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The pharmacological treatment of epilepsy: recent advances and future perspectives

The pharmacological treatment of epilepsy: recent advances and future perspectives The pharmacological armamentarium against epilepsy has expanded considerably over the last three decades, and currently includes over 30 different antiseizure medications. Despite this large armamentarium, about one third of people with epilepsy fail to achieve sustained seizure freedom with currently available medications. This sobering fact, however, is mitigated by evidence that clinical outcomes for many people with epilepsy have improved over the years. In particular, physicians now have unprecedented opportunities to tailor treatment choices to the characteristics of the individual, in order to maximize efficacy and tolerability. The present article discusses advances in the drug treatment of epilepsy in the last 5 years, focusing in particular on comparative effectiveness trials of second-generation drugs, the introduction of new pharmaceutical formulations for emergency use, and the results achieved with the newest medications. The article also includes a discussion of potential future developments, including those derived from advances in information technology, the development of novel precision treatments, the introduction of disease modifying agents, and the discovery of biomarkers to facilitate conduction of clinical trials as well as routine clinical management. Keywords: Epilepsy, Seizures, Drug therapy, Antiepileptic drugs, Antiseizure medications, Advances, Review Background the ASMs introduced after 1985, usually referred to as The modern treatment of epilepsy started with the intro- second-generation drugs, have some safety advantages duction of phenobarbital in 1912. The advent of pheny- over older generation agents, but have not increased toin in the late thirties marked another milestone, substantially the proportion of patients who achieve because it was made possible by the introduction of ani- complete freedom from seizures [3]. For many of these mal models of antiseizure activity [1]. Similar models patients, the feasibility of epilepsy surgery, or alternative also played a key role in the subsequent development of therapies, should be given early consideration [4, 5]. many other antiseizure medications (ASMs). Today, the Despite the fact that pharmacoresistance has been pharmacological armamentarium against epilepsy little affected by the introduction of newer medications, includes more than 30 drugs (Table 1). These drugs dif- the drug treatment of epilepsy has made major advances fer in their pharmacokinetics, efficacy, and adverse effect in the last 50 years. In particular, we learnt how to profile, thereby offering unprecedented opportunities to individualize drug selection based on specific patient tailor treatment choices to individual needs [2]. Some of characteristics such as age, gender, epilepsy syndrome, seizure type, comorbidities, comedications, and other factors affecting clinical response [6]. We also learnt Correspondence: perucca@unipv.it This article is dedicated to the memory of Professor Alan Richens (1938–2021), how to optimize response by careful titration and adjust- my mentor and dear friend, in recognition of his outstanding contribution to ment of dosage, and use of serum drug levels whenever advancing the pharmacological treatment of epilepsy. indicated [7]. We made major progress in understanding Department of Internal Medicine and Therapeutics, Division of Clinical and Experimental Pharmacology, University of Pavia, Via Ferrata 9, 27100 Pavia, drug interactions, and recognizing the relative merits Italy and indications of monotherapy and polytherapy [8, 9]. Department of Neuroscience, Central Clinical School, Monash University, Likewise, we improved our knowledge of the natural Melbourne, Victoria 3004, Australia © The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Perucca Acta Epileptologica (2021) 3:22 Page 2 of 11 Table 1 Years of introduction in the market of currently available antiseizure medications. For all drugs, year of introduction refers to either Europe or the United States of America. The table does not include a number of drugs approved before 1970, but rarely used today 1900–1950 1951–1985 1986–2000 2001–2015 2015–2021 Phenobarbital Carbamazepine Felbamate Eslicarbazepine acetate Brivaracetam Phenytoin Clobazam Fosphenytoin Lacosamide Cannabidiol Clonazepam Gabapentin