Long-term safety of adjunctive cenobamate in patients with uncontrolled focal seizures: Open-label extension of a randomized clinical study

Jacqueline A French, Steve S Chung, Gregory L Krauss, Sang Kun Lee, Maciej Maciejowski, William E Rosenfeld, Michael R Sperling, Marc Kamin, Jacqueline A French, Steve S Chung, Gregory L Krauss, Sang Kun Lee, Maciej Maciejowski, William E Rosenfeld, Michael R Sperling, Marc Kamin

Abstract

Objective: This study was undertaken to examine long-term (up to 7.8 years) retention rate, safety, and tolerability of the antiseizure medication (ASM) cenobamate as adjunctive treatment in the open-label extension (OLE) of study YKP3089C013 (C013; ClinicalTrials.gov: NCT01397968).

Methods: Patients who completed the 12-week, multicenter, multinational, double-blind, randomized, placebo-controlled C013 study, which examined adjunctive cenobamate treatment of adults with uncontrolled focal seizures, were eligible to enroll in the OLE. During the OLE, dose adjustments of cenobamate and concomitant ASMs were allowed. Safety assessments included frequency of treatment-emergent adverse events (TEAEs) and serious TEAEs, TEAE severity, and TEAEs leading to discontinuation. Probability of patient continuation in the OLE was examined using a Kaplan-Meier analysis.

Results: One hundred forty-nine patients entered the OLE (median duration of cenobamate treatment = 6.25 years). As of the data cutoff, 57% of patients (85/149) remained in the OLE (median treatment duration = 6.8 years, range = 6.4-7.8 years). The median modal daily cenobamate dose was 200 mg (range = 50-400 mg). The probability of treatment continuation at 1-6 years of cenobamate treatment was 73%, 67%, 63%, 61%, 60%, and 59%, respectively. Among patients who continued at 1 year (n = 107), the probability of continuing at Years 2-5 was 92%, 87%, 83%, and 82%. The most common discontinuation reasons were patient withdrawal (19.5%, 29/149), adverse event (10.1%, 15/149), and lack of efficacy (5.4%, 8/149). TEAEs leading to discontinuation in 1% or more of patients were fatigue (1.3%, 2/149), ataxia (1.3%, 2/149), and memory impairment or amnesia (1.3%, 2/149). Dizziness (32.9%, 49/149), headache (26.8%, 40/149), and somnolence (21.5%, 32/149) were the most frequently reported TEAEs and were primarily mild or moderate in severity.

Significance: Long-term retention in the C013 OLE study demonstrated sustained safety and tolerability of adjunctive cenobamate treatment up to 7.8 years in adults with treatment-resistant focal seizures taking one to three ASMs.

Keywords: epilepsy; focal seizures; long-term; retention; safety.

Conflict of interest statement

J.A.F.: Salary support to New York University: Epilepsy Foundation; consultant/advisor (on behalf of the Epilepsy Study Consortium): Adamas, Aeonian/Aeovian, Anavex, Arkin Holdings, Arvelle, Athenen Therapeutics/Carnot Pharma, Baergic, Biogen, BioXcel, Cavion, Cerebral, Cerevel, Crossject, CuroNZ, Eisai, Eliem, Encoded, Engage, Engrail, Epiminder, Equilibre, Fortress, Greenwich, GW Pharma, Janssen, Knopp, Lundbeck, Marinus, Mend Neuroscience, Merck, NeuCyte, Neurocrine, Otsuka, Ovid, Passage, Praxis, Redpin, Sage, SK Life Science, Sofinnova, Stoke, Supernus, Synergia Medical, Takeda, UCB Pharma, West Therapeutic Development, Xenon, Xeris, Zogenix, Zynerba; research support: Epilepsy Research Foundation, Epilepsy Study Consortium (funded by Andrews Foundation, Eisai, Engage, Lundbeck, Pfizer, SK Life Science, Sunovion, UCB Pharma, Vogelstein Foundation), Epilepsy Study Consortium/Epilepsy Foundation (funded by Engage, Neurelis, SK Life Science, UCB Pharma), GW/One8 Foundation/FACES, National Institute of Neurological Disorders and Stroke; editorial board: Lancet Neurology, Neurology Today; travel reimbursement: Arvelle, Biogen, Cerevel, Engage, Epilepsy Study Consortium, Epilepsy Foundation, Lundbeck, NeuCyte, Otsuka, Sage, UCB Pharma, Xenon, Zogenix. S.S.C.: Consultant/advisor: Adamas, Eisai, SK Life Science, UCB Pharma; speaker: Eisai, Greenwich Biosciences, Sunovion, UCB Pharma; research support: Engage, SK Life Science, UCB Pharma. G.L.K.: Consultant/advisor: Adamas, Eisai, Otsuka, Shire; research support: Biogen, SK Life Science, UCB Pharma, Upsher‐Smith. S.K.L.: Consultant/advisor: Eisai, SK Life Science, UCB Pharma. M.M.: Speaker: Biogen, Merck, Novartis, Roche; research support: Roche. W.E.R.: Consultant/advisor: SK Life Science; speaker: Eisai, Greenwich Biosciences (GW Pharmaceuticals), SK Life Science, Sunovion, UCB Pharma; research support: Greenwich Biosciences, Marinus, Medtronic, Neurelis, Ovid, SK Life Science, Takeda, UCB Pharma, Upsher‐Smith. M.R.S.: Consultant/advisor: Medtronic; speaker: Eisai, International Medical Press, Medscape, NeurologyLive, Projects in Knowledge; research support: Cavion, Cerevel, Eisai, Engage, Medtronic, Neurelis, SK Life Science, Takeda, UCB Pharma, Xenon. M.K.: Employee, SK Life Science. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

