Generic Antiepileptic Drugs – Safe or Harmful in Patients with Epilepsy?

Generic antiepileptic drugs (AED) are significantly cheaper than brand name drugs, and may reduce overall health care expenditures. Regulatory bodies in Europe and North America require bioequivalence between generic and innovator drugs with regard to area under the plasma concentration–time curve (AUC) and peak plasma concentration (Cmax); strict cutoff values have been defined. The main issue is if bioequivalence ensures therapeutic equivalence. Are switches from brand to generic, or between generic AEDs entirely safe or potentially harmful in patients with epilepsy?

We summarized and evaluated the available evidence from bioequivalence, health care utilization, and clinical studies on safety of generic AEDs. In most cases, variations in AUC and Cmax were negligible when comparing innovator and generic AEDs. Due to interindividual pharmacokinetic and pharmacodynamic variability, measured differences between innovator and generic drugs may be the same as differences between different lots of the same brand. Studies from several countries based on insurance data have reported an increase in health care usage after switch from brand to generic AEDs; switchback rates are significantly higher for AEDs compared to other compounds. Patients may be confused, and nonadherence may increase, when AEDs are switched between manufacturers, perhaps due to changes in medication shape and color. But clinical studies do not report changes in seizure frequency and tolerability attributable to generics.

Sufficient evidence indicates that most generics are bioequivalent to innovator AEDs; they do not pose a relevant risk for patients with epilepsy. However, some patients are reluctant towards variations in color and shape of their AEDs which may result in nonadherence. We recommend administering generics when a new AED is initiated. Switches from brand to generic AEDs for cost reduction and between generics, which is rarely required, generally seem to be safe, but should be accompanied by thorough counseling of patients on low risks.

NeuroPace Launches Next Generation RNS System, the World’s Only Brain-Computer Interface for the Treatment of Refractory Epilepsy

NeuroPace, Inc. announced on June 1 the launch of its Next Gen RNS® System for the treatment of refractory epilepsy, which affects an estimated 1 million people in the United States alone. The RNS System is a type of brain-computer interface that treats seizures by continuously monitoring brain waves, recognizing each patient’s unique “seizure onset fingerprint,” and automatically responding with imperceptible electrical pulses before seizures occur.

Epilepsy is a chronic disorder originating in the brain, characterized by unpredictable seizures. Approximately 50 million people worldwide have epilepsy, making it one of the most common neurological diseases globally. In the United States, more people live with epilepsy than autism spectrum disorder, Parkinson’s disease, multiple sclerosis and cerebral palsy combined. About one-third of individuals living with epilepsy are refractory to medications.

“NeuroPace revolutionized epilepsy therapy in 2013 with the introduction of the world’s first closed-loop, brain-responsive neuromodulation system—the only device that applies brain-computer interface technology to successfully treat refractory focal onset epilepsy,” said NeuroPace CEO Frank Fischer. “We have maintained our relentless focus on product innovation, and are excited to make the Next Gen RNS System—with twice the longevity and twice the memory in the same size device—available to our physician customers and their patients.”

The Next Gen RNS System is a major advance over the existing system. The battery life of the RNS Neurostimulator has more than doubled from 3.9 to 8.4 years at medium stimulation settings, which will allow patients to live their lives with fewer interruptions. The amount of available memory has also doubled, which will allow physicians to review a wider set of brain activity data.

UCB Receives CHMP Positive Opinion for Adjunctive Use of BRIVIACT as Paediatric Treatment for Epilepsy Patients

UCB announced on June 1 that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a positive opinion for BRIVIACT(R) (brivaracetam) to extend the therapeutic indication to include adjunctive therapy in the treatment of partial onset seizures with or without secondary generalisation in patients with epilepsy from 4 years of age.

The European Commission is expected to make a decision based on this CHMP positive opinion over the coming weeks. When approved, BRIVIACT’s paediatric indication will represent an important new treatment option for children with epilepsy, their family and care-givers, as well as European healthcare professionals.