Perampanel Cenobamate Diazepam Lamotrigine Pregabalin Everolimus Ethosuximide Levetiracetam Rufinamide Fenfluramine Midazolam Lorazepam Stiripentol Primidone Oxcarbazepine Valproic acid Tiagabine Topiramate Vigabatrin Zonisamide history of epilepsy syndromes, and characterized prog- efficacious, generally devoid of adverse effects on mood and nostic factors for seizure recurrence for patients in cognitive function, and with a low potential to cause adverse whom discontinuation of ASMs can be considered after drug interactions, even though lamotrigine metabolisn can an adequate period of freedom from seizures [10]. be affected by a variety of concurrently administered drugs The purpose of the present article is to provide a [6]. One drawback of lamotrigine is the need for gradual ti- concise overview of some advances in research on the tration in order to minimize the risk of serious skin rashes, drug treatment of epilepsy made in the last 5 years, and and therefore it may not be the most appropriate drug for to discuss currently unmet needs as well as develop- use in patients with frequent severe seizures requiring a ments which are likely to occur in the foreseeable future. prompt onset of antiseizure activity. The findings from the SANAD studies that valproate Advances in characterizing the comparative is superior to lamotrigine, topiramate and levetiracetam effectiveness and safety of ASMs in the treatment of patients with generalized epilepsy A number of recent clinical trials and observational are consistent with other lines of evidence. In particu- studies have provided valuable information which can lar, a recent study from Denmark found that failure to assist physicians in making rational treatment selections. achieve seizure freedom with valproate was the single As a follow-up to the initial Standard and New Antiepileptic most important predictor of pharmacoresistance in a Drugs (SANAD) trials, which found lamotrigine to be super- cohort of 137 adults with idiopathic (genetic) general- ior to carbamazepine, oxcarbazepine, topiramate and gaba- ized epilepsy [15]. The superior efficacy of valproate in pentin in time to treatment failure in patients with mostly controlling seizures associated with generalized epi- focal epilepsy [11], and valproate to be superior to lamotri- lepsy, however, creates a dilemma in the treatment of gine and topiramate in patients with mostly generalized and females of childbearing potential. In fact, valproate is unclassified epilepsy [12], two more recent SANAD trials regarded by theEuropeanMedicineAgencyascontra- have been completed. In the first of these trials, 990 adults indicated for use as first-line treatment in these women and children with newly diagnosed focal epilepsy were ran- (unless the conditions of a rigorous pregnancy preven- domized to receive lamotrigine, levetiracetam or zonisamide, tion programme are fulfilled), due to the higher risk of and followed-up for 2 years [13]. In the per-protocol analysis, inducing teratogenic effects as well as impaired postna- lamotrigine was associated with a better 12-month remission tal cognitive development in the offspring [16, 17]. from seizures compared with both levetiracetam and zonisa- With respect to teratogenic potential of ASMs, prospective mide. In the second SANAD-II trial, which used a similar pregnancy registries have contributed greatly to characterize protocol and enrolled 520 newly diagnosed adults and chil- risks associated with individual medications. A particularly dren, valproate was found to be more effective than levetirac- important advance was the 2018 publication of data from etam in controlling seizures in a pooled cohort of patients the international EURAP registry [18]. This study, based on with generalized or unclassified epilepsy [14]. These trials analysis of 7355 prospective pregnancies exposed to 8 differ- used a pragmatic design mimicking routine clinical practice, ent ASM monotherapies provides risk estimates non only even though the possibility of assessment bias due to the for specific ASMs, but also for different doses of the most open-label, unblinded design cannot be excluded. When commonly used drugs. Overall, the lowest prevalence of considered together with other available lines of evidence, major congenital malformations (MCMs) in the offspring these findings confirm that lamotrigine should be regarded was associated with exposure to levetiracetam (2.8% preva- as one of the treatments of first choice for patients with