Research progress of cenobamate in the treatment of epilepsy_Journal of Epilepsy

Authors：

 JING Yingzhong ¹ ,  LIU Yaqing ²

1. Department of Comprehensive ICU, Xigu Hospital of Lanzhou University Second Hospital, Lanzhou 730060, China;
2. Department of Neurology, Lanzhou University Second Hospital, Lanzhou 730030, China;

Corresponding author：

LIU Yaqing, Email: liuyaqing_2008@126.com

Keywords：

Cenobamate; Epilepsy; Focal seizures; Mechanism of action; Efficacy

DOI：

10.7507/2096-0247.202306011

Video：

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Cenobamate is one of the latest antiseizure medications (ASMs) developed for the treatment of focal onset seizures in adult patients. Cenobamate is characterized by a peculiar pharmacology. The mechanisms responsible for its anti-seizure activity include enhancement of the inactivated state of voltage-gated sodium channels with blockade of the persistent sodium current and positive allosteric modulation of GABAa receptors at a non-benzodiazepine binding site. Studies showed that cenobamate appears to be an effective treatment for focal epilepsy, showing reductions in seizure frequency, increased responder rates, and high rates of seizure freedom, and is well tolerated and safe. This article reviews the mechanism, pharmacokinetic characteristics, clinical efficacy, and safety of cenobamate as a novel anti-seizure drug

Citation： JING Yingzhong, LIU Yaqing. Research progress of cenobamate in the treatment of epilepsy. Journal of Epilepsy, 2023, 9(5): 411-416. doi: 10.7507/2096-0247.202306011 Copy

