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.”

Updated Recommendations on the Optimal Clinical Management of Children Receiving Dietary Therapies for Epilepsy

Ketogenic dietary therapies (KDT) are established, effective nonpharmacologic treatments for intractable childhood epilepsy. For many years KDT were implemented differently throughout the world due to lack of consistent protocols. In 2009, an expert consensus guideline for the management of children on KDT was published, focusing on topics of patient selection, pre?KDT counseling and evaluation, diet choice and attributes, implementation, supplementation, follow?up, side events, and KDT discontinuation. It has been helpful in outlining a state?of?the?art protocol, standardizing KDT for multicenter clinical trials, and identifying areas of controversy and uncertainty for future research.

Now one decade later, the organizers and authors of this guideline present a revised version with additional authors, in order to include recent research, especially regarding other dietary treatments, clarifying indications for use, side effects during initiation and ongoing use, value of supplements, and methods of KDT discontinuation. Additionally, authors completed a survey of their institution’s practices, which was compared to responses from the original consensus survey, to show trends in management over the last ten years.

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.

GW Pharmaceuticals and U.S. Subsidiary Greenwich Biosciences Announces the Unanimous Positive Result of FDA Advisory Committee Meeting for First Plant-Based Pharmaceutical [CBD] Treatment for Seizures in Patients with Two Rare, Severe Forms of Epilepsy

GW Pharmaceuticals, a biopharmaceutical company focused on discovering, developing and commercializing novel therapeutics from its proprietary cannabinoid product platform, along with its U.S. subsidiary Greenwich Biosciences, today announced that the Peripheral and Central Nervous System Drugs Advisory Committee of the U.S. Food and Drug Administration (FDA) unanimously recommended supporting the approval of the New Drug Application (NDA) for the investigational cannabidiol oral solution (CBD), also known as Epidiolex, for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome (LGS) and Dravet syndrome in patients two years of age and older. If approved, Epidiolex would be the first pharmaceutical formulation of purified, plant-based CBD, a cannabinoid lacking the high associated with marijuana, and the first in a new category of anti-epileptic drugs (AEDs). This public meeting was presented live through FDA’s website.

LGS and Dravet syndrome, which develop in childhood, are devastating forms of epilepsy with high morbidity and mortality rates and a significant burden on families and caregivers. More than 90% of patients with LGS or Dravet syndrome have multiple seizures per day, which puts them at constant risk for falls and injury. Physicians who treat LGS and Dravet syndrome patients struggle to reduce the sheer volume of dangerous seizures with currently available therapies. If approved, Epidiolex would be the first-ever FDA-approved medicine for Dravet syndrome patients.

“We are pleased by the Advisory Committee’s unanimous recommendation to approve Epidiolex, which would provide an important treatment option for patients with LGS and Dravet syndrome, two of the most severe and treatment-resistant forms of epilepsy,” said Justin Gover, GW’s Chief Executive Officer. This favorable outcome marks an important milestone in our company’s unwavering commitment to address the significant unmet need for patients with LGS and Dravet syndrome and our resolve to study Epidiolex under the highest research and manufacturing standards. We look forward to our ongoing discussions with the FDA as it continues to review the Epidiolex NDA.

Experts Weigh Risks of Epilepsy Drug in Pregnancy, as EU Considers Safety Recommendations

As the European Commission considers whether to introduce a partial ban on use of the epilepsy drug valproate in pregnancy over risks to unborn babies, researchers in The BMJ discuss the arguments and the implications for patients and healthcare professionals.

Valproate is an effective treatment for epilepsy, bipolar disorder and migraine. For some women with epilepsy, it may be the only effective treatment option.

But the drug carries a 10% chance of causing physical abnormalities and a 30-40% risk of developmental problems such as autism and developmental delay in children born to mothers who take it. In the UK alone, around 20,000 children have been harmed since valproate was introduced in the 1970s.