focal lence), lamotrigine (2.9%) and oxcarbazepine (3.0%). Preva- seizures. Lamotrigine offers the advantage of being lence estimates were intermediate for topiramate (3.9%), Perucca Acta Epileptologica (2021) 3:22 Page 3 of 11 carbamazepine (5.5%), phenytoin (6.4%) and phenobarbital have been introduced into the market. Key features of (6.5%), and highest for valproate (10.3%). An increased risk each of these medications are summarized in Table 2. with increasing dose was identified for lamotrigine and The history of these drugs is illustrative of different carbamazepine, and was most prominent for phenobarbital strategies being used in developing novel ASMs. and valproate. In particular, the prevalence of MCMs (with The development of brivaracetam followed a paradigm 95% confidence intervals) associated with phenobarbital ex- which has been in place for a very long time, i.e. the posure was 2.7% (0.3–9.5%) at doses < 80 mg/day, 6.2% (3.0– structural modification of an already existing medication 11.1%) at doses > 80 to < 130 mg/day and 11.7% (4.8–22.6%) with the aim of improving its pharmacological profile. at doses > 130 mg/day. For valproate, the prevalence of Examples of other ASMs developed with this strategy in- MCMs was 6.3% (4.5–8.6%) at doses < 650 mg/day, 11.3% clude methylphenobarbital and primidone (both struc- (9.0–13.9%) at doses > 650 to ≤ 1450 mg/day and 25.2% turally related to phenobarbital), the phenytoin (17.6–34.2%) at doses > 1450 mg/day. These findings are im- derivative fosphenytoin, and oxcarbazepine and eslicar- portant because they alert physicians about the need to con- bazepine acetate, which represent successive modifica- sider teratogenic risks not only in relation to type of ASM tions of the carbamazepine structure. In fact, prescribed, but also in relation to dose. A subsequent levetiracetam itself was originally developed with the EURAP investigation documented a clear-cut decrease in the aim of improving the pharmacological profile of pirace- prevalence of MCMs over the period from 2000 to 2013 tam, and its antiseizure activity was discovered by [19]. Specifically, there was a 27% decrease in prevalence of chance. Brivaracetam was selected for development after MCMs between pregnancies enrolled in the period 2010– extensive preclinical screening of a large numbers of le- 2013 compared with those enrolled in the period 2000–2005 vetiracetam derivatives. Compared with levetiracetam, (Fig. 1). Further analysis of these data provided a strong indi- brivaracetam has higher affinity for the synaptic vesicle cation that the improvement in pregnancy outcomes over 2A (SV2A), and a similar pharmacological profile [20]. time was related to changes in ASM prescription patterns, Brivaracetam has been found to be superior to placebo including a major decline in the proportion of pregnancies in adjunctive-therapy trials in focal epilepsy, but its exposed to valproate. In fact, a reduction in teratogenic risk activity profile in other seizure types has not yet been is one of the important advances associated with the intro- definedinwell designedcontrolledtrials. Onelimita- duction of second-generation ASMs [3]. tion of brivaracetam is its lack of efficacy when added-on to levetiracetam, presumably due to compe- Introduction of novel ASMs tition between the two drugs for the SV2A binding During the last 5 years, five novel ASMs (brivaracetam, site. The still unanswered question about brivarace- cannabidiol, cenobamate, everolimus and fenfluramine) tam is whether, and to what extent, its efficacy and Fig. 1 Prevalence of major congenital malformations (MCMs) following prenatal exposure to monotherapy with antiseizure medications (ASMs) among cases enrolled in the EURAP international registry during three different periods. Number of exposures during each period (listed in brackets) refer to the eight most common monotherapies, which accounted for 96.7 to 98.1% of all monotherapy exposures. Based on data from Tomson et al [19]. Perucca Acta Epileptologica (2021) 3:22 Page 4 of 11 Table 2 Summary of the pharmacological and clinical profile of antiseizure medications (ASMs) introduced in the market after 2015 Brivaracetam Cannabidiol Cenobamate Everolimus Fenfluramine Chemical Levetiracetam derivative Cannabinoid Carbamate derivative Rapamycin derivative Amphetamine derivative structure Approved Treatment of focal Treatment of seizures Treatment of focal Add-on treatment of Treatment of seizures epilepsy seizures in patients aged associated