1.	GBD 2016 Neurology Collaborators. Global, regional, and national burden of neurological disorders, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol, 2019, 18(5): 459-480.
2.	Kalilani L, Sun X, Pelgrims B, et al. The epidemiology of drug-resistant epilepsy: a systematic review and meta-analysis. Epilepsia, 2018, 59(12): 2179-2193.
3.	Tomson T, Beghi E, Sundqvist A, et al. Medical risks in epilepsy: a review with focus on physical injuries, mortality, traffic accidents and their prevention. Epilepsy Re, 2004, 60(1): 1-16.
4.	SK Life Science I. Drug approval package: XCOPRI [Available from:https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/212839Orig1s000TOC.cfm.
5.	Nakamura M, Cho JH, Shin H, et al. 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: 175-182.
6.	Sharma R, Nakamura M, Neupane C, et al. Positive allosteric modulation of GABA(A) receptors by a novel antiepileptic drug cenobamate. Eur J Pharmacol, 2020, 879: 173117.
7.	Agrawal SK, Fehlings MG. Mechanisms of secondary injury to spinal cord axons in vitro: role of Na+, Na(+)-K(+)-ATPase, the Na(+)-H+ exchanger, and the Na(+)-Ca2+ exchanger. J Neurosci, 1996, 16(2): 545-552.
8.	Pearn ML, Niesman IR, Egawa J, et al. Pathophysiology associated with traumatic brain injury: current treatments and potential novel therapeutics. Cell Mol Neurobiol, 2017, 37(4): 571-585.
9.	Wiciński M, Puk O, Malinowski B. Cenobamate: neuroprotective potential of a new antiepileptic drug. Neurochem Res, 2021, 46(3): 439-446.
10.	Çiçek SS. Structure-dependent activity of natural GABA(A) receptor modulators. Molecules, 2018, 23(7): 1512.
11.	Vernillet L, Greene SA, Kamin M. Pharmacokinetics of cenobamate: results from single and multiple oral ascending-dose studies in healthy subjects. Clin Pharmacol Drug Dev, 2020, 9(4): 428-443.
12.	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.
13.	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.
14.	French JA, Chung SS, Krauss GL, et al. Long-term safety of adjunctive cenobamate in patients with uncontrolled focal seizures: Open-label extension of a randomized clinical study. Epilepsia, 2021, 62(9): 2142-2150.
15.	Klein P, Aboumatar S, Brandt C, et al. Long-term efficacy and safety from an open-label extension of adjunctive cenobamate in patients with uncontrolled focal seizures. Neurology, 2022, 99(10): e989-e998.
16.	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.
17.	Sperling MR, 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. Epilepsia, 2021, 62(12): 3005-3015.
18.	Elizebath R, Zhang E, Coe P, et al. Cenobamate treatment of focal-onset seizures: Quality of life and outcome during up to eight years of treatment. Epilepsy Behav. 2021;116: 107796.
19.	Abou-Khalil B, Aboumatar S, Klein P, et al. Efficacy of cenobamate for uncontrolled focal seizures in patients with previous epilepsy-related surgery: post hoc analysis of a phase 3, multicenter, open-label study. Epilepsy Res, 2022, 184: 106952.
20.	Lattanzi S, Trinka E, Zaccara G, et al. Third-generation antiseizure medications for adjunctive treatment of focal-onset seizures in adults: a systematic review and network meta-analysis. Drugs, 2022, 82(2): 199-218.
21.	Peña-Ceballos J, Moloney PB, Munteanu T, et al. Adjunctive cenobamate in highly active and ultra-refractory focal epilepsy: a "real-world" retrospective study. Epilepsia, 2023, 64(5): 1225-1235.
22.	Makridis KL, Bast T, Prager C, et al. Real-world experience treating pediatric epilepsy patients with cenobamate. Front Neurol, 2022, 13: 950171.
23.	Varughese RT, Shah YD, Karkare S, et al. Adjunctive use of cenobamate for pediatric refractory focal-onset epilepsy: a single-center retrospective study. Epilepsy Behav, 2022, 130: 108679.
24.	Makridis KL, Friedo AL, Kellinghaus C, et al. Successful treatment of adult Dravet syndrome patients with cenobamate. Epilepsia, 2022, 63(12): e164-e171.
25.	Darpo B, Sager PT, Xue H, et al. A phase 1 clinical study evaluating the effects of cenobamate on the QT interval. Clin Pharmacol Drug Dev, 2022, 11(4): 523-534.
26.	Buckley CT, Waters OR, DeMaagd G. Cenobamate: a new adjunctive agent for drug-resistant focal onset epilepsy. Ann Pharmacother, 2021, 55(3): 318-329.
27.	Lattanzi S, Trinka E, Zaccara G, et al. Adjunctive cenobamate for focal-onset seizures in adults: a systematic review and meta-analysis. CNS Drugs, 2020, 34(11): 1105-1120.
28.	Roberti R, De Caro C, Iannone LF, et al. Pharmacology of cenobamate: mechanism of action, pharmacokinetics, drug-drug interactions and tolerability. CNS Drugs, 2021, 35(6): 609-618.
29.	SK Life Science I. Assess the influence of cenobamate on the pk of cytochrome p450 (cyp) probe drugs as a means of predicting drug-drug interactions, Available from: https://clinicaltrials.gov/ct2/show/results/NCT03234699?view=results.

