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.

New Review Study Supports Ability of Epidiolex to Reduce Seizure Frequency in Dravet, Lennox-Gastaut Patients

The objective was to review the efficacy, safety, pharmacology and pharmacokinetics of pure, plant-derived cannabidiol (CBD; Epidiolex) in the treatment of Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS).

The review, “Epidiolex (Cannabidiol): A New Hope for Patients With Dravet or Lennox-Gastaut Syndromes,” was published in Annals of Pharmacotherapy.

“The frequency and severity of seizures have profound impacts on quality of life, risk for injury (eg, convulsive seizures in [Dravet syndrome], drop seizures in [Lennox-Gastaut syndrome]), health care use, and increased risk for mortality,” the researchers wrote.

It is carbohydrate neutral and compatible with ketogenic diets — a diet high in fats and low in carbs that has been shown to reduce the frequency of seizures and improve cognitive function in children with Dravet syndrome.

Previous clinical trials have found that Epidiolex effectively reduces the frequency of epileptic seizures when used in combination with other anti-epileptic medications.

Researchers in this study reviewed the main findings of these trials regarding the safety, efficacy, and tolerability of Epidiolex for the treatment of children with Dravet and Lennox-Gastaut syndromes.

Cannabidiol Improves Frequency and Severity of Seizures and Reduces Adverse Events in an Open-Label Add-On Prospective Study

The objective of this study was to characterize the changes in adverse events, seizure severity, and frequency in response to a pharmaceutical formulation of highly purified cannabidiol (CBD; Epidiolex®) in a large, prospective, single-center, open-label study.

Researchers initiated CBD in 72 children and 60 adults with treatment-resistant epilepsy (TRE) at 5?mg/kg/day and titrated it up to a maximum dosage of 50?mg/kg/day. At each visit, they monitored treatment adverse events with the adverse events profile (AEP), seizure severity using the Chalfont Seizure Severity Scale (CSSS), and seizure frequency (SF) using seizure calendars.

Data for the enrollment and visits at 12, 24, and 48?weeks was analyzed. Researchers recorded AEP, CSSS, and SF at each follow-up visit for the weeks preceding the visit (seizures were averaged over 2-week periods). Of the 139 study participants in this ongoing study, at the time of analysis, 132 had 12-week, 88 had 24-week, and 61 had 48-week data. Study retention was 77% at one year.

There were no significant differences between participants who contributed all 4 data points and those who contributed 2 or 3 data points in baseline demographic and AEP/SF/CSSS measures. For all participants, AEP decreased between CBD initiation and the 12-week visit (40.8 vs. 33.2; p?<?0.0001) with stable AEP scores thereafter (all p???0.14). Chalfont Seizure Severity Scale scores were 80.7 at baseline, decreasing to 39.2 at 12?weeks (p?<?0.0001) and stable CSSS thereafter (all p???0.19). Bi-weekly SF decreased from a mean of 144.4 at entry to 52.2 at 12?weeks (p?=?0.01) and remained stable thereafter (all p???0.65). Analyses of the pediatric and adult subgroups revealed similar patterns. Most patients were treated with dosages of CBD between 20 and 30?mg/kg/day.

For the first time, this prospective, open-label safety study of CBD in treatment-resistant epilepsy provides evidence for significant improvements in the adverse event profile, Chalfont seizure severity scale, and seizure frequency at 12?weeks that are sustained over the 48-week duration of treatment.

Epilepsy Research Findings: July 2018

This month’s promising epilepsy news includes the FDA approval of the cannabidiol-based drug EPIDIOLEX® for the treatment of seizures associated with Dravet Syndrome and Lennox-Gastaut Syndrome, two forms of epilepsy that are challenging to treat. This decision brings hope to families facing these difficult diagnoses. In addition, a report discusses epilepsy genetics and the utility of next-generation sequencing in the diagnosis of early-life epilepsies.

In more sobering news, a study shows that the incidence of Sudden Unexpected Death in Epilepsy (SUDEP), once thought to be greater in adults than in children, may be the same in both populations. However, we have included a report discussing the recent discovery of a potential biomarker for SUDEP, which could lead to preventative measures for this devastating occurrence.