with LGS, DS seizures in adults focal seizures associated with DS in indications 1 month and older or TSC in patients 1 year associated with TSC in patients 2 years of age (United of age and older patients aged 2 years and older. States) and older Main SV2A modulator Several, including Blockade of persistent mTOR inhibition Several, including indirect mechanisms GPR55 antagonism, sodium currents and stimulation of 5-HT and 2C of action desensitization of increase of phasic and 5-HT receptors as well 1D TRPV1channels, tonic GABA inhibition. as interactions with σ1- enhanced adenosine- receptors mediated signaling, and GABAergic effects. Oral Complete (100%) About 6% in the fasting About 90% Variable About 80% bioavailability state. About 25% when taken with a high-fat meal Main route CYP2C19-mediated CYP2C19 and CYP3A4- UGT2B7- and UGT2B4- CYP3A4-mediated CYP-mediated of hydroxylation and mediated oxidation, and mediated glucuronida- metabolism metabolism, involving elimination hydrolysis other metabolic tion and CYP-mediated conversion to the active pathways oxidation metabolite norfenfluramine Half-life About 9 h About 15 h after a single About 50–60 h About 30 h Fenfluramine = about 20 dose, and about 60 h h. Norfenfluramine = after multiple dosing about 24 to 48 h Most Sommnolence, fatigue, Somnolence, anorexia, Dizziness, fatigue, Stomatitis, pyrexia, Anorexia, decreased common dizziness, coordination diarrhea, fatigue, sleep somnolence, ataxia, pneumonia, diarrhea, weight, diarrhea, adverse disturbances, mood and disorders, behavioral dysarthria, visual hypercholesterolemia constipation, effects behavioural disturbances disturbances disturbances, somnolence, fatigue, gastrointestinal coordination disturbances disturbances, behavioral disturbances Other Hypersensitivity reactions Hypersensitivity reactions, Hypersensitivity reactions Hypersensitivity Cardiac valvulopathy, adverse increased liver enzymes, reactions, infections, pulmonary hypertension, effects of pneumonia renal failure, serotonin syndrome potential myelosuppression concern Main drug Serum brivaracetam levels Cannabidiol inhibits the Serum cenobamate Serum everolimus Serum fenfluramine levels interactions can be increased by metabolism of several levels are decreased by levels can be increased are increased by the cannabidiol, and drugs. In particular, it phenytoin. Cenobamate by inhibitors of P-gp combination of moderately reduced by increases markedly the increases serum and by CYP3A4 inhibi- stiripentol with clobazam. enzyme inducing ASMs. serum levels of phenytoin levels, and can tors, and decreased by Use together with other Brivaracetam increases norclobazam, the active modify the serum levels inducers of P-gp / serotoninergic drugs may serum levels of carbama- metabolite of clobazam of several other drugs CYP3A4 involve a risk of zepine-10,11-epoxide precipitating a serotonin syndrome Abbreviations: CYP cytochrome P450; DS Dravet syndrome; GABA gamma-aminobutyric acid, GPR55 G protein-coupled receptor 55, LGS Lennox-Gastaut syndrome; mTOR mechanistic target of rapamycin; P-gp P-glycoprotein, TRPV1 transient receptor potential vanilloid type 1, TSC tuberous sclerosis complex, UGT uridine 5′-diphospho-glucuronosyltransferase tolerability profile differs from that of levetiracetam. Another ASM recently approved for the treatment of It has been suggested that brivaracetam is less likely focal seizures is cenobamate, a carbamate derivative to cause irritability and other behavioral disturbances which is also structurally related to previously developed compared with levetiracetam [20]. However, evidence drugs [22]. During clinical development, three confirmed on this remains inconclusive, because to date there cases of DRESS (Drug Reaction with Eosinophilia and have been no randomized head-to-head trials compar- Systemic Symptoms), including one fatality, were ing these two drugs [21]. reported when cenobamate was titrated rapidly (weekly Perucca Acta Epileptologica (2021) 3:22 Page 5 of 11 or faster titration). Consequently, a revised dosing [26]. In these trials, many patients received concomitant scheme involving initiation at a small dose and slow ti- treatment with clobazam, and the improvement in tration at 2-week intervals has been implemented. In a seizure control observed after adding cannabidiol could safety study, no cases of DRESS were reported when be ascribed at least in part to a drug interaction. In fact, 1339 patients were titrated using the slow titration cannabidiol