Phase 3 Trial Targets Rare Form of Pediatric Epilepsy with No Approved Therapies

Characterized by seizures that often begin in infancy, followed by significant developmental delays, CDKL5 deficiency disorder (CDD) is a rare, genetic condition first identified in 2004. Although it is known to be caused by mutations in the CDKL5 gene, found on the X-chromosome, the cause of the mutation remains unknown, making it that much more difficult to develop effective treatment.

Although the true incidence of CDKl5 deficiency disorder is unknown, more children are diagnosed with the condition as awareness spreads. To date, there are no specific therapies available to those with the disorder, and anti-epilepsy medications that are available are not very effective; this leaves a large unmet medical need. However, another treatment option is set to be further explored in a pivotal phase 3 trial in children and young adults.

The treatment in question? Oral ganaxolone, developed by Marinus Pharmaceuticals, Inc.

A neurosteroid developed to prevent anti-seizure activity by calming the brain and restoring its electrical balance, ganaxolone has a method of action that is unique compared with the epilepsy medications that currently exist on the market. By binding to unique GABA_A receptors, the neurosteroid has proven to hinder the spread of seizures and prevent new ones from occurring in previous animal studies.

“We are excited to offer the CDKL5 patient community, for the first time, participation in a pivotal study of ganaxolone that may have the potential to reduce the seizure burden of the disorder,” Christopher M. Cashman, Marinus’ chief executive officer said in a recent statement.

The double-blind, placebo-controlled, phase 3 trial, referred to as the Marigold Study, aims to enroll about 70 patients all between 2 and 21 years of age who have a confirmed disease-associated CDKL5 gene variant. After a baseline period, patients will be randomized into 1 of 2 arms: those who will receive up to 1,800 mg/day of ganaxolone for 17 weeks in addition to existing anti-seizure treatment and those who will receive placebo for 17 weeks with existing anti-seizure treatment. After treatment, those who meet certain eligibility requirements will then have the opportunity to receive the investigational drug in the open-label phase of the trial.

The primary efficacy endpoint of the trial will be the percent of reduction in seizures, while secondary outcome measures will include non-seizure-related endpoints to collect behavioral and sleep disturbance changes that had been seen as improvements in previous studies examining the drug.

Previous data yielded from a phase 2 open-label study evaluating the use of ganaxolone in addition to baseline treatment resulted in a “sizable and durable” reduction in the frequency of seizures experienced by the CDD patients treated. A big increase in the number of seizure-free days were also reported in those who received ganaxolone, with some even reporting behavioral benefits.

“After seeing long-term results from our phase 2 trial showing that ganaxolone provides a meaningful reduction in the number of seizures for children with CDD, as well as an impressive increase in seizure-free days, we focused our efforts to expedite the initiation of this registration study,” Cashman added. “CDKL5 patients are in need of new treatment options and we look forward to working with the entire community in the conduct of this study.”

An orphan drug designation was granted to Marinus in June 2017 for the use of ganaxolone in patients with CDD.