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Marinus Announces Ganaxolone Orphan Epilepsy Program Updates Including Planned Clinical Program in Tuberous Sclerosis Complex

Marinus Pharmaceuticals, Inc. announced clinical and regulatory updates for its orphan seizure programs in tuberous sclerosis complex (TSC), CDKL5 deficiency disorder (CDD) and PCDH19-related epilepsy (PCDH19-RE).

“The decision to expand our epilepsy program in TSC was strategically informed by the discovery of a new potential epilepsy biomarker, Allo-S, in our Phase 2 study in PCDH19-related epilepsy,” said Scott Braunstein, M.D., Chief Executive Officer of Marinus. “This led us to additional analyses that identified TSC as another rare genetic disorder that may be similarly impacted by Allo-S levels. We look forward to initiating a Phase 2 trial in the first half of 2020 to provide a potential targeted treatment option for these patients with limited approved therapies.”

Marinus intends to initiate a Phase 2, open label study to evaluate the safety and tolerability of adjunctive ganaxolone treatment in patients with seizures associated with TSC. Patient stratification from the Company’s PCDH19-related epilepsy Phase 2 trial identified a subpopulation of patients with improved ganaxolone responses, those with low levels of allopregnanolone-sulfate (Allo-S). Based on these data, the Company performed a biomarker analysis to identify other rare genetic epilepsies that may benefit from the GABA_A-receptor modulatory effects of ganaxolone and today announced TSC as the next planned orphan epilepsy program to study the effect of ganaxolone on seizures as well as the expanded utility of a potential biomarker.

The planned Phase 2 study will be conducted at approximately 4-6 sites in the United States and enroll approximately 20-40 patients ages 2 to 65. Patients will undergo a 4-week baseline period followed by a 12-week treatment period. The primary endpoint for the study is percent change in 28-day primary seizure frequency through the end of the 12-week treatment period relative to the 4-week baseline period.

News from American Epilepsy Society Meeting 2019

Sepsis Linked to Elevated Risk for New-Onset Epilepsy in Young Individuals

Patients with sepsis, particularly younger patients and those with chronic kidney disease, may be at an elevated risk for new-onset epilepsy, according to research presented at the 2019 American Epilepsy Society Annual Meeting, held December 6-10, 2019, in Baltimore, Maryland.

Researchers conducted a population-based, retrospective, matched-cohort study to estimate the risk for new-onset epilepsy among patients hospitalized in the intensive care unit (ICU) for sepsis treatment. Researchers collected data from the patients in the Discharge Abstract Database between 2010 and 2015.

“These findings indicate that sepsis may be an unrecognized epilepsy risk factor,” the researchers concluded. “Possible mechanisms include damage to the blood-brain barrier as a result of renal dysfunction, persisting inflammation after the acute episode, and increased risk of cardiovascular events following sepsis.”

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Variable Long-Term Cognitive Changes in Pediatric Epilepsy

Children with pediatric epilepsy who undergo surgery may experience changes in verbal and nonverbal IQ, particularly when associated with abnormal electroencephalogram (EEG), according to research presented at the 2019 American Epilepsy Society Annual Meeting.

Researchers sought to assess the long-term, postsurgery cognitive outcomes of patients with pediatric epilepsy. Investigators assessed 24 participants, all of whom had pharmacoresistant epilepsy. Participants underwent a neuropsychological evaluation that included intellectual functioning assessments (overall IQ, verbal IQ, and nonverbal IQ), as well as an evaluation of postsurgical seizure status.

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Teenagers With Epilepsy Frequently Post Online Messages Related to Suicide

Using artificial tools to collect and analyze conversations and comments about epilepsy posted online, researchers revealed that 7.8% of all posts by teenagers with epilepsy were related to suicide, compared with 3.2% of adult posts, according to study results presented at the American Epilepsy Society 2019 Annual Meeting.

Previous studies have reported that roughly 30%-50% of patients with epilepsy may suffer from depression and the incidence of suicide in this population was found to be approximately 12%, which is 22% higher than the general population.2 The goal of the current study was to assess the major motivations for suicide thoughts among teenagers and adults with epilepsy, using artificial tools to analyze online conversations.

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Apnea and Arrhythmia Associated With Increased Mortality Among Patients With Epilepsy

Cardiac arrhythmias with or without apnea among patients with epilepsy are associated with increased mortality risk. This risk may play an important role in cases of sudden unexpected death in epilepsy (SUDEP), according to study results presents at the American Epilepsy Society 2019 Annual Meeting.

Previous studies have reported that cardiac arrhythmias and apnea may play a significant part in cases of SUDEP, the second most common cause potential life-years lost in patients with epilepsy. The incidence rate of SUDEP is 1.16 cases per 1000 patients, but may be higher in those with intractable epilepsy.

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Re-Annotation of 191 Developmental and Epileptic Encephalopathy-Associated Genes Unmasks De Novo Variants in SCN1A

The developmental and epileptic encephalopathies (DEE) are a group of rare, severe neurodevelopmental disorders, where even the most thorough sequencing studies leave 60–65% of patients without a molecular diagnosis. Here, researchers explore the incompleteness of transcript models used for exome and genome analysis as one potential explanation for a lack of current diagnoses. Therefore, we have updated the GENCODE gene annotation for 191 epilepsy-associated genes, using human brain-derived transcriptomic libraries and other data to build 3,550 putative transcript models. These annotations increase the transcriptional “footprint” of these genes by over 674 kb.

