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.

Switching Brain Circuits On and Off Without Surgery

In the maze of our brains, there are various pathways by which neural signals travel. These pathways can go awry in patients with neurological and psychiatric diseases and disorders, such as epilepsy, Parkinson’s, and obsessive-compulsive disorder. Researchers have developed new therapeutic strategies to more precisely target neural pathways involved in these conditions, but they often require surgery.

The latest findings from the laboratory of Mikhail Shapiro, assistant professor of chemical engineering at Caltech, are now showing how scientists and doctors might, in the future, selectively turn neural circuits on and off–without the need for surgery. The new study, featured in the July 9 online edition of Nature Biomedical Engineering, demonstrates how the method–which involves a trio of therapies: ultrasound waves, gene therapy, and synthetic drugs–can be used to specifically alter memory formation in mice.

“By using sound waves and known genetic techniques, we can, for the first time, noninvasively control specific brain regions and cell types as well as the timing of when neurons are switched on or off,” says Shapiro, who is also a Schlinger Scholar and a Heritage Medical Research Institute Investigator. The work has implications for basic research in animals and for the future treatment of neurological and psychiatric conditions.

The researchers say they hope to continue testing in animals with models of diseases such as epilepsy. Many patients with epilepsy currently undergo surgery to cut out the regions of their brain where seizures are thought to be triggered. With the ATAC method, specific brain areas could, in theory, be switched off temporarily without surgery.

Clinical Trial: Does Brivaracetam Have Faster Onset Time & Greater Effect Than Levetiracetam in Epilepsy Pts Using PPR Pharmacodynamic Efficacy Endpoint

The main purpose of this study is to see whether brivaracetam has a faster onset time and greater effect than levetiracetam in subjects with photosensitive seizures. Part 1 of the study will compare the effects of levetiracetam 1500 mg with the effects of brivaracetam 100 mg. Part 2, will compare the effects of levetiracetam 1500 mg with the effects of brivaracetam 100 mg or will compare the effects of levetiracetam 500mg with the effects of brivaracetam 25 mg.

Estimated study start date: June 1, 2018
Estimated study completion date: February 2019

Eligibility Criteria

Ages Eligible for Study: 18 Years to 65 Years (Adult, Older Adult)
Sexes Eligible for Study: All
Accepts Healthy Volunteers: No

Inclusion Criteria

  • Patients between 18 and 65 years of age
  • Male or female
  • PPR at minimum at 60,50,40,30,25,20,18 or 16 Hz as upper threshold
  • Drug naïve or at most with up to 4 AEDs, not being LEV or BRV

 

Exclusion Criteria

  • Current treatment with more than 4 AEDs
  • LEV or BRV as current treatment or used in the previous month.
  • History of severe side-effects or psychological side-effects with LEV or BRV use
  • Being pregnant or insufficiently protected against pregnancy (see also ref 31) or lactating Female
  • Serious internal medical disease (renal/hepatic/cardiovascular disease) as deemed by the on-site physician (WER)
  • History of psychiatric disease that has been a reason for acute hospitalisation for their condition of depression, schizophrenia, mania, delirium or aggressive behaviour
  • History of status epilepticus
  • History of significant ethanol or illicit drug use

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%).

Study Using i2b2 Could Help Standardize Use of Therapeutic Comas for Epileptic Patients

Status epilepticus (SE), a dangerous condition in which epileptic seizures follow one another for a duration of five or more minutes without the victim’s regaining consciousness between them, is the second most common neurological emergency in the United States, with a recorded maximum of around 150,000-plus cases per year. In 60-70 percent of cases, the patient responds to antiepileptic medications and benzodiazepines.

But a combination of those medications doesn’t always work, says Wolfgang Muhlhofer, M.D., an assistant professor of neurology in the University of Alabama at Birmingham Epilepsy Center. Up to 44 percent of status epilepticus cases progress to refractory status epilepticus (RSE), where the patient doesn’t respond to those drugs, and more extreme treatments have to be used.

“These emergencies require prompt and effective treatment,” Muhlhofer said. “The longer SE is going on, the higher the chances of brain damage or the body’s being unable to compensate for the trauma, leading to other complications like cardiac arrest or kidney or heart failure. There’s a lot of risk associated with this condition.”

Muhlhofer wanted to analyze RSE patients in a more systematic way, with the hopes of determining more specific guidelines regarding the lengths of what he calls “therapeutic coma.” He designed a study of adult patients, admitted to UAB or University of California, San Francisco Medical Center during a seven-year period, who were placed in an artificial coma and who had a seizure recurrence within the first 48 hours of lightening the patient’s sedative medications.

