Introduction: The PERMIT study is the largest pooled analysis of perampanel (PER) clinical practice data conducted to date., Methods: This post-hoc analysis of PERMIT investigated the effectiveness, safety and tolerability of PER when used as early add-on therapy (after failure of one or two previous antiseizure medications) in comparison with late add-on therapy (after failure of three or more previous antiseizure medications). Retention and effectiveness were assessed after 3, 6, and 12 months, and at the last visit (last observation carried forward). Effectiveness was assessed by seizure type (total seizures, focal seizures, generalized tonic-clonic seizures [GTCS]) and assessments included seizure freedom rate and responder rate. Safety and tolerability were assessed by evaluating adverse events (AEs) and discontinuation due to AEs., Results: The Full Analysis Set included 1184 and 2861 PWE treated with PER as early and late add-on therapy, respectively. Compared to the late add-on subgroup, the early add-on subgroup was characterized by later mean age at epilepsy onset, shorter mean duration of epilepsy, lower rates of intellectual disability and psychiatric comorbidity, and lower frequency of seizures per month, suggesting a less severe form of epilepsy in this subgroup. After 12 months, retention was significantly higher in the early versus late add-on subgroup (67.7% vs. 62.4%; p = 0.004). At the last visit, responder rates in the early versus late add-on subgroup were significantly higher for total seizures (68.2% vs. 39.3%; p < 0.001), focal seizures (65.0% vs. 36.8%; p < 0.001) and GTCS (83.7% vs. 67.2%; p < 0.001), as were seizure freedom rates (total seizures, 35.9% vs. 11.9% [ p < 0.001]; focal seizures, 29.4% vs. 8.7% [ p < 0.001]; GTCS, 69.0% vs. 48.1% [ p < 0.001]). Incidence of AEs was significantly lower in the early versus late add-on subgroup (42.1% vs. 54.7%; p < 0.001), as was the rate of discontinuation due to AEs over 12 months (15.0% vs. 18.1%; p = 0.031)., Discussion: This study demonstrated that PER was effective and generally well tolerated when initiated as early or late add-on therapy, but it was significantly more effective and better tolerated when initiated early. These findings support PER's use as a broad-spectrum, early add-on therapy for use in PWE with focal and generalized seizures., Competing Interests: ES received grants and personal fees from UCB Pharma, Eisai and personal fees from Esteve and Bial. AS reports personal fees and grants from Angelini Pharma, Desitin Arzneimittel, Eisai, GW Pharmaceuticals companies/Jazz Pharmaceuticals, Marinus Pharma, Precisis, Takeda, UCB Pharma/Zogenix, and UNEEG medical. JJR-U received speaker's fees from UCB, Bial, Eisai, GW Pharma, Esteve and Cyberonics. RS has received institutional/ research support in the last 2 years from various pharma: UCB, Eisai, Bial, Jazz pharma, LivaNova and Angellini. He is the chief investigator or co-Investigator in various grants from - NIHR, NHS England, SBRI, ESPRC, ESRC and Bailey Thomas. He is involved in projects with Neuronostics, UnEEG and NELLI. He is a lead stakeholder of the not for profit ‘SUDEP and Seizure Safety Checklist' and the mobile app based on the checklist - EpSMon. XR-O received honoraria and/or research funds from Bial, Eisai, Esteve, GW Pharma, NewBridge, Novartis, UCB Pharma and Zogenix. SA received honoraria and/or research funding from Arvelle, Eisai, GW Pharma, Zogenix, Advicenne, UCB Pharma and Zogenix. PB has received speaker's or consultancy fees from Bial, Eisai, LivaNova, Lusofarmaco and Proveca. ET reports personal fees from EVER Pharma, Marinus, Arvelle, Angelini, Argenix, Medtronic, Bial-Portela & Ca, NewBridge, GL Pharma, GlaxoSmithKline, Boehringer Ingelheim, LivaNova, Eisai, UCB, Biogen, Genzyme Sanofi, and Actavis. His institution received grants from Biogen, UCB Pharma, Eisai, Red Bull, Merck, Bayer, the European Union, FWF Osterreichischer Fond zur Wissenschaftsforderung, Bundesministerium für Wissenschaft und Forschung, and Jubiläumsfond der Österreichischen Nationalbank. RM and RS-F are employees of Eisai Europe Ltd. VV has received honoraria and/or research funds from Angelini, Arvelle, Bial, Eisai, Esteve, GW Pharma, NewBridge, Novartis, Takeda, UCB Pharma and Zogenix. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declare that this study received funding from Eisai Ltd. The funder had the following involvement with the study: study and manuscript preparation., (Copyright © 2023 Liguori, Santamarina, Strzelczyk, Rodríguez-Uranga, Shankar, Rodríguez-Osorio, Auvin, Bonanni, Trinka, McMurray, Sáinz-Fuertes and Villanueva.)