Epilepsy is a common neurological disorder characterized by seizures.4 There are approximately 3.4 million people in the U.S. living with epilepsy, and approximately 65 million worldwide.5 The majority of people with epilepsy (60%) have partial-onset seizures, which are located in just one part of the brain.6
People with epilepsy are also at risk for accidents and other health complications including falling, drowning, car accidents, depression and anxiety and SUDEP.3
Despite the availability and introduction of many new AEDs, overall treatment outcomes for people with epilepsy have not improved in 20 years1 and the CDC states that nearly 60 percent of people with epilepsy are still experiencing seizures, showcasing a great unmet need for patients and their families.2 Additionally, while some patients may experience a reduction in seizure frequency with current treatments, they continue to live with seizures.2 The impact of continued seizures can be debilitating and life-altering and the complications of epilepsy can include depression and anxiety, cognitive impairment and SUDEP (sudden unexpected death in epilepsy).3
SK Life Science, Inc., a subsidiary of SK Biopharmaceuticals Co., Ltd., an innovative biopharmaceutical company focused on developing and bringing to market treatments for central nervous system (CNS) disorders, announced today that the U.S. Food and Drug Administration (FDA) has accepted the filing of its New Drug Application (NDA) for cenobamate. Cenobamate, an investigational antiepileptic drug for the potential treatment of partial-onset seizures in adult patients, is the first molecule discovered and developed from inception through to the submission of an NDA without partnering or out-licensing from a Korean pharmaceutical company. SK life science plans to commercialize cenobamate independently.
The NDA submission is based on data from pivotal trials that evaluated the efficacy and safety of cenobamate. Results from the clinical trial program, which enrolled more than 1,900 patients, have been presented at medical conferences including the American Academy of Neurology (AAN) and the American Epilepsy Society (AES) Annual Meetings.
“The FDA’s acceptance of our NDA filing is a critical step toward our goal of introducing a new treatment option for people with uncontrolled epilepsy,” said Marc Kamin, M.D., chief medical officer at SK life science. “We look forward to working with the FDA during their review of our data on cenobamate.”
Cenobamate (YKP3089) was discovered by SK Biopharmaceuticals and SK life science and is being investigated for the potential treatment of partial-onset seizures in adult patients.
Cenobamate’s mechanism of action is not fully understood, but it is believed to work through two separate mechanisms: enhancing inhibitory currents through positive modulation of GABA-A receptors and decreasing excitatory currents by inhibiting the persistent sodium current.
Global trials for adults with partial-onset seizures are ongoing to evaluate cenobamate safety. Additional clinical trials are investigating cenobamate safety and efficacy in other seizure types.
The U.S. Food and Drug Administration (FDA) accepted the filing of the New Drug Application for cenobamate for the potential treatment of partial-onset seizures in adults in February 2019.
Cenobamate is not approved by the FDA or any other regulatory authorities. Safety and efficacy have not been established.
1. Chen Z, Brodie MJ, Liew D, Kwan P. Treatment outcomes in patients with newly diagnosed epilepsy treated with established and new antiepileptic drugs: a 30-year longitudinal cohort study. https://www.ncbi.nlm.nih.gov/pubmed/29279892 Published online December 26, 2017.
2. Center for Disease Control and Prevention. Active Epilepsy and Seizure Control in Adults — United States, 2013 and 2015. https://www.cdc.gov/mmwr/volumes/67/wr/mm6715a1.htm?s_cid=mm6715a1 Accessed December 27, 2018.
3. Epilepsy Foundation. Staying Safe. https://www.epilepsy.com/learn/seizure-first-aid-and-safety/staying-safe Accessed November 20, 2018.
4. Epilepsy Foundation. What Is Epilepsy? https://www.epilepsy.com/learn/about-epilepsy-basics/what-epilepsyAccessed November 20, 2018.
5. Epilepsy Foundation. Facts about Seizures and Epilepsy. https://www.epilepsy.com/learn/about-epilepsy-basics/facts-about-seizures-and-epilepsy Accessed November 20, 2018.
