Aquestive Therapeutics Announces Completion of Diazepam Buccal Film Adult Epilepsy Monitoring Unit (EMU) Clinical Study with Positive Topline Results

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.”

Generic Clobazam Tablets, Oral Suspenion Receives FDA Approval for Lennox-Gastaut Syndrome

The FDA has approved abbreviated new drug applications for several companies including Breckenridge Pharmaceutical, Amneal Pharmaceuticals, and Upsher-Smith to immediately market a generic version of clobazam (Onfi) (Lundbeck) tablets, CIV, 10 mg and 20 mg, and clobazam oral suspension, CIV, 2.5 mg/mL, for adjunctive treatment of seizures associated with Lennox-Gastaut Syndrome in patients 2 years of age and older.

Clobazam’s exact mechanism of action is not fully understood, however, it’s thought to involve the potentiation of GABAergic neurotransmission, a result from binding at the benzodiazepine site of the GABAA receptor.

Pharmacokinetics of Clobazam Oral Soluble Film

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.

Acetaminophen Can Reduce Recurrence of Febrile Seizures

Acetaminophen can reduce the risk for febrile seizure (FS) recurrence during the same fever episode among infants and children, according to a study published in Pediatrics.

Shinya Murata, M.D., Ph.D., from Hirakata City Hospital in Osaka, Japan, and colleagues conducted a single-center, randomized controlled study involving children and infants (age range, 6 to 60 months) with FSs. To examine the effectiveness of acetaminophen, recurrence rates were compared for patients in whom rectal acetaminophen was administered every six hours until 24 hours after the first convulsion and for patients in whom no antipyretics were administered. FS recurrence during the same fever episode was assessed as the primary outcome measure.

Efficacy of Levetiracetam for Reducing Rolandic Discharges in Comparison with Carbamazepine and Valproate Sodium in Rolandic Epilepsy

PURPOSE: The main purpose of this study was to compare the efficacy of levetiracetam (LEV) with the older antiepileptic drugs (AEDs) for preventing atypical evolution in children with Rolandic epilepsy (RE). Accordingly, the present study compared the efficacy of older AEDs (carbamazepine (CBZ) and valproate sodium (VPA)) with LEV in reducing rolandic discharges (RDs) on interictal electroencephalogram (EEG) in children with RE.

METHODS: Patients in this heterogenous study were subdivided into CBZ, VPA and LEV groups in accordance with the initial monotherapy. The CBZ and VPA groups were studied retrospectively, but the LEV group was studied prospectively. Appearances of discharges were counted and these rates were computed. In comparison with the baseline RD frequency, EEG response to AED treatment was classified such as complete disappearance and response (?50% reduction in RD frequency). The time taken to attain complete disappearance or response in EEG responders was assessed for each AED treatment group.

RESULTS: Responders comprised 10 (11.2%) of the 89 patients treated with CBZ, 41 (56.2%) of the 73 patients with VPA, and 25 (71.4%) of the 35 patients with LEV. Mean interval to achievement of EEG response in the CBZ, VPA, and LEV groups were 36.3, 23.1, and 14.7 months, respectively. EEG response was achieved significantly more rapidly with LEV than with CBZ (p?<?0.001) or VPA (p?<?0.005). Seizure control was not significantly different in all 3 investigated drugs.

CONCLUSIONS: Levetiracetam seems to be superior to carbamazepine and valproate sodium in its ability to suppress rolandic discharges in children with rolandic epilepsy.

VNS Therapy

LivaNova VNS Therapy System for Drug-Resistant Epilepsy Could Save $77K Per Patient Over Five Years

LivaNova PLC, a medical technology company, said a new cost analysis found that the company’s Vagus Nerve Stimulation Therapy (VNS Therapy) System results in lower resource utilization and lower cost for drug-resistant epilepsy patients when compared to continued treatment with anti-epileptic drugs (AEDs). The analysis, published in Advances in Therapy and supported by LivaNova, showed initial costs for the VNS Therapy device, including placement and programming, were estimated to be offset 1.7 years post-implant and equated to an estimated net cost savings of $77,480 per patient over five years. The net cost savings are due primarily to a reduction in seizure-related hospitalizations, resulting in a 21.5 percent decrease in costs compared to treatment with AEDs alone.

“Not only did the analysis demonstrate a significant cost savings associated with VNS Therapy treatment in comparison to AED treatment alone, but this savings is based on a very important health outcome— the reduction of seizure frequency,” said Bryan Olin, LivaNova senior vice president for Clinical, Quality Assurance and Regulatory Affairs. “By reducing seizure frequency with VNS Therapy, we may also see a positive impact on patients’ quality of life.”

Progress Report on New Antiepileptic Drugs: A Summary of the Fourteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XIV). II. Drugs in More Advanced Clinical Development

The Fourteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XIV) took place in Madrid, Spain, on May 13?16, 2018 and was attended by 168 delegates from 28 countries. The conference provided a forum for professionals involved in basic science, clinical research, regulatory affairs, and clinical care to meet and discuss the latest advances related to discovery and development of drugs and devices aimed at improving the management of people with epilepsy.

