Experience of perampanel monotherapy beyond initial titration to achieve seizure freedom in patients with focal-onset seizures with newly diagnosed or currently untreated recurrent epilepsy: A post hoc analysis of the open-label Study 342 (FREEDOM)

Ryan Edbert Husni, Leock Y Ngo, Hirofumi Senokuchi, Anna Patten, Hidetaka Hiramatsu, Kazuaki Watanabe, Takamichi Yamamoto, Ryan Edbert Husni, Leock Y Ngo, Hirofumi Senokuchi, Anna Patten, Hidetaka Hiramatsu, Kazuaki Watanabe, Takamichi Yamamoto

Abstract

Objective: This post hoc analysis evaluated whether continued treatment with perampanel monotherapy beyond initial titration may be appropriate for patients with focal-onset seizures (FOS) with currently untreated epilepsy to achieve seizure freedom with an effective dose.

Methods: Study 342 (NCT03201900; FREEDOM) is a single-arm, open-label, Phase III study of perampanel monotherapy. Patients aged ≥12 years with untreated FOS received perampanel 4 mg/d in a 32-week Treatment Phase (6-week Titration and 26-week Maintenance Periods); in case of seizure(s) during Maintenance Period, patients could enter a 30-week Treatment Phase (4-week Titration and 26-week Maintenance Periods) to be up-titrated to perampanel 8 mg/d. The primary endpoint was seizure-freedom rate during Maintenance Period in the modified Intent-to-Treat (mITT) Analysis Set (patients who had ≥1 post-dose efficacy measurement during Maintenance Period); safety was monitored. This analysis of 4-mg/d efficacy data assessed the proportion of patients achieving seizure freedom during the Maintenance Period (responders) relative to patients with an early/later response (depending on seizure status during the Titration Period).

Results: In the mITT population (n = 73), 46 patients were 4-mg/d responders; of whom, 37 (80.4%) were early responders and nine (19.6%) were later responders. The mean (standard deviation) percent reductions in FOS frequency from baseline at the end of the 4-mg/d Titration Period were 100.0% (0.0%; early responders) and 46.3% (97.3%; later responders). Among the 27 4-mg/d nonresponders, nine (33.3%) patients who had an early response experienced seizure(s) during the subsequent 4-mg/d Maintenance Period. Safety outcomes were similar, regardless of responder status, without new safety concerns.

Significance: Some patients with untreated FOS may benefit from continued treatment beyond initial titration of perampanel monotherapy to achieve seizure freedom, suggesting that it may not be appropriate to make treatment decisions to discontinue or switch from perampanel monotherapy solely based on seizure response before an effective dose has been reached.

Keywords: Titration Phase; antiseizure medication; early response; initial treatment; maintenance dose; seizure freedom.

Conflict of interest statement

Ryan Edbert Husni, Hirofumi Senokuchi, Hidetaka Hiramatsu, and Kazuaki Watanabe are employees of Eisai Co., Ltd. Leock Y Ngo is an employee of Eisai Inc. Anna Patten is an employee of Eisai Europe Ltd. Takamichi Yamamoto has received speaker's honoraria from Daiichi‐Sankyo, Eisai, LivaNova, Otsuka Pharmaceutical, and UCB Japan; participated in advisory boards for Eisai; and served as Sponsor's Responsible Medical Officer for the FREEDOM Trial (Study 342).

© 2021 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.

Figures

FIGURE 1
FIGURE 1
Criteria for a patient in the mITT Analysis Set to be included in the 4‐mg/d responder or nonresponder group. mITT, modified Intent‐to‐Treat; N/A, not applicable. aFor patients who did not achieve seizure freedom during the 4‐mg/d Maintenance Period, the decision whether to further up‐titrate perampanel to 8 mg/d was based on the investigator's judgment of the patient's clinical tolerability and safety
FIGURE 2
FIGURE 2
Patient flow for the mITT Analysis Set showing 4‐mg/d responders and nonrespondersa in Study 342. mITT, modified Intent‐to‐Treat. aPatients were considered nonresponders even if they went on to achieve seizure freedom during the 8‐mg/d Treatment Phase. bEarly responders were seizure free from the start of treatment
FIGURE 3
FIGURE 3
Mean percent reductions in seizure frequency from Baseline at Weeks 2 and 6 during the Titration Period of Study 342 for 4‐mg/d responder and nonrespondera patients. aPatients were considered nonresponders even if they went on to achieve seizure freedom during the 8‐mg/d Treatment Phase

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Source: PubMed

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