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New Epilepsy Drugs, Expanded Therapy Options
How the Experts Choose

Article In Brief

Newly-approved epilepsy drugs and other therapies in development may be effective in treating cases that were once resistant to treatment, epileptologists say. But while experts said they appear promising, they also were not ready to skip older options for which more data are available.

New epilepsy medications and other products in the pipeline may soon start to chip away at the stubborn one-third of epilepsy cases that are resistant to treatment, epileptologists told Neurology Today in a series of telephone interviews. What's more, they said, the new therapies may also offer the possibility of seizure control with fewer side effects.

Among the recent advances in epilepsy care are a much-anticipated new drug for uncontrolled focal seizures in adults, an added indication approved for the first cannabidiol (CBD)-based medication for children with uncontrolled seizures associated with several rare conditions, and rescue medications in the form of nasal sprays.

Epilepsy researchers said the new drugs and others in development will begin to fill niches in both adult and pediatric epilepsy care and expand treatment options for some patients.

“There have been dramatic changes in the past few years, and there are even more dramatic ones on the horizon,” said James W. Wheless, MD, FAAP, FAAN, professor and chief of pediatric neurology at the University of Tennessee Health Science Center.

But Dr. Wheless said that in spite of the progress achieved in recent years in developing new treatments, “seizure freedom rates haven't improved dramatically. We haven't found the Holy Grail yet.”

Researchers anticipate that some genetic-based therapies will likely be in the next wave of epilepsy treatments. The general approach is to target underlying genetic causes of epilepsy rather than treating the symptom—seizures.

“We have come to understand that epilepsy has many causes,” said Dr. Wheless, who is working with companies that are developing therapies that would target the SCN1A gene, which is implicated in Dravet syndrome.

“The goal is to modify the one good copy of the gene that these patients' have, which will correct the channel defect,” he said. “This should restore ‘normal’ brain function and dramatically improve the symptoms, one of which is uncontrolled seizures.”

Newer Treatment Options

Some of the newer treatment options include cenobamate (Xcopri), which was approved by the US Food and Drug Administration (FDA) in November 2019 as an adjuvant therapy for treatment-resistant partial-onset seizures in adults. The experts said the drug is a noteworthy addition, but it is too soon to say whether it will be a game changer for many patients.

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“Seizure freedom rates havent improved dramatically. We havent found the Holy Grail yet.”—DR. JAMES W. WHELESS

Gregory L. Krauss, MD, professor of neurology at Johns Hopkins University who was a co-investigator for the drug's clinical trials, said that in two placebo-controlled regulatory trials, about 60 percent had marked seizure reduction (greater than 50 percent) and 20 percent became seizure free, despite having highly treatment-resistant epilepsy.

Dr. Krauss said that two-thirds of his 49 patients have continued cenobamate treatment for up to eight years, and 12 achieved long-term seizure freedom. The drug's mechanism of action is not fully understood, though its strong efficacy may relate to its activity as a selective sodium channel blocker, preferentially inhibiting a persistent sodium current, Dr. Krauss said. It also may enhance release of the gamma aminobutyric acid inhibitory neurotransmitter.

Several patients in clinical trials developed serious allergic reactions with DRESS syndrome (drug reaction with eosinophilia and systemic symptoms). In a subsequent open-label safety study, more than 1,300 patients started treatment using very low, slowly titrated initial doses and they did not develop the syndrome.

Dr. Krauss said the while cenobamate was approved for patients with intractable epilepsy, it may have broader potential.

“The question is how patients with less refractory epilepsy than those enrolled in the placebo-controlled trials will do and so far, based on the large safety study results and our initial clinical use, cenobamate looks pretty effective,” he said.

Cannabidiol

A CBD therapy (Epidiolex), the first FDA-approved medication derived from marijuana—was approved in July for a new indication—seizures associated with tuberous sclerosis complex. The therapy was approved in 2018 to treat seizures related to two other rare conditions, Lennox-Gastaut syndrome and Dravet syndrome.

