Achieving Seizure Freedom in Patients With Drug-Resistant Epilepsy
A number of presentations at AES2020 reported encouraging data on the treatment of drug-resistant epilepsy. These included findings from studies of adjunctive cenobamate in adults with uncontrolled focal epilepsy, data on expanded access use of cannabidiol (CBD), results of further investigation of fenfluramine, and research on genetically linked epilepsies.
Following these presentations, our featured expert, Gregory L. Krauss, MD, was interviewed by Conference Reporter Editor-in-Chief Tom Iarocci, MD. Clinical perspectives from Dr Krauss on these emerging data are presented here.
Professor, Department of Neurology
“Newer treatments are linked to reduced seizure frequency with improved tolerability compared with previous generations of antiseizure medications. However, there continues to be an unmet need to provide seizure control and to treat highly refractory seizure types.”
Newer treatments are linked to reduced seizure frequency with improved tolerability compared with previous generations of antiseizure medications. However, there continues to be an unmet need to provide seizure control and to treat highly refractory seizure types.
Cenobamate was approved by the US Food and Drug Administration for adults with uncontrolled focal epilepsy based on efficacy and safety data from 2 phase 2 studies and safety data from a large, long-term, ongoing, open-label, phase 3 safety study (NCT02535091). The latter included more than 1300 patients in whom gradual titration from initial 12.5-mg-per-day doses of cenobamate and 2-week titration steps were not associated with the occurrence of drug reactions with eosinophilia and systemic symptoms (ie, drug reaction with eosinophilia and systemic symptoms syndrome). Cenobamate was well tolerated in long-term therapy.
We reported a post hoc analysis of seizure outcomes for 249 subjects at 10 US study sites in abstract 340 from AES2020. A major finding was that nearly 34% of patients treated with cenobamate in the safety study became seizure free for 12 or more months during treatment. These were all drug-resistant patients, and this proportion with seizure freedom has not been reported with other anticonvulsants. Most patients were treated with cenobamate 200 to 300 mg per day; fatigue, dizziness, and somnolence were the most common adverse effects and were often reversed with lower cenobamate doses or by decreasing doses of concomitant antiseizure medications. Most patients who had focal evolving-to-bilateral tonic-clonic seizures reported that these ceased early in their treatment. All seizure types responded with an average seizure reduction of greater than 70%; their tonic-clonic seizures—the most disabling seizure type—generally stopped.
Quality of life in epilepsy is important to measure when assessing patients with drug-resistant epilepsy. Low quality of life for patients with epilepsy is frequently associated with medication adverse effects and mood disturbances. Even with significant reductions in seizure frequency (usually indexed by the >50% seizure responder rate), most patients in adjunctive treatment trials for treatment-resistant focal onset epilepsy do not have improved scores on the Quality of Life in Epilepsy Inventory-31 (QOLIE-31). However, in surgical trials and population studies of newly diagnosed patients with epilepsy, those with marked seizure reduction or seizure freedom often report improved quality of life. Cenobamate, however, is one of the first treatments for drug-resistant epilepsy in which a major proportion of patients are strong responders or achieve seizure freedom.
In abstract 988, we tracked 49 patients, of whom 37 continued for 3 to 8 years with adjunctive cenobamate treatment. The majority had marked seizure reduction (>75% seizure reduction) and many became seizure free. The strong responders (>75%, >90%, and 100% responses) had increasingly high QOLIE-31 scores compared with the nonresponders (<50% seizure reduction). A domain that was particularly associated with high QOLIE scores in the high cenobamate responders was favorable energy/fatigue scores.
Elsewhere at AES2020, we saw encouraging progress in identifying and understanding the genetic epilepsies. There were hundreds of presentations about the genetics of epilepsy and the potential targets for treating genetically linked epilepsies. These included identifying polygenic scores associated with increased risks for epilepsy, identifying new genetic variants associated with epilepsy, and understanding how some somatic mutations may cause focal seizures. It appears that, similar to current sickle cell treatment trials, CRISPR (also known as clustered regularly interspaced short palindromic repeat) and other methods may eventually help treat genetic disorders associated with seizures and intellectual disability. These methods are largely being explored at the preclinical level.
