Eslicarbazepine acetate tolerance

Efficacy, Safety, and Tolerability of Eslicarbazepine Acetate in Post-Stroke Epilepsy: Real-World Evidence from the Euro-Esli Study

Cerebrovascular disease may account for almost 50% of new cases of epilepsy in patients older than age 65. A recent systematic review with network metanalysis of randomized controlled trials (RCT) of antiepileptic drugs (AED) for the treatment of post-stroke epilepsy was inconclusive due to the small number of trials (n=2) included. Our aim was to conduct an exploratory subgroup analysis of data from patients included in Euro-Esli study to evaluate the efficacy, safety and tolerability of eslicarbazepine acetate (ESL) in post-stroke epilepsy.

The Euro-Esli study was an exploratory, pooled analysis of data from 14 European clinical practice studies, that included 2079 patients. Responder rate (?50% seizure frequency reduction from baseline) and seizure freedom rate (seizure freedom at least since prior visit) were assessed after 3, 6 and 12 months of ESL treatment, and at last visit, as many patients were followed for >1 year. Adverse events (AEs) and AEs leading to ESL discontinuation were assessed throughout follow-up. Subgroup analyses were conducted for patients who had vascular vs. non-vascular aetiology of epilepsy.

This population subanalysis included 1656 patients, of whom 76 (4.6%) had post-stroke epilepsy and 60.5% were male (n=46). Patients with post-stroke epilepsy were older (60.4 vs. 42.9 years; pvs. 23.7 years; pvs. 19.4 years; pvs. 13.8 seizures/month; pvs. 4.4; pvs. 1.1; pvs. 31.7%; p=0.003); than in patients without post-stroke epilepsy as was the percentage of responders (72.9% vs. 60.6%; p=0.040). AEs (36.0% vs. 35.8%; p=0.966) and withdrawal due to AEs (6.8% vs. 14.5%; p=0.063) differences between patients with post-stroke epilepsy and without post-stroke epilepsy were not statistically significant. The most common AEs were somnolence, dizziness, instability and fatigue. As of the 12-month follow up visit, the mean time in treatment with ESL in patients with post-stroke epilepsy was 11.2 months and in patients without post-stroke epilepsy was 10.2 months (p=0.023; Log Rank test). The percentage of patients who discontinued for any reason, at 12 months, was higher in patients without post-stroke epilepsy, than in patients with epilepsy with vascular aetiology (22.6% vs. 12.2%; p=0.035).

In this post-hoc analysis of data pooled from a large cohort of patients treated in the real-world clinical setting in Europe, ESL was effective and well tolerated in a small subgroup of patients with post-stroke epilepsy.

Long-Term Safety Experience of NAYZILAM™ in Subjects with Seizure Clusters

Nayzilam™ (USL261; midazolam nasal spray, MDZ NS) is a novel nasal spray formulation of MDZ specifically developed as an acute rescue treatment for seizures in the outpatient setting for patients who require control of intermittent episodes of increased seizure activity (ie, acute repetitive seizures [ARS], seizure clusters [SC]).

This novel nasal spray formulation of MDZ provides convenient, non-invasive drug administration without active inhalation and can easily be given by caregivers when patients are experiencing an episode. The safety and efficacy of MDZ NS was evaluated in a randomized, double-blind, placebo-controlled, Phase 3 study (ARTEMIS-1; NCT01390220). This open label extension to ARTEMIS-1 was conducted to evaluate long-term safety and efficacy of repeated treatment of SC episodes (ARTEMIS-2, NCT01529034). Efficacy data are reported in a separate abstract (Sequeira et al, AES 2018).

The open-label ARTEMIS-2 study supports the long-term safety of repeated usage of MDZ NS in the outpatient setting to treat SCs. MDZ NS potentially offers caregivers a novel and reliable means of rescue treatment for patients experiencing SCs.