BRIVIACT is the newest medicine in the family of the synaptic vesicle protein 2A (SV2A) anti-epileptic drugs (AED) – a class of medicines discovered and developed by UCB. BRIVIACT demonstrates a high and selective affinity for SV2A in the brain which may contribute to its anticonvulsant effects.

“We’re very proud to be at the forefront of global epilepsy management, and to be able to provide healthcare professionals, their patients and their family members with new and additional choices to support them in their individual epilepsy journeys.” said Jeff Wren, Executive Vice-President, Head of UCB’s Neurology Patient Value Unit. “Today’s positive CHMP opinion for BRIVIACT(R) is another important step forwards in our efforts to realize true patient value and to further improve the lives of this highly impacted patient population by providing additional treatment options.”

Comparative Effectiveness of Levetiracetam vs Phenobarbital for Infantile Epilepsy

Objective: To compare the effectiveness of levetiracetam vs phenobarbital for nonsyndromic infantile epilepsy.

Main Outcomes and Measures: The binary outcome was freedom from monotherapy failure at 6 months, defined as no second prescribed antiepileptic medication and freedom from seizures beginning within 3 months of initiation of treatment. Outcomes were adjusted for demographics, epilepsy characteristics, and neurologic history, as well as for observable selection bias using propensity score weighting and for within-center correlation using generalized estimating equations.

Results: Of the 155 infants in the study (81 girls and 74 boys; median age, 4.7 months [interquartile range, 3.0-7.1 months]), those treated with levetiracetam (n?=?117) were older at the time of the first seizure than those treated with phenobarbital (n?=?38) (median age, 5.2 months [interquartile range, 3.5-8.2 months] vs 3.0 months [interquartile range, 2.0-4.4 months]; P?<?.001). There were no other significant bivariate differences. Infants treated with levetiracetam were free from monotherapy failure more often than those treated with phenobarbital (47 [40.2%] vs 6 [15.8%]; P?=?.01). The superiority of levetiracetam over phenobarbital persisted after adjusting for covariates, observable selection bias, and within-center correlation (odds ratio, 4.2; 95% CI, 1.1-16; number needed to treat, 3.5 [95% CI, 1.7-60]).

Conclusions and Relevance: Levetiracetam may have superior effectiveness compared with phenobarbital for initial monotherapy of nonsyndromic epilepsy in infants. If 100 infants who received phenobarbital were instead treated with levetiracetam, 44 would be free from monotherapy failure instead of 16 by the estimates in this study. Randomized clinical trials are necessary to confirm these findings.

Study: Efficacy of Antiepileptic Drugs in the Adjunctive Treatment of Refractory Partial-Onset Seizures – Meta-Analysis of Pivotal Trials

OBJECTIVE: In the absence of randomized clinical trials (RCTs) assessing the relative efficacy of antiepileptic drugs (AEDs), meta-analyses are useful resources for informing treatment choices. This meta-analysis assesses the relative efficacy and tolerability of AEDs for adjunctive treatment of refractory partial onset seizures (POS).

METHODS: A systematic literature review was conducted to identify pivotal AED trials serving as the basis for US Food and Drug Administration (FDA) approval.

INCLUSION CRITERIA:
1) double-blind, placebo-controlled, parallel-group design, with 8- to 14-week maintenance period; 2) enrolled patients ?16years with refractory POS, including complex partial seizures; 3) study was conducted between 1993 and 2013; and; 4) patients received FDA-approved dosage. Outcomes analyzed: 1) 50% responder rate (?50% reduction from baseline in seizure frequency); 2) seizure freedom (proportion of seizure-free patients); and 3) discontinuation due to adverse events (AEs). DerSimonian and Laird random-effects model was used to derive odds ratios (OR) and 95% confidence intervals (CI).

