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 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.

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.

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.

OBJECTIVE:
With the recognition of epilepsy as a network disease that disrupts the organizing ability of resting-state brain networks, vagus nerve stimulation (VNS) may control epileptic seizures through modulation of functional connectivity. We evaluated preoperative 2-deoxy-2[18 F]fluoro-D-glucose (FDG) positron emission tomography (PET) in VNS-implanted pediatric patients with refractory epilepsy to analyze the metabolic connectivity of patients and its prognostic role in seizure control.

METHODS:
Preoperative PET data of 66 VNS pediatric patients who were followed up for a minimum of 1 year after the procedure were collected for the study. Retrospective review of the patients’ charts was performed, and five patients with inappropriate PET data or major health issues were excluded. We conducted an independent component analysis of FDG-PET to extract spatial metabolic components and their activities, which were used to perform cross-sectional metabolic network analysis. We divided the patients into VNS-effective and VNS-ineffective groups (VNS-effective group, ?50% seizure reduction; VNS-ineffective group, <50% reduction) and compared metabolic connectivity differences between groups using a permutation test.

RESULTS:
Thirty-four (55.7%) patients showed >50% seizure reduction from baseline frequency 1 year after VNS. A significant difference in metabolic connectivity evaluated by preoperative FDG-PET was noted between groups. Relative changes in glucose metabolism were strongly connected among the areas of brainstem, cingulate gyrus, cerebellum, bilateral insula, and putamen in patients with <50% seizure control after VNS.

SIGNIFICANCE:
This study shows that seizure outcome of VNS may be influenced by metabolic connectivity, which can be obtained from preoperative PET imaging. This study of metabolic connectivity analysis may contribute in further understanding of the mechanism of VNS in intractable seizures.

Aquestive Therapeutics announced the completion of a pharmacokinetic epilepsy monitoring unit (EMU) study demonstrating that its investigational diazepam buccal film (DBF), tentatively named LibervantTM, provides comparable bioavailability whether administered between seizures (interictal) or during and shortly after seizures (ictal/peri-ictal) in adult patients with poorly controlled tonic-clonic seizures or focal seizures with impaired awareness.

DBF, a novel formulation of diazepam as a small, thin film strip placed inside the cheek, is under development for the management of selected patients with refractory epilepsy who require intermittent use of diazepam to control episodes of increased seizure activity.

“Often it can be very difficult to administer treatment during periods of increased seizure activity. Currently, the only non-injected formulation of diazepam approved for the acute treatment of seizures is a rectally-applied gel,” said Keith J. Kendall, Chief Executive Officer of Aquestive Therapeutics. “These pharmacokinetic findings, taken together with other DBF studies, will help advance the development of Libervant as an alternative to currently approved therapies. We are very excited to have achieved this critical milestone in the program.”

Objective: Clobazam oral soluble film (COSF) is a novel dosage form under development for the adjunctive treatment of seizures associated with Lennox?Gastaut syndrome. The present study was undertaken to assess the pharmacokinetics of clobazam administered as single doses of COSF 20 and 10 mg compared with clobazam tablets (CTAB) 20 and 10 mg in healthy adults. A secondary objective was to assess the safety and tolerability of single doses of COSF 20 and 10 mg.

Methods: A total of 51 adult volunteers were enrolled in a single?dose, open?label, randomized four?sequence, four?period, crossover study with treatments (A) COSF 20 mg, (B) CTAB 20 mg, (C) COSF 10 mg, and (D) CTAB 10 mg. Pharmacokinetic sampling for clobazam and N?desmethylclobazam was carried out until 21 days postdose with a 28?day washout. Subjects were monitored for adverse events (AEs) throughout the study. Visual inspections of the administration site were performed before and after COSF administration to monitor for mucosal irritation.

Results: COSF at single doses of 10 and 20 mg was bioequivalent to CTAB at equivalent doses for both clobazam and its active metabolite N?desmethylclobazam. The pharmacokinetics of both formulations was dose?proportional at doses of 10 and 20 mg. The number of AEs and the number of subjects experiencing AEs were dose?related across the treatment groups, with somnolence the most common event. None of these events was severe or serious, and most were mild. There was no evidence for local irritation at the administration site following COSF.

Significance: COSF is a novel clobazam dosage form that is bioequivalent to CTAB. Because of its ease of administration, COSF may be expected to improve adherence, reduce likelihood of dosing error, and provide more accurate dosing than formulations of clobazam that are currently available.