Xenon Expands Ion Channel Neurology Pipeline With Addition Of Xen496, A Phase 3 Ready Potassium Channel Modulator For The Treatment Of Epilepsy

Xenon Pharmaceuticals Inc., a clinical stage, neurology-focused biopharmaceutical company, today reported the expansion of its ion channel product pipeline with XEN496 (active ingredient ezogabine), a Kv7 potassium channel modulator for the potential treatment of epilepsy. Based on feedback from the U.S. Food and Drug Administration (FDA), Xenon anticipates initiating a single, pivotal Phase 3 clinical trial in approximately mid-2019 examining XEN496`s efficacy as a precision medicine treatment of KCNQ2 epileptic encephalopathy (KCNQ2-EE) or EIEE7, which is a rare, severe, pediatric epilepsy caused by loss-of-function missense mutations in the KCNQ2 gene that encodes for the Kv7.2 channel. Published case reports where physicians have used ezogabine in infants and young children with KCNQ2-EE suggest that XEN496 may be efficacious in this often hard-to-treat patient population.

Ezogabine, also known as retigabine, is the only anti-epileptic drug previously approved by the FDA with a mechanism of action that potentiates Kv7-mediated potassium current. Ezogabine was originally approved by the FDA in June 2011 as an adjunctive treatment for adults with focal seizures with or without secondary generalization. GlaxoSmithKline (GSK) marketed ezogabine in various jurisdictions – as Potiga in the U.S. and Trobalt in Europe – but withdrew the drug from the market worldwide in June 2017 citing commercial reasons.

Dr. Simon Pimstone, Xenon`s Chief Executive Officer, said, “We have done an immense amount of diligence leading up to the addition of XEN496 to our novel and robust pipeline of ion-channel, anti-epileptic drugs. Based on feedback from key opinion leaders, advocacy groups, pre-existing literature, and promising data generated to date, we believe there is tremendous support for us to vigorously pursue the development and commercialization of XEN496 in order to reach the pediatric KCNQ2-EE patient population as rapidly as possible.”

Improving Electronic Care For Young Outpatients Who Have Epilepsy

Abstract

PURPOSE: The purpose of this study was to review electronic tools that might improve the delivery of epilepsy care, reduce medical care costs, and empower families to improve self-management capability.

METHOD: We reviewed the epilepsy-specific literature about self-management, electronic patient-reported or provider-reported outcomes, on-going remote surveillance, and alerting/warning systems.

CONCLUSIONS: The improved care delivery system that we envision includes self-management, electronic patient (or provider)-reported outcomes, on-going remote surveillance, and alerting/warning systems. This system and variants have the potential to reduce seizure burden through improved management, keep children out of the emergency department and hospital, and even reduce the number of outpatient visits.

Brain-Protein Study Could Lead To New Epilepsy Drugs

Research identifying the role of a specific protein in the brain in triggering epileptic seizures could spark creation of a new family of medications to help patients with the disease, according to Dr. Gabriel Martz, director of the Epilepsy Center at the Hartford HealthCare Ayer Neuroscience Institute.

The research, published in a recent issue of the academic journal Nature Communications, suggests that the protein collybindin, previously not thought to be relevant in the brain activity that activates or inhibits seizures, could actually play a role. A new medication, he says, could target the collybindin or its binding site in the brain to help curb seizures.

“We have many drugs on the market but most work in fairly similar ways,” Dr. Martz says. “This could lead to a new way of approaching the problem and of reducing cortical excitability, which many people think is the route of the problem of seizures.”

The research, conducted by neuroscientists at the University of Nevada, Las Vegas, expands the understanding of the signaling between neurons in epilepsy. Regulating the proteins in the brain that control cell signaling may lead to better therapies for stopping or preventing seizures entirely.

“This is a new piece in a big and age-old puzzle,” Dr. Martz says. “It is a stepping-off point for other research that will likely teach us more about how the brain works and may help improve the treatment for seizures, depending on whether medications that work on this protein can be identified and would be safe to take.”

Aquestive Therapeutics Announces Tentative FDA Approval for Sympazan™ (clobazam) Oral Film

Aquestive Therapeutics, Inc. announced Sympazan™ (clobazam) oral film has received tentative approval by the US Food and Drug Administration (FDA), for the adjunctive treatment of seizures associated with Lennox-Gastaut Syndrome (LGS) in patients 2 years of age or older. Currently, clobazam is marketed as ONFI® and offered in two formulations – either tablet or oral suspension.

“We saw a need in the LGS community for a simpler, more consistent way to administer a full dose of clobazam – and we are now one step closer to bringing this important treatment to patients, caregivers and physicians,” said Keith J. Kendall, Chief Executive Officer of Aquestive Therapeutics. “This tentative approval for Sympazan is a key milestone for Aquestive, as it represents the first in a series of late stage proprietary products Aquestive plans to commercialize once they are approved. We believe Sympazan and our other products in development solve important therapeutic problems, and will meaningfully improve the lives of patients and their caregivers.”