RESULTS: A total of 29 publications for 11 AEDs (eslicarbazepine, ezogabine, gabapentin, lacosamide, levetiracetam, perampanel, pregabalin, tiagabine, topiramate, vigabatrin, and zonisamide) were included in the meta-analysis. Tiagabine 56mg/day (OR 8.82, 95% CI: 2.77-28.11), pregabalin 600mg/day (OR 8.08, 95% CI: 5.45-11.98), and vigabatrin 3000mg/day (OR 6.23, 95% CI: 1.46-26.20) had the highest OR versus placebo of 50% response. The odds of seizure freedom were ?7 times greater than placebo for levetiracetam 3000mg/day (OR 11.00, 95% CI: 2.08-58.06), vigabatrin 3000mg/day (OR 7.41, 95% CI: 1.31-41.84), and ezogabine 1200mg/day (OR 7.09, 95% CI: 0.36-58.06). Patients were more likely to discontinue any AED (except low-dose pregabalin) than placebo.

CONCLUSION: In this meta-analysis of >9000 patients, those treated with AEDs were more likely than placebo to achieve seizure response or freedom. Patients receiving pregabalin, tiagabine, and vigabatrin had the highest odds of ?50% reduction in seizures, and patients receiving ezogabine, levetiracetam, and vigabatrin had the highest odds of seizure freedom.

Clinical trial: Registry of Subjects With Drug Resistant Epilepsy and Treated With the VNS Therapy System. (CORE-VNS)

Summary: Multicenter global post-market registry of subjects diagnosed with drug resistant epilepsy and treated with the VNS Therapy System. The purpose of this registry is to evaluate clinical outcome and safety data in subjects with drug resistant epilepsy treated with the VNS Therapy System. The study will collect outcomes for subjects treated with VNS Therapy in a real-world setting.

Primary Outcome Measures Include: Seizure Frequency, Maximum Seizure Free Period, Seizure Severity

Study start date: February 5, 2018
Estimated study completion date: March 31, 2027

Eligibility Criteria

Ages Eligible for Study: Child, Adult, Senior
Sexes Eligible for Study: All
Accepts Healthy Volunteers: No
Sampling Method: Non-Probability Sample

Inclusion Criteria:

  • Clinical diagnosis of drug resistant epilepsy treated with VNS Therapy. Eligible subjects include those not previously treated with VNS Therapy as well as subjects receiving replacement generators.
  • Able and willing to comply with the frequency of study visits.
  • Subject, or legal guardian, understands study procedures and voluntarily signs an informed consent in accordance with institutional policies. In the event that the subject is under the age of 18, the subject may also be required (per EC/IRB) to sign an assent affirming their agreement to participate.

 

Exclusion Criteria:

  • There are no exclusion criteria in this study. Investigators should refer to the local instructions for use for VNS Therapy.

LYRICA (pregabalin) Oral Solution CV Phase 3 Trial in Pediatric Epilepsy Meets Primary Endpoint

Pfizer Inc. announced positive top-line results of a Phase 3 study examining the use of LYRICA (pregabalin) Oral Solution CV as adjunctive therapy for partial onset seizures in pediatric epilepsy patients one month to less than four years of age. Results showed that adjunctive treatment with LYRICA 14 mg/kg/day resulted in a statistically significant reduction in seizure frequency versus placebo, the primary efficacy endpoint. Treatment with LYRICA at the lower dose (7 mg/kg/day) did not result in a statistically significant reduction in seizure frequency versus placebo. The study was a post-marketing requirement by the U.S. Food and Drug Administration (FDA). LYRICA is not approved as adjunctive therapy for partial onset seizures in pediatric epilepsy patients one month to less than four years of age.

The Phase 3 top-line results reinforce the efficacy and safety profile of LYRICA for pediatric epilepsy patients, said James M. Rusnak, M.D., Ph.D., Chief Development Officer, Internal Medicine, Pfizer Inc. These findings add to the data available for LYRICA in the pediatric patient population for a complex and difficult-to-treat condition.

The LYRICA Pediatric Epilepsy Program is composed of a total of six studies in patients with epilepsy evaluating LYRICA as adjunctive therapy, four of which have been completed and two of which are actively enrolling. For more information, visit www.clinicaltrials.gov.