6. National Institute of Neurological Disorders and Stroke. The Epilepsies and Seizures: Hope through Research. https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Hope-Through-Research/Epilepsies-and-Seizures-Hope-Through#3109_9 Accessed November 20, 2018.
The US Food and Drug Administration (FDA) has granted expanded approval of perampanel (Fycompa, Esai Inc) for the treatment of “partial-onset seizures (POS) with or without secondary generalized seizures” in patients as young as 4 years, the manufacturer reports.
The expanded indication is for both monotherapy and adjunctive use in patients 4 years of age and older.
The drug was initially approved in 2012 as adjunctive treatment for POS. This was followed in 2015 by approval as adjunctive treatment for primary generalized tonic-clonic seizures in patients with epilepsy who were at least 12 years of age, and in 2017 as monotherapy for POS with or without secondary generalized seizures in the same age group.
To date, the drug “is approved in 55 countries and has treated more than 200,000 patients worldwide across all indications,” the company reported in a press release.
The new approval for the antiepileptic drug (AED) includes both film-coated tablet and oral suspension formulations. The former is available in 2-, 4-, 6-, 8-, 10-, and 12-mg doses; the latter is available at a dose of 0.5 mg/mL.
“Taking an AED as prescribed every day is a critical part of reaching the goal of seizure freedom for pediatric patients,” Jesus Eric Piña-Garza, MD, pediatric neurologist at TriStar Medical Group Children’s Specialists, Nashville, Tennessee, said in the same release.
“With Fycompa, children and their parents now have a once-daily dosing option with a long half-life that can fit into their increasingly busy lives,” added Piña-Garza.
AMPA Receptor Antagonist
It is currently estimated that approximately 470,000 US children have epilepsy. Of these, up to 40% will have uncontrolled seizures even with existing treatments.
The company notes that “breakthrough seizures” can also occur because of a number of factors, including illness, loss of sleep, and missed medication doses.
“Fycompa has a long half-life and in a pharmacokinetic study, it has been demonstrated that in the event of a missed dose, plasma levels remain relatively stable,” it adds.
The drug is a selective, noncompetitive alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist.
In addition to past phase 3 trials of adults with POS, two safety studies of children with epilepsy aged 4 to 11 years have been conducted. In the safety studies, 225 pediatric patients received the drug at baseline, 110 were exposed to the drug for at least 6 months, and 21 were exposed for at least a year. Adverse reactions “were similar to those seen in patients 12 years of age and older,” the company reports. It adds that final results of these studies will be presented at an upcoming medical meeting.
The company notes that perampanel, “like other AEDs, may cause suicidal thoughts or actions in a very small number of people, about 1 in 500.” It also may cause psychiatric problems, such as new or worse aggressive behavior or hostility, hallucinations, paranoia, confusion, extreme changes in mood, or memory difficulties.
Other adverse events (AEs) may include dizziness, sleepiness, increased risk for falls, and serious allergic reactions. The most commonly reported AEs include dizziness, tiredness, irritability, falls, nausea and vomiting, and weight gain.
The US Drug Enforcement Administration has designated the product as a federally controlled substance (CIII).
A recent study conducted by Duquesne University professor John Tomko has linked high dosages of the epilepsy drug Gabapentin to opioid abuse. Based on the findings of the study, Tomko recommends prescribing and distributing Gabapentin with more scrutiny and oversight.
Gabapentin, brand name Neurontin, has been formally approved by the Food and Drug Administration (FDA) to treat symptoms of epilepsy, such as seizures and post herpetic neuralgia, a type of pain caused by shingles. According to Tomko, however, Gabapentin has been used off-label (i.e., not approved by the FDA) to treat other ailments such as back pain, anxiety, bipolar disorder, migraines and more.
Tomko’s study found that subjects in UPMC Mercy’s Behavioral Health units were twice as likely to test positive for illicit drug abuse and Hepatitis C when they were taking more than 1800 milligrams of Gabapentin a day.
Courtesy of John Tomko
John Tomko is an associate professor at the university’s School of Pharmacy.