While artificial coma is the agreed-upon treatment for RSE patients, Muhlhofer says there isn’t an evidence-based consensus on how long patients should be kept in this state, and recent studies of this patient population have shown that, the longer a patient is kept in an artificial coma, the more likely they are to have complications during their hospitalizations or, worse, permanent problems with physical and cognitive functions.

Brand Name to Generic Substitution of Levetiracetam in Patients with Epilepsy

PURPOSE: Levetiracetam is one of the most widely used antiepileptic drugs, but the evidence related to the safety of substitution from brand name to generic levetiracetam is scarce. The present study evaluated the risk of increased frequency of seizures after replacement of a brand-name levetiracetam with a generic product.

METHODS: We enrolled patients with epilepsy who were treated with branded levetiracetam for at least 6 months of sustained use. Patients were advised to switch to the generic levetiracetam. We analyzed data from 6 months before, to 6 months after, generic substitution. Increased seizure frequency was defined as a? 50% increase in seizure frequency after conversion date compared with seizure frequency before the conversion date. We analyzed changes in seizure frequency and performed subgroup analysis according to changes in seizure frequency.

RESULTS: We analyzed 148 epilepsy patients. Among the 148 patients, 109 (73.6%) were seizure-free before substitution and 105 patients remained seizure-free after switching. After generic substitution, an increased seizure frequency was noted in seven patients (4.7%), and a decreased seizure frequency was noted in 10 (6.8%). Patients with decreased seizure frequency were significantly younger (p?=?0.035) than those with an unchanged seizure frequency.

CONCLUSION: This study suggests that the risk of increased seizure frequency after generic substitution was minimal. The generic substitution of levetiracetam was generally safe, although larger prospective studies are warranted to corroborate our findings.

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

Sunovion Pharmaceuticals Inc. announced that Health Canada has approved the use of Aptiom (eslicarbazepine acetate) as monotherapy for partial-onset seizures in adults with epilepsy. All patients who participated in the monotherapy trial were newly or recently diagnosed with epilepsy.

APTIOM is now indicated in Canada as monotherapy and as adjunctive therapy for the treatment of partial-onset seizures (POS) in adults with epilepsy.

Partial-onset seizures are the most common type of seizures experienced by people living with epilepsy and, given these seizure’s unpredictable nature, can have a significant impact on their lives, said Eduard Bercovici, M.D., Epileptologist, director of the Southern Ontario Epilepsy Clinic. This new indication for APTIOM in Canada helps provide an additional treatment option for health care professionals and patients with partial-onset seizures.

The SNDS approval is supported by data from a Phase 3, double-blind, active controlled, non-inferiority study in which APTIOM met its primary efficacy endpoint of non-inferiority to the active comparator, carbamazepine controlled release (CBZ-CR).

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.

Use of Brivaracetam in Genetic Generalized Epilepsies and for Acute, Intravenous Treatment of Absence Status Epilepticus

SIGNIFICANCE: Use of brivaracetam in genetic generalized epilepsies is well tolerated, and 50% responder rates are similar to those observed in the regulatory trials for focal epilepsies. An immediate switch from levetiracetam to brivaracetam at a ratio of 15:1 is feasible. The occurrence of psychobehavioral adverse events seems less prominent than under levetiracetam, and a switch to brivaracetam can be considered in patients with levetiracetam-induced adverse events.

OBJECTIVE: The objective of this study was to evaluate effectiveness, retention, and tolerability of brivaracetam (BRV) in genetic generalized epilepsies (GGE) in clinical practice.

METHODS: A multicenter, retrospective cohort study recruiting all patients that started BRV in 2016 and 2017.

RESULTS: A total of 61 patients (mean age = 29.8, range = 9-90 years, 41 female [67%]) were treated with BRV. They were difficult to control, with 2.4 failed antiepileptic drugs (AEDs) in the past, taking 1.9 AEDs on average at baseline.

The length of exposure to BRV ranged from 7 days to 24 months, with a mean retention time of 7.9 months, resulting in a total exposure time to BRV of 483 months. The retention rate was 82% at 3 months and 69% at 6 months. Efficacy at 3 months was 36% (50% responder rate), with 25% seizure-free for 3 months. Patients with juvenile myoclonic epilepsy showed a responder rate of 60%, with 40% being free of any seizures. Long-term 50% responder rate was present in 17 patients (28%; 11 seizure-free [18%]) for >6 months and in 14 patients (23%; 10 seizure-free [16%]) for >12 months.

Treatment-emergent adverse events were observed in 26% of the patients, with the most common being somnolence, ataxia, and psychobehavioral adverse events. Use of intravenous BRV with bolus injection of 200-300 mg in two females with absence status epilepticus was well tolerated, but did not result in cessation of status epilepticus.