A Powerful Drug Derived from Marijuana Just Got a Major Green Light on its Way to FDA Approval

Business Insider – An experimental drug derived from cannabis to treat epilepsy is on the brink of becoming the first of its kind to win US government approval.

On Thursday, a panel of outside experts convened by the Food and Drug Administration voted unanimously in favor of the drug’s safety and effectiveness. Their recommendation will play a key role in the FDA’s approval decision for the drug, which is made by GW Pharmaceuticals.

If the FDA gives final approval — a decision is expected in June — the new drug would be sold under the name Epidiolex as a syrup. It would be the first drug whose active ingredient is cannabidiol, the compound in marijuana thought to be responsible for many of its therapeutic effects.

Cannabidiol, or CBD, doesn’t contain THC, marijuana’s main psychoactive ingredient, and is not linked with euphoria or the drug’s characteristic high. CBD appears to help reduce seizures, at least in two of the hardest-to-treat forms of epilepsy, known as Lennox-Gastaut syndrome and Dravet syndrome. That’s according to two large clinical trials the FDA considered Tuesday ahead of the vote.

GW Pharma’s long road to FDA approval

In the absence of a research-backed drug, some desperate parents of children with epilepsy have turned to CBD oils and other CBD-based products at dispensaries — but most of those are not heavily regulated.

Laura Lubbers, the chief scientific officer of a nonprofit called Cure that funds epilepsy research, told Business Insider her group saw GW’s drug as a “long-awaited” treatment. That’s especially true for patients who haven’t responded to other drugs.

“What’s different with this drug is that this is a well-studied and well-controlled product,” Lubbers said.

Because GW Pharmaceuticals was able to show that its product addresses a critical need, it was able to apply for a designation to fast-track the Food and Drug Administration’s often protracted approval process.

One clinical trial of the drug looked at its effects in 225 young people with Lennox-Gastaut syndrome. The researchers split the study participants into groups and gave them either a high dose of the drug, a low dose, or a placebo for 14 weeks. The results were presented at an American Academy of Neurology meeting last year, and they showed that participants in the high-dose group saw their seizure occurrence drop by 42%. Those given the low dose saw a decrease of roughly 37%. By comparison, those given the placebo saw only a 17% reduction in seizure occurrence.

The second trial, the results of which were published in May 2017 in the New England Journal of Medicine, looked at 120 children with Dravet syndrome. Half were given the drug, and half received a placebo. Forty-three percent of the participants given the drug saw their seizures reduced by half, and 5% stopped having seizures entirely. The group given the placebo saw barely any improvement.

The FDA vote and the future of cannabis-derived drugs

While Epidiolex would be the first cannabidiol-based drug to land FDA approval, the agency has already given the green light to other drugs that contain a lab-made version of THC. Sold under the brand names Marinol and Syndros, the drugs are designed to treat some negative side effects of chemotherapy and AIDS, such as nausea, loss of appetite, and weight loss.

In its public meeting on Thursday, a panel of outside scientists convened by the FDA decided that Epidiolex was safe and effective. Their unanimous vote serves as a recommendation that will be considered when the final decision on whether to approve the drug is made.

“This is clearly a breakthrough drug for an awful disease,” John Mendelson, a panel member and senior scientist at the Friends Research Institute, said after the vote.

Epidiolex would be designed to treat only two types of epilepsy, so FDA approval would mean the drug would be prescribed for a small group of patients. But medical professionals could technically prescribe it “off-label” for other conditions as well. (The anesthetic ketamine, for example, may be prescribed this way for some hard-to-treat forms of depression.)

“We would expect that once this is approved as a drug it’s quite likely this will be tried in other populations off-label so it has a big opportunity to affect others,” Lubbers said.

According to the Centers for Disease Control and Prevention, epilepsy affects more than 3.4 million Americans. Though GW Pharma’s current drug focuses only on two rare types of the condition, the company has said it is exploring treatments for various other forms of epilepsy, too.

If this initial drug gets the green light, that approval will likely galvanize new research into other marijuana-based drugs as well.

