Drug-Resistant Epilepsy and Related Clinical Trials and Registries
Numerous real-world studies and post hoc analyses on drug-resistant epilepsy were presented at AES2020. These presentations expand our knowledge of antiseizure medication efficacy, particularly as relates to commonly encountered patterns of adjunctive treatment for focal epilepsy.
Following these presentations, our featured expert, Sara Hocker, MD, FAAN, was interviewed by Conference Reporter Editor-in-Chief Tom Iarocci, MD. Dr Hocker’s clinical perspectives on these emerging findings are presented here.
Professor of Neurology
“Taken together, these studies may help us to better understand the mechanisms of drug resistance and the mechanisms of epileptogenesis.”
There has been a move to try to improve our understanding of the mechanisms of the development of resistance and the development of epilepsy itself, and many of the abstracts in this section reflect these efforts.
The study on eslicarbazepine acetate presented in abstract 774 is an example of a real-world study that aimed, in part, to determine whether the baseline seizure burden influenced response to therapy. This was a post hoc analysis of a phase 4 clinical trial in patients with uncontrolled focal seizures. The 2 arms were (1) adjunctive eslicarbazepine acetate as a first add-on therapy in patients maintained on a stable dose of levetiracetam or lamotrigine and (2) eslicarbazepine acetate as later adjunctive therapy following current or prior use of 1 to 2 antiseizure drugs. We know that eslicarbazepine acetate works by inhibiting voltage-gated sodium channels, especially in rapid firing neurons. Further, we have seen that the expression of some ion channels has been shown to be altered in animal models of mesial temporal lobe epilepsy with hippocampal sclerosis, and gene knockout or pharmacologic antagonism of these affected channels may interfere with epileptogenesis. In a mouse model of carbamazepine-resistant epilepsy, eslicarbazepine acetate was associated with seizure reduction and, more interestingly, the prevention of morphological and functional changes that typically occur during epileptogenesis. Thus, taken together, these studies may help us to better understand the mechanisms of drug resistance and the mechanisms of epileptogenesis.
Also presented at AES2020 were 2 post hoc analyses of phase 3, multicenter, open-label studies of cenobamate, a novel tetrazole alkyl carbamate derivative. In the first study, in which the efficacy of cenobamate for the treatment of uncontrolled focal seizures was evaluated, high rates of sustained seizure freedom (≥12 months) were associated with cenobamate, supporting the phase 3 study findings of durable seizure frequency reduction with cenobamate in adults with uncontrolled focal seizures (abstract 340). The second post hoc analysis evaluated how dose reductions of lamotrigine and carbamazepine impacted the efficacy and tolerability of cenobamate in 1347 patients (abstract 334). Greater dose reductions of lamotrigine and carbamazepine were associated with greater retention rates among those on cenobamate. The efficacy of cenobamate also was not significantly compromised, and adverse events decreased with reductions in the concomitant antiseizure medications. This was interesting because, in general, a principle of treating treatment-resistant epilepsy is that of rational combination therapy, where you are targeting different mechanisms of action to increase the efficacy. With cenobamate, researchers are showing that you actually end up, in practice, sometimes reducing the other drugs to allow for increasing the dose of cenobamate; by doing this, they are getting higher treatment success. Cenobamate was not included in the 2018 American Academy of Neurology and the American Epilepsy Society treatment guideline. As more data emerge, such as those that are being reported here, I expect that we will see cenobamate included in updated guidelines.
Finally, a global pooled analysis study of data from 3496 patients with focal and generalized tonic-clonic seizures found perampanel to be effective and well tolerated under everyday clinical practice conditions, although psychiatric adverse events such as depression were reported in 22.5% of patients (abstract 518). It is not known whether these impacts were predominant in patients with a history of psychiatric disorders; thus, perampanel should not necessarily be withheld because of a history of depression in patients who may otherwise benefit from this medication.
Aboumatar S, Cantu D, Blum D, Zhang I, Grinnell T. Efficacy of adjunctive eslicarbazepine acetate in patients with focal seizures, according to baseline seizure frequency: a post-hoc analysis of data from a phase IV clinical trial [abstract 774]. Abstract presented at: AES2020; December 4-8, 2020.
Doeser A, Dickhof G, Reitze M, et al. Targeting pharmacoresistant epilepsy and epileptogenesis with a dual-purpose antiepileptic drug. Brain. 2015;138(pt 2):371-387. doi:10.1093/brain/awu339
D’Souza W, Trinka E, Wu T, et al. Effectiveness and tolerability of perampanel in epilepsy patients treated in routine clinical practice: a global pooled analysis study [abstract 518]. Abstract presented at: AES2020; December 4-8, 2020.
Ferrari L, Nisman A, Sperling M, Rosenfeld W. Post-hoc analysis of a phase 3, open-label study of cenobamate for treatment of uncontrolled focal seizures: effects of dose reductions to concomitant lamotrigine and carbamazepine [abstract 334]. Abstract presented at: AES2020; December 4-8, 2020.
Kanner AM, Ashman E, Gloss D, et al. Practice guideline update summary: efficacy and tolerability of the new antiepileptic drugs I: treatment of new-onset epilepsy: report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology. 2018;91(2):74-81. doi:10.1212/WNL.0000000000005755
Leong ECS, Seneviratne U. “Benign” temporal lobe epilepsy with hippocampal sclerosis: a forgotten entity? Epilepsy Behav Rep. 2020;14:100407.doi:10.1016/j.ebr.2020.100407
Sperling M, Abou-Khalil B, Aboumatar S, et al. Efficacy of cenobamate for uncontrolled focal seizures: post-hoc analysis of a phase 3, multicenter, open-label study [abstract 340]. Abstract presented at: AES2020; December 4-8, 2020.
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. Epilepsia. 2020;61(6):1099-1108. doi:10.1111/epi.16525
Steinhoff BJ, Patten A, Williams B, Malhotra M. Efficacy and safety of adjunctive perampanel 4 mg/d for the treatment of focal seizures: a pooled post hoc analysis of four randomized, double-blind, phase III studies. Epilepsia. 2020;61(2):278-286. doi:10.1111/epi.16428
Weissinger F, Losch F, Winter Y, Brecht S, Lendemans D, Kockelmann E. Effectiveness of eslicarbazepine acetate in dependency of baseline anticonvulsant therapy: results from a German prospective multicenter clinical practice study. Epilepsy Behav. 2019;101(pt A):106574. doi:10.1016/j.yebeh.2019.106574
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