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RADNOR, Pa.—Marinus Pharmaceuticals Inc., a biopharmaceutical company developing therapeutics to treat epilepsy and neuropsychiatric disorders, recently announced that ganaxolone, the only product in its pipeline, did not meet its primary endpoint in a Phase 3 clinical trial in adults with drug-resistant focal onset seizures. While the drug was generally safe and well tolerated, ganaxolone did not demonstrate a statistically significant difference from placebo. As such, Marinus will discontinue its program in adult focal onset seizures and focus its efforts on advancing ganaxolone in status epilepticus and pediatric orphan indications.
Ganaxolone, a central nervous system-selective GABAA modulator, is being developed in three different dose forms—intravenous, capsule and liquid—intended to maximize therapeutic reach to adult and pediatric patient populations in both acute and chronic care settings. Ganaxolone acts on a well-characterized synaptic and extrasynaptic GABAA target known for antiseizure and antianxiety activity. The drug has been studied in more than 1,300 subjects, both pediatric and adult, at therapeutically relevant dose levels and treatment regimens for up to two years.
Epileptic seizures require chronic treatment, often over a lifetime. While available antiepileptic drugs are efficacious for many patients, chronic treatment is complicated by side effects, including cardiovascular risks, liver enzyme induction, kidney stones, behavioral changes, sedation and adverse effects on cognitive function, drug tolerance and reproduction. More than five million people are being treated for epilepsy in the United States, Europe and Japan, but 30 to 35 percent of patients do not achieve acceptable seizure control with single or multiple medications.
In a conference call, various Marinus officials said that the clinical trial was well conducted and that a possible reason for the surprising failure of the drug in the Phase 3 trial could be the high dropout rate in the drug component as opposed to the placebo component. While stopping the ganaxolone program in adult focal epilepsy, the company is “committed to its ability to help reduce seizures and will leverage its mechanism of action on the best opportunities for patients and shareholders,” according to Christopher M. Cashman, CEO of Marinus Pharmaceuticals.
Cashman added, “We are disappointed with the outcome of this study and the unfortunate impact on the epilepsy community and particularly the patients suffering from drug-resistant focal onset seizures who are benefiting from ganaxolone treatment. We remain confident in the safety profile of ganaxolone and its ability to effectively reduce seizures in targeted patient populations. We are committed to building our ganaxolone franchise and are confident in the potential of ganaxolone in the treatment of status epilepticus and pediatric orphan seizure and behavior disorders. We will provide an update in the upcoming weeks on our clinical programs in these indications. We are looking into pediatric applications and fragile X syndrome.”
Dr. Yaakko Lappalainen, director of clinical development, said that this was the third or fourth drug tried on some of the study subjects. He related that the Phase 3 multinational, double-blind, randomized, placebo-controlled study was conducted at 61 sites in the United States, Germany, Poland, Australia, Bulgaria and Russia.
The safety profile of ganaxolone in this study was consistent with previously conducted studies. Overall, ganaxolone was generally safe and well tolerated with no imbalance between the ganaxolone and placebo group in the number of patients with serious adverse events reported. The most common adverse events reported at greater rates than placebo were somnolence, dizziness and fatigue. The majority of these adverse events were rated as mild in severity. There were 44 patients on ganaxolone that discontinued the study compared to 26 patients on placebo. The most common reason for discontinuation was an adverse event.
Dr. Albena Patroneva, chief medical officer of Marinus, commented, “The design, conduct, patient demographics and median separation versus placebo were similar to our positive Phase 2 trial and other studies conducted with recently approved antiepileptic drugs. While we did not see the incremental efficacy at a higher dose that we were hoping to achieve, ganaxolone continued to display a good safety profile, a key attribute for the product’s future development. We will leverage the findings from this study in the conduct of our ongoing and future studies in pediatric orphan indications and status epilepticus.”