure types.

The investigators, led by Orrin Devinsky, MD, director of the Comprehensive Epilepsy Center at NYU Langone Health in New York, New York, sought to determine the safety and efficacy of ganaxolone, with a primary end point of the mean percentage change in the 28-day frequency of major seizures—defined as generalized tonic, clonic, tonic-clonic, or tonic-spasm seizures.

“Although a synthetic analog of the endogenous progesterone metabolite, allopregnanolone, [Ganaxolone] lacks both nuclear progesterone receptor activity and hormonal effects with chronic dosing,” Devinsky and colleagues wrote. “[Ganaxolone] activates synaptic and extrasynaptic GABA_A [type A gamma aminobutyric acid] receptors at a site distinct from benzodiazepines and barbiturates; it does not induce tolerance.”

Currently, there are 6 available antiepileptic therapies used to treat LGS, but all carry with them serious adverse events (AEs), and few result in the halting or slowing of seizures for patients with LGS. Ganaxolone was examined in 8 patients (aged 2-15 years) with severe and treatment-resistant generalized tonic-clonic and drop seizures. All 8 patients were on stable doses of antiepileptic drugs.

In the study, patients were given oral ganaxolone titrated at doses of 63 mg/day for patients under 30 kg in weight, or up to 1800 mg/day.

After 26 weeks on the therapy, a 32% reduction of major seizures was seen (range, —80% to 40%; P = .195) for patients. Seizure-free days increased by 33% (range, 0 to 170%; P = .031) by week 26. The Wilcoxon signed-rank test was used to determine changes that differed from 0.

“[Ganaxolone] has anticonvulsant activity with an acceptable safety and tolerability profile in doses of 900 to 1800 mg in adults and children,” the investigators wrote. “We hypothesized that [ganaxolone] could reduce the frequency of major seizures in children with treatment-refractory LGS and potentially increase seizure-free days.”

In total, 5 of the 8 subjects reported AEs that were considered potentially associated with ganaxolone. Three subjects reported an episode of somnolence, 1 subject reported an incidence of vomiting, and 1 subject reported an incidence of increased seizure activity. No serious AEs were reported in the trial.

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