Perampanel Does Not Worsen Myoclonic or Absence Seizures in Patients With Epilepsy

Christian Brandt, MD, head, department of general epileptology, Bethel Epilepsy Centre

Christian Brandt, MD

Data from a post hoc analysis of Study 332 (NCT01393743) has shown that adjunctive treatment with perampanel (Fycompa, Eisai) does not result in the overall worsening of myoclonic or absence seizures.¹

Presented at the 2019 International Epilepsy Congress, June 22-26, in Bangkok, Thailand, the phase 3 data included 163 patients with epilepsy during the double-blind and open-label extension phases of the original study.

All told, in the double-blind phase, myoclonic seizure worsening occurred in 29.2% of patients, while absence seizure worsening transpired in 29.6% of patients in the perampanel group. In comparison, placebo-treated patients experienced respective worsening of 30.4% and 45.5% in myoclonic and absence seizures. In the open-label extension, myoclonic and absence seizures worsened by 15.2% and 17.3% of the 138 total patients, respectively.

Led by Christian Brandt, MD, head, department of general epileptology, Bethel Epilepsy Centre, the investigators wrote that their “assessments for myoclonic and absence seizures included: number of seizure days and seizure-free days, seizure worsening (increased seizure frequency per 28 days from double-blind or pre-perampanel baseline) and monitoring of treatment-emergent adverse events.”

In the double-blind phase, myoclonic and absence seizures were reported in 47 (placebo, n = 23; perampanel, n = 24) and 60 patients (placebo, n = 33; perampanel, n = 27) , respectively. Brandt et al. observed a mean decrease in seizure days from a baseline of 7.6 to 6.3 and 7.6 to 6.7 days, for decreases of 19.1% (range, —100 to 169.7) and 21.3% (range, –100 to 1876.5)of myoclonic and absence seizures, respectively, for those treated with perampanel. For placebo, myoclonic and absence seizure days were reduced from 2.5 to 1.0 and 5.5 to 4.5 days, or 51.7% (range, –100 to 306.8) and 25.2% (range, –100 to 165.7), respectively.

The percent of seizure-free days in the double-blind phase increased by 1.4% (range, —15.2 to 10.3) and 1.0% (range, –12 to 9.4) for myoclonic and absence seizures, respectively, in the perampanel group, from baseline counts of 20.4 and 20.4 days to 21.7 and 21.3 days. In comparison, baseline seizure-free days for the placebo group were respectively 25.5 and 22.5 days, which improved to 27.1 and 23.5 days, for a change of 0.5% (range, –3.1 to 9.9 days) and 0.4% (range, –14 to 20.4) for myoclonic and absence seizures.

During the open-label extension, 46 and 52 patients of 138 total experienced myoclonic and absence seizures, respectively. The median percent change from baseline (pre-perampanel treatment) for seizure days was -77.3% and -66.1% for myoclonic and absence seizures, respectively, while seizure-free days increased by 1.2% and 1.5%, for myoclonic and absence seizures, respectively.

"This post hoc analysis provides further preliminary evidence to suggest that perampanel does not exacerbate myoclonic or absence seizures in patients with [idiopathic generalised epilepsy], warranting further research into the use of perampanel as a broad-spectrum [anti-seizure drug] for the treatment of these generalised seizure types," Brandt et al. concluded.

“Treatment-emergent adverse events were consistent with the known safety profile of perampanel during both the double-blind and [open-label extension] phases,” Brandt and colleagues noted. In the original study, the most frequent treatment-emergent adverse events with perampanel were dizziness, occurring in 32.1% of patients, and fatigue, occurring in 14.8% of patients. Study 332, conducted by Jacqueline French, MD, et al, also previously showed that in comparison with placebo, a greater median percent change in primary generalized tonic-clonic seizure frequency per 28 days was observed with perampanel, with a change of 276.5% against 238.4% (P <.0001). Additionally, responder rates of ≥50% were 64.2% with the study drug compared to 39.5% with placebo (P <.0019). During maintenance, 12.3% of those in the placebo group and 30.9% of perampanel-treated patients achieved seizure-freedom.²

The first in class, noncompetitive antagonist of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor has previously shown success in a number of areas of epilepsy treatment, including secondary generalized seizures. At the American Epilepsy Society 2018 annual meeting, data from Study 307 showed that participants with ≥12 years of secondarily generalized seizures achieved seizure-free status with perampanel during the Studies 304 (NCT00699972), 305 (NCT00699582), or 306 (NCT00700310), or the open-label extension of Study 307 (NCT00735397). As well, it revealed that patients who were previously seizure free sustained their seizure freedom during the open-label extension of Study 307, which further supports the long-term use of perampanel in patients with secondarily generalized seizures.³

Trevor Resnick, MD, of Nicklaus Children’s Hospital, previously shared his insight regarding perampanel in a NeurologyLive^® Insights video series, noting that its advantage is its long half-life. “From a compliance standpoint, it’s great. And, specifically, in terms of its effectiveness for generalized seizures, both partial, both secondary generalized seizures and primary generalized seizures, have a very robust response,” he said.

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REFERENCES

1. Brandt C, Wechsler RT, O’Brien TJ, et al. Perampanel does not worsen myoclonic and absence seizures. Presented at: IEC 2019; June 22 to 26, 2019; Bangkok, Thailand. Poster 317.

2. French JA, Krauss GL, Wechsler RT, et al. Perampanel for tonic-clonic seizures in idiopathic generalized epilepsy A randomized trial. Neurology. 2015;85(11):950-7. doi: 10.1212/WNL.0000000000001930.

3. Krauss G, Perucca E, Kwan P, 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&#8208;label extension of phase III randomized trials: Study 307. Epilepsia. 2018;59(4):866—876. doi: 10.1111/epi.14044.