Marinus Pharmaceuticals Initiates Phase 3 Study in Children with PCDH19-Related Epilepsy

Marinus Pharmaceuticals announced it is initiating a single global pivotal Phase 3 clinical study (Violet Study) evaluating oral ganaxolone in children with PCDH19-related epilepsy (PCDH19-RE), a rare genetic epilepsy. If successful, the Violet Study is intended to support the regulatory filings for approval of ganaxolone in this underserved and refractory patient population.

The Violet Study is a global, double-blind, randomized, placebo-controlled pivotal Phase 3 clinical study evaluating ganaxolone in children with PCDH19-RE. The study will enroll up to 70 patients between the age of 1 and 17 with a confirmed PCDH19 mutation. All patients that meet eligibility will be stratified into one of two biomarker groups and randomized (ganaxolone or placebo) within each stratum. The trial will consist of an 8-week prospective baseline period to collect seizure data, followed by a 17-week double-blind treatment phase.

Patients randomized to ganaxolone will titrate over four weeks to a dose of up to 600 mg of ganaxolone oral liquid suspension three times a day and maintain that dose for the following 13-weeks. After the double-blind period, all patients who meet certain eligibility requirements will have the opportunity to receive ganaxolone in an open label phase of the study. The company expects to begin screening patients for enrollment into the study in the second quarter of 2019 and data from the study are estimated to be available in 2021.

How Often is Antiseizure Drug-Free Ketogenic Diet Therapy Achieved?

The ketogenic diet (KD) is often started not only for seizure reduction but also to potentially wean antiseizure drugs (ASDs) in children with epilepsy. Although there have been several publications regarding ASD reduction on the KD, it is unknown how often complete medication withdrawal occurs.

Researchers reviewed the charts of all children started on the KD at Johns Hopkins Hospital and Johns Hopkins All Children’s Hospital from 1/11 to 4/18. Children were defined as achieving drug-free diet (DFD) status if they started the KD on at least 1 ASD and achieved a period of time where they were on the KD alone.

Over the time period, 232 children were evaluated; drug-free diet status occurred in 43 (18.5%), of which 32 (13.8% of the full cohort) remained off antiseizure drugs for the remainder of their ketogenic diet treatment course. Eleven children restarted antiseizure drugs after a mean of 7 months. Children achieving drug-free diet therapy were more likely to be younger, have fewer antiseizure drugs at ketogenic diet onset, have Glut1 deficiency or epilepsy with myoclonic-atonic seizures, but were less likely to have Lennox-Gastaut syndrome or a gastrostomy tube.

NeuroCycle Therapeutics Awarded NIH SBIR Grant to Study Next-Generation Treatment of Dravet Syndrome

NeuroCycle Therapeutics, Inc. announced it had been awarded a $0.5M Small Business Innovation Research grant from the National institute of Neurological Disorders and Stroke (NINDS) to evaluate its advanced subtype-selective GABAA receptor modulators, NCT10004 and NCT10015, in models of Dravet Syndrome (Award Number R43NS107051).

This grant builds upon the company’s strategy to develop a portfolio of small molecule drug candidates that maximize efficacy and minimize side effects through selective targeting of the central nervous system.

Latest Genetic Sequencing Techniques Reveal New Disease Mutations Associated With Epilepsy and Dravet Syndrome

Next-generation sequencing techniques have revealed that genetic mutations in the KCND3 gene may be responsible for more types of epilepsy than previously thought, and new candidate genes associated with Dravet syndrome have been identified, a new study reports.

The study, “Gene mutational analysis in a cohort of Chinese children with unexplained epilepsy: identification of a new KCND3 phenotype and novel genes causing Dravet syndrome,” was published in the journal Seizure.

1 in 5 Pediatric Epilepsy Readmissions Preventable

While 1 in 5 pediatric epilepsy readmissions were scheduled, an additional 20% were judged to be preventable, according to a new report.

An interdisciplinary team from the Cincinnati Children’s Hospital Medical Center was established to review and characterize 30-day readmissions from patients admitted for epilepsy between May 2014 and October 2016. The team was made up of inpatient and outpatient neuroscience nurses, care managers, a quality outcomes manager, and child neurology physicians who individually reviewed the data.

“There was no prior data of this sort, so we were not sure what we were going to find when we started the study,” study author Marissa Vawter-Lee, MD told MD Magazine®. Other studies had found that pediatric epilepsy readmission rates hovered around 6-10% but they did not describe the readmitted patients.

The investigators classified 21.5% of the readmissions as “preventable” and 64.9% as not preventable. The most common preventable causes for readmissions were problems with the discharge care plan or medication management, the study authors said.

A Neuropsychological Model for the Pre-Surgical Evaluation of Children with Focal-Onset Epilepsy: An Integrated Approach

This review explores the complexities of pre-surgical neuropsychological assessment for children with focal-onset epilepsy. A model is proposed outlining a range of factors that potentially influence the neuropsychological formulation. These factors include a developmental, epilepsy, psychological and cognitive dimension, together with family and social context and intrinsic factors. This model is child-centered and recognizes that these factors will be weighted differently for each individual. In some instances the neuropsychological profile might suggest localized and lateralized function, but there are significant limitations to this approach in the context of the contemporary view of epilepsy as a network disorder.

This review recognizes that a range of issues impact on neuropsychological function in children with focal-onset epilepsy, including the connectivity between neural systems and the dynamic nature of development. The aim of this review is to provide a neuropsychological framework to enhance and support clinical decision-making in the pre-surgical evaluation of children with focal-onset epilepsy.

