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Full data have been published on ganaxolone (Ztalmy) for cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder, which won FDA approval last month.

Results from the pivotal demonstrated that patients receiving the drug experienced a median 30.7% decline in major motor seizures over 4 weeks, versus a median 6.9% decrease in a placebo group, according to Elia Pestana Knight, MD, of the Cleveland Clinic, and colleagues.

This translated to a median difference of 27.1 percentage points of decline (95% CI 9.6-47.9), they stated in . Results also were presented at the American Academy of Neurology annual meeting held in Seattle and online.

CDKL5 deficiency disorder arises from defects in a single gene, CDKL5, and is seen in one in about 40,000 live births. Patients develop severe seizures along with broader developmental impairments, vision abnormalities, sleep problems, and poor muscle tone. While the 1:40,000 incidence makes it rare, it's one of the most common forms of epilepsy with a specific genetic cause.

Ganaxolone is not a gene therapy, however. It's a modified version of allopregnanolone, the major metabolite of progesterone, and acts to modulate GABA_A receptors as a way to prevent seizures. The oral drug's anti-seizure effect seemed clear in rodent models and in earlier clinical studies.

Perhaps more significantly, drugmaker Marinus Pharmaceuticals sees this mechanism as including refractory status epilepticus (in an IV formulation) and tuberous sclerosis complex, with phase III trials now underway. Marinus has also developed a second-generation version that's now in phase I testing for Lennox-Gastaut syndrome. (At one point, the company targeted postpartum and postmenopausal depression as potential indications for ganaxolone, but it appears to have dropped those programs.)

The current data on ganaxolone, based on 101 patients randomized to ganaxolone or placebo in Marigold, add detail to the information available when it was approved in March. For example, while the FDA listed the effects on median 28-day seizure frequency, the primary outcome, the new data also cover a series of secondary efficacy endpoints, and more specifics on adverse events (AEs).

For example, a responder analysis showed that 24% of the ganaxolone group achieved at least a 50% reduction in 28-day seizure frequency, versus 10% of the placebo group, which fell just short of statistical significance. More ganaxolone patients also were rated by parents or caregivers as improved to some degree (63% vs 44%, though not statistically significant), with similar findings for clinician ratings.

For safety, the published paper listed rates for nearly 30 types of AEs. As the FDA noted, somnolence and sedation were the most common, but the agency didn't give percentages. Pestana Knight and colleagues did: 34% of those taking ganaxolone had somnolence considered treatment-related versus 6% of controls, and sedation was reported for 6% of the ganaxolone group (as well as 4% of the placebo group). However, the FDA omitted mention of other AEs seen more often with ganaxolone, which included pyrexia (18% vs 8%), salivary hypersecretion (6% vs 2%), and upper respiratory infection (10% vs 6%). Serious treatment-emergent AEs were uncommon and differed little between groups.

Median patient age was about 6, and medications they were taking prior to study entry included valproate, levetiracetam, clobazam (Onfi), and vigabatrin (Sabril). Median 28-day major motor seizure frequency at baseline was about 50.

At that extreme rate, the roughly 30% reduction meant that ganaxolone recipients were still experiencing on the order of 35 major seizures per 28-day period. In an , Deepak Gill, MBBS, of the Children's Hospital at Westmead in Sydney, acknowledged that this "might seem disappointing," but he argued that it is indeed "a worthwhile outcome" in the same range as other treatments, such as pharmaceutical-grade cannabidiol (Epidiolex), that have been welcomed into the clinical arsenal.

Still, Gill observed that more could be learned about "parents' and caregivers' perspectives" about the modest benefit, and that Marigold's 17-week duration was too short to tell whether the reduction in seizures is sustained long-term. He expressed pleasure that some of these questions will likely be addressed in an ongoing open-label extension. And overall, Gill said he was optimistic about ganaxolone's place in treatment for CDKL5 deficiency disorder.