is a powerful inhibitor of cytochrome scheme, and the drug has since been approved in the CYP2C19 and by this mechanism increases more than U.S. and Europe [23]. In the pivotal adjunctive-therapy three-fold the serum concentration of norclobazam, randomized trial in patients with refractory focal sei- the active metabolite of clobazam. There is, however, zures that led to regulatory approval, the most remark- also evidence that cannabidiol retains independent able finding was the relatively high proportion of antiseizure activity, unrelated to its interaction with patients who achieved seizure freedom (21% in the 400 clobazam [27]. mg/day cenobamate group versus 1% in the placebo Another ASM recently introduced for the treatment of group) [24]. This contrasts with seizure freedom rates seizures associated with Dravet syndrome is fenflur- ranging from 0 to 6.5% in comparable trials with other amine, which was first marketed in the sixties and widely second-generation ASMs [25]. Comparisons of outcome used in Europe and the U.S. for over 30 years as an ap- data across trials, however, should be interpreted cau- petite suppressant, either as racemic fenfluramine or as tiously, because of differences in clinical settings and its d-enantiomer dexfenfluramine. In 1997, fenfluramine characteristics of the patients. Moreover, seizure free- and dexfenfluramine were withdrawn from the market dom data in randomized clinical trials refer to limited following the discovery of their association with cardiac assessment periods (typically, a 12-week maintenance valvulopathy and pulmonary hypertension. Prior to its period) and can be inflated by the last-observation- withdrawal from the market, however, fenfluramine had carried-forward (LOCF) analysis, whereby patients who been found to improve seizure control in a small cohort did not experience seizures but exited the trial prema- of patients with Dravet syndrome, who were allowed to turely are still counted as seizure-free in the final ana- continue treatment with the drug [28]. These observa- lysis. In the pivotal cenobamate trial, the proportion of tions led to recent conduction of randomized placebo- randomized patients who were seizure-free during the controlled adjunctive therapy trials, which demonstrated entire 12-week maintenance period and did not exit the a robust seizure-suppressing effect in patients with Dra- trial prematurely was 14%, which is still a relatively high vet syndrome, and subsequent regulatory approval for proportion [24]. this indication both in Europe and the United States All three remaining ASMs introduced in the last [29]. Recent data suggest that fenfluramine may also be 5 years share a common feature, i.e. they were approved useful for the treatment of seizures associated with for orphan indications. Specifically, cannabidiol was ap- Lennox-Gastaut syndrome [30]. To date, no evidence of proved for the treatment of seizures associated with Dra- cardiovascular toxicity has been found in patients with vet syndrome, Lennox-Gastaut syndrome and tuberous epilepsy treated with fenfluramine, possibly because the sclerosis complex, fenfluramine was approved for the doses used for seizure protection are generally lower treatment of seizures associated with Dravet syndrome, than those used originally for appetite suppression. Yet, and everolimus was approved for the add-on treat- there are still many unanswered questions concerning ment of focal seizures in patients with tuberous scler- fenfluramine, including the serum levels of parent drug osis complex (Table 2). Introduction of ASMs for and its active de-ethylated metabolite norfenfluramine orphan indications is a novel development, made pos- required for seizure suppression in children in compari- sible by increased awareness of the unmet needs asso- son with those known to be associated with cardiovascu- ciated with many rare epilepsies and by regulatory lar toxicity in adults [29]. The potential efficacy and incentives to develop drugs for these indications, par- safety advantages of developing individual enantiomers ticularly for children. In fact, only 2 of the 25 ASMs of fenfluramine and norfenfluramine should also be con- developed prior to 2015 were developed for orphan sidered [29]. indications, compared with 3 out of 5 ASMs devel- The last medication discussion in this section, everoli- oped in the last 5 years. mus, is an inhibitor of mTOR (mammalian Target Of Cannabidiol is one of the many active principles con- Rapamycin). Its