Long-Term Efficacy of Add-On Lacosamide Treatment in Children and Adolescents with Refractory Epilepsies – A Single?Center Observational Study

Objective: To assess long?term efficacy and tolerability of lacosamide (LCM) as adjunctive treatment through a retrospective study in children and adolescents with refractory epilepsies.

Methods: All patients consecutively treated with LCM as add?on for refractory focal and generalized epilepsy and followed at the Neuroscience Center of Excellence of the Meyer Children’s Hospital of Florence between January 2011 and September 2015 were included in the study. Responder rate, relapse?free survival, and retention rate were calculated. Tolerability was assessed by reporting adverse events.

Results: A total of 88 individuals (41 female) aged 4 months to 18 years (median 10.5 years; mean ± SD 10.6 ± 4.8 years) received add?on LCM treatment for refractory epilepsy. Thirty?four patients (38.6%) were responders with a median time to relapse of 48 months. Nine (26.4%) of the 34 responders were seizure?free. For all 88 patients, the probability of remaining on LCM without additional therapy was 74.4% at 6 months, 47.7% at 12 months, 27.9% at 24 months, 18.0% at 48 months, and 8.2% at 72 months of follow?up. No statistically significant differences in relapse and retention time were observed with regard to epilepsy and seizure types, duration and course of epilepsy, number and type of antiepileptic drugs (AEDs; sodium channel blockers vs others) used in add?on. The most frequent adverse events were dermatological (4/11) and behavioral (3/11).

Significance: This study documents a real?world progressive and significant loss of lacosamide efficacy over time in a pediatric population. Further prospective studies on larger populations are required to confirm the remarkable loss of lacosamide efficacy over time.

What Modern Day Challenges Affect Epilepsy Treatment?

Researchers recently published an article in The Lancet Neurology discussing the difficulties facing seizure detection in patients with epilepsy.

Epilepsy is a neurological disorder that is characterized by short repetitive epileptic seizures. These seizures can be harmful to the individual depending on the circumstances in which they occur, such as a seizure while driving. This disorder is set apart from other neurological disorders since there is a broad range of different physiological changes that can cause it, leading to a large variation in symptoms and making it difficult to treat. While 70% of sufferers can be treated with pharmacological agents, 30% have no reliable anti-epileptic drugs that are effective for their particular type of epilepsy.

In a recent study, Christian Elger and Christian Hoppe determined that a key challenge facing patients is that over 50% of patients under-report the number of seizures they experience, which has a serious impact on how well doctors are able to determine what treatments are most suitable for them. This also calls into question many of the previously published research on epilepsy treatments. They recently published this report in The Lancet Neurology.

Critical Review: Can Mutation?Mediated Effects Occurring Early in Development Cause Long?Term Seizure Susceptibility in Genetic Generalized Epilepsies?

Summary: Epilepsy has a strong genetic component, with an ever?increasing number of disease?causing genes being discovered. Most epilepsy?causing mutations are germ line and thus present from conception. These mutations are therefore well positioned to have a deleterious impact during early development. Here [researchers] review studies that investigate the role of genetic lesions within the early developmental window, specifically focusing on genetic generalized epilepsy (GGE). Literature on the potential pathogenic role of sub?mesoscopic structural changes in GGE is also reviewed.

Evidence from rodent models of genetic epilepsy support the idea that functional and structural changes can occur in early development, leading to altered seizure susceptibility into adulthood. Both animal and human studies suggest that sub?mesoscopic structural changes occur in GGE.

The existence of sub?mesoscopic structural changes prior to seizure onset may act as biomarkers of excitability in genetic epilepsies. [Researchers] also propose that presymptomatic treatment may be essential for limiting the long?term consequences of disease?causing mutations in genetic epilepsies.

Hope for New Treatment of Severe Epilepsy

Researchers at Lund University in Sweden believe they have found a method that in the future could help people suffering from epilepsy so severe that all current treatment is ineffective.