Earlier this year, the European Medicines Agency recommended that valproate should not be used in pregnancy unless the woman has epilepsy that has not responded to alternative medications. It should not be prescribed to women of childbearing age unless they use contraception. But surveys show that many women with epilepsy are still unaware of the risks.

Responses from expert advisory groups and regulators have varied, from those advocating shared decision making and informed patient choice about taking valproate in pregnancy, to restricted use when other treatments have failed, to prohibition of valproate in pregnancy coupled with a pregnancy prevention programme in all women taking it.

Consultant neurologists Heather Angus-Leppan and Rebecca Liu say, despite international consensus on the harmful effects of valproate during pregnancy, its use may be warranted in certain situations.

In a linked editorial, consultant perinatal psychiatrists Angelika Wieck and Sarah Jones explain that, if the European Commission accepts the recommendations, all women of childbearing age who are being prescribed valproate will require regular review and must follow a pregnancy prevention programme.

Open-Label Phase 2 Trial of ZYN002 in Developmental and Epileptic Encephalopathies

Zynerba Pharmaceuticals announced that it has initiated the Phase 2 BELIEVE 1 (Open Label Study to Assess the Safety and Efficacy of ZYN002 Administered as a Transdermal Gel to Children and Adolescents with Developmental and Epileptic Encephalopathy [DEE]) clinical trial.

As quoted in the press release: “DEE is a heterogeneous group of epilepsy syndromes that involve significant developmental impairment or regression of developmental progress, and are highly resistant to treatment,” said Dr. Liza Squires, Zynerba’s Chief Medical Officer. “Little attention is paid to DEE outside of Lennox-Gastaut and Dravet syndromes despite the high unmet need. The BELIEVE 1 study will assess children and adolescents with a variety of epilepsy syndromes that are characterized as DEE. Our goal is to deliver an effective, well tolerated, and easy to administer therapeutic option for individuals living with DEE and their families.”

Hackensack University Medical Center Earns Top-Tier Accreditation From the National Association of Epilepsy Centers

Hackensack Meridian Health Hackensack University Medical Center is pleased to announce that it has received a two-year National Association of Epilepsy Centers (NAEC) accreditation at Level 4, the top level of accreditation presented by the NAEC.

“I want to commend our team members for achieving this significant accreditation,” said Ihor S. Sawczuk, M.D., FACS. “They are emblematic of our mission to provide the highest quality and most compassionate care for our patients and their families.”

According to the NAEC, Level 4 epilepsy centers have the professional expertise and facilities to provide the highest level medical and surgical evaluation and treatment for patients with complex epilepsy.

Tuberous Sclerosis Alliance Salutes FDA Approval of Afinitor® DISPERZ as the First Adjunctive Treatment Approved in the US for Patients Aged 2 Years and Older with Tuberous Sclerosis Complex (TSC)-Associated Partial-Onset Seizures

The Tuberous Sclerosis Alliance (TS Alliance) shared that the U.S. Food and Drug Administration has approved the drug Afinitor, manufactured by Novartis Pharmaceuticals, to treat partial-onset seizures in patients with tuberous sclerosis complex (TSC). TSC is a rare genetic disease that causes tumors to form in vital organs; it’s also the leading genetic cause of both epilepsy and autism.

“In TSC, 85 percent of individuals have seizures at some point in their lifetime. But very importantly and urgently, more than 60% experience intractable epilepsy, and this new indication for Afinitor means they now have a much-needed new treatment option,” said TS Alliance President & CEO Kari Luther Rosbeck. “Afinitor is the first mTOR inhibitor approved in the United States for the treatment of epilepsy and further demonstrates TSC as a model system for developing new therapies.”

Afinitor (everolimus) was previously approved by the FDA for the treatment of adult and pediatric patients aged 1 year and older with TSC who have subependymal giant cell astrocytoma (SEGA) and adults with renal angiomyolipomas.