While there have been dramatic stories in the media of young patients whose relentless seizures were helped by the therapy, clinical experience with cannabidiol is still new.

“I've had some real success with a handful of patients who have drug-resistant epilepsy,” said Shawniqua Williams Roberson, MD, assistant professor of neurology at Vanderbilt University Medical Center. Her enthusiasm, however, has been tempered by the drug's side effects, including significant diarrhea and somnolence, that her patients have experienced.

Dr. Williams Roberson said that in general, and not just with cannabidiol, she tends to adopt new medications into her practice slowly because she wants to wait for post-approval reports that may provide a fuller picture of side effects and efficacy.

“In general, I don't see the new drugs as first-line agents because we have a number of agents that are quite reliable and likely to work,” she said. “Why expose the patient to the unknown potential for side effects of a new drug when it does not offer a substantially better chance of seizure freedom than others I have yet to try?”

But some newer therapies are worth trying for certain patients, some neurologists said. Diazepam nasal spray (Valtoco) and midazolam nasal spray (Nayzikam) are rescue medications approved for the acute treatment of seizure clusters. They are considered a welcome alternative to rectally-administered diazepam.

Dr. Wheless said the rescue nasal sprays can be life-changing for families who fear venturing very far from home because their child might have seizures and not be near a hospital.

“It really empowers the families and can change the quality of life for the entire family,” he said.

Fenfluramine (Fintepla) was approved by the FDA in June for the treatment of seizures associated with Dravet syndrome. The drug comes with a warning that it can cause valvular heart disease and pulmonary arterial hypertension.

New Approaches in Development

Jacqueline A. French, MD, FAAN, professor of neurology at NYU Langone Health, said the excitement around new and emerging treatments for epilepsy was evident during a conference in August that focused on new therapies in the research and development pipeline.

“The pipeline for epilepsy therapies is just exploding, which is a wonderful thing to see,” said Dr. French, who is chief medical officer for the Epilepsy Foundation, which sponsored the conference. “There is a renewed enthusiasm for tackling the unmet needs in epilepsy.”

She said emerging therapies are likely to include disease-modifying drugs that target genetic underpinnings of disease.

“Most therapies up to now have been symptomatic treatments. They can stop seizures, but they leave the disease unchanged,” she said.

Dr. French coauthored an article published in Epilepsy Currents in March that advocated for changing the name used to describe drugs from antiepileptic drugs (AEDs) to antiseizure medicines (ASMs).

“Using the term ‘antiepileptic’ to describe these compounds is misleading because it suggests an action on the epilepsy itself,” she wrote along with Emilio Peruca, MD, PhD, of the University of Pavia in Italy.

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“The pipeline for epilepsy therapies is just exploding, which is a wonderful thing to see. There is a renewed enthusiasm for tackling the unmet needs in epilepsy.”—DR. JACQUELINE A. FRENCH

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“The question is how patients with less refractory epilepsy than those enrolled in the placebo-controlled trials will do and so far, based on the large safety study results and our initial clinical use, cenobamate looks pretty effective.”—DR. GREGORY L. KRAUSS

Figure

“Changing someone who is seizure-free to another medicine ends up being a big decision.”—DR. SHERYL R. HAUT

“Using appropriate terminology is especially important at a time when innovative treatments targeting the development of epilepsy and its comorbidities are being actively pursued,” the article said.

The International League Against Epilepsy is considering the issue, Dr. French said.

For now, much of the attention in epilepsy care is expected to be on cenobamate. Dr. French, who participated in a randomized phase 2 trial and the open-label testing of the drug conducted primarily to look at safety concerns, said it is too soon to make any firm conclusions about the drug's potential, noting that it will take time for more data on efficacy, safety and tolerability to emerge from clinical use.