Results of Phase 3 Study of Cannabidiol Oral Solution in Lennox-Gastaut Syndrome Show Significant Reduction in Drop Seizures

GW Pharmaceuticals plc along with its U.S. subsidiary Greenwich Biosciences announced the publication of results from a Phase 3 study of cannabidiol oral solution (Epidiolex®) in patients with Lennox-Gastaut syndrome (LGS), a rare, severe and difficult-to-treat form of childhood-onset epilepsy. In this study, both evaluated doses of cannabidiol oral solution significantly reduced the monthly frequency of drop seizures compared to placebo in highly treatment-resistant patients when added to existing treatment.

“This publication in The New England Journal of Medicine marks another landmark for GW Pharmaceuticals with data again published by a top-tier, peer-reviewed journal. It offers further evidence for cannabidiol oral solution as a potential future treatment option for patients with this devastating condition,” said Justin Gover, GW’s Chief Executive Officer. “We are now in the latter stages of the FDA’s review of our New Drug Application and look forward to a decision from FDA in late June. If approved, we expect to make this important potential new medicine available to U.S. patients with LGS in the second half of the year.”

FutureNeuro and GreenLight Medicines Partner to Develop Treatments for Epilepsy

A new partnership between FutureNeuro, the SFI Research Centre for Chronic and Rare Neurological diseases based at RCSI, and GreenLight Medicines, an indigenous Irish biopharmaceutical company, has been formed to develop new cannabis-based treatments for drug resistant epilepsies, and in particular, childhood epilepsies.

The research will explore how cannabidiol (CBD) and other non-psychoactive molecules from the cannabis plant can reduce seizures. It will also look at optimizing the effectiveness of this new approach to treat epilepsy.

“This project has strong alignment with FutureNeuro’s strategic goal to bring novel treatments to patients in Ireland with difficult to control epilepsy” said Professor David Henshall, academic supervisor on the project and FutureNeuro Director. [Dr. Henshall is a former CURE grantee]

Dr. Colin Doherty, National Clinical Lead for Epilepsy and a Principal Investigator at the FutureNeuro Centre said, “The use of cannabis to treat epilepsy offers a tantalising new horizon for severe disabling seizures. The mechanism by which CBD exerts its antiepileptic effects is currently unknown, and this impactful research will help to provide clinical evidence of its long-term efficacy, as well as data on any long-term side effects.”

Rush is First to Use Microburst Vagus Nerve Stimulation for Drug-Resistant Epilepsy

Epilepsy patients who have not responded to standard drug treatments may benefit from a new therapy that delivers high frequency bursts of electrical stimulation, called microbursts, to the brain. Rush University Medical Center in Chicago is the first health care provider in the world to provide this treatment, known as microburst vagus nerve stimulation.

The treatment is akin to a heart pacemaker. A surgeon places an electronic pulse generator under the skin in the chest and attaches it to the left vagus nerve, which runs down the side of the body from the stem of the brain through the neck and chest to the abdomen.

The device sends regular electrical pulses through the vagus nerve to the brain to prevent epileptic seizures from occurring. The stimulator’s settings can be changed according to each patient’s needs using a special programming wand, with no additional surgery needed.

The study consists of two groups of patients with epilepsy, enrolling up to 40 patients in total at approximately 15 sites in the United States. The first group will include 20 patients with primary generalized tonic-clonic seizures. The second group will consist of 20 patients with partial onset seizures, including complex partial seizures with or without secondary generalization.

Each patient will participate in the study for a minimum of 15 months. The study will measure the percent change in seizure frequency and occurrence of stimulation-related adverse events in comparison to a patient’s baseline. Activation of various areas of the brain in response to stimulation will be assessed using functional magnetic resonance imaging or fMRI. Patients also will be evaluated to assess changes from baseline in seizure severity, quality of life, antiepileptic drug use, suicidality and adverse events.