Summaries of all highlighted studies follow below. I’ve organized the findings into four categories: Treatment Advances, Diagnostic Advances, Research Discoveries, and Also Notable.

Treatment Advances

First Prescription Formulation of Cannabidiol (CBD) Approved for Lennox-Gastaut Syndrome 

The US Food and Drug Administration (FDA) approved EPIDIOLEX® (cannabidiol/CBD) for the treatment of seizures associated with Lennox-Gastaut Syndrome (LGS) in patients two years of age or older. EPIDIOLEX® is the first prescription pharmaceutical formulation of highly purified CBD and the first in its class of antiepileptic drugs.

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New Technique Fine-Tunes Treatment for Severe Epilepsy Cases 

An advance by researchers will enable surgeons to more precisely target areas of the brain which cause debilitating symptoms in a subset of epilepsy patients. The technology, called magnetoencephalography or MEG, measures small amounts of magnetic-electrical activity on the surface of epileptic brain areas, and researchers have developed a novel way to employ it.

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Treating Refractory Epilepsy with Transcutaneous Vagal Nerve Stimulation 

This study found that transcutaneous vagal nerve stimulation (t-VNS) had no or minimal side effects and significantly reduced seizures in about one third of the enrolled patients.

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Sunovion Announces Health Canada Approval of Aptiom (eslicarbazepine acetate) as Monotherapy to Treat Partial-Onset Seizures in Adults with Epilepsy

Health Canada approved the use of Aptiom (eslicarbazepine acetate) as monotherapy for partial-onset seizures in adults with epilepsy.

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Diagnostic Advances

Next-Generation Sequencing May Improve Pediatric Epilepsy Treatment

Next-generation sequencing can improve treatment efficacy and reduce hospitalization in children with drug-resistant epilepsy, according to a study published in CNS Neuroscience & Therapeutics.

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Prediction Method for Epileptic Seizures Developed 

Scientists have proposed a generalized, patient-specific seizure-prediction method that can alert epilepsy sufferers of the likelihood of a seizure within 30 minutes, according to a paper published in Neural Networks.

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Research Discoveries

Incidence of Sudden Unexpected Death in Epilepsy in Children is Similar to Adults

SUDEP may be more common in children than widely reported, with the incidence rate of definite/probable SUDEP in children being similar to rates reported in adults.

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Heart Rate Variability in Epilepsy: A Potential Biomarker of Sudden Unexpected Death in Epilepsy Risk

These findings suggest that autonomic dysfunction is associated with SUDEP risk in patients with epilepsy due to sodium channel mutations. The relationship of heart rate variability to SUDEP merits further study; heart rate variability may eventually have potential as a biomarker of SUDEP risk. This would allow for more informed counseling of patients and families, and also serve as a useful outcome measure for research aimed at developing therapies and interventions to reduce SUDEP risk.

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Also Notable

Comparative Effectiveness of Levetiracetam vs Phenobarbital for Infantile Epilepsy

This study reports that levetiracetam may have superior effectiveness compared with phenobarbital for initial monotherapy of nonsyndromic epilepsy in infants. If 100 infants who received phenobarbital were instead treated with levetiracetam, 44 would be free from monotherapy failure instead of 16 by the estimates in this study. Randomized clinical trials are necessary to confirm these findings.

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Variability in Gene-Sequencing Panels Could Mean Missed Early-Life Epilepsy Diagnoses

Variability among next-generation sequencing (NGS) panels for early-life epilepsies could cause some confirmed epilepsy genes to be missed, researchers report. NGS panels have demonstrated utility for diagnosing genetic variants linked to early-life epilepsies, but little is known about the variability in genes tested among clinically available NGS panels.

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Generic Antiepileptic Drugs — Safe or Harmful in Patients with Epilepsy?

Sufficient evidence indicates that most generic antiepileptic drugs (AEDs) are bioequivalent to innovator AEDs; they do not pose a relevant risk for patients with epilepsy. However, some patients are reluctant towards variations in color and shape of their AEDs which may result in nonadherence. This report recommends administering generics when a new AED is initiated. Switches from brand to generic AEDs for cost reduction and between generics, which is rarely required, generally seem to be safe, but should be accompanied by thorough counseling of patients on low risks.

