Rare Daily Staff

Marinus Pharmaceuticals reported positive topline data from its open-label phase 2 trial evaluating safety and efficacy of adjunctive oral ganaxolone treatment in 23 patients with seizures associated with tuberous sclerosis complex.

The primary endpoint showed a median 16.6 percent reduction in 28-day primary endpoint seizure frequency relative to the four-week baseline period, with 30.4 percent of patients achieving a 50 percent or more seizure reduction. During the trial, patients with focal seizures showed a median 25.2 percent reduction in focal seizure frequency.

“We believe the totality of the data is encouraging and supports advancing to phase 3. There was notable activity in focal seizures, a meaningful 50 percent response rate, and consistent results in this refractory patient population, including patients on both cannabidiol and everolimus,” said Joseph Hulihan, chief medical officer of Marinus.

Tuberous sclerosis complex (TSC) is a rare genetic disorder that affects many organs and causes non-malignant tumors in the brain, skin, kidney, heart, eyes, and lungs. The condition is caused by inherited mutations in either the TSC1 gene or the TSC2 gene. TSC occurs with a frequency of 1:6,000 and a mutation is found in 85 percent of patients. While the disease phenotype can be extremely variable, neurologic manifestations such as epilepsy can be seen in up to 90 percent of TSC patients. TSC is a leading cause of genetic epilepsy, often occurring in the first year of life as either focal seizures or infantile spasms. There are currently limited approved treatments for TSC.

The phase 2 CALM trial was an open-label trial to evaluate the safety and tolerability of adjunctive ganaxolone treatment in patients with seizures associated with TSC. The trial enrolled 23 patients ages 2 to 32 who underwent a four-week baseline period followed by a 12-week treatment period where they received up to 600 mg of ganaxolone (oral liquid suspension) three times a day. Patients who met eligibility criteria were able to continue ganaxolone treatment during a 24-week extension to the trial.

The primary endpoint for the trial was percentage change in 28-day TSC-associated seizure frequency during the 12-week treatment period relative to the four-week baseline period. Secondary outcome measures included percentage of patients experiencing a greater than or equal to 50 percent reduction in 28-day TSC-associated seizure frequency through the end of the 12-week treatment period compared to the 4-week baseline period.

The secondary endpoint of 50 percent responder rate at 30.4 percent was consistent with the Marigold phase 3 CDKL5 deficiency disorder trial of 24.5 percent. Patients with focal seizures (n=19) showed a median 25.2 percent reduction in focal seizure frequency, the most common seizure type in TSC patients. The proportion of patients who achieved at least a 50 percent reduction in TSC-associated seizures was 36.4 percent in patients on concomitant everolimus and 25.0 percent on patients on concomitant cannabidiol.

Ganaxolone was generally well-tolerated with somnolence reported as the most common adverse event, consistent with previous trials; in addition, one treatment-related serious adverse event of seizure was reported in the trial.

Ganaxolone, a positive allosteric modulator of GABAA receptors, is an experimental product being developed in intravenous and oral formulations intended to maximize therapeutic reach to adult and pediatric patient populations in both acute and chronic care settings. Ganaxolone exhibits anti-seizure and anti-anxiety activity via its effects on synaptic and extrasynaptic GABAA receptors. Ganaxolone has been studied in more than 1,800 pediatric and adult subjects across various indications at therapeutically relevant dose levels and treatment regimens for up to more than two years.

A global phase 3 randomized, double blind, placebo-controlled trial (TrustTSC) of adjunctive ganaxolone in approximately 160 TSC patients is expected to begin enrollment during the fourth quarter of 2021. The primary endpoint is percent change in 28-day TSC-associated seizure frequency.

The FDA has granted orphan drug designation to ganaxolone for treatment in TSC. The FDA’s Office of Orphan Drug Products grants orphan status to support the development of medicines for rare disorders that affect fewer than 200,000 people in the U.S. Orphan drug designation provides certain benefits, including market exclusivity upon regulatory approval, if received, exemption of FDA application fees and tax credits for qualified clinical trials.

Photo: Joseph Hulihan, chief medical officer of Marinus

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