Electronic Pump Delivers Drugs to the Brain to Stop Seizures

Researchers have engineered an electronic drug delivery tool that pumps seizure-stopping molecules directly to the source of the problem in the brain. The device, reported in the journal Science Advances, offers an alternative to conventional, systemic drugs that can cause unwanted side effects throughout the body.

The device, a microfluidic ion pump, uses an electrical potential to move drug molecules from a reservoir on the device across a short channel and out the tip of the device. The pump can be implanted in the brain at the site of a problem, such as a focal point of a seizure, where it will deliver the drug when needed.

The pump technology is based on the concept of electrophoresis: the transport of molecules through a fluid or gel under the influence of an electrical field. When a voltage is applied, electrons withdraw from the source electrode, and positively charged ions—in this case positively charged drug molecules—are driven out of the reservoir, across the ion-conducting membrane, and out of the device for delivery

ZX008 Reduces Convulsive Seizures in Majority of Patients with Lennox-Gastaut Syndrome in Pilot Study

OBJECTIVE: Lennox-Gastaut syndrome (LGS) is a drug-resistant, childhood onset electroclinical epilepsy syndrome with multiple seizure types and diagnostic electroencephalogram findings. ZX008 (fenfluramine HCl oral solution) was well tolerated and reduced seizure frequency in Dravet syndrome, prompting this phase 2, open-label, dose-finding study of add-on ZX008 in patients with LGS (NCT02655198).

METHODS: Eligible treatment-refractory patients with LGS aged 3-18 years with ?4 documented convulsive seizures (CS) in the prior 4 weeks were administered adjunctive ZX008 twice daily at an initial dose of 0.2 mg/kg/d, with incremental dose escalations up to 0.8 mg/kg/d or 30 mg/d (maximum dose) every 4 weeks in nonresponders (<50% reduction in CS frequency). After 20 weeks (core study), responders were offered entry into a long-term extension study. Seizures were captured via diary. Cardiac safety was monitored by Doppler echocardiography and electrocardiogram.

RESULTS: Thirteen patients were enrolled (mean age = 11.7 years, range = 3-17). Ten (77%) patients completed 20 weeks of ZX008 treatment. During the core study, there was a 53% median reduction (N = 13) in CS; median reduction was 60% in the 10 completers. Eight patients (62%) had a ?50% CS reduction; three (23%) patients had a ?75% reduction. Nine (69%) patients entered the long-term extension study. At 15 months (n = 9), median reduction in CS was 58%; six (67%) patients had a ?50% reduction, and three (33%) patients had a ?75% reduction. The most common adverse events were decreased appetite (n = 4, 31%) and decreased alertness (n = 2, 15%). No echocardiographic signs of cardiac valvulopathy or pulmonary hypertension were observed.

SIGNIFICANCE: ZX008 provided clinically meaningful reduction (?50%) in convulsive seizure frequency in the majority of patients with Lennox-Gastaut syndrome in this pilot study and was generally well tolerated. A phase 3, randomized, controlled study is ongoing.

FDA Approves Diacomit (stiripentol) for Seizures Associated with Dravet Syndrome

The FDA approved Diacomit (stiripentol) for seizures associated with Dravet syndrome in patients 2 years of age and older taking clobazam.

Dravet syndrome is a rare genetic condition that usually appears during the first year of life with prolonged fever-related seizures. Later, other types of seizures typically appear, and additionally, status epilepticus, a potentially life-threatening state of continuous seizure activity requiring emergency medical care, may occur. Children with Dravet syndrome typically experience poor development of language and motor skills, hyperactivity, and difficulty relating to others.

The efficacy of Diacomit was established in two multicenter placebo-controlled double-blind randomized studies (Study 1 and Study 2). Patients enrolled in the studies were required to be aged between 3 years and under 18 years with Dravet syndrome that was inadequately controlled with clobazam and valproate, and experiencing at least 4 generalized clonic or tonic-clonic seizures per month.

Clinical Trial: A Study to Assess the Safety and Efficacy of Lacosamide Versus Placebo (a Pill Without Active Medication) in Patients With Idiopathic Generalised Epilepsy Who Are Already Taking Anti-epileptic Medications (VALOR)

The VALOR study is investigating whether Lacosamide (Vimpat®)—when taken with current anti-epileptic medicine—helps decrease the number of seizures patients experience. This study enrolls children and adults who are at least 4 years or older, have epilepsy with primary generalized tonic-clonic seizures, had at least 2 seizures in the past 12 weeks, and are on a stable dose of anti-epileptic medicines. Patients have a 50% chance of receiving placebo; they have the opportunity to receive Lacosamide for another two years afterwards in an open-label extension study. The study is running in a total of 23 countries, including the United States.