“The TS Alliance played an important role in educating the TSC community about the EXIST-3 Phase III clinical trial of Afinitor, helping raise awareness of the opportunity to participate in the study. The success of this clinical trial ultimately led to this approved indication,” shared Steven L. Roberds, PhD, Chief Scientific Officer of the TS Alliance. “The TS Alliance-sponsored Patient Focused Drug Development meeting in June 2017 provided the opportunity for adults and parents of children with TSC to speak directly to the FDA about the unmet medical needs of TSC and how the TSC community weighed the risk and benefit of mTOR inhibitors to reduce the burden of refractory epilepsy in TSC.”

Study: Determination of Minimal Steady-State Plasma Level of Diazepam Causing Seizure Threshold Elevation in Rats

SIGNIFICANCE: Diazepam elevates seizure threshold at steady-state plasma concentrations lower than previously recognized. The minimally effective plasma concentration provides a reference that may be considered when estimating the diazepam exposure required for acute seizure treatment.

OBJECTIVE: Diazepam, administered by the intravenous, oral, or rectal routes, is widely used for the management of acute seizures. Dosage forms for delivery of diazepam by other routes of administration, including intranasal, intramuscular, and transbuccal, are under investigation. In predicting what dosages are necessary to terminate seizures, the minimal exposure required to confer seizure protection must be known. Here we administered diazepam by continuous intravenous infusion to obtain near-steady-state levels, which allowed an assessment of the minimal levels that elevate seizure threshold.

METHODS: The thresholds for various behavioral seizure signs (myoclonic jerk, clonus, and tonus) were determined with the timed intravenous pentylenetetrazol seizure threshold test in rats. Diazepam was administered to freely moving animals by continuous intravenous infusion via an indwelling jugular vein cannula. Blood samples for assay of plasma levels of diazepam and metabolites were recovered via an indwelling cannula in the contralateral jugular vein.

RESULTS: The pharmacokinetic parameters of diazepam following a single 80-?g/kg intravenous bolus injection were determined using a noncompartmental pharmacokinetic approach. The derived parameters Vd , CL, t1/2? (distribution half-life) and t1/2? (terminal half-life) for diazepam were, respectively, 608 mL, 22.1 mL/min, 13.7 minutes, and 76.8 minutes, respectively. Various doses of diazepam were continuously infused without or with an initial loading dose. At the end of the infusions, the thresholds for various behavioral seizure signs were determined. The minimal plasma diazepam concentration associated with threshold elevations was estimated at approximately 70 ng/mL. The active metabolites nordiazepam, oxazepam, and temazepam achieved levels that are expected to make only minor contributions to the threshold elevations.

Focus on Epilepsy in Older Adults

Rush University Medical Center issued the following news release on March 29:

Diagnosing and treating epilepsy in adults age 65 and older can be complex, and it may take time to find the right treatment. Rush has launched the first comprehensive epilepsy clinic in Chicago dedicated to treating epilepsy in older adults, serving a population that is often not optimally treated.

“Because epilepsy symptoms can be similar to dementia or heart arrhythmias, patients often are undiagnosed or misdiagnosed. Epilepsy often presents differently in older adults and can be subtle,” said Dr. Rebecca O’Dwyer, a neurologist at Rush and assistant professor in the Department of Neurological Sciences at Rush Medical College.

“While epilepsy in older patients is difficult to detect and often is confused with other conditions, which also include stroke and traumatic brain injury, when identified it can usually be easily controlled.”

Currently, one in four newly diagnosed epilepsy patients is 65 or older, and it’s estimated that by 2020, about half of all people living with epilepsy will be 65 or older.

The clinic will offer the latest research, diagnostic and treatment options, include the following:

  • Individualized medication regimens, with access to clinical trials for emerging treatments
  • Access to caregiver support services and groups
  • Systematic cognitive testing
  • Electroencephalographic (EEG) video monitoring
  • Single photon emission computerized tomography (SPECT)
  • Computerized brain mapping
  • Neuromodulatory or surgical therapies
  • Participation in prospective clinical studies