1. GBD 2016 Neurology Collaborators. Global, regional, and national burden of neurological disorders, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol, 2019, 18(5): 459-480.
2. Kalilani L, Sun X, Pelgrims B, et al. The epidemiology of drug-resistant epilepsy: a systematic review and meta-analysis. Epilepsia, 2018, 59(12): 2179-2193.
3. Tomson T, Beghi E, Sundqvist A, et al. Medical risks in epilepsy: a review with focus on physical injuries, mortality, traffic accidents and their prevention. Epilepsy Re, 2004, 60(1): 1-16.
4. SK Life Science I. Drug approval package: XCOPRI [Available from:https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/212839Orig1s000TOC.cfm.
5. Nakamura M, Cho JH, Shin H, et al. 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: 175-182.
6. Sharma R, Nakamura M, Neupane C, et al. Positive allosteric modulation of GABA(A) receptors by a novel antiepileptic drug cenobamate. Eur J Pharmacol, 2020, 879: 173117.
7. Agrawal SK, Fehlings MG. Mechanisms of secondary injury to spinal cord axons in vitro: role of Na+, Na(+)-K(+)-ATPase, the Na(+)-H+ exchanger, and the Na(+)-Ca2+ exchanger. J Neurosci, 1996, 16(2): 545-552.
8. Pearn ML, Niesman IR, Egawa J, et al. Pathophysiology associated with traumatic brain injury: current treatments and potential novel therapeutics. Cell Mol Neurobiol, 2017, 37(4): 571-585.
9. Wiciński M, Puk O, Malinowski B. Cenobamate: neuroprotective potential of a new antiepileptic drug. Neurochem Res, 2021, 46(3): 439-446.
10. Çiçek SS. Structure-dependent activity of natural GABA(A) receptor modulators. Molecules, 2018, 23(7): 1512.
11. Vernillet L, Greene SA, Kamin M. Pharmacokinetics of cenobamate: results from single and multiple oral ascending-dose studies in healthy subjects. Clin Pharmacol Drug Dev, 2020, 9(4): 428-443.
12. 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.
13. 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.
14. French JA, Chung SS, Krauss GL, et al. Long-term safety of adjunctive cenobamate in patients with uncontrolled focal seizures: Open-label extension of a randomized clinical study. Epilepsia, 2021, 62(9): 2142-2150.
15. Klein P, Aboumatar S, Brandt C, et al. Long-term efficacy and safety from an open-label extension of adjunctive cenobamate in patients with uncontrolled focal seizures. Neurology, 2022, 99(10): e989-e998.
16. 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.
17. Sperling MR, 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. Epilepsia, 2021, 62(12): 3005-3015.
18. Elizebath R, Zhang E, Coe P, et al. Cenobamate treatment of focal-onset seizures: Quality of life and outcome during up to eight years of treatment. Epilepsy Behav. 2021;116: 107796.
19. Abou-Khalil B, Aboumatar S, Klein P, et al. Efficacy of cenobamate for uncontrolled focal seizures in patients with previous epilepsy-related surgery: post hoc analysis of a phase 3, multicenter, open-label study. Epilepsy Res, 2022, 184: 106952.
20. Lattanzi S, Trinka E, Zaccara G, et al. Third-generation antiseizure medications for adjunctive treatment of focal-onset seizures in adults: a systematic review and network meta-analysis. Drugs, 2022, 82(2): 199-218.
21. Peña-Ceballos J, Moloney PB, Munteanu T, et al. Adjunctive cenobamate in highly active and ultra-refractory focal epilepsy: a "real-world" retrospective study. Epilepsia, 2023, 64(5): 1225-1235.
22. Makridis KL, Bast T, Prager C, et al. Real-world experience treating pediatric epilepsy patients with cenobamate. Front Neurol, 2022, 13: 950171.
23. Varughese RT, Shah YD, Karkare S, et al. Adjunctive use of cenobamate for pediatric refractory focal-onset epilepsy: a single-center retrospective study. Epilepsy Behav, 2022, 130: 108679.
24. Makridis KL, Friedo AL, Kellinghaus C, et al. Successful treatment of adult Dravet syndrome patients with cenobamate. Epilepsia, 2022, 63(12): e164-e171.
25. Darpo B, Sager PT, Xue H, et al. A phase 1 clinical study evaluating the effects of cenobamate on the QT interval. Clin Pharmacol Drug Dev, 2022, 11(4): 523-534.
26. Buckley CT, Waters OR, DeMaagd G. Cenobamate: a new adjunctive agent for drug-resistant focal onset epilepsy. Ann Pharmacother, 2021, 55(3): 318-329.
27. Lattanzi S, Trinka E, Zaccara G, et al. Adjunctive cenobamate for focal-onset seizures in adults: a systematic review and meta-analysis. CNS Drugs, 2020, 34(11): 1105-1120.
28. Roberti R, De Caro C, Iannone LF, et al. Pharmacology of cenobamate: mechanism of action, pharmacokinetics, drug-drug interactions and tolerability. CNS Drugs, 2021, 35(6): 609-618.
29. SK Life Science I. Assess the influence of cenobamate on the pk of cytochrome p450 (cyp) probe drugs as a means of predicting drug-drug interactions, Available from: https://clinicaltrials.gov/ct2/show/results/NCT03234699?view=results.

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