Indirect treatment comparison of cenobamate to other ASMs for the treatment of uncontrolled focal seizures

Abstract

Objective: The efficacy and safety of cenobamate relative to other antiseizure medications (ASMs) has not been evaluated. An indirect treatment comparison (network meta-analysis) was performed to determine if adjunctive cenobamate increases the odds ratio (OR) for 50% responder rate or for withdrawals due to treatment-emergent adverse events (TEAEs) leading to ASM discontinuation versus adjunctive therapy with other ASMs. Methods: A systematic literature review was conducted to identify randomized, double-blind, placebocontrolled trials (maintenance phase 12 weeks) assessing adjunctive ASMs in adults with uncontrolled focal seizures. Cenobamate was compared to a group of seven other ASMs, and to subgroups of branded (brivaracetam, eslicarbazepine acetate, lacosamide, and perampanel) and older (lamotrigine, levetiracetam, and topiramate) ASMs at FDA-recommended daily maintenance doses (FDA-RDMD), at all doses, and at maximum and minimum daily doses. Statistical significance was set at p < 0.05. Results: Twenty-one studies were eligible for analysis. The placebo-adjusted 50% responder rate for FDA-RDMD of cenobamate was superior (OR 4.200; 95% CI 2.279, 7.742) to FDA-RDMD of all seven assessed (OR 2.202 95% CI 1.915, 2.532; p = 0.044) and branded ASMs (OR 2.148; 95% CI 1.849, 2.494; p = 0.037). There was no significant difference for 50% responder rate between FDA-RDMD of cenobamate and FDA-RDMD of older ASMs (OR 2.617; 95% CI 1.767, 3.878; p = 0.202). No significant differences were identified for 50% responder rate when comparing all doses and maximum/minimum doses of cenobamate to all seven, branded, and older ASMs. Cenobamate demonstrated comparable TEAE withdrawal rates to all seven ASMs, branded ASMs, and older ASMs across each of the four dose ranges (all p > 0.05). Significance: Patients receiving FDA-RDMD of cenobamate were more likely to have 50% seizure reduction compared with FDA-RDMD of the seven assessed ASMs and branded ASMs, without an increase in treatment discontinuation due to TEAEs.

Onset of efficacy and adverse events during Cenobamate titration period

“…However, in a recently published meta‐analysis, it was concluded that cenobamate was associated with a higher responder rate and a better likelihood of providing seizure freedom compared to brivaracetam, eslicarbazepine acetate, lacosamide, and perampanel 17 . The superiority of cenobamate for seizure reduction was reported in a recent review that showed that FDA‐recommended maintenance doses nearly doubled the chances of ≥50% seizure reduction and found that the tolerability profile of cenobamate was consistent with other ASMs in its class 18 …”

“…17 The superiority of cenobamate for seizure reduction was reported in a recent review that showed that FDA-recommended maintenance doses nearly doubled the chances of ≥50% seizure reduction and found that the tolerability profile of cenobamate was consistent with other ASMs in its class. 18 Interactions occurring between concomitant ASMs with varying mechanisms of action may lead to tolerability issues that affect patient compliance. Cenobamate acts as a CYP2C19 inhibitor, significantly increasing exposure to concomitant phenytoin or phenobarbital therapies when used as adjunctive treatment.…”

In silico screening for clinical efficacy of antiseizure medications: Not all central nervous system drugs are alike

“…In addition, higher lipophilicity leads to unnecessary nonspecific partitioning into brain tissue 32,33 . In two recent indirect comparisons of ASM efficacy in patients with focal seizures, 34,35 the relative responder rate was highest for molecules with TPSA value > 90 (Figure 2). The exact nature of the nonspecific drug disposition sites within epileptogenic brain tissue requires further investigation.…”

“…Correlation between the topological polar surface area (TSPA) of antiseizure medications and the odds ratio versus placebo for reduction of seizure frequency in patients with focal seizures. Values are based on data from Privitera et al (A,B) 35 and Lattanzi et al (C) 34 . (A,B) Correlation between the TPSA of antiseizure medications and ≥50% responder rate across all studied doses (A) or the ≥50% responder rate at maximal dose in each study (B) 35 .…”

“…Values are based on data from Privitera et al (A,B) 35 and Lattanzi et al (C) 34 . (A,B) Correlation between the TPSA of antiseizure medications and ≥50% responder rate across all studied doses (A) or the ≥50% responder rate at maximal dose in each study (B) 35 . (C) Correlation between the TPSA and the surface under the cumulative ranking curve (SUCRA).…”