© 2021 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.

Figures

FIGURE 1
FIGURE 1
Kaplan–Meier plot of continuation during the open‐label extension (OLE). Event = early discontinuation from OLE. Patients who completed the study and patients ongoing at the date of data cutoff are considered censored
FIGURE 2
FIGURE 2
Kaplan–Meier plot of continuation during the open‐label extension (OLE) in the patients who remained in the OLE at 12 months. Event = early discontinuation from OLE. Patients who completed the study and patients ongoing at the date of data cutoff are considered censored
FIGURE 3
FIGURE 3
Patient disposition and reason for discontinuation (open‐label extension [OLE] population). aAn additional three patients completed the OLE as reported on the end of study case report form. The patients completed 9.0 months, 11.0 months, and 12.3 months of treatment in the OLE
FIGURE 4
FIGURE 4
Long‐term retention rates during open‐label extension (OLE) studies. BRV, brivaracetam; CNB, cenobamate; LAC, lacosamide; LEV, levetiracetam; PER, perampanel

References

    1. Keam SJ. Cenobamate: first approval. Drugs. 2020;80(1):73–8.
    1. Nakamura M, Cho JH, Shin HS, Jang IS. Effects of cenobamate (YKP3089), a newly developed anti‐epileptic drug, on voltage‐gated sodium channels in rat hippocampal CA3 neurons. Eur J Pharmacol. 2019;855:175–82.
    1. Sharma R, Nakamura M, Neupane C, Jeon BH, Shin H, Melnick SM, et al. Positive allosteric modulation of GABAA receptors by a novel antiepileptic drug cenobamate. Eur J Pharmacol. 2020;879:173117.
    1. Guignet M, Campbell A, White HS. Cenobamate (XCOPRI): can preclinical and clinical evidence provide insight into its mechanism of action? Epilepsia. 2020;61(11):2329–39.
    1. Chung SS, French JA, Kowalski J, Krauss GL, Lee SK, Maciejowski M, et al. Randomized phase 2 study of adjunctive cenobamate in patients with uncontrolled focal seizures. Neurology. 2020;94(22):e2311–22.
    1. Krauss GL, Klein P, Brandt C, Kun Lee S, Milanov I, Milovanovic M, 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.
    1. Perucca E, Wiebe S. Not all that glitters is gold: a guide to the critical interpretation of drug trials in epilepsy. Epilepsia Open. 2016;1(1–2):9–21.
    1. Chung S, Wang N, Hank N. Comparative retention rates and long‐term tolerability of new antiepileptic drugs. Seizure. 2007;16(4):296–304.
    1. Ben‐Menachem E, Sander JW, Privitera M, Gilliam F. Measuring outcomes of treatment with antiepileptic drugs in clinical trials. Epilepsy Behav. 2010;18(1–2):24–30.
    1. Fisher RS, Cross JH, French JA, Higurashi N, Hirsch E, Jansen FE, et al. Operational classification of seizure types by the International League Against Epilepsy: position paper of the ILAE Commission for Classification and Terminology. Epilepsia. 2017;58(4):522–30.
    1. Scheffer IE, Berkovic S, Capovilla G, Connolly MB, French J, Guilhoto L, et al. ILAE classification of the epilepsies: position paper of the ILAE Commission for Classification and Terminology. Epilepsia. 2017;58(4):512–21.
    1. Ben‐Menachem E, Gabbai AA, Hufnagel A, Maia J, Almeida L, Soares‐da‐Silva P. Eslicarbazepine acetate as adjunctive therapy in adult patients with partial epilepsy. Epilepsy Res. 2010;89(2–3):278–85.
    1. Mohanraj R, Brodie MJ. Early predictors of outcome in newly diagnosed epilepsy. Seizure. 2013;22(5):333–44.
    1. Thieffry S, Klein P, Baulac M, Plumb J, Pelgrims B, Steeves S, et al. Understanding the challenge of comparative effectiveness research in focal epilepsy: a review of network meta‐analyses and real‐world evidence on antiepileptic drugs. Epilepsia. 2020;61(4):595–609.
    1. Kwok CS, Johnson EL, Krauss GL. Comparing safety and efficacy of "third‐generation" antiepileptic drugs: long‐term extension and post‐marketing treatment. CNS Drugs. 2017;31(11):959–74.