“In mice studies, we succeeded in reducing seizure activity by intervening in an area of the brain that is not the focus of the epileptic seizures, but is directly connected to it through a network of neurons. If we get the same result in further, long-term studies, it could pave the way for treatment of severe epilepsy,” says Mérab Kokaia, professor and director of the Epilepsy Centre at Lund University.

In the study, published in the research journal Scientific Reports, researchers succeeded in reducing epileptic activity in the hippocampus, an area of the brain which is important for memory and learning, among other things. In the most severe cases, this is exactly the part of the brain where epileptic seizures usually start.

The researchers used a method known as chemogenetics, which enables them to reduce activity in the specific areas and nerve cells involved in an epileptic seizure, whereas other parts and cells in the body remain unaffected. This is in contrast to current drugs that affect more or less all parts and cells of the body, potentially leading to side-effects.

“Very few similar studies have been carried out previously, and this is the first study in which we succeeded in reducing the epileptic activity in one area of the brain by using chemogenetics to affect another area, not the seizure focus. This opens up the possibility of treating epilepsy in areas of the brain that cannot be surgically removed or treated directly,” explains Mérab Kokaia.

Study: Effects of [Mutations in Genes] UGT2B7, SCN1A and CYP3A4 on the Therapeutic Response of Sodium Valproate Treatment in Children with Generalized Seizures

PURPOSE: This study aims to evaluate the associations between genetic polymorphisms and the effect of sodium valproate (VPA) therapy in children with generalized seizures.

METHODS: A total of 174 children with generalized seizures on VPA therapy were enrolled. Steady-state trough plasma concentrations of VPA were analyzed. Seventy-six single nucleotide polymorphisms involved in the absorption, metabolism, transport, and target receptor of VPA were identified, and their associations with the therapeutic effect (seizure reduction) were evaluated using logistic regression adjusted by various influence factors.

RESULTS: rs7668282 (UGT2B7, T?>?C, OR?=?2.67, 95% CI: 1.19 to 5.91, P?=?0.017) was more prevalent in drug-resistant patients than drug-responsive patients. rs2242480 (CYP3A4, C?>?T, OR?=?0.27, 95% CI: 0.095 to 0.79, P?=?0.017) and rs10188577 (SCN1A, T?>?C, OR?=?0.40, 95% CI: 0.17 to 0.94, P?=?0.035) were more prevalent in drug-responsive patients compared to drug-resistant patients.

CONCLUSION: In children with generalized seizures on VPA therapy, polymorphisms of UGT2B7, CYP3A4, and SCN1A genes were associated with seizure reduction. Larger studies are warranted to corroborate the results.

Study: Diagnostic Outcomes for Genetic Testing of 70 Genes in 8565 Patients with Epilepsy and Neurodevelopmental Disorders

Significance: Using a combined approach of next generation sequencing and exon?level array comparative genomic hybridization, testing identified a genetic etiology in 15.4% of patients in this cohort and revealed the age at molecular diagnosis for patients. Our study highlights both high? and low?yield genes associated with epilepsy and neurodevelopmental disorders, indicating which genes may be considered for molecular diagnostic testing.

Objective: We evaluated >8500 consecutive, unselected patients with epilepsy and neurodevelopmental disorders who underwent multigene panel testing to determine the average age at molecular diagnosis and diagnostic yield of 70 genes.

Methods: We reviewed molecular test results for 70 genes known to cause epilepsy and neurodevelopmental disorders using next generation sequencing (NGS) and exon?level array comparative genomic hybridization (aCGH). A positive result was defined as the presence of 1 or 2 pathogenic or likely pathogenic (P/LP) variants in a single gene, depending on the mode of inheritance of the associated disorder.