use in the treatment of focal seizures as- tained in the Cannabis plant, which has been used as an sociated with tuberous sclerosis complex (TSC) has been herbal remedy in China as early as 2000 BC. Unlike prompted by evidence linking the pathogenesis of TSC tetrahydrocannabidol (THC), cannabidiol lacks unwar- to mTOR overactivation [31]. Accordingly, everolimus is ranted psychoactive effects. Its antiseizure efficacy in its an example of a novel strategy in drug development, i.e. approved indications has been demonstrated in several a precision treatment targeting the etiology of the dis- adjunctive-therapy randomized placebo-controlled trials ease. Everolimus has been found to be effective in Perucca Acta Epileptologica (2021) 3:22 Page 6 of 11 reducing tumor growth as well as drug-resistant seizures used at times as a rescue treatment, but they can be in TSC patients. Up to 40% of TSC patients show a sig- associated with drawbacks in this setting, such as nificant improvement in seizure control when given ad- slower or suboptimal absorption, need for patient co- junctive treatment with everolimus. In the pivotal trial operation (which is not always feasible) and risk of that led to its regulatory approval for use as ASM, seiz- aspiration [36]. ure frequency decreased progressively over time during treatment, suggesting a possible disease modifying effect Future perspectives [32]. However, a clinically relevant antiepileptogenic or Extensive research is ongoing in many areas, and im- disease-modifying effect has not yet been clearly demon- portant advances leading to improved epilepsy outcomes strated. The age at which treatment is initiated may be are likely to occur in a not too distant future. A few rele- important for the final outcome, but controlled trials in vant examples will be discussed below. children below 2 years of age have not yet been com- pleted [31]. Increased application of technological tools to epilepsy Cannabidiol, fenfluramine and everolimus are also ex- management amples of drugs approved initially for other indications. In recent years, information technology (IT)-based appli- In fact, cannabidiol was first marketed in a fixed com- cations have been increasingly utilized in epilepsy bination product with THC as a nasal spray for the management, as shown by the widespread use of smart- treatment of spasticity associated with multiple sclerosis, phones to record seizures in the out-hospital setting, fenfluramine was used initially as an appetite suppres- and the expanding opportunities offered by Internet- sant, and everolimus was first approved for the treat- based services in areas such as distant education and ment of advanced kidney cancer, subependymal giant telemedicine [37]. Smartphone applications (apps) are cell astrocytoma (SEGA) associated with TSC, pancreatic also being increasingly used to assist people with epi- neuroendocrine tumors, and other tumors. The repur- lepsy to manage and cope with their disease. Most of posing for use in epilepsy of drugs initially approved for these apps focus on issues such as treatment manage- other indications is one of the options being pursued in ment, medication adherence, health care communica- the effort to develop precision treatments (see below). tion, and seizure tracking [38]. Other apps are aimed at assisting healthcare professionals (HCPs), on example Introduction of novel formulations being tools to improve epilepsy diagnosis in non- Advances in epilepsy treatment can be achieved not only specialist settings [39, 40]. We recently designed a by developing novel drugs, but also by improving the smartphone app to help HCPs in selecting ASM selec- pharmaceutical formulation of already available medica- tion for patients with seizure onset at age 10 years or tions. One area where particularly significant advances above, particularly in settings where no specialized ex- have been made in the last 5 years is the development of pertise is available [41, 42]. This app is freely available novel formulations of ASMs for the treatment of seizure on the Internet (www.epipick.org). In a recent validation clusters and acute repetitive seizures in the out-of-hospital study, selection of ASMs recommended by the app setting [33]. Until 2018, the only FDA-approved rescue based on individual patient characteristics was found to ASM for out-of-hospital use was diazepam rectal gel. In be associated with improved seizure outcomes and fewer 2019, the FDA approved two additional products for this