Action

FDA has approved Ztalmy (ganaxolone) to treat seizures associated with cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) in patients 2 years of age and older. This is the first treatment for seizures associated with CDD and the first treatment specifically for CDD.

Disease or Condition

CDD is a rare developmental epileptic encephalopathy (dysfunction of the brain) caused by CDKL5 gene mutations. The CDKL5 gene is responsible for making proteins that are important for normal brain functioning and development.

Patients with CDD typically have infantile-onset epilepsy that responds poorly to currently available treatments. Other symptoms include hypotonia (poor muscle tone), severe developmental and cognitive delays with little or no speech production, fine and gross motor impairment (including inability to walk for most patients), cortical visual impairment, behavioral abnormalities, and sleep and digestive difficulties. Although rare, the incidence of CDD is believed to be between 1 in 40,000-60,000 live births, making it one of the most common genetic forms of epilepsy.

Effectiveness

The effectiveness of Ztalmy to treat seizures associated with CDD in patients 2 years of age and older was established in a double-blind, randomized, placebo-controlled study in participants aged 2 to 19 years of age.

Participants had confirmed CDKL5 gene mutations, seizures inadequately controlled by at least two previous treatment regimens, and a minimum average of 16 major motor (convulsive) seizures per 28 days during a two-month period prior to screening.

Participants were mostly female (79%; consistent with CDD demographics), and 96% were also receiving other drugs to treat their seizures at the baseline (beginning) of the study. The most common other drugs were valproate, levetiracetam, clobazam, and vigabatrin.

To determine if the treatment worked, the effect of Ztalmy on the percentage change in the 28-day frequency of major motor seizures from a 6-week prospective baseline phase during the 17-week double-blind treatment phase was evaluated. At the end of the treatment phase, participants treated with Ztalmy had a 31% median reduction in 28-day frequency of major motor seizures, compared to a 7% reduction for those receiving the placebo, a statistically significant difference.

Safety Information

Ztalmy can cause somnolence (sleepiness) and sedation. These risks increase if patients use Ztalmy with central nervous system depressants, such as alcohol. Health care providers should monitor patients for suicidal behavior and thoughts.

Patients should not use Ztalmy if they are taking other medicines that act as moderate or strong cytochrome P450 (CYP) 3A4 inducers (e.g., rifampin, St John’s Wort), as these therapies may lower the efficacy of Ztalmy. If use of such drugs is unavoidable, health care providers should consider increasing Ztalmy while not exceeding the maximum recommended daily dosage. When stopping the medication, patients should gradually reduce Ztalmy to minimize the risk of increased seizure frequency and status epilepticus (seizures that lasts longer than five minutes or more than one seizure within a five-minute period).

More safety information is available in the Ztalmy prescribing information.

Designations

Ztalmy received an orphan drug designation and priority review for this approval.