Marinus Reports Positive Top-Line Results from Trial of Rare Epilepsy Drug; Receives BARDA Contract

Rare Daily Staff

Marinus Pharmaceuticals reported positive top-line results from its phase 3 clinical Marigold study evaluating the use of oral ganaxolone in children and young adults with CDKL5 deficiency disorder, a rare, genetic epilepsy with refractory seizures.

CDKL5 deficiency disorder (CDD) is a serious and rare genetic disorder that is caused by a mutation of the cyclin‑dependent kinase‑like 5 (CDKL5) gene, located on the X chromosome that encodes proteins essential for normal brain function. It predominantly affects females and is characterized by early‑onset, difficult‑to‑control seizures and severe neuro‑developmental impairment. Most children affected by CDD cannot walk normally, talk, or care for themselves. Many also suffer from scoliosis, visual impairment, gastrointestinal difficulties and sleep disorders. There are no treatments approved specifically for CDD. Genetic testing is available to determine if a patient has a mutation in the CDKL5 gene.

Marinus’ ganaxolone is a positive allosteric modulator of GABAA receptors that is being developed in intravenous and oral formulations as an anti-seizure medication. Unlike benzodiazepines, ganaxolone exhibits anti-seizure, antidepressant and anti-anxiety activity via its effects on synaptic and extra-synaptic GABAA receptors.

The global, double-blind, placebo-controlled, phase 3 Marigold study enrolled 101 patients. Children and young adults ages 2 to 21 with a confirmed, disease-related CDKL5 gene variant were eligible to enroll. Following a 6-week baseline period, trial participants were randomized to receive either oral ganaxolone (up to 1,800 mg/day) or placebo for 17 weeks, in addition to their existing anti-seizure treatment. Following the double-blind phase, patients were eligible to continue receiving ganaxolone in an open-label extension.

In the trial, patients given ganaxolone showed a significant 32.2 percent median reduction in 28-day major motor seizure frequency, compared to a 4.0 percent reduction for those receiving the placebo, achieving the primary efficacy endpoint of the trial of percentage change in 28-day frequency of major motor seizures during the double-blind phase relative to the 6-week prospective baseline period. Ganaxolone was generally well tolerated with a safety profile consistent with previous clinical studies. The most frequent adverse event was somnolence.

Based on these results, Marinus plans to submit an New Drug Application for ganaxolone in the treatment of CDD to the U.S. Food and Drug Administration in mid-2021 and a Marketing Authorization Application for ganaxolone for the treatment of CDD to the European Medicines Agency by the end of Q3 2021.

“The Marigold Study has two important firsts. It’s the first double-blind placebo controlled study providing evidence of efficacy specific to CDD and the first phase 3 trial to examine three times a day dosing of ganaxolone in pediatric patients,” said Scott Braunstein, CEO of Marinus Pharmaceuticals. “We believe we are one step closer to providing the first treatment indicated for CDD, and plan to continue our investments in the oral ganaxolone franchise.”

Although the trial showed numerical trends favoring ganaxolone across several predefined secondary endpoints, these trends did not meet statistical significance. Marinus is planning to present the top-line results at an upcoming scientific meeting.

“CDD is a severe genetic epilepsy that can cause hundreds of seizures for patients each day,” said Scott Demarest, principal investigator at Children’s Hospital Colorado; principal investigator of the International CDKL5 Clinical Research Network;  and assistant professor of pediatrics-neurology at the University of Colorado. “Existing antiepileptic medications fail to produce an adequate and durable response in the majority of patients. The positive results from Marinus’ trial demonstrate that ganaxolone can provide significant seizure reduction in patients with CDD, an important advance for the CDD community.”

The company plans to launch an Expanded Access Program in the fourth quarter, which will allow patients who were not able to participate in the clinical trial to begin receiving treatment with ganaxolone under a treatment protocol.

Marinus received a Rare Pediatric Disease designation from the FDA for ganaxolone for the treatment of CDD. The company is also testing ganaxolone in a phase 2 trial in Tuberous Sclerosis Complex, as well as a phase 2 biomarker driven proof of concept trial in PCDH19-related epilepsy.

Marinus also reported that it received a five-year cost-sharing contract with the Chemical Medical Countermeasures division of the Biomedical Advanced Research and Development Authority (BARDA), part of the U.S. Department of Health and Human Services. This agreement includes $21 million in non-dilutive funding to support the phase 3 clinical trial Marinus is planning in refractory status epilepticus, a life-threatening condition caused by exposure to nerve agents, and preclinical studies of ganaxolone in nerve agent exposure animal models.

Marinus may receive up to approximately $30 million in additional optional funding contingent on favorable clinical and preclinical outcomes. The BARDA contract enables Marinus to expand development of ganaxolone for treatment of RSE caused by nerve agent toxicity and supports manufacturing, supply chain, clinical, regulatory, and toxicology activities. Marinus will be responsible for cost-sharing in the amount of $33 million if all development options are completed.

Photo: Scott Braunstein, CEO of Marinus Pharmaceuticals