Using SCN1A as a case study, due to its close phenotype/genotype correlation with Dravet syndrome, the team screened 122 people with Dravet syndrome or a similar phenotype with a panel of exon sequences representing eight established genes and identified two de novo SCN1A variants that now – through improved gene annotation – are ascribed to residing among our exons. These two (from 122 screened people, 1.6%) molecular diagnoses carry significant clinical implications.

Furthermore, the team identified a previously classified SCN1A intronic Dravet syndrome-associated variant that now lies within a deeply conserved exon. These findings suggest the potential gains of thorough gene annotation in improving diagnostic yields for genetic disorders.

Drug Development for Rare Paediatric Epilepsies: Current State and Future Directions

Rare diseases provide a challenge in the evaluation of new therapies. However, orphan drug development is of increasing interest because of the legislation enabling facilitated support by regulatory agencies through scientific advice, and the protection of the molecules with orphan designation.

In the landscape of the rare epilepsies, very few syndromes, namely Dravet syndrome, Lennox-Gastaut syndrome and West syndrome, have been subject to orphan drug development. Despite orphan designations for rare epilepsies having dramatically increased in the past 10 years, the number of approved drugs remains limited and restricted to a handful of epilepsy syndromes.

In this paper, researchers describe the current state of orphan drug development for rare epilepsies. They identified a large number of compounds currently under investigation, but mostly in the same rare epilepsy syndromes as in the past. A rationale for further development in rare epilepsies could be based on the match between the drug mechanisms of action and the knowledge of the causative gene mutation or by evidence from animal models. In case of the absence of strong pathophysiological hypotheses, exploratory/basket clinical studies could be helpful to identify a subpopulation that may benefit from the new drug.

The team provides some suggestions for future improvements in orphan drug development such as promoting pediatric drug investigations, better evaluation of the incidence and the prevalence, together with the natural history data, and the development of new primary outcomes.

Children with Early Onset of Febrile Seizures May Be at Heightened Risk for Cognitive Dysfunction

Experts intended to examine cognitive functioning in 4-5-year-old children who had encountered febrile seizures (FS) and to evaluate the significance of complex, recurrent and early compared with late-onset FS. Drawn from the general child population of 4-year-old children attending their health check-up at child healthcare centers in Gothenburg, Sweden, the sample comprised of 73 children, screen positive for FS.

It was discovered that children with early onset of FS and especially those with recurrent FS may be at heightened risk for poorer verbal and processing speed functioning and hence at risk of acquiring cognitive, executive dysfunctions. Moreover, they would probably profit from neuropaediatric and neuropsychological follow-up.

Pediatric Status Epilepticus: Identification of Prognostic Factors Using the New ILAE Classification After 5 Years of Follow-Up

Objective: Status epilepticus (SE) is the most common neurologic emergency in childhood. This study aimed to report on a large cohort of pediatric patients with SE, applying the International League Against Epilepsy (ILAE) Classification for SE to identify prognostic factors.

Methods: The research team included 173 children treated at “Bambino Gesù” Children’s Hospital in Rome for SE exceeding 30 minutes (mean age 4.43 ± 4.93 years old, median 2.28, interquartile range [IQR] 0.41-7.32; follow-up for a mean of 4.9 ± 3.4 years, median 8.75, IQR 4,58-12.63). A multivariate model was constructed to predict neurocognitive outcome, recurrence of SE, development of epilepsy, and mortality. Adjusted odds ratios [ORs] were calculated with 95% confidence interval (OR, 95% CIs).

Results: The researchers observed a different prevalence of etiologies for the different semiologies (P < .05) and for each age group (P < .05), overlapping only in part with the recent ILAE classification. After SE, patients showed 69.9% epilepsy (drug-resistant in half of them), 23.1% worsening of neurologic findings on examination, 28.9% cognitive deficit, and 28.3% recurrent SE. At multivariate analysis: superrefractory SE was correlated to an increased risk of developing cognitive (OR 6.00, 95% CI 2.09, 17.31) or neurologic sequelae (OR 4.9, 95% CI 1.75, 19.77). A similar finding was observed for patients with onset in the neonatal period for cognitive (OR 4.84, 95% CI 1.13, 17.3) and neurologic sequelae (OR 9.03, 95% CI 2.40, 34.04). Recurrence of SE was associated with unknown etiology (OR 6.15, 95% CI 1.43, 26.76), and myoclonic semiology (OR 6.1, 95% CI 1.23, 29.3). Patients with acute symptomatic etiology (OR 0.12, 95% CI 0.04, 0.40) had a lower risk for developing epilepsy.

Significance: Age at onset and duration of status epilepticus (SE) were critical independent variables associated with worse neurocognitive outcome. The risk of developing epilepsy was lower after acute symptomatic and febrile SE. Semiology and age at onset correlate with etiology of SE. For this reason, ILAE classification with respect to four axes seems an appropriate advancement.