Several studies investigated fenfluramine treatment for Dravet syndrome and Lennox-Gastaut syndrome. An open-label extension study of patients with Dravet syndrome (abstract 978) showed that fenfluramine provided durable reductions in monthly convulsive seizure frequency for up to 3 years, with 3 patients reported as being seizure free during the entire open-label extension. Another study presented in abstract 1057 suggested that adults with Dravet syndrome treated with fenfluramine may experience comparable clinical benefit and tolerability to that of children and adolescents.
It is often difficult to reduce disabling seizures in patients with developmental encephalopathies and seizures, including those with Lennox-Gastaut syndrome. An expanded access program for Epidiolex (CBD) was initiated in 2014 to include patients with severe forms of epilepsy that do not always meet the current indications of Dravet syndrome, Lennox-Gastaut syndrome, or tuberous sclerosis complex in patients 1 year of age and older. In abstract 123, a registry explored the use of CBD through this expanded access program. The registry included patients who ranged from 9 months to 23 years of age who had many other syndromes, many of which were developmental encephalopathies with seizures. These patients often had multiple and complex seizure types and very severe epilepsy. CBD showed marked efficacy for treating multiple seizure types. Add-on CBD therapy in the expanded access program produced sustained reduction in convulsive and nonconvulsive seizure subtypes for up to 144 weeks with an acceptable safety profile. Patients averaged slightly greater than 50% seizure reduction for the various seizure types. Patients were often treated with high doses (20-25 mg/kg/day), and the most common side effects were not serious; some patients reported diarrhea that required dose reductions. CBD often markedly increases clobazam metabolite, and clobazam doses were decreased in most patients. The most remarkable finding was the strong efficacy in patients with very severe epilepsy that was refractory to other treatments. A caveat is that the high response rates compared with controlled pivotal trials may partially reflect the open extension study design; however, patients with a variety of epilepsy syndromes had long, stable treatment responses.
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
ClinicalTrials.gov. Safety and pharmacokinetic study of YKP3089 as adjunctive therapy in subjects with partial onset seizures. Accessed December 11, 2020. https://clinicaltrials.gov/ct2/show/NCT02535091
Comi AM, Bebin EM, Checketts D, et al. Efficacy and safety of cannabidiol (CBD) in patients with treatment-resistant epilepsies (TRES) in the expanded access program (EAP): additional efficacy data for convulsive and nonconvulsive seizure subtypes [abstract 123]. Abstract presented at: AES2020; December 4-8, 2020.
Damian C, Whitehall R, Keough K, et al. Cannabidiol (CBD) and tetrahydrocannabinol (THC) as adjunctive therapy in drug resistant epilepsy: the Texas experience [abstract 992]. Abstract presented at: AES2020; December 4-8, 2020.
Gutierrez E, Elizabeth R, Coe P, Yang J, Zhang E, Krauss GL. Strong cenobamate treatment responses are associated with high QOLIE scores after three to eight years of treatment [abstract 988]. 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 II: treatment-resistant epilepsy: report of the American Epilepsy Society and the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Epilepsy Curr. 2018;18(4):269-278. doi:10.5698/1535-75220.127.116.119
Krauss GL, Klein P, Brandt C, et al. Safety of adjunctive treatment with cenobamate in patients with uncontrolled focal seizures – authors’ reply. Lancet Neurol. 2020;19(4):288-289. doi:10.1016/S1474-4422(20)30077-6
O’Connell BK, Gloss D, Devinsky O. Cannabinoids in treatment-resistant epilepsy: a review. Epilepsy Behav. 2017;70(pt B):341-348. doi:10.1016/j.yebeh.2016.11.012
Perry S, Knupp K, Wirrell E, et al. Fenfluramine (FINTEPLA) provides comparable clinical benefit in adults and children with Dravet syndrome: real-world experience from the US early access program [abstract 1057]. Abstract presented at: AES2020; December 4-8, 2020.
Scheffer I, Devinsky O, Perry S, et al. Efficacy and tolerability of adjunctive FINTEPLA (fenfluramine hydrochloride) in an open-label extension study of Dravet syndrome patients treated for up to 3 years [abstract 978]. Abstract presented at: AES2020; December 4-8, 2020.
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
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