2020 Epilepsy Review: Much to Be Excited About

Eric Segal, MD

The epilepsy therapeutics space was one of the few bright spots of 2020, with many pharmacologic options emerging for patients. Over the past 10 years, some therapies offered marginal improvements in efficacy and adverse effect profile compared with earlier generations of antiseizure medications (ASMs). The mold was broken in 2020 with a paradigm shift in what clinicians consider effective therapies, and agents that offer a significant improvement in quality of life.

In 2020, ASMs to treat focal seizure in adults, as well as seizures in Dravet syndrome, received FDA approval. Cenobamate (Xcopri) is a novel tetrazole alkyl carbamate derivative thought to work on both sodium and gamma-aminobutyric acid channels. In phase 2 study results, adults with focal epilepsy had median seizure reductions of 55.6%, 38.7% had a 75% or greater seizure reduction, and 28.3% were seizure-free in a post hoc analysis of the maintenance phase.¹ In a dose-comparison study of cenobamate by Krauss and colleagues, median seizure reduction of 400 mg/D was 55%, and in the maintenance phase of the modified intent-to-treat cohort, the same dosing resulted in 65% seizure reduction.² Although it is not possible to directly compare these rates of seizure freedom and reduction with pivotal trials of other ASMs, these rates are higher than those shown in the meta-analysis and pooled analysis of lamotrigine, gabapentin, topiramate, tiagabine, levetiracetam, zonisamide, pregabalin, lacosamide, eslicarbazepine, perampanel, and brivaracetam.³ If real-world experience is similar to the results of these pivotal trials, cenobamate may represent a new threshold for ASM efficacy in the treatment of focal epilepsy.

Similar paradigm changes may be afoot in the treatment of Dravet syndrome. In 2017, a North American consensus panel recommended valproic acid or clobazam as first-line therapies, with stiripentol, topiramate, or ketogenic diet as second-line treatments.⁴ Also in 2017, cannabidiol (Epidiolex) was FDA approved after demonstrating a median seizure frequency reduction of 43%.⁵ Fenfluramine (Fintepla), FDA approved in 2020 as well, demonstrated median seizure frequency reduction of 75% in its pivotal trial.⁶ As in the case of cenobamate, head-to-head comparisons of Dravet-specific therapies such as stiripentol, fenfluramine, and cannabidiol cannot be made. However, such impressive seizure reductions seen with both cenobamate and fenfluramine beg the question: Should we consider redefining what is considered a “significant” seizure reduction?

The abortive therapy space in epilepsy had languished with a paucity of therapies until 2019. The most recent FDA approval prior to then occurred in 1997 with rectal diazepam (Diastat), designed to allow caregivers to give an emergency-use medication to abort acute repetitive seizures. At the end of 2019, clinicians were given permission to prescribe FDA-approved nasal midazolam (Nayzilam) for patients 12 years and older. Its ease of use and clear dosing guidelines make it a valuable option for teenagers and adults. In 2020, nasal diazepam (Valtoco) also became available to US prescribers for patients 6 years and older; its advantages include dosing flexibility and long shelf life. Both of these nasal therapies met a previously unmet need for children and adults with epilepsy: an agent that can be quickly administered with greater social acceptability.

The focuses of epilepsy studies currently underway range from tantalizing first-in-class medications, new uses of older therapies, and even gene therapy, giving hope for more exciting developments in the coming year, even as we can reflect on the advances that emerged in 2020 in both prophylactic and abortive treatments for epilepsy.

Here’s to 2021….

REFERENCES
1. Chung SS, French JA, Kowalski J, et al. Randomized phase 2 study of adjunctive cenobamate in patients with uncontrolled focal seizures. Neurology. 2020;94(22):e2311-e2322. doi:10.1212/ WNL.0000000000009530
2. 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. Lancet Neurol. 2020;19(1):38-48. doi: 10.1016/S1474-4422(19)30399-0
3. Vossler DG. Remarkably high efficacy of cenobamate in adults with focal-onset seizures: a double-blind, randomized, placebo-controlled trial. Epilepsy Curr, 2020;20(2):85-87. doi:10. 1177/1535759720903032
4. Wirrell EC, Laux L, Donner E, et al. Optimizing the diagnosis and management of Dravet syndrome: recommendations from a North American consensus panel. Pediatr Neurol, 2017;68:18-34. doi:10. 1016/j.pediatrneurol.2017.01.025
5. Devinsky O, Cross JH, Laux L, et al; Cannabidiol in Dravet Syndrome Study Group. Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome. N Engl J Med. 2017;376(21):2011-2020. doi:10.1056/NEJMoa1611618
6. Lagae L, Sullivan J, Knupp K, et al; FAiRE DS Study Group. Fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome: a randomised, double-blind, placebo-controlled trial. Lancet. 2019;394(10216):2243-2254. doi:10. 1016/S0140-6736(19)32500-0