Zynerba Pharmaceuticals Announces Twelve Month ZYN002 Data from STAR 2 Study in Patients with Focal Seizures at the 2018 Annual Meeting of the American Academy of Neurology (AAN)

Zynerba Pharmaceuticals, Inc., a clinical-stage specialty neuropsychiatric pharmaceutical company dedicated to developing and commercializing innovative pharmaceutically-produced transdermal cannabinoid treatments for rare and near-rare neurological and psychiatric disorders with high unmet medical needs, is reporting new longer term open label clinical data today in the Emerging Science session of the 2018 Annual Meeting of the American Academy of Neurology (AAN) in Los Angeles, CA.

In a poster presentation entitled, “Transdermal Cannabidiol (CBD) Gel for the Treatment of Focal Epilepsy in Adults” (poster P4.468), Dr. John Messenheimer presents additional data from ongoing STAR 2 (Synthetic Transdermal CAnnabidiol for the TReatment of Epilepsy) 24-month open label extension study evaluating ZYN002 cannabidiol (CBD) transdermal gel in adult patients with focal seizures. The presentation includes data through twelve months of open label exposure to ZYN002.

The key findings include that responses to ZYN002 in the STAR 2 open label extension, as measured by reductions in focal seizures from the baseline period of STAR 1, are associated with continued treatment with ZYN002. In addition, ZYN002 was shown to be well tolerated through 12 months of treatment in STAR 2.

“These data continue to suggest that focal seizures may be reduced with longer-term exposure to transdermally-delivered CBD,” said Dr. Liza Squires, Zynerba’s Chief Medical Officer. “In this population of patients, the use of ZYN002 for an additional 12 months in STAR 2 was well tolerated and appeared to result in clinically meaningful seizure reductions both across and within the originally randomized STAR 1 groups. These data continue to provide insight into the potential for ZYN002 in certain epilepsies, and we look forward to initiating a Phase 2b study in adult refractory focal seizures in the second half of 2018.”

Zogenix Announces Presentation of New Efficacy and Safety Data from its First Pivotal Phase 3 Clinical Trial of ZX008 in Dravet Syndrome

Zogenix, Inc., a pharmaceutical company developing therapies for the treatment of rare central nervous system (CNS) disorders, today announced additional data from analyses of its first Phase 3 trial (Study 1) of the company’s investigational drug, ZX008 (low-dose fenfluramine hydrochloride), for the adjunctive treatment of seizures associated with Dravet syndrome. Top-line results from Study 1 were previously reported in September 2017. The additional Study 1 results were presented in two late-breaker poster presentations at the Emerging Science session at the 2018 American Academy of Neurology (AAN) Annual Meeting being held April 21-27 in Los Angeles, California (see study data here and here).

As previously reported, Study 1 met its primary objective of demonstrating that ZX008, at a dose of 0.8 mg/kg/day, is superior to placebo as an adjunctive therapy in the treatment of Dravet syndrome in children and young adults based on change in the frequency of convulsive seizures between the 6-week baseline observation period and the 14-week treatment period (p<0.001).

“It is highly encouraging to see that the efficacy and tolerability in this subgroup of patients who had previously failed treatment with stiripentol was comparable to the full Study 1 population,” said Rima Nabbout, M.D., Ph.D., Department of Pediatric Neurology, Reference Center for Rare Epilepsies, and one of the poster’s authors. “As stiripentol is a commonly used antiepileptic drug, it is important to understand how tolerable and effective ZX008 is in this subgroup of patients.”

Study: Usage of EpiFinder Clinical Decision Support Application in the Assessment of Epilepsy

Background: The diagnosis of epilepsy is at times elusive for both neurologists and nonneurologists, resulting in delays in diagnosis and therapy. The development of screening methods has been identified as a priority in response to this diagnostic and therapeutic gap.

EpiFinder is a novel clinical decision support tool designed to enhance the process of information gathering and integration of patient/proxy respondent data. It is designed specifically to take key terms from a patient’s history and incorporate them into a heuristic algorithm that dynamically produces differential diagnoses of epilepsy syndromes.

Objective: The objective of this study was to test the usability and diagnostic accuracy of the clinical decision support application EpiFinder in an adult population.

Highlights:

  • Clinical decision support tools can be implemented in the adult EMU setting.
  • Support tools can adapt to user input creating dynamic epilepsy specific differentials.
  • Algorithms can predict classification between epilepsy and an alternative diagnosis.

Study: Vagus Nerve Stimulation for 6- to 12-Year-Old Children with Refractory Epilepsy – Impact on Seizure Frequency and Parenting Stress Index

OBJECTIVES: Refractory epilepsy (RE) is frequently associated with neuropsychological impairment in children and may disrupt their social development. Vagus nerve stimulation (VNS) had been reported to have beneficial effects on behavioral outcomes. The aim of this study was to compare Parenting Stress Index (PSI) scores before and after VNS device implantation in children with RE, especially those who experienced seizure frequency reduction.

METHODS: We conducted a one-group pretest-posttest study in school age children with RE. Seizure frequency and PSI were recorded at 12months after VNS device implantation.

RESULTS: Treatment with VNS was significantly associated with reduced seizure frequency and parental stress as measured by PSI. Factors contributing to seizure frequency included idiopathic/cryptogenic etiology and neurobehavioral comorbidities. In children with reduced seizure frequency, statistically significant improvements in the child domain of the PSI on the subscales of mood and reinforces parent were found. In the parent domain, the scores for social isolation were reduced.

