MARINUS

MARINUS: A double-blind randomized, placebo-controlled study to evaluate the safety, tolerability, efficacy, and pharmacokinetics of intravenous ganaxolone as adjunctive therapy to treat subjects with status epilepticus

Supported by: Marinus Pharmaceuticals

Principal Investigator at BMC: Anna Cervantes-Arslanian, MD

Primary Research Contact: TBD

Summary

Status epilepticus (SE) is defined as a prolonged self-sustaining seizure or recurrent seizures without recovery of consciousness between seizures, and is a neurological emergency that requires aggressive treatment to stop the seizures and prevent long-term consequences, such as alteration of neuronal networks, neuronal injury, permanent neurological damage and/or neuronal death. Studies have shown that SE can cause neuronal death via excitotoxic mechanisms as a result of excessive neuronal firing. Furthermore, convulsive SE is associated with many complications, including cardiac arrhythmias, rhabdomyolysis, pulmonary edema, electrolyte and glucose imbalance, and temperature disturbances. The primary goal of SE treatment is to gain control of the seizures rapidly and avoid complications, and treatment typically occurs in stages. In general, the treatment of SE is very aggressive and particularly urgent for convulsive status epilepticus (CSE).

The current therapies for SE have inherent risks, and few therapies are approved for the treatment of SE; the urgent need for more efficacious therapies remains. Resistance to treatment has been partially attributed to the internalization of post-synaptic GABAA-receptors and externalization of glutamate receptors. As prolonged epileptiform bursting results in a reduction of GABAA-mediated synaptic inhibition, antiepileptic treatments which rely on enhancing intrasynaptic GABAA neurotransmission become less effective the longer SE continues.

Ganaxolone is a potent allosteric positive modulator of GABAA receptors in the brain at a site distinct from the site of action of benzodiazepine receptor agonists and barbiturates. By enhancing the GABAA receptor function, ganaxolone provides an alternative mechanism in the treatment of seizures, and serves as effective therapy in the management of SE. Ganaxolone has been shown to stop SE in 2 distinct pre-clinical models of benzodiazepine-resistant SE. This study targets plasma concentrations of ganaxolone that mimic concentrations associated with anticonvulsant effects in preclinical animal models of SE and that are expected to demonstrate anticonvulsant properties in humans. As such, this is a double-blind, randomized, placebo-controlled study to evaluate the safety, tolerability, efficacy of adjunctive IV ganaxolone in subjects with SE.

Enrollment Criteria

Inclusion Criteria:

1. Subject, subject’s parent, guardian, or LAR must provide signature of informed consent, and, once capable (per the investigator’s hospital guidelines), there must be documentation of consent/assent by the subject indicating the subject is aware of the investigational nature of the study, is able and willing to participate in the study, and is aware of the required restrictions and procedures.
2. Male or female subjects 12 years of age and older at the time of the first dose of study drug
3. Clinical and/or electrographic seizures defined as:
   1. Documented clinical seizures (convulsive SE): greater than 5 minutes’ duration prior to treatment with study drug (per International League Against Epilepsy, ILAE)
      • OR
   2. Electrographic criteria (one must apply):
      1. 10 minutes of continuous seizure activity on EEG (per ILAE)
      2. Intermittent EEG seizure activity for more than 50% of the previous 60 minutes
      3. If less than 60 minutes of EEG is available, then intermittent electrographic seizures activity must be present for greater than 50% of the available duration of the EEG AND the electrographic seizure activity must be at least 10 minutes when taken in aggregate
4. Subject on concurrent 2nd line IV AED therapy with fosphenytoin/phenytoin, valproic acid, levetiracetam, or lacosamide
5. BMI <40 or, if not able to be calculated at screening, assessed by investigator as not morbidly obese

Exclusion Criteria:

1. Life expectancy of less than 24 hours
2. Anoxic brain injury as the primary cause of SE
3. Recent (<24 hour) traumatic brain injury as the primary cause of SE
4. Administered anesthesia for treatment of SE
5. Subjects who are intubated for the administration of an IV anesthetic drug (a 3rd line treatment) to treat SE. Subjects who are intubated for air protection are not excluded
6. Subjected is known or suspected to be pregnant upon screening
7. Use of pressors except as maintenance therapy for anesthetic use associated with hypotension
8. To the best knowledge of the investigator, has allergy to progesterone or allopregnanolone medications/supplements
9. If renal impairment is suspected (eGFR of 45 or lower) and subject is not on dialysis
10. To the best knowledge of the investigator, subject has hepatic insufficiency at screening, for example alanine transferase or aspartate transferase level more than 5 times the upper limit of normal (ULN), or total bilirubin more than 2 times ULN at the screening visit
11. Subject with a durable medical care agreement that would not allow hospital to administer their standard of care for treatment of SE
12. Subjects on an investigational drug that is not recommended by treatment guidelines are required to have a reasonable expectation that the investigational study drug has been cleared form their system, that is, that five half-lives have elapsed
13. Subject who has a history or evidence of a medical condition that, in the investigator’s judgment, would expose subject to an undue risk of a significant adverse event or interfere with assessments of safety or efficacy during the course of the study

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