Antiseizure drug yields durable seizure frequency reduction, lowers concomitant medication burden

In the treatment of adults with uncontrolled focal seizures, the long-term, open-label use of cenobamate appears to produce high rates of sustained 100-percent and ≥90-percent seizure reduction, with parallel decreases in concomitant antiseizure medication (ASM) doses, according to two separate post hoc analyses of a phase III C021 trial.

Out of the 214 patients who received a dose of cenobamate in the maintenance phase (median, 29.5 months), 28 (13.1 percent) achieved sustained seizure freedom and 86 (40.2 percent) attained ≥90-percent seizure reduction during their entire maintenance treatment duration. Overall, 87 (36.3 percent) patients experienced freedom from seizures for ≥12 months straight at any time during the trial. [Epilepsia 2021;doi:10.1111/epi.17091]

The post hoc analysis included 240 patients (mean age at baseline 41.8 years, 56.3 male, mean seizure frequency at screening 18.1/28 days) with uncontrolled focal seizures taking stable doses of up to three ASMs. They received increasing daily doses of cenobamate (12.5, 25, 50, 100, 150, 200 mg/day) over 12 weeks at 2-week intervals, with further increases to 400 mg/day by 50-mg/day increments biweekly allowed during the maintenance phase.

Retention was high, with 177 (73.8 patients) patients remaining on cenobamate throughout the analysis period (median, 2.7 years). The ≥50-percent responder rates were 48.1 percent during weeks 1–4 (12.5–25 mg/day), 61.7 percent during weeks 5–8 (50–100 mg/day), and 71.7 percent for the total treatment duration.

The most common treatment-emergent adverse events (TEAEs) were fatigue (34.6 percent), dizziness (32.1 percent), and somnolence (29.6 percent).

“This post hoc analysis of a subset of patients from the open-label safety study demonstrates durable and sustained improvement in seizure control in adults treated with cenobamate,” said the investigators, led by Dr Michael Sperling of the Thomas Jefferson University in Philadelphia, US.

“Robust seizure reduction was also noted for all assessed focal seizure types, including focal to bilateral tonic–clonic (FBTC) seizures, the type most associated with morbidity and mortality,” they added.

The rates of seizure freedom achieved with the drug, according to Sperling and colleagues, are striking and may potentially reduce the risk of death and injury.

“This study is also the first analysis to demonstrate efficacy with cenobamate using the FDA-approved titration regimen. Using a start-low, go-slow cenobamate titration schedule, patients started to have seizure reduction within the first 4 weeks of titration at doses of 12.5–25 mg/day, with further reduction observed in the following 4-week intervals through week 12,” the investigators said.

“Despite [this] 12-week titration regimen, many patients respond during the first 4–8 weeks of titration, providing time to safely titrate patients to the desired maintenance dose,” they noted.

Concomitant ASM doses reduced

At the same time, there were dose reductions in concomitant ASMs observed throughout cenobamate treatment. The reductions were greater for patients who remained on cenobamate than for those who discontinued. [Epilepsia 2021;doi:10.1111/epi.17092]

The concomitant ASM dose reductions “likely led to greater patient retention due to the combination of appropriate levels of efficacy and reduced concomitant drug burden in a population who were largely taking two to three concomitant ASMs at baseline,” noted a team of researchers led by Dr William Rosenfeld of the Comprehensive Epilepsy Care Center for Children and Adults in St. Louis, Missouri, US.

In general, dose decreases for all concomitant ASMs occurred during titration or early maintenance phases and were mostly caused by central nervous system (CNS)–related adverse events such as somnolence, dizziness, unsteady gait, and fatigue. Lacosamide, levetiracetam, lamotrigine, zonisamide, and clobazam were the most frequently used concomitant ASMs.

Of the 177 patients who remained on cenobamate throughout the analysis, 24.6 percent discontinued one or more concomitant ASMs completely. Responder rates from ≥50 percent through 100 percent were generally similar, and no concomitant ASM was associated with the achievement of seizure freedom during adjunctive cenobamate treatment.

“This post hoc analysis of a subset of the C021 study provides some direction to physicians on adjusting concomitant ASMs when adding on cenobamate treatment… Doses of concomitant phenytoin, phenobarbital, clobazam, valproate, and lacosamide, in particular, may be gradually reduced early on when adding cenobamate treatment to avoid possible tolerability issues,” according to Rosenfeld and colleagues.

“As physicians in this trial became more experienced and learned about possible interactions and how to minimize them, concomitant ASM doses were reduced earlier in cenobamate titration. Thus, for general neurologic practice, ASM dose reductions may occur sooner than seen here, depending on the early efficacy and tolerability observed while titrating patients onto cenobamate,” they added.