Epilepsy Research Findings: November 2019

Among the interesting research published this past month are advances in epilepsy genetics that may help predict who is at risk for developing epilepsy and a novel gene therapy concept for treating temporal lobe epilepsy. Research has also furthered our understanding of how epilepsy may impact cognition – even when seizures are controlled by medication.

In this update, we also feature the results of the “Seize the Truth about Epilepsy Perceptions” survey. This national survey of adult epilepsy patients, caregivers, and healthcare professionals explores the physical, social, emotional, and financial consequences associated with epilepsy.

Summaries of these research discoveries and news highlights are below.

Research Discoveries & News

Epilepsy Genetics: Risk scores are being used to investigate the genetic risk of epilepsy in a large sample of people with and without epilepsy. The international team led by the Cleveland Clinic is using this model to work towards a more personalized method of epilepsy diagnosis and treatment. Learn more
Epilepsy Gene Therapy: A new gene therapy concept has been developed for the treatment of temporal lobe epilepsy. In a “proof-of-concept” study, the researchers demonstrated that strategically delivering a specific gene to the place in the brain where seizures start can suppress them on demand in animal models. Learn more
Understanding Epilepsy: A new, national survey of adult epilepsy patients, caregivers, and healthcare professionals (HCPs) revealed a wide range of challenges in the management of the condition. The findings range from significant disconnects that occur in conversations among patients, caregivers, and HCPs to revelations about the far-reaching impact of epilepsy. Learn more
Epilepsy and Cognition: A study by Stanford University School of Medicine investigators may help explain why even people benefiting from medications for their epilepsy often continue to experience bouts of difficulty thinking, perceiving, and remembering clearly. The cause is a pathological buzz of electrical brain activity, called a high-frequency oscillation, that interferes with the brain’s normal activity. Learn more
Seizures in Newborns: Utilizing a mouse model of hypoxic-ischemic seizures has shed light on why seizures in newborns may lead to behavioral issues and learning disabilities much later, according to a study from University of Virginia Children’s Hospital. This research suggests that the brain’s learning and memory centers are among the regions most affected by seizures caused by inadequate oxygen and blood flow. Learn more

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Le Bonheur Children’s Hospital Launches Infantile Epilepsy Center

Le Bonheur Children’s Hospital has launched an Infantile Epilepsy Center that focuses on the potentially devastating diagnosis of infantile spasms and other rare epilepsies that affect children under two-years-old.

The seizures typically present as small involuntary movements, crunches or spasms and require a rapid diagnosis to prevent developmental delay or worsening of prior development.

“Infants are not just small children,” said Sarah Weatherspoon, MD, an assistant professor of Pediatric Neurology at the University of Tennessee Health Science Center and Director of the Infantile Epilepsy Center at Le Bonheur Children’s. “Infantile epilepsy requires specific techniques, diagnostics and treatments.”

The center is part of Le Bonheur’s Comprehensive Epilepsy Program and includes neurology, neurodiagnostics, neuropsychology, neuroradiology, neuro-ophthalmology, genetics, clinical nutrition, pediatrics and speech therapy/feeding assessment.

Seizures in Babies: UVA Sheds Light on Why They Have Lifelong Effects

A doctor at University of Virginia Children’s is using an elegant new approach to mapping brain activity to shed light on what happens during seizures in newborns that can lead to behavioral issues and learning disabilities much later.

New research by UVA neonatologist Jennifer Burnsed, MD, and colleagues suggests that the brain’s learning and memory centers are among the regions most affected by seizures caused by inadequate oxygen and blood flow. That lack of oxygen and blood, called hypoxia-ischemia, is a leading cause of death and disability in newborns. It is often caused by an event around the time of birth, such as a detached placenta or umbilical cord accidents.

“When babies have these brain injuries early on, it’s really hard for us to predict outcomes, especially in the babies who are not as severely affected. A lot of them will look pretty good when they leave [intensive care] and then, several years later, when they go to school, things pop up — behavioral problems, cognitive problems, learning disabilities,” Burnsed said. “That’s one of the things that’s always frustrated me as a clinician, so we have brought that question into the lab, to try to figure out exactly what is going on in the neonatal brain.”

Seizures in Infancy in the Offspring of Women with Epilepsy

In this investigation, researchers evaluated the seizure incidence in the first year of life in infants born to mothers with epilepsy and factors contributing to the incidence of seizure.

Investigators found that seizures occurred in the progeny of 47 pregnancies by the end of a year following pregnancy (2.4%), including febrile seizures in 18, the latter rate being higher than the 0.40% and 0.59% rates recorded in the recent literature for the same situation in the general population. Infant seizures were more likely in the offspring of generalized mothers vs focal epilepsy and generalized epilepsy mothers in those who during pregnancy were not seizure-free. In infants with fetal malformations, seizures were also more likely, especially those that were not discovered until after the first postnatal month.

Such results may help to warn mothers with epilepsy about the risk that their offspring will suffer seizures in the first year of life. They also indicate the desirability of achieving maternal seizure control during pregnancy.

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