Eligibility Criteria:

Ages Eligible for Study: 4 Years and older (Child, Adult, Older Adult)
Sexes Eligible for Study: All
Accepts Healthy Volunteers: No

Inclusion Criteria:

  • Subject with a confirmed diagnosis at least 24 weeks prior to Visit 1 and a disease onset prior to 30 years of age, consistent with idiopathic generalized epilepsy (IGE) experiencing primary generalizedtonic-clonic (PGTC) seizures (Type IIE) that are classifiable according to the International League Against Epilepsy (ILAE) Classification of Epileptic Seizures (ILAE, 1981)
  • Subject has 3 PGTC seizures during the 16-week Combined Baseline (12-week Historical Baseline plus 4-week Prospective Baseline)
  • If a brain magnetic resonance imaging (MRI)/computed tomography (CT) scan has been performed, there must be no evidence of any progressive abnormality or any lesion likely to be associated with partial-onset seizures
  • Subject has been maintained on a stable dose regimen of 1 to 2 non-benzodiazepine marketed Antiepileptic drugs (AEDs) OR 1 to 3 AEDs (with 1 AED identified as a benzodiazepine) for at least 28 days prior to Visit 1 with or without additional concurrent stable Vagus nerve stimulation (VNS)
  • Subjects are required to have had an electroencephalogram (EEG) report consistent with IGE (eg, generalized 3Hz epileptiform discharges and a normal EEG background) confirmed by a Central Reviewer

 

Exclusion Criteria:

  • History of partial onset seizures or EEG findings indicating partial onset seizures
  • Symptomatic generalized epilepsy, e.g. Lennox-Gastaut Syndrome
  • Lifetime history of suicide attempt, or suicidal ideation in past 6 months
  • Women of child bearing potential must practice contraception according to protocol requirements
  • Regular use of clozapine, monoamine oxidase (MAO-A) inhibitors, barbiturates (for indication other than epilepsy) within 28 days prior to Visit 1
  • Use of Vigabatrin within the last 6 months

Clinical Trail: A Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of Intravenous Brivaracetam in Subjects >= 1 Month to < 16 Years of Age With Epilepsy

The BELLE study is investigating whether Brivaracetam (Briviact®) given intravenously (into the vein) is safe for children and what it does in the body. This study enrolls children who are between 1 month and 16 years of age who have epilepsy and are currently treated with at least one anti-epileptic medicine. All children will receive Brivaracetam in the study, which can take between 3 and 68 days, depending on the child’s condition. The study is running in a total of eight countries, including the US.

Eligibility Criteria:

Ages Eligible for Study: 1 Month to 16 years (child)
Sexes Eligible for Study: All
Accepts Healthy Volunteers: No

Inclusion Criteria:

  • Male or female from >= 1 month to < 16 years of age. For subjects who are < 1 year from birth and who were preterm infants, the corrected gestational age should be used for this entry requirement
  • Weight >= 3 kg (6.6 lbs)
  • Diagnosis of epilepsy
  • Acceptable candidate for venipuncture and intravenous (iv) infusion
  • Treatment with >=1 anti epileptic drug (AED; including BRV) without a change of dose regimen for at least 7 days prior to Screening
  • No treatment with vagus nerve stimulation (VNS), OR the subject is being treated with VNS and the settings have been constant for >=7 days prior to Screening
  • For female subjects: not of childbearing potential, OR of childbearing potential and not sexually active/negative pregnancy test, OR of childbearing potential and sexually active/negative pregnancy test/uses medically acceptable contraceptive methods

Exclusion Criteria:

  • Subject has previously received iv Brivaracetam (BRV) in this study
  • Subject is being treated with BRV at a dose >5mg/kg/day (rounded) or >200mg/day for subjects with body weights >40kg
  • Subject requires or is likely to require a change in concomitant antiepileptic drug(s) (AED[s]), dose of concomitant AED(s), or formulation of AED(s) during the 7 days prior to the intravenous (iv) pharmacokinetic (PK) Period
  • Subject is likely, in the opinion of the Investigator, to require rescue medication during the Initiating Oral BRV (IOB) Treatment or iv PK Periods
  • Subject has experienced generalized convulsive status epilepticus in the 28 days prior to Screening or during the Screening Period

New Guidelines for the Treatment of New-Onset Epilepsy: AAN, AES Update Practice Guidelines

The American Academy of Neurology (AAN) and the American Epilepsy Society (AES) have provided new recommended practice guidelines for the management of new-onset and treatment-resistant epilepsy with anti-epileptic drugs (AEDs). The new guidelines highlight the evidence supporting the use of lamotrigine, vigabatrin, levetiracetam, pregabalin, gabapentin, and zonisamide for reducing the frequency of seizures in new-onset focal epilepsy and treatment-resistant epilepsy.

An expert subcommittee was formed consisting of members of the AAN and AES to update the 2004 evidence-based guidelines on epilepsy treatment with AEDs. Based on recent evidence, the investigators recommend the use of gabapentin and topiramate in adults and children with newly diagnosed epilepsy.

Class I and II studies support the use of rufinamide, ezogabine, clobazam, perampanel, and immediate-release pregabalin as add-on therapy in adults with treatment-resistant focal epilepsy; however, the adverse events associated with these therapies warrant careful consideration prior to prescribing. Other studies (class I, II, and III) suggest eslicarbazepine at 800 mg/day and 1200 mg/day may possibly be effective in treatment-resistant adult epilepsy.