Cannabidiol Reduces Seizures in Patients with Lennox-Gastaut Syndrome: Interim Analysis of an Open-Label Extension Study

Objective: Patients with Lennox-Gastaut syndrome (LGS) who completed 1 of 2 randomized, double-blind, placebo-controlled trials of add-on cannabidiol (CBD) (GWPCARE3, NCT02224560 or GWPCARE4, NCT02224690) were invited to enroll in an open-label extension (OLE) study evaluating the long-term safety and efficacy of CBD (GWPCARE5, NCT02224573). This study is an interim analysis of the safety, efficacy, and patient-reported outcomes from this trial.

Methods: Patients received a pharmaceutical formulation of highly purified CBD oral solution (Epidiolex; 100 mg/mL), titrated from 2.5 to 20 mg/kg/d over a 2-week titration period, in addition to their existing medications. Doses could be reduced if not tolerated or increased up to 30 mg/kg/d if thought to be of benefit.

Results: This interim analysis was based on a November 2016 data cut. Of 368 patients who completed treatment in GWPCARE3 and GWPCARE4, 366 (99.5%) enrolled in the OLE study (GWPCARE5). Median treatment duration was 38 weeks at a mean modal dose of 23 mg/kg/d. Most patients (92.1%) experienced adverse events (AEs), primarily of mild (32.5%) or moderate (43.4%) severity. The most common AEs were diarrhea (26.8%), somnolence (23.5%), and convulsion (21.3%). 35 patients (9.6%) discontinued treatment due to AEs. Liver transaminase elevations were reported in 37 patients (10.1%), of whom 29 were receiving concomitant valproic acid; 34 cases resolved spontaneously or with dose modification of CBD or concomitant medication. Median reduction from baseline in drop seizure frequency (quantified monthly over 12-week periods) ranged from 48% to 60% through week 48. Median reduction in monthly total seizure frequency ranged from 48% to 57% across all 12-week periods through week 48. 88% of patients/caregivers reported an improvement in the patient’s overall condition per the Subject/Caregiver Global Impression of Change scale.

Significance: In this study, long-term add-on cannabidiol treatment had an acceptable safety profile in patients with LGS and led to sustained reductions in seizures.

Zogenix Submits New Drug Application to FDA and Marketing Authorization Application to European Medicines Agency for FINTEPLA® for the Treatment of Dravet Syndrome

Zogenix, Inc. announced it has completed its rolling submission of a New Drug Application (NDA) to the FDA and submitted a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) for FINTEPLA (ZX008, low-dose fenfluramine) for the treatment of seizures associated with Dravet syndrome. Dravet syndrome is an intractable and difficult-to-treat epilepsy that begins in infancy and is associated with frequent, severe, and potentially life-threatening seizures, developmental delay, and cognitive impairment.

Both applications are based on data from two pivotal Phase 3 trials in Dravet syndrome and an interim analysis from an ongoing open-label extension study, which included 232 patients treated for up to 21 months.

Lisuride Shows Promise as Dravet Syndrome Treatment, Zebrafish Study Suggests

Lisuride, an anti-parkinson medicine with demonstrated anti-seizure effects, was able to stop epileptic activity in a model of convulsant Dravet syndrome zebrafish, researchers report. The study with that finding, “Drug repurposing for Dravet syndrome in scn1Lab?/? mutant zebrafish,” was published in Epilepsia.

Recent studies have used a zebrafish model of Dravet syndrome to reveal the role of pharmacologic modulation of the serotonin (5-HT) system in treating drug-resistant seizures. Serotonin is a chemical known as a neurotransmitter (used to transmit messages between nerve cells). It plays a key role in the central nervous system (CNS) and the body’s function in general.

“With the aim to bring novel therapeutics to the market together with reducing the costs associated with traditional de novo drug development, many efforts are underway to repurpose existing drugs,” researchers wrote.

As such, investigators from the University of Leuven in Belgium, preformed a literature search on already marketed medicines that could affect the serotonin system.

They found three compounds that filled these criteria: rizatriptan (a headache medicine, brand name Maxalt), lisuride (antiparkinson medicine, brand names Dopergin, Proclacam, and Revanil) and efavirenz (an anti-HIV medicine, brand name Sustiva, among others).

They then investigated the feasibility of repurposing the above-mentioned marketed medicines as anti-epileptic drugs, particularly in difficult-to-treat epilepsy conditions like Dravet syndrome.

IT Startup Launches Software to Encourage Physician-Family Conversations About Epilepsy

Physicians can now be alerted to pediatric patients’ risk of sudden unexpected death in epilepsy, or SUDEP, during routine primary care visits by using software developed and commercialized by a researcher-entrepreneur at the Indiana University School of Medicine.

Digital Health Solutions LLC, founded by Dr. Stephen Downs, has created a module about SUDEP for its Child Health Improvement through Computer Automation, or CHICA, system. Families answer questions on an electronic tablet about several health topics, including epileptic seizures.

“For children who have seizures, CHICA asks follow-up questions about frequency, medication adherence and barriers to accessing care,” said Downs, who is the Jean and Jerry Bepko Professor of Pediatrics at the IU School of Medicine. “The program shares this information with the physician. It also makes a reminder, through the patient’s electronic health record, for the physician to discuss SUDEP with the family. The physician can document discussing SUDEP and provide computer-generated educational materials.”