adverse effects compared with use of ASMs not recom- indication, namely intranasal midazolam [34] and intrana- mended by the app [43]. In the future, individualized sal diazepam [35]. Use of these medications is associated ASM selection is likely to empowered by more sophisti- with a rapid onset of antiseizure effect, thereby stopping cated technology, including artificial intelligence (ma- seizures before they progress to established status epilepti- chine learning)-based approaches. In a recent study, a cus. The intranasal route is generally well accepted by machine learning approach combining clinical, genetic patients and caregivers, as it avoids the social embarrass- and clinical trial data derived from individual patients ment associated with use of the rectal route. permitted to construct a computerized model that pre- Alternative non-rectal rescue formulations of benzo- dicted response to a specific ASM [44]. diazepines for out-of-hospital use have been available In addition to facilitating treatment selection, technol- in other countries for a number of years. In particu- ogy will increasingly assist patients and physicians in lar, a rapidly absorbed buccal formulation of midazo- monitoring response to treatment through a variety of lam has been available in Europe since 2011 [36]. tools, including seizure detection devices [45]. Efforts Innovative formulations of ASMs under development are also ongoing into development of sophisticated tech- as potential rescue therapy for emergency use include nology, including artificial intelligence, for the prediction a diazepam buccal film, and an inhaled formulation of epileptic seizures [46]. This could pave the way to in- of alprazolam [33]. Oral formulations can also be novative treatment strategies, such as the intermittent Perucca Acta Epileptologica (2021) 3:22 Page 7 of 11 use of ASMs prior to the time at which a seizure is pre- and electrophysiological measures, other clinical or dicted to occur. laboratory data, or a combination of these [56, 57]. Bio- markers could potentially be used for different purposes, Precision therapies for example to improve diagnostic accuracy, to identify In recent years, our understanding of the molecular ongoing epileptogenesis and its mechanisms, to pre- mechanisms involved in the pathogenesis of epilepsies dict seizure response (or lack of response) to specific has improved considerably. One area where advances treatments, to assess the probability of seizure recur- have been greatest is the genetics of the epilepsies, and rence after treatment withdrawal, or to evaluate sus- in particular the discovery of gene mutations responsible ceptibility to adverse drug effects. Some biomarkers, for a large proportion of patients with developmental such as the HLA-B*15:02 antigen to identify individ- and epileptic encephalopathies (DEEs) [47]. The elucida- uals at high risk of carbamazepine-induced serious tion of an epileptogenic mutation permits to establish cutaneous adverse reactions among Han Chinese and the functional abnormality responsible for the epilepsy other South Asian ethnic groups, are already in rou- in the affected individual, and to identify (or develop) tine clinical use [58]. precision-therapy medications that may be able to cor- With respect to potential therapeutic advances, identi- rect such abnormality. One example of a precision ther- fication and validation of biomarkers could improve apy is the utilization of the ketogenic diet to control treatment outcomes in many ways [56, 57, 59]. First, seizures associated with Glucose Transporter Type 1 biomarkers could be used to identify individuals at high (GLUT1) deficiency syndrome. In this condition, GLUT1 risk of developing epilepsy after an epileptogenic insult, deficiency results in impaired brain uptake of glucose thereby permitting selection of these individuals for clin- and consequent neuronal dysfunction, which can be ical trials of potential antiepileptogenic therapies. Sec- overcome by supplying the brain with an alternative ond, identification of biomarkers predictive of seizure source of energy [48]. As discussed in recent reviews recurrence could facilitate decision on whether to start [49–51], precision treatments targeting the mechanisms or withhold ASM therapy in patients who experienced a responsible for epilepsy in individuals with specific gene single seizure. Third, biomarkers predictive of a favor- mutations may involve use of drugs previously approved able response to a specific