Results: Overall, 22 genes were found to have a high yield of positive findings by genetic testing, with SCN1A and KCNQ2 accounting for the greatest number of positive findings. In contrast, there were no positive findings in 16 genes. Most of the P/LP variants were sequence changes identified by NGS (90.9%), whereas ~9% were gross deletions or duplications detected by exon?level aCGH. The mean age of molecular diagnosis for the cohort was 5 years, 8 months (ranging from 1 week to 47 years). Recurrent P/LP variants were observed in 14 distinct genes, most commonly in MECP2, KCNQ2, SCN1A, SCN2A, STXBP1, and PRRT2. Parental testing was performed in >30% of positive cases. All variants identified in CDKL5, STXBP1, SCN8A, GABRA1, and FOXG1 were de novo, whereas 85.7% of variants in PRRT2 were inherited.

Study: Computer-Assisted Planning for the Insertion of Stereoelectroencephalography Electrodes for the Investigation of Drug-Resistant Focal Epilepsy: an External Validation Study

OBJECTIVE: One-third of cases of focal epilepsy are drug refractory, and surgery might provide a cure. Seizure-free outcome after surgery depends on the correct identification and resection of the epileptogenic zone. In patients with no visible abnormality on MRI, or in cases in which presurgical evaluation yields discordant data, invasive stereoelectroencephalography (SEEG) recordings might be necessary. SEEG is a procedure in which multiple electrodes are placed stereotactically in key targets within the brain to record interictal and ictal electrophysiological activity. Correlating this activity with seizure semiology enables identification of the seizure-onset zone and key structures within the ictal network.

The main risk related to electrode placement is hemorrhage, which occurs in 1% of patients who undergo the procedure. Planning safe electrode placement for SEEG requires meticulous adherence to the following: 1) maximize the distance from cerebral vasculature, 2) avoid crossing sulcal pial boundaries (sulci), 3) maximize gray matter sampling, 4) minimize electrode length, 5) drill at an angle orthogonal to the skull, and 6) avoid critical neurological structures.

The authors provide a validation of surgical strategizing and planning with EpiNav, a multimodal platform that enables automated computer-assisted planning (CAP) for electrode placement with user-defined regions of interest.

Study: Correlates of Stigma in Adults with Epilepsy – A Systematic Review of Quantitative Studies

OBJECTIVES: The aim of this review was to identify quantitative correlates, predictors, and outcomes of stigma in adults with epilepsy living in Western countries.

METHODS: To identify relevant literature, four academic databases (PsycINFO, CINAHL, PubMed, and Scopus) were systematically searched using key terms related to stigma and epilepsy.

RESULTS: Thirty-three research papers reporting findings from 25 quantitative studies of correlates of stigma in epilepsy were identified. The findings suggest that stigma can be predicted by demographic, illness-related, and psychosocial factors, although associations were found to be highly culturally specific. Outcomes of stigma in people with epilepsy were replicated more consistently across cultures, and its impact was significant. Detrimental effects included both worse physical health, including less effective management of the condition, and reduced psychological well-being, including difficulties such as depression and anxiety.

IMPLICATIONS: Educational initiatives and therapeutic interventions that aim to address stigma in people with epilepsy are recommended; however, these need to be culturally informed to ensure that they are valid and effective.

Study: Type 2 Diabetes May Raise Risk of Epilepsy

A new study finds a link between type 2 diabetes and epilepsy and they say that severe hypoglycemia may play a role.

Researchers conducted a cohort study using Taiwan’s National Health Insurance claims involving 751,792 people with type 2 diabetes. They matched those individuals with 824,253 control subjects. They followed the cohort until an incidence of epilepsy or to the end of 2011 (subjects were identified between 2002-2003).

They found that after a 10-year follow-up, those with type 2 diabetes had a higher incidence rate of epilepsy compared to the control subjects. Researchers controlled for factors like severe hypoglycemia and found that type 2 diabetes raised the risk for epilepsy by some 50%, according to the study abstract.

Stratified analysis showed that type 2 diabetes and severe hypoglycemia “were both independent risk factors for epilepsy,” write the study authors.

The researchers conclude that their findings indicate that severe hypoglycemia in those with type 2 diabetes may raise the risk of epilepsy and that type 2 diabetes itself may also raise the risk for epilepsy, whether severe hypoglycemia is experienced, or not.