Tomko noted that these off-label prescriptions of Gabapentin are often unclear.
“Many of these off-label uses have little positive data supporting their use or may even have outcomes that do not support their use,” Tomko said. “Previous works have shown that patients may be using [Gabapentin] to enhance the effect of illicit opiates or opiate replacement treatments such as methadone or buprenorphine.”
It is this link between Gabapentin and opiates with which Tomko’s study was concerned. The study was first prompted by a correlation between patients visiting UPMC Mercy’s mental health units who tested positive for drugs of abuse, and who had also been prescribed Gabapentin for off-label purposes. While other previous studies have shown that Gabapentin is often abused, Tomko’s study sought to provide a model that can predict opiate abuse when a patient requests a high dose of Gabapentin from his or her doctor.
The study, which lasted from December 2015 to January 2017, focused on all patients admitted to UPMC Mercy Behavioral Health units. Tomko’s research found that, of the 23.3 percent of patients who were prescribed Gabapentin, only 6.7 percent were taking the drug for an FDA-approved purpose. This, combined with the fact that 67.2 percent of Gabapentin users were taking 1800 milligrams a day or more, suggested to researchers that there was a problem with the use of Gabapentin among patients. Of particular note was the fact that 9 percent of patients prescribed Gabapentin were doing so with an “undetermined reason for use,” according to Tomko.
Tomko stressed that this study identifies Gabapentin as a drug used to enhance the effect of opioids, rather than as a gateway drug to opioid abuse itself. Being the first study of its kind to provide a predictive model for drug abuse, Tomko hopes that the findings of his study will cause doctors to consider prescribing Gabapentin with more scrutiny.
“If a patient is persistent in their requests, a physician may wish to inquire more about the reasons for the request and perhaps even request a urine drug screen to rule out illicit substance use,” Tomko said.
He believes that the findings of this study support potentially considering Gabapentin as a controlled substance by the Drug Enforcement Administration.
Douglas J. Bricker, dean of the School of Pharmacy at Duquesne, praised Tomko and his study.
“The research conducted by Tomko provides primary care physicians and other healthcare prescribers with pertinent information to recognize that patients who are prescribed or who ask for higher doses of Gabapentin should be aware of the association between this behavior and Substance Use Disorders,” Bricker said. “In this era of extensive opioid misuse, having predictive warning tools … can be very beneficial in combating the overuse and misuse of opioids.”
Tomko’s study adds not only to the existing body of work surrounding Gabapentin and its potential for misuse, but also provides a clear indication that high doses of the drug — often prescribed for unclear or off-label purposes — is linked to abuse of opioids.
Tomko and his team hope that this study will help physicians recognize more subtle signs of substance abuse and will raise awareness of substance use disorders.
Overall treatment outcomes in patients with epilepsy have failed to improve, despite the proliferation of several newer antiepileptic drugs (AEDs) with different mechanisms, according to a recent study published in JAMA Neurology.
“Despite the availability of over 15 new drugs, overall seizure control in newly diagnosed patients has not fundamentally changed,” said senior author, Patrick Kwan, MD, PhD, Department of Medicine, The University of Melbourne, Parkville, Australia. “Newer AEDs are generally effective, and many have favorable safety profiles, but all have been reported to have efficacy similar to the established AEDs when used as monotherapy or adjunctive treatment.”
In a previous study, Dr. Kwan and colleagues initially followed 470 patients with newly diagnosed epilepsy between 1982 and 1998. They found that greater than one-third of patients continued to experience seizures despite AED treatment. Furthermore, subjects who exhibited no response to first or second AED regimens were likely to manifest refractory epilepsy.
In this current study, Dr. Kwan and colleagues sought to assess whether the overall treatment outcomes have changed with the advent of these additional drugs. They analyzed an expanded cohort of 1,795 newly diagnosed patients followed up from 1982 to 2014 at the Epilepsy Unit at the Western Infirmary.