Sheryl R. Haut, MD, professor of neurology at Albert Einstein College of Medicine and director of the Adult Epilepsy Program at Montefiore Medical Center, said that in addition to pharmacological interventions for epilepsy, surgical treatments such as thermal ablation have also expanded. Surgery is still seen as the ideal option for many patients with intractable seizures. She said there is also an important role in epilepsy care for alternative approaches, such as using meditation or mindfulness to reduce stress.

Dr. Haut, who participated in clinical testing of both cenobamate and cannabidiol, said she and her colleagues who work in epilepsy centers continue to “have a healthy respect for the efficacy and experience with the older drugs.” Insurance coverage also influences prescribing decisions, she added, particularly since many older drugs are available in cheaper generic forms.

“Changing someone who is seizure-free to another medicine ends up being a big decision,” she said, even if the person has some milder side effects. Some drug changes, involving switching from a potentially teratogenic drug, are necessitated by a female patient's desire to become pregnant.

Dr. Haut said that while “seizure freedom is the goal for which we aim,” in tailoring a patient's treatment, “there is a long list of positive outcomes that have to also be our goals.”

“The impact of epilepsy is far-reaching,” she said, noting that improvements in quality of life are a measure that doesn't necessarily get enough attention.

Disclosures

Dr. Haut has received consulting fees from Alden Health. Dr. Williams Roberson has received fees for an in-kind gift of a dinner from LivaNova. Dr. French receives NYU salary support from the Epilepsy Foundation and for consulting work and/or attending scientific advisory boards on behalf of the Epilepsy Study Consortium for Aeonian/Aeovian, Anavex, Arvelle Therapeutics, Inc., Athenen Therapeutics/Carnot Pharma, Axovant, Biogen, BioXcel Therapeutics, Blackfynn, Cerebral Therapeutics, Cerevel, Crossject, CuroNZ, Eisai, Encoded Therapeutics, Engage Therapeutics, Epiminder, Epitel, Fortress Biotech, Greenwich Biosciences, GW Pharma, Ionis, Janssen Pharmaceutica, Knopp Biosciences, Lundbeck, Marinus, Merck, NeuCyte, Inc., Neurocrine, Otsuka Pharmaceutical Development, Ovid Therapeutics Inc., Passage Bio, Pfizer, Praxis, Redpin, Sage, SK Life Sciences, Stoke, Sunovion, Supernus, Takeda, UCB Inc., Xenon, Xeris, Zogenix. She has also received research grants from Biogen, Cavion, Eisai, Engage, GW Pharma, Lundbeck, Neurelis, Ovid, Pfizer, SK Life Sciences, Sunovion, UCB, Xenon and Zogenix as well as grants from the Epilepsy Research Foundation, Epilepsy Study Consortium, and NINDS. She is on the editorial board of Lancet Neurology and Neurology Today. She has received travel reimbursement related to research, advisory meetings, or presentation of results at scientific meetings from the Epilepsy Study Consortium, the Epilepsy Foundation, Arvelle Therapeutics, Inc., Biogen, Cerevel, Engage, Lundbeck, NeuCyte, Inc., Otsuka, Sage, UCB, Xenon, Zogenix.

Link Up for More Information

• Krauss GL, Klein P, Brandt C, et al. Safety and efficacy of adjunctive cenobamate (YKP3089) in patients with uncontrolled focal seizures: a multicentre, double-blind, randomised, placebo-controlled, dose-response trial https://www.thelancet.com/journals/laneur/article/PIIS1474-4422(19)30399-0/fulltext. Lancet Neurol 2020; 19(1):38–48.
• Sperling MR, Klein P, Aboumatar S, et al. Cenobamate (YKP3089) as adjunctive treatment for uncontrolled focal seizures in a large, phase 3, multicenter, open-label safety study https://onlinelibrary.wiley.com/doi/full/10.1111/epi.16525, Epilepsia 2020; 61(6):1099–1108.
    • Chung SS, French JA, Kowalski J, et al. Randomized phase 2 study of adjunctive cenobamate in patients with uncontrolled focal seizures https://n.neurology.org/content/94/22/e2311. Neurology 2020; 94(22):e-2311–e2322.
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