New Surgery Treats Epilepsy With Electrode Brain Stimulation

Beginning Monday, patients with epilepsy will have a new option to reduce the number and severity of life-limiting seizures, avoiding radical surgery that removes a part of the brain.

Called deep-brain stimulation, the treatment uses electrodes implanted in the thalamus, a structure located near the center of the brain that receives information from the senses and sends signals to the cerebral cortex.

The electrodes are controlled by a device implanted in the chest, similar to a pacemaker, and patients have a remote-control device that can adjust the amount of stimulation or even turn it off for periods of time.

Deep-brain stimulation is much less aggressive than traditional surgery. The neurostimulator device is implanted in the chest and two leads are brought under the skin to the top of the head, with one being inserted into each thalamus on either side of the brain. Each lead has four contacts. “You can stimulate any or all of them in any combination,” Gerrard said.

After the stimulator is implanted, programming it is done over time, with “adjustments made depending on any potential side effects patients are having” and how well it is working to reduce the number and severity of seizures. Each patient is given a programmer “that allows them to interact with the device,” Gerrard said. “It’s kind of like a parental programmer for the television. In some patients, as they become more familiar with the device and their stimulator . . . they may change their programs at home.”

GW Pharmaceuticals Announces Second Positive Phase 3 Pivotal Trial for EPIDIOLEX® (Cannabidiol) Oral Solution CV in Patients with Dravet Syndrome

GW Pharmaceuticals announces positive top-line results of the second randomized, double-blind, placebo-controlled Phase 3 clinical trial of EPIDIOLEX® (cannabidiol or CBD) CV in the treatment of seizures associated with Dravet syndrome, a rare and severe form of childhood-onset epilepsy.

In this trial, EPIDIOLEX, when added to the patient’s current treatment, achieved the primary endpoint of reduction in convulsive seizures for both dose levels (10 mg/kg per day and 20 mg/kg per day) with high statistical significance compared to placebo. Both EPIDIOLEX doses also demonstrated statistically significant improvements on all key secondary endpoints.

“The positive results from this trial follow the recent FDA approval, DEA rescheduling and U.S. launch of EPIDIOLEX for the treatment of seizures associated with Dravet syndrome and Lennox-Gastaut Syndrome in patients two years and older. These data show an effective dose range in Dravet syndrome that is consistent with our FDA approved label, and which allows for dosing flexibility to address individual patient needs,” stated Justin Gover, GW’s CEO.

Clinical Use and Efficacy of Levetiracetam for Absence Epilepsies

BACKGROUND:
Levetiracetam is prescribed for a broad spectrum of seizure types but does not have a specific indication for absence epilepsy. Researchers hypothesized that levetiracetam is commonly prescribed for children with absence epilepsies and evaluated the efficacy of this medication for absence epilepsy treatment in clinical practice. They also hypothesized that electroencephalographic (EEG) findings could help predict levetiracetam efficacy.

METHODS:
This study reviews the charts of all patients treated for new-onset absence epilepsies at our pediatric neurology clinic between January 2011 and January 2016. Among 158 children diagnosed with absence epilepsies, 72 were treated with levetiracetam.

RESULTS:
Levetiracetam was discontinued in 74% (n = 53/72) because of incomplete seizure control (59%, n = 35/72) and/or intolerable side effects (41%, n = 24/72) after a median 8.5 months (interquartile range 2, 17 months). Among patients for whom levetiracetam was effective, 44% (n = 8/18) had polyspikes on their initial EEG, versus 27% (n = 14/52) of patients for whom levetiracetam was discontinued ( P = .17). The maximal prescribed dose was lower for children in whom levetiracetam was effective (29 ± 13 mg/kg/d) than those for whom levetiracetam failed (42 ± 20 mg/kg/d; P = .005).

CONCLUSION:
In routine clinical practice, levetiracetam is often chosen for patients with absence seizures. However, only about one-quarter of children with absence epilepsy in this study became seizure free with levetiracetam. When effective, levetiracetam can control absence epilepsy at a relatively low dose. Lack of seizure control requiring continued dose escalation should prompt early consideration of a therapeutic medication transition.