The team followed 1,795 patients (53.7% male; median age: 33 years) in the current study for at least 2 years or until death. Median follow-up for the study was 11 years. They assessed the probability of attaining 1-year seizure freedom for each AED regimen, and used multivariable models to assess the associations between risk factors and AED treatment outcome after controlling for demographic and clinical characteristics.
The researchers defined an AED regimen as either monotherapy or a combination of two or more drugs. All initial regimens were montherapies.
During last follow-up, 1,440 patients (80.2%) received AED monotherapy and 355 patients (19.8%) took combinations of two or more AEDs.
In total, 1,144 patients (63.7%) were seizure free for 12 or more months, and 993 subjects (55.3%) became seizure free after treatment with a single AED. Further, 820 subjects (45.7%) attained at least 1 year of seizure freedom with their first AED monotherapy, and 208 subjects (28.0%) attained this freedom with a second regimen.
The team found that if an initial AED failed, second regimens led to seizure freedom 11.6% of the time and third regimens were effective in 4.4%.
“In our cohort, there had been a continual increase in the use of the new AEDs, both as initial and subsequent treatments, since the early 1990s,” the authors wrote. “Yet compared with our initial analysis in the first 470 patients, the seizure-free rate observed in the present study (63.7%) was virtually unchanged from that of 16 years ago (64.0%).”
Results of the present study also confirmed previous observations by the researchers that the chances of becoming seizure free drops with each subsequent AED regimen.
“Most patients who attain control do so with the first or second AED. The probability of achieving seizure freedom diminishes substantially with each subsequent AED regimen tried. More than one-third of patients experience epilepsy that remains uncontrolled,” the researchers concluded, adding that most newer AED drugs have similar mechanisms to old ones, and novel therapies are needed.
“We’re not being nihilistic and saying there’s no hope—for individual patients who tried a second and a third [regimen], there is a respectable chance [for seizure freedom]. But it does get harder after you try two or three drugs,” Dr. Kwan noted.
“Patients, their families, and doctors are desperate for new paradigms and novel approaches to treat epilepsy. We need new approaches, more adventurous approaches, rather than pouring more money into getting another ‘me-too’ drug out there,” he reflected.
Source: MDLinx.com article by N. Saleh, MD, MS
The US Food and Drug Administration (FDA) has accepted the New Drug Application (NDA) for an investigational nasal spray therapy intended for the acute treatment of seizure clusters.
Midazolam Nasal Spray—from global biopharmaceutical company UCB, Brussels, Belgium (UCB)—has been previously granted Orphan Drug and Fast Track designations by the FDA. It’s now set for a potential market approval in early 2019.
The spray’s application is supported by data from the phase 3 Acute Rescue Therapy in Epilepsy with Midazolam Intranasal Spray (ARTEMIS 1) trial, in which a 5mg intranasal dose of the therapy was tested for efficacy and safety in 292 patients with seizure clusters in a randomized, double-blind, placebo-controlled setting.
Investigators had tested for a primary endpoint of seizure termination within 10 minutes following therapy administration, as well as no recurring seizures from 10 minutes to 6 hours following administration. The study had concluded in March.
UCB has previously acquired the midazolam nasal spray from research foundation Proximagen in June, with both companies collaborating on the NDA filing. If approved, midazolam would be the first new therapy approved for seizure clusters in 17 years.
Seizure clusters—estimated to affect 150,000-plus US patients with refractory epilepsy—are commonly unpredictable events, even in patients adhering to anti-epileptic therapy regimens. The condition often drives annual rates of emergency room visits and hospitalizations, and require an acute care plan with immediate patient access.
Jeff Wren, head of Neurology and executive vice president at UCB, said that managing seizure clusters remains a challenge for “thousands of patients and caregivers.”
“There is an unmet need for effective and convenient acute treatment of seizure clusters that can rapidly end ongoing seizures and potentially prevent or delay their reoccurrence,” Wren said in a statement. “With midazolam nasal spray, UCB hopes to expand and diversify the treatment choices we provide to the epilepsy community, complementing our already strong epilepsy portfolio and providing additional solutions to help patients.”
Source: By Kunzmann for MDMag.com