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Health Care Expenditures Among Elderly Patients with Epilepsy in the United States

Epilepsy is common among elderly individuals, and health care expenditures among this growing group are two times higher than in those without epilepsy.

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Open-Label Use of Highly Purified CBD (Epidiolex®) in Patients with CDKL5 Deficiency Disorder and Aicardi, Dup15q, and Doose Syndromes

OBJECTIVE: We studied our collective open-label, compassionate use experience in using cannabidiol (CBD) to treat epilepsy in patients with CDKL5 deficiency disorder and Aicardi, Doose, and Dup15q syndromes.

METHODS: We included patients aged 1-30?years with severe childhood-onset epilepsy who received CBD for ?10?weeks as part of multiple investigator-initiated expanded access or state access programs for a compassionate prospective interventional study: CDKL5 deficiency disorder (n?=?20), Aicardi syndrome (n?=?19), Dup15q syndrome (n?=?8), and Doose syndrome (n?=?8). These patients were treated at 11 institutions from January 2014 to December 2016.

RESULTS: The percent change in median convulsive seizure frequency for all patients taking CBD in the efficacy group decreased from baseline [n?=?46] to week 12 (51.4% [n?=?35], interquartile range (IQR): 9-85%) and week 48 (59.1% [n?=?27], IQR: 14-86%). There was a significant difference between the percent changes in monthly convulsive seizure frequency during baseline and week 12, ?2(2)?=?22.9, p?=?0.00001, with no difference in seizure percent change between weeks 12 and 48. Of the 55 patients in the safety group, 15 (27%) withdrew from extended observation by week 144: 4 due to adverse effects, 9 due to lack of efficacy, 1 withdrew consent, and 1 was lost to follow-up.

SIGNIFICANCE: This open-label drug trial provides class III evidence for the long-term safety and efficacy of CBD administration in patients with treatment-resistant epilepsy (TRE) associated with CDKL5 deficiency disorder and Aicardi, Dup15q, and Doose syndromes. Adjuvant therapy with CBD showed similar safety and efficacy for these four syndromes as reported in a diverse population of TRE etiologies. This study extended analysis of the prior report from 12?weeks to 48?weeks of efficacy data and suggested that placebo-controlled randomized trials should be conducted to formally assess the safety and efficacy of CBD in these epileptic encephalopathies.

Open-label use of Highly Purified CBD (Epidiolex®) in Patients with CDKL5 Deficiency Disorder and Aicardi, Dup15q, and Doose Syndromes

OBJECTIVE: Researchers studied their collective open-label, compassionate use experience in using cannabidiol (CBD) to treat epilepsy in patients with CDKL5 deficiency disorder and Aicardi, Doose, and Dup15q syndromes.

METHODS: The study included patients aged 1-30?years with severe childhood-onset epilepsy who received CBD for ?10?weeks as part of multiple investigator-initiated expanded access or state access programs for a compassionate prospective interventional study: CDKL5 deficiency disorder (n?=?20), Aicardi syndrome (n?=?19), Dup15q syndrome (n?=?8), and Doose syndrome (n?=?8). These patients were treated at 11 institutions from January 2014 to December 2016.

RESULTS: The percent change in median convulsive seizure frequency for all patients taking CBD in the efficacy group decreased from baseline [n?=?46] to week 12 (51.4% [n?=?35], interquartile range (IQR): 9-85%) and week 48 (59.1% [n?=?27], IQR: 14-86%). There was a significant difference between the percent changes in monthly convulsive seizure frequency during baseline and week 12, ?2(2)?=?22.9, p?=?0.00001, with no difference in seizure percent change between weeks 12 and 48. Of the 55 patients in the safety group, 15 (27%) withdrew from extended observation by week 144: 4 due to adverse effects, 9 due to lack of efficacy, 1 withdrew consent, and 1 was lost to follow-up.

SIGNIFICANCE: This open-label drug trial provides class III evidence for the long-term safety and efficacy of CBD administration in patients with treatment-resistant epilepsy (TRE) associated with CDKL5 deficiency disorder and Aicardi, Dup15q, and Doose syndromes. Adjuvant therapy with CBD showed similar safety and efficacy for these four syndromes as reported in a diverse population of TRE etiologies. This study extended analysis of the prior report from 12?weeks to 48?weeks of efficacy data and suggested that placebo-controlled randomized trials should be conducted to formally assess the safety and efficacy of CBD in these epileptic encephalopathies.

