SK Life Science’s investigational agent cenobamate has shown an ability to significantly reduce focal-onset seizures in doses of 100, 200, and 400-mg compared to placebo. An NDA was filed for the therapy in early 2019.
Gregory L. Krauss, MD
Cenobamate, an investigational antiepileptic therapy which acts as a sodium channel antagonist, has proved positive in a new clinical trial, with results suggesting that the SK Life Science agent can produce significant reductions in focal-onset seizures with adjunctive therapy.1
The effect was observed in a dose-related fashion in the maintenance phase of the study which included 437 patients, with cenobamate being assessed in doses of 100, 200, and 400 mg, all of which resulted in significant reductions in median seizure frequency. Additionally, responder rates during the maintenance phase of the study were significantly higher for all doses of cenobamate.
"This is the first publication showing the results of a randomized, controlled clinical trial of cenobamate in adults with uncontrolled focal seizures," said lead author Gregory L. Krauss, MD, professor of neurology, Johns Hopkins University, in a statement.2 "The results demonstrated significant dose-related reductions in seizure frequency with cenobamate during the maintenance phase compared to placebo. Encouragingly, a high number of patients had zero seizures during the maintenance phase in the 200 mg and 400 mg groups."
The full cohort of patients were randomized 1:1:1:1 to either 100 mg (n = 108), 200 mg (n = 110), 400 mg (n= 111) cenobamate, or placebo (n = 108), with 434 (98% [n = 106] of placebo, 100% of the 100-mg group, 99% [n = 109] of the 200-mg group, and 100% of the 400-mg group) were included in the modified intention-to-treat population, and 397 (94% [n = 102] of placebo group, 94% [n = 102] of the 100-mg group, 89% [n = 98] of the 200-mg group, and 86% [n = 95] of the 400-mg group) were included in the modified intention-to-treat maintenance phase population.
All told, the median changes in seizure frequency for those randomized to cenobamate were —35.5% (interquartile range [IQR], −62.5 to −15.0; P = .0071) for the 100-mg group, −55.0% (IQR, −73.0 to −23.0; P <.0001) for the 200-mg group, and −55.0% (IQR, −85.0 to −28.0; P <.0001) for the 400-mg group. In comparison, the placebo group experienced a median change of −24.0% (IQR, −45.0 to −7.0).
"More than one-third of patients with epilepsy have uncontrolled seizures and treatment outcomes for these patients have not substantially improved over the past 20 years,"i said Marc Kamin, MD, chief medical officer, SK Life Science, in a statement. "Based on the results in the maintenance phase of the study, a post-hoc analysis of the number of patients needed to treat to get someone to 0 focal seizures was 10 for the 200-mg dose and 5 for the 400-mg dose. We are encouraged by these results as they suggest that cenobamate may be able to help patients with focal seizures who have not yet achieved adequate seizure control."
Responder rates during the 12-week maintenance phase were 25% (26 of 102 patients) for the placebo group, compared to 40% (41 of 102; odds ratio [OR], 1.97; 95% CI, 1.08—3.56; P = .0365) for the 100-mg dose group, 56% (55 of 98; OR, 3.74; 95% CI, 2.06—6.80; P <.0001) for the 200-mg dose group, and 64% (61 of 95; OR, 5.24; 95% CI, 2.84—9.67; P <.0001) for the 400-mg dose group.
During the maintenance phase, 4%, 11% and 21% of patients treated with cenobamate 100 mg, 200 mg, and 400 mg, respectively, reported no focal seizures, compared with only 1% of placebo-treated patients.
“This benefit was supported by a conservative analysis of seizure-free rates during the maintenance phase among patients completing the study (preventing dropouts from counting as seizure-free) and using the modified intention-to-treat population as the denominator,” Krauss and colleagues wrote, noting that the analysis also showed high seizure-free rates for patients treated with 200 mg (9.2%) and 400 mg (14.4%).
“Regardless of the analysis method used, it remains difficult to interpret seizure freedom in clinical trials given the constraints of the study designs (ie, inability to adjust concomitant antiepileptic drugs), which do not reflect real-life practice. Nonetheless, seizure freedom is of great clinical significance to patient quality of life and the rates reported in this study are notable relative to all other pivotal studies of antiepileptic drug treatment in uncontrolled focal seizures over the past 25 years,” they concluded.
Treatment-emergent adverse events (AEs) occurred at similar rates of 70% (76 of 108) patients in the placebo group, 65% (70 of 108) in the 100-mg group, 76% (84 of 110) in the 200-mg group, and 90% (100 of 111) in the 400-mg group. AEs led to discontinuation in 5% (n = 5) patients in the placebo group, 10% (n = 11) in the 100-mg dose group, 14% (n = 15) in the 200-mg dose group, and 20% (n = 22) in the 400-mg dose group. A single serious case of drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome occurred in the 200-mg cenobamate group, though no deaths were reported.
In previously published study findings, cenobamate was shown to reduce the incidence of DRESS, with the use of a low-dose, slow titration strategy, with no occurrence of DRESS in a study including 1339 patients. Patients were administered gradually increasing doses of cenobamate 12.5 mg, 25 mg, 50 mg, 100 mg, 150 mg, and 200 mg/day at 2-week intervals. Additionally, biweekly increases of 50 mg/day to increase the dosage to 400 mg/day were allowed.3
“This drug, based on my opinion after treating more than 60 patients, is the most startlingly effective anticonvulsant drug that I've ever used in an investigational trial,” investigator Michael Sperling, MD, director, Jefferson Comprehensive Epilepsy Center and the Jefferson Clinical Neurophysiology Laboratory, told NeurologyLive in January. “I've been involved investigational trials since the late 1980s and this one remarkably reduces seizure frequency and seizure severity. I have seen a number of patients who have become seizure-free after starting this drug.”
Earlier this year, the FDA accepted a new drug application (NDA) for the treatment of partial-onset seizures in adults, using supporting data from its pivotal trials, which included more than 1900 patients.4
1. 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. Published online November 13, 2019. doi: 10.1016/S1474-4422(19)30399-0.
2. Results of a Randomized Study of the Safety and Efficacy of Cenobamate in Adults with Uncontrolled Focal Seizures Published in The Lancet Neurology [press release]. Paramus, NJ: SK Life Science; Published November 13, 2019. prnewswire.com/news-releases/results-of-a-randomized-study-of-the-safety-and-efficacy-of-cenobamate-in-adults-with-uncontrolled-focal-seizures-published-in-the-lancet-neurology-300957940.html. Accessed November 15, 2019.
3. Sperling M, Klein P, Kamin M. Safety of cenobamate (YKP3089) as adjunctive treatment for uncontrolled partial seizures in a large, multi-center, open-label study. Presented at: American Epilepsy Society Annual Meeting; New Orleans, LA; December 2, 2018. aesnet.org/meetings_events/annual_meeting_abstracts/view/500991.
4. SK life science announces FDA acceptance of NDA submission for cenobamate, an investigational antiepileptic drug [press release]. Fair Lawn, NJ: SK Life Science; Published February 4, 2019. sklifescienceinc.com/pdf/SKLSI%20NDA%20Acceptance%20Press%20Release%20-FINAL-Updated%202-3-19.pdf. Accessed November 15, 2019.