Ben Philpot, PhD

Can Genetic Therapy Help Kids with Angelman Syndrome Overcome Seizures?

Angelman syndrome is a genetic disease with no cure. Children grow up with severe intellectual disabilities and a range of other problems, arguably the worst of which are epileptic seizures. Now scientists at the UNC School of Medicine have found evidence that genetic therapy may prevent the enhanced seizure susceptibility.

Published in the Journal of Clinical Investigation, the research marks the first time scientists were able to reduce seizure susceptibility in mice by activating a dormant copy of the UBE3A gene so it could replace the faulty mutant version. While replacing the faulty gene in juveniles reduced seizures, replacing the faulty gene in adult mice had no effect.

The UNC scientists also found evidence that the loss of this gene in Angelman syndrome promotes seizures by impairing the normal activity of inhibitory neurons – cells that normally keep brain circuits from being overstimulated.

“This result implies that if you want to limit epilepsy in Angelman syndrome, you’ll need at least to restore the function of UBE3A in inhibitory neurons,” Philpot said.

Perampanel Well-Tolerated for Long-Term Epilepsy Treatment

Purpose
To evaluate long-term tolerability, safety and efficacy of adjunctive perampanel in a Phase II, multicenter, open-label, dose-ascending Study 231 (NCT00849212) and its extension (Study 233; NCT00903786) in Japanese patients with refractory partial-onset seizures (POS), with/without secondarily generalized seizures.

Methods
In Study 231, patients received adjunctive perampanel less than or equal to 12 mg/day during a 10-week treatment period. Patients completing Study 231 could enter Study 233 (less than or equal to 316-week treatment period). Assessments included monitoring of treatment-related treatment-emergent adverse events (TEAEs), median percent change in seizure frequency per 28 days, 50% responder and seizure-freedom rates. During Study 231, a pharmacokinetic analysis assessed the effects of enzyme-inducing antiepileptic drugs.

Results
Overall, 23/30 (76.7%) patients completed Study 231; 21/30 (70.0%) received perampanel ?8?mg/day and 10/30 (33.3%) achieved a maximum tolerated dose of 12?mg/day. Median percent change in seizure frequency per 28 days was –35.0%. 50% responder rate was 37.0%; 4 (13.3%) patients achieved seizure freedom. Twenty-one patients entered Study 233. Mean duration of exposure was 195 weeks; 9 (42.9%) patients received perampanel for ?208 weeks. Seizure control was sustained for 316 weeks in 3/21 (14.3%) patients; 2 achieved seizure freedom. Treatment-related TEAEs were tolerable; the most common was dizziness (Study 231, 53.3%; Study 233, 14.3%). Mean perampanel plasma concentrations were lower with concomitant carbamazepine vs non-inducers (152.7 ng/mL vs 389.4 ng/mL across perampanel groups); small patient numbers for non-inducers (n = 2) should be considered when interpreting these data.

Conclusion
Adjunctive perampanel demonstrated a favorable safety profile and long-term tolerability in Japanese patients with refractory POS for less than or equal to 316 weeks.

Aquestive Therapeutics Announces U.S. Food and Drug Administration (FDA) Approval for SYMPAZAN™ (clobazam) Oral Film

Aquestive Therapeutics announced that the FDA approved SYMPAZAN™ (clobazam) oral film for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome (LGS) in patients 2 years of age or older. SYMPAZAN is the first and only oral film FDA-approved to treat seizures associated with LGS. Previously, clobazam was marketed as ONFI® and offered in two formulations – either tablet or oral suspension.

“Aquestive Therapeutics is pleased to bring SYMPAZAN to the LGS community,” said Keith J. Kendall, Chief Executive Officer of Aquestive Therapeutics. “Treating LGS can be difficult; patients may have a hard time swallowing oral medications. We’re optimistic SYMPAZAN can help address unmet medical needs and be an important treatment option for this patient population.”