Research Sheds Light on Composition of Cannabis Used to Treat Children with Epilepsy

study has found Australian parents who turned to medicinal cannabis to treat children with epilepsy overwhelmingly (75%) considered the extracts as “effective”. Contrary to parental expectations, extracts generally contained low doses of cannabidiol (CBD) – commonly considered to be a key therapeutic element and that has been successfully used in recent clinical trials to treat epilepsy.

The research, which commenced two years ago by the University of Sydney’s Lambert Initiative for Cannabinoid Therapeutics, not only sheds light on the composition of cannabis used in the community but also reveals the legal, bureaucratic, and cost issues faced by families who relied on the products, as well as demonstrating the barriers to accessing medicinal cannabis.

The study found that the main psychoactive ingredient in cannabis, tetrahydrocannabidiol (THC), and the closely related compound THCA, were present in most extracts, although the quantity was generally not enough to produce intoxicating effects. Just over half the extracts were associated with a seizure reduction of 75%-100%, which reinforces observations from animal studies and case reports of anticonvulsant effects of THC and THCA. As well, 65% were associated with other beneficial effects like improved cognition (35%) and language skills (24%).

First Prescription Formulation of Cannabidiol (CBD) Approved for Lennox-Gastaut Syndrome

The LGS Foundation is pleased to announce that the US Food and Drug Administration (FDA) has approved EPIDIOLEX® (cannabidiol / CBD) for the treatment of seizures associated with Lennox-Gastaut syndrome (LGS) in patients two years age or older. EPIDIOLEX® is the first prescription pharmaceutical formulation of highly purified CBD and the first in its class of anti-epileptic drugs.

“Today’s announcement gives individuals with Lennox-Gastaut Syndrome and their families much-needed hope,” says LGS Foundation Executive Director Christina SanInocencio. “Lennox-Gastaut syndrome is a devastating form of epilepsy and despite currently available FDA-approved medications and a poly-therapy approach to treatment, the majority of individuals with LGS will continue to have life-long, debilitating seizures, along with cognitive impairment and abnormal waves on the EEG (electroencephalogram).”

Cannabidiol (CBD) is a compound derived from the cannabis plant that does not produce a “high” and has been an increasing focus of medical research in epilepsy. Recently, study results from the clinical trial of EPIDIOLEX® published in the New England Journal of Medicine showed to significantly reduce the number of seizures in patients with Lennox-Gastaut Syndrome.

Along with the FDA’s approval for EPIDIOLEX® for seizures associated with Lennox-Gastaut syndrome, the approval is also indicated for another form of rare epilepsy that begins in childhood called Dravet syndrome.

The adult motor phenotype of Dravet syndrome is Associated with Mutation of the STXBP1 Gene and Responds Well to Cannabidiol Treatment

Dravet syndrome is a terrible disease generally caused by mutations of the SCN1A gene. Recently others genes such as STXBP1 have been involved in the pathogenesis of the disease. The STXBP1 mutation in patients with Dravet Syndrome may additionally causes several parkinsonian features usually attributed to carriers of the SCN1A mutation. Management continues to be difficult; that is why Cannabidiol emerged as valid option for treatment of this condition.

Inadequate Regulation Contributes to Mislabeled Online Cannabidiol Products

Researchers from the University of Pennsylvania, Veterans Affairs San Diego, RTI international, Americans for Safe Access, Palo Alto University, and Johns Hopkins University analyzed the content of 84 cannabidiol (CBD) products purchased on the internet and compared the results to their advertised concentrations. Products were mislabeled with 26% containing less CBD than labeled and 43% containing more, indicating a high degree of variability and poor standardization of online products.

Notably, the oil-based products were more likely to be accurate (45% compared to 25% for tincture and 12.5% for vaporization liquid) and had a smaller percentage of deviation. Oil based products also had a higher range of concentration. In addition to CBD mislabeling, ?-9-tetrahydrocannabibolic acid (THC) was detected in 21% of samples. This study also notes that products containing THC could have sufficient enough concentrations to produce intoxication in children.