Marinus Pharmaceuticals Inc.’s GABAA receptor agonist Ztalmy (ganaxolone), has won U.S. FDA approval for treating seizures associated with cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder. It is the first therapy indicated specifically for the rare genetic condition and is now approved for patients ages 2 and older, earning Marinus a rare pediatric disease priority review voucher.

The Radnor, Pa.-based company announced the approval March 18, ahead of a March 20 PDUFA date, and said it expects to make Ztalmy commercially available in the U.S. in July. It had previously hoped for a June launch.

With the approval, Marinus transitions to a commercial company. Last year, it launched discussions with payers and began filling out its sales and commercial infrastructure, including bringing on board 16 field representatives.

The announcement strongly boosted the company’s stock (NASDAQ:MRNS), which climbed by as much as 44% from its previous close in late-afternoon trading before closing 16.4% higher at $10 per share.

CDKL5 deficiency disorder (CDD), a rare form of genetic epilepsy, is caused by a mutation of the CDKL5 gene, which is located on the X chromosome and is responsible for encoding proteins essential for normal brain function. While it’s characterized primarily by difficult-to-control seizures starting in infancy, the condition can also affect intellectual and gross motor skill development as well as result in a number of other types of impairment, including visual impairment, sensory problems, sleeping disorders and gastrointestinal issues. CDD’s estimated prevalence is one if 40,000 to 60,000 newborns, with girls comprising roughly 90% of diagnoses.

Described as positive allosteric modulator of GABAA receptors, ganaxolone is designed to work by regulating brain activity, specifically modulating both the synaptic and extrasynaptic GABAA receptors.

The NDA, accepted for review in September, was based on data from the phase III Marigold study, a double-blind, placebo-controlled trial that enrolled 101 patients between the ages of 2 and 19 with confirmed disease-related CDKL5 gene variant. Primary endpoint data showed that those treated with ganaxolone had a 30.7% median reduction in 28-day major motor seizure frequency vs. a 6.9% reduction for placebo, achieving the trial’s primary endpoint (p=0.0036). In Marigold’s open label extension study, participants treated for at least 12 months experienced a median 49.6% reduction in major motor seizure frequency. In the clinical development program, Ztalmy demonstrated efficacy, safety and tolerability with the most common adverse reactions being somnolence, pyrexia, salivary hypersecretion and seasonal allergy.

An open-label extension showed that patients receiving ganaxolone for at least 12 months experienced a median 49.6% reduction in major motor seizure frequency.

Ganaxolone is also under review for CDD in Europe. The EMA initially granted the company’s request for an accelerated assessment, though the marketing authorization application later converted to standard review to allow sufficient time to respond to questions as part of the review process. An opinion by the EMA’s Committee for Medicinal Products for Human Use is now expected by the end of 2022.

In Europe, Marinus has partnered with Orion Corp. through an August deal in which Orion paid €25 million (about $30 million at the time of the deal) in up-front cash. Marinus is eligible to receive up to an additional €97 million in research and development, reimbursement and cash milestone payments based on specific clinical and commercial achievements, as well as tiered royalty payments.

Approval in CDD is expected to be just the tip of the iceberg for ganaxolone. Marinus has aims to build out a full oral ganaxolone franchise for orphan epilepsy indications, with a phase III study having recently enrolled its first participant for tuberous sclerosis complex, a genetically defined rare epilepsy. Top-line data is expected in the first half of 2024.

The company also is in the planning stages for phase II development with a different formulation of ganaxolone in Lennox-Gastaut syndrome, a phenotypically defined rare epilepsy.

An intravenous (I.V.) version of ganaxolone is in development for acute seizure disorders such as status epilepticus, which is described as the second most common neurologic emergency in the U.S. at roughly 150,000 cases per year. Phase III development is ongoing, though Marinus temporarily paused the Raise trial in February due to the impact of the COVID-19 omicron variant on hospital resources and an unexpected interruption of clinical supply material. That trial is now expected to wrap up in the second half of 2023.

Marinus also has an ongoing program for the U.S. Biomedical Advanced Research and Development Authority, which has agreed to fund $51 million of an $84 million contract for the company to support clinical development of I.V. ganaxolone for individuals exposed to nerve gas, such as sarin.