    1. Toledo M, Beale R, Evans JS, Steeves S, Elmoufti S, Townsend R, et al. Long‐term retention rates for antiepileptic drugs: a review of long‐term extension studies and comparison with brivaracetam. Epilepsy Res. 2017;138:53–61.
    1. Chung SS, Hogan RE, Blatt I, Lawson PB, Nguyen H, Clark AM, et al. Long‐term safety and sustained efficacy of USL255 (topiramate extended‐release capsules) in patients with refractory partial‐onset seizures. Epilepsy Behav. 2016;59:13–20.
    1. Chung SS, Johnson JK, Brittain ST, Baroldi P. Long‐term efficacy and safety of adjunctive extended‐release oxcarbazepine (Oxtellar XR®) in adults with partial‐onset seizures. Acta Neurol Scand. 2016;133(2):124–30.
    1. Bootsma HP, Ricker L, Hekster YA, Hulsman J, Lambrechts D, Majoie M, et al. The impact of side effects on long‐term retention in three new antiepileptic drugs. Seizure. 2009;18(5):327–31.
    1. Ben‐Menachem E, Baulac M, Hong SB, Cleveland JM, Reichel C, Schulz AL, et al. Safety, tolerability, and efficacy of brivaracetam as adjunctive therapy in patients with focal seizures, generalized onset seizures, or Unverricht‐Lundborg disease: an open‐label, long‐term follow‐up trial. Epilepsy Res. 2021;170:106526.
    1. Toledo M, Whitesides J, Schiemann J, Johnson ME, Eckhardt K, McDonough B, et al. Safety, tolerability, and seizure control during long‐term treatment with adjunctive brivaracetam for partial‐onset seizures. Epilepsia. 2016;57(7):1139–51.
    1. Rosenow F, Kelemen A, Ben‐Menachem E, McShea C, Isojarvi J, Doty P. Long‐term adjunctive lacosamide treatment in patients with partial‐onset seizures. Acta Neurol Scand. 2016;133(2):136–44.
    1. Rosenfeld W, Fountain NB, Kaubrys G, Ben‐Menachem E, McShea C, Isojarvi J, et al. Safety and efficacy of adjunctive lacosamide among patients with partial‐onset seizures in a long‐term open‐label extension trial of up to 8 years. Epilepsy Behav. 2014;41:164–70.
    1. Krakow K, Walker M, Otoul C, Sander JW. Long‐term continuation of levetiracetam in patients with refractory epilepsy. Neurology. 2001;56(12):1772–4.
    1. Krauss GL, Perucca E, Kwan P, Ben‐Menachem E, Wang XF, Shih JJ, et al. Final safety, tolerability, and seizure outcomes in patients with focal epilepsy treated with adjunctive perampanel for up to 4 years in an open‐label extension of phase III randomized trials: study 307. Epilepsia. 2018;59(4):866–76.
    1. Rektor I, Krauss GL, Bar M, Biton V, Klapper JA, Vaiciene‐Magistris N, et al. Perampanel Study 207: long‐term open‐label evaluation in patients with epilepsy. Acta Neurol Scand. 2012;126(4):263–9.
    1. Rektor I, Krauss GL, Inoue Y, Kaneko S, Williams B, Patten A, et al. Assessment of the long‐term efficacy and safety of adjunctive perampanel in tonic‐clonic seizures: analysis of four open‐label extension studies. Epilepsia. 2020;61(7):1491–502.
    1. Novy J, Bartolini E, Bell GS, Duncan JS, Sander JW. Long‐term retention of lacosamide in a large cohort of people with medically refractory epilepsy: a single centre evaluation. Epilepsy Res. 2013;106(1–2):250–6.
    1. Wehner T, Mannan S, Turaga S, Vallabhaneni K, Yip HM, Wiggans C, et al. Retention of perampanel in adults with pharmacoresistant epilepsy at a single tertiary care center. Epilepsy Behav. 2017;73:106–10.
    1. Depondt C, Yuen AW, Bell GS, Mitchell T, Koepp MJ, Duncan JS, et al. The long term retention of levetiracetam in a large cohort of patients with epilepsy. J Neurol Neurosurg Psychiatry. 2006;77(1):101–3.
    1. Sperling MR, Klein P, Aboumatar S, Gelfand M, Halford JJ, Krauss GL, 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):1099–108.
    1. Mohanraj R, Brodie MJ. Measuring the efficacy of antiepileptic drugs. Seizure. 2003;12(7):413–43.

Source: PubMed

Patrocinadores y Colaboradores

Condiciones médicas

Intervenciones de drogas

3
Suscribir