FDA Approves Ztalmy: First Therapy for CDKL5 Deficiency Seizures

Key Takeaways

• FDA approved Ztalmy on March 18, 2022, under NDA 215904—first and only therapy specifically for CDD-related seizures [FDA]
• Marigold Phase 3 trial (NCT03572933) of 101 patients showed 30.7% median reduction in major motor seizure frequency versus 6.9% placebo (p=0.0036) [ClinicalTrials.gov]
• Ganaxolone is a neuroactive steroid and positive allosteric modulator of GABA-A receptors
• Most common adverse events: somnolence, pyrexia, and upper respiratory tract infections
• Developed by Marinus Pharmaceuticals; addresses critical unmet need in rare genetic epileptic encephalopathy

What Is CDKL5 Deficiency Disorder?

CDKL5 deficiency disorder (CDD) is a rare developmental epileptic encephalopathy caused by pathogenic variants in the CDKL5 gene. The condition is characterized by early-onset, treatment-resistant seizures that typically begin within the first months of life. Affected individuals also experience severe developmental delays, impaired motor function, and often lack independent ambulation by age 2. Prior to Ztalmy's approval, treatment options were limited to off-label use of conventional antiepileptic drugs with variable efficacy.

What Did the Marigold Clinical Trial Show?

The Marigold study (NCT03572933) was a Phase 3, double-blind, randomized, placebo-controlled trial evaluating ganaxolone in patients with CDD. The trial enrolled 101 patients aged 2–21 years with a genetically confirmed CDKL5 variant, seizure onset by age 1, and failure to control seizures with at least 2 anti-seizure medications.

Patients received ganaxolone oral suspension (63 mg/kg/day for patients ≤28 kg or 1800 mg/day for patients >28 kg) or placebo three times daily for 17 weeks. The primary endpoint was percentage change in 28-day major motor seizure frequency.

Results demonstrated a statistically significant benefit: patients receiving ganaxolone achieved a 30.7% median reduction in major motor seizure frequency compared to a 6.9% reduction in the placebo group, representing a median difference of 27.1% (p=0.0036). This data supported the FDA's conclusion that Ztalmy provides a meaningful clinical benefit for CDD patients.

How Does Ztalmy Work?

Ztalmy contains ganaxolone, a neuroactive steroid that functions as a positive allosteric modulator of GABA-A receptors. GABA is the primary inhibitory neurotransmitter in the central nervous system. By enhancing GABA-A receptor function, ganaxolone increases inhibitory neurotransmission, which helps counteract the hyperexcitability that underlies seizure activity. This mechanism differs from many traditional antiepileptic drugs, offering a distinct pharmacological approach for patients with CDD.

What Is the Regulatory History?

Marinus Pharmaceuticals submitted New Drug Application 215904 for ganaxolone in CDKL5 deficiency disorder. The FDA granted the application Priority Review and Orphan Drug Designation, reflecting the serious unmet medical need and the rarity of CDD. The agency approved Ztalmy on March 18, 2022, making it the first FDA-approved therapy specifically indicated for CDD-related seizures.

Following approval, the Drug Enforcement Administration classified ganaxolone as a Schedule V controlled substance, indicating it has a low potential for abuse relative to substances in Schedule IV. This scheduling reflects ganaxolone's mechanism as a GABA-A modulator, similar to other controlled antiepileptic agents.

What Are the Safety Considerations?

In the Marigold trial, adverse events occurred in 86% of ganaxolone-treated patients versus 88% of placebo-treated patients. The most common adverse reactions were somnolence, pyrexia, and upper respiratory tract infections. Serious adverse events were reported in 12% of the ganaxolone group and 10% of the placebo group. Treatment discontinuation due to adverse events occurred in 4% of ganaxolone patients versus 8% of placebo patients.

Healthcare providers should monitor patients for CNS depression effects, including sedation and dizziness. The drug label includes warnings about the potential for increased suicidal thoughts and behavior, a risk associated with antiepileptic drugs generally.

What Is the Market Impact?

The CDKL5 deficiency disorder patient population in the United States is small, estimated in the low thousands. Prior to Ztalmy's approval, no therapies were specifically approved for CDD, leaving patients and caregivers with limited options. Ztalmy's approval as a first-in-class, disease-specific antiseizure medication addresses this critical gap.

The approval also has implications for future research. The successful development pathway for Ztalmy in a rare genetic epilepsy may inform approaches to other rare neurodevelopmental disorders with seizure manifestations.

Frequently Asked Questions

Primary Sources

1. U.S. Food and Drug Administration. Approval Letter for Ztalmy (NDA 215904). March 18, 2022.
2. ClinicalTrials.gov. Study of Adjunctive Ganaxolone Treatment in Children and Young Adults with CDKL5 Deficiency Disorder (Marigold Study). NCT03572933. June 2018–May 2021.
3. Marinus Pharmaceuticals. Ztalmy (ganaxolone) Prescribing Information. 2022.

Related Profiles

• Ganaxolone
• CDKL5 Deficiency Disorder
• Marinus Pharmaceuticals

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