This progress report provides a summary of findings on investigational compounds for which data from both preclinical studies and studies in patients were presented. The compounds reviewed include anakinra, cannabidiol, cannabidivarin, fenfluramine, ganaxolone, medium?chain fatty acids, padsevonil, and the valproic derivatives valnoctamide and sec?butylpropylacetamide. On June 25, 2018, the US Food and Drug Administration approved a standardized formulation of cannabidiol oral solution for the treatment of seizures associated with Lennox-Gastaut syndrome and Dravet syndrome in patients 2 years and older.

The report shows that there continues to be a steady flow of potential antiepileptic drugs progressing to clinical development. Many of these compounds show innovative mechanisms of action, and some have already been tested in placebo?controlled randomized controlled trials, with promising efficacy and safety results.

Pilot Study: Rapamycin has Positive Effects on Seizures in Tuberous Sclerosis Complex in Years 1-2 but Effects Decline After Year 2

PURPOSE: The purpose of this study was to evaluate the long-term results of eight cases diagnosed with tuberous sclerosis complex (TSC) and receiving rapamycin therapy because of epileptic seizures and/or accompanying TSC findings.

METHOD: Rapamycin therapy was initiated at a dose of 1.5?mg/m2. Seizure frequency, electroencephalographic (EEG) findings, renal and cranial imaging findings, and cutaneous lesions over 3- to 6-month periods during follow-up and treatment were evaluated.

RESULTS: Four girls and four boys aged 4-16?years at the start of rapamycin therapy and now aged 9-24?years were evaluated. Duration of rapamycin therapy was 1-5?years, and the monitoring period after commencement of rapamycin therapy lasted 5-8?years. Positive effects were observed at 9-12?months in three out of six cases of renal angiomyolipoma (AML) and in the second year of treatment in one. An increase in AML dimensions was observed in three cases after treatment was stopped. Seizure control was established in the first year of rapamycin therapy in all cases. An increased frequency of seizures was observed in three cases after the second year of treatment. No seizure recurrence was determined in the second year of treatment with rapamycin in five out of eight cases. Recurrence of seizure was observed in 6-12?months after the discontinuation of rapamycin in three cases.

CONCLUSION: Rapamycin therapy exhibits positive effects on epileptic seizures in cases of TSC in 1-2 ?years but these positive effects on seizure control of rapamycin therapy decline after the second year. Larger case series are still needed to determine the duration and effectiveness of treatment in childhood.

High Vigabatrin Dosage is Associated with Lower Risk of Infantile Spasms Relapse Among Children with Tuberous Sclerosis Complex

After initially successful treatment of infantile spasms, the long-term cumulative risk of relapse approaches 50%, and there is no established protocol to mitigate this risk. Although vigabatrin may be an effective means to prevent relapse, there is little guidance as to ideal duration and dosage. Using a cohort of children with infantile spasms and tuberous sclerosis complex (TSC), we evaluated the potential association of post-response VGB treatment and the rate of infantile spasms relapse. Patients with infantile spasms and clinical response to vigabatrin were identified among a multicenter prospective observational cohort of children with TSC. For each patient we recorded dates of infantile spasms onset, response to vigabatrin, relapse (if any), and quantified duration and dosage of vigabatrin after response. Time to relapse as a function of vigabatrin exposure was evaluated using survival analyses.

We identified 50 children who responded to VGB. During a median follow-up of 16.6 months (IQR 10.3-22.9), 12 (24%) patients subsequently relapsed after a median of 7.8 months (IQR 3.1-9.6). Relapse occurred after VGB discontinuation in four patients, and during continued VGB treatment in the remaining eight cases. In survival analyses, risk of relapse was unaffected by the presence or absence of VGB treatment (HR 0.31, 95%CI 0.01-28.4, P?=? 0.61), but weighted-average dosage was associated with marked reduction in relapse risk: Each 50 mg/kg/d increment in dosage was associated with 61% reduction in risk (HR 0.39, 95%CI 0.17 – 0.90, P?=? 0.026).

This study suggests that the risk of infantile spasms relapse in TSC may be reduced by high-dose vigabatrin treatment.

Eisai Announces FDA Approval of FYCOMPA in Pediatric Patients as Young as Four Years Old for the Treatment of Partial-Onset Seizures

Eisai Inc. announced today that it received approval from the FDA for an indication expansion for Eisai’s antiepileptic drug (AED) Fycompa (perampanel) to cover partial-onset seizures in pediatric patients with epilepsy 4 years of age and older. Fycompa was designated for Priority Review by the FDA, and was approved approximately six months after submission.

Through this latest approval, Fycompa is indicated for monotherapy and adjunctive use in the treatment of partial-onset seizures (with or without secondarily generalized seizures) in patients with epilepsy 4 years of age and older. This approval was based on the interim results of a Phase III clinical study (Study 311) as well as the results from a Phase II clinical study (Study 232) in pediatric patients with epilepsy. Both studies confirmed the safety and efficacy of Fycompa were similar between adult and pediatric patients.