LGS is a severe form of epilepsy that begins in early childhood and is characterized by multiple types of seizures and intellectual disability.3 LGS patients often have difficulty swallowing pills and large volume suspensions due to physical limitations, behavioral or cognitive impact.4,5 Challenges with treatment administration can lead to uncertain and inconsistent dosing, and increase the burden of care, particularly for patients that may be combative or resistant to treatment.

“Many LGS patients have a hard time swallowing pills and suspensions. This can make administering medication hard for caregivers,” says Christina SanInocencio, Executive Director of the LGS Foundation. “We believe SYMPAZAN will be welcomed by patients and caregivers impacted by LGS and searching for treatment solutions.”

SYMPAZAN is a formulation based on Aquestive’s proven PharmFilm® technology. Multiple pharmacokinetic studies were conducted to compare SYMPAZAN with ONFI. Based on the studies, SYMPAZAN oral film was demonstrated to be bioequivalent to clobazam tablets and have comparable safety profiles.

First FDA-Approved Cannabis-Based Drug Now Available in the US

Epidiolex, the first cannabis-based medication approved by the US Food and Drug Administration, is now available by prescription in all 50 states.

The twice-daily oral solution is approved for use in patients 2 and older to treat two types of epileptic syndromes: Dravet syndrome, a rare genetic dysfunction of the brain that begins in the first year of life, and Lennox-Gastaut syndrome, a form of epilepsy with multiple types of seizures that begins in early childhood, usually between ages 3 and 5.

Although Epidiolex is approved only for the treatment of two rare seizure disorders, doctors can now prescribe the medication “off-label” for other conditions. According to the US Department of Health and Human Services, this is both legal and common; one in five of all medications prescribed is for off-label use.

Subcentimeter Epilepsy Surgery Targets by Resting State Functional Magnetic Resonance Imaging Can Improve Outcomes in Hypothalamic Hamartoma

OBJECTIVE:
The purpose of this study is to investigate the outcomes of epilepsy surgery targeting the subcentimeter-sized resting state functional magnetic resonance imaging (rs-fMRI) epileptogenic onset zone (EZ) in hypothalamic hamartoma (HH).

METHODS:
Fifty-one children with HH-related intractable epilepsy received anatomical MRI-guided stereotactic laser ablation (SLA) procedures. Fifteen of these children were control subjects (CS) not guided by rs-fMRI. Thirty-six had been preoperatively guided by rs-fMRI (RS) to determine EZs, which were subsequently targeted by SLA. The primary outcome measure for the study was a predetermined goal of 30% reduction in seizure frequency and improvement in class I Engel outcomes 1 year postoperatively. Quantitative and qualitative volumetric analyses of total HH and ablated tissue were also assessed.

RESULTS:
In the RS group, the EZ target within the HH was ablated with high accuracy (>87.5% of target ablated in 83% of subjects). There was no difference between the groups in percentage of ablated hamartoma volume (P = 0.137). Overall seizure reduction was higher in the rs-fMRI group: 85% RS versus 49% CS (P = 0.0006, adjusted). The Engel Epilepsy Surgery Outcome Scale demonstrated significant differences in those with freedom from disabling seizures (class I), 92% RS versus 47% CS, a 45% improvement (P = 0.001). Compared to prior studies, there was improvement in class I outcomes (92% vs 76%-81%). No postoperative morbidity or mortality occurred.

SIGNIFICANCE:
For the first time, surgical SLA targeting of subcentimeter-sized EZs, located by rs-fMRI, guided surgery for intractable epilepsy. These outcomes demonstrated the highest seizure freedom rate without surgical complications and are a significant improvement over prior reports. The approach improved freedom from seizures by 45% compared to conventional ablation, regardless of hamartoma size or anatomical classification. This technique showed the same or reduced morbidity (0%) compared to recent non-rs-fMRI-guided SLA studies with as high as 20% permanent significant morbidity.