CONCLUSIONS: Treatment with VNS was significantly associated with reduced seizure frequency and improved PSI scores, especially within the child domain on the mood and reinforces parent subscales. These findings suggest that VNS reduced not only seizure frequency but also the psychological burden on children with RE.

The Epilepsy Foundation Launches a New Research Study to Find Biomarkers for Treatment of Focal Seizures in People with Epilepsy

The Epilepsy Foundation announced on April 24 the launch of a new Human Epilepsy Project study of focal seizures to better understand the long-term challenges of living with focal seizures and determine biomarkers of epilepsy severity and treatment response. The biomarkers research study, HEP2, will monitor 200 people with treatment-resistant focal seizures over a two-year period to measure changes in seizure frequency, treatments used, presence of comorbidities — such as depression and anxiety — healthcare costs, and quality of life. HEP2 is the second in a group of registry-based studies called the Human Epilepsy Project, a joint initiative of the Epilepsy Foundation and the Epilepsy Study Consortium to improve the care of people with epilepsy.

“This new research study is another step in our efforts to better understand focal epilepsy and uncover data that will help accelerate therapies to help people with epilepsy have seizure-free lives,” said Dr. Brandy Fureman, Vice President for Research & New Therapies, Epilepsy Foundation. “We believe HEP2 could have a major impact on prevention strategies, treatments and cures for those who have not responded to current treatments.”

HEP2 is enrolling participants at designated study centers throughout the U.S., including New York, Connecticut, Pennsylvania, Tennessee, Minnesota, and California. The study will also have an international center in Finland. The HEP2 study will follow 200 participants between the ages of 16 and 65 who have a history of focal epilepsy, have four or more seizures per month and have tried four or more drugs to control seizures without success.

Study: Different as Night and Day – Patterns of Isolated Seizures, Clusters, and Status Epilepticus.

Abstract: With the exception of SE in children, our data suggest that more severe patterns favor daytime. This suggests distinct day/night preferences for different seizure patterns in children and adults.

Using approximations based on presumed U.S. time zones, we characterized day and nighttime seizure patterns in a patient-reported database, Seizure Tracker. A total of 632 995 seizures (9698 patients) were classified into 4 categories: isolated seizure event (ISE), cluster without status epilepticus (CWOS), cluster including status epilepticus (CIS), and status epilepticus (SE). We used a multinomial mixed-effects logistic regression model to calculate odds ratios (ORs) to determine night/day ratios for the difference between seizure patterns: ISE versus SE, ISE versus CWOS, ISE versus CIS, and CWOS versus CIS. Ranges of OR values were reported across cluster definitions.

In adults, ISE was more likely at night compared to CWOS (OR = 1.49, 95% adjusted confidence interval [CI] = 1.36-1.63) and to CIS (OR = 1.61, 95% adjusted CI = 1.34-1.88). The ORs for ISE versus SE and CWOS versus SE were not significantly different regardless of cluster definition. In children, ISE was less likely at night compared to SE (OR = 0.85, 95% adjusted CI = 0.79-0.91). ISE was more likely at night compared to CWOS (OR = 1.35, 95% adjusted CI = 1.26-1.44) and CIS (OR = 1.65, 95% adjusted CI = 1.44-1.86). CWOS was more likely during the night compared to CIS (OR = 1.22, 95% adjusted CI = 1.05-1.39).

Serotonin Reuptake Inhibitors May Improve Obstructive Sleep Apnea in Depression With and Without Epilepsy

study of adults with both obstructive sleep apnea (OSA) and depression has demonstrated a link between the use of serotonin reuptake inhibitors (SRIs) and reduced severity of OSA in subjects with and without epilepsy. However, those with epilepsy displayed a more significant correlation between SRI use and reduced severity of OSA. This research was presented at the 70th annual American Academy of Neurology meeting, held April 21-27, 2018, in Los Angeles, California.

The results suggest that SRIs may serve as a potential treatment for OSA and depression, both in patients with and without epilepsy.

Study: The Direct Cost of Epilepsy in Children – Evidence from the Medical Expenditure Panel Survey, 2003-2014

INTRODUCTION: Epilepsy is frequent in children and often requires complex healthcare interventions. There is a paucity of recent and detailed healthcare expenditures among children with epilepsy in the United States (US).

METHODS: Data on children (aged ?17years) from the Medical Expenditure Panel Survey-Household Component (MEPS-HC) from 2003 to 2014 were analyzed. Unadjusted overall and specific cost components were compared between children with epilepsy and those without epilepsy. We used a two-part model with gamma distribution and log link for the estimation of independent incremental cost incurred by epilepsy in children. Unadjusted and adjusted mean expenditures and aggregate burden of epilepsy were estimated.

RESULTS: Out of 54,393,387 (weighted) US children, 457,873 (0.84%) had epilepsy. Children with epilepsy had nearly six times higher healthcare expenditure than those without epilepsy ($2024 [95% confidence interval (CI): 1917-2130] vs. $12,577 [95% CI: 7922-17,231]). Unadjusted inpatient expenditure for epilepsy ($4418 [95% CI: 1550-7285) was ten times higher than that for children without epilepsy, representing more than one-third of unadjusted total direct cost. The adjusted difference in medical expenditure between children with and those without epilepsy was $8317 (95% CI: 3701-13,363). The annual unadjusted aggregate cost of epilepsy in children was approximately $5.8 billion. The annual adjusted difference in cost of epilepsy between children with and those without epilepsy was $3.8 billion.

CONCLUSION: Unadjusted and adjusted medical expenditure among children with epilepsy is high. The high expenditure is essentially driven not only by inpatient expenditure but also by home healthcare, outpatient, and medication healthcare expenditures.

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.