medication would be valuable for other indications, a process known as drug repurpos- to select patients to be enrolled in clinical trials of that ing. One example of repurposed drug is the mTOR in- medication, thereby increasing responder rate and spar- hibitor everolimus for the treatment of seizures ing non-responders the burden of receiving placebo or associated with TSC, as discussed above in this article. an ineffective treatment. Fourth, biomarkers could the- Approaches to identify repurposed drugs for specific oretically be used to monitor response to treatment, by monogenic epilepsies have been described [52]. In some informing physicians at an early stage on whether the cases, improved outcomes can be achieved not by ad- prescribed medication has the required efficacy and ministering additional drugs, but by removing medica- safety in a specific individual. Lastly, and most im- tions that can paradoxically aggravate seizures in these portantly, biomarkers could in the future inform phy- patients [49]. Importantly, precision therapies are applic- sicians on which ASM is most likely to control able not only to genetic epilepsies, but also to epilepsies seizures effectively and with fewest adverse effects. due to other etiologies, such metabolic, inflammatory or This may change radically treatment paradigms: for immune-mediated causes [53]. example, the value of a drug which is effective in At present, application of precision therapies in the achieving complete seizure control in 5% of patients management of epilepsy is still in its early days, and with pharmacoresistant epilepsy would be greatly en- will likely expand as further knowledge accrues and hanced if we had a biomarker that can identify be- newer and more effective targeted treatments are in- forehand thosepatientswho areresponsivetothat troduced. For genetic epilepsies, targeted (precision) drug. In that scenario, we would use that drug only treatments have been reported to improve outcomes in responsive patients, thereby increasing the success in a considerable proportion patients with identified rate to 100%. gene mutations [54], although a more recent survey In practice, in most situations it is unlikely that a gave a more sober assessment of the current impact single biomarker will provide optimal information for of these treatments [55]. any intended purpose. More realistically, break- throughs are likely to come from algorithms that Biomarker-guided therapies utilize a combination of biomarkers and other clin- The search for biomarkers continues to be a hot topic in ical information. The development of artificial epilepsy research. Biomarkers can be based on a variety intelligence-based tools can facilitate greatly these of measures such as genetic, molecular, cellular, imaging, approaches [44]. Perucca Acta Epileptologica (2021) 3:22 Page 8 of 11 Table 3 A list of investigational drugs currently in clinical melatonin, erythropoietin, vitamins and other dietary constit- development as potential treatments for epilepsy. The list is not uents [68, 70, 72–74], as well as medications already ap- exhaustive and does not include medications approved for proved for other indications, such as metformin [75], other indications and currently being tested for potential montelukast [76], atorvastatin, ceftriaxone, and losartan [62]. repurposing in epilepsy Whether these properties documented in animal models Anavex 2–73 Omaveloxolone (RTA 408) translate into benefit in the clinical setting remains to be Ataluren OV 329 demonstrated. Of note, a number of precision treatments di- rected at specific etiologies of epilepsy could exhibit disease- Carisbamate Sec-butylpropylacetamide modifying effects, although it is possible that any medication CVL 865 (PF-03672865) Soticlestat (TAK 935, OV935) acting on a single molecular pathway may not address all the CX8998 Vatiquinone (EPI-743) complex comorbidities associated with aberrant neural net- Ganaxolone Vixotrigine (CNV 1014802) works [61]. Huperzyne A XEN 496 As discussed above, clinical trials of investigational JJ 40411813 XEN 1101 new drugs could be facilitated by development of bio- markers to detect the occurrence of epileptogenesis at NBI 921352 (XEN 901) an early stage, to identify drug responsive patients and to monitor response to treatment. Despite claims to the Novel drugs and the search for disease-modifying therapies contrary [77], demonstrating that a chronically adminis- The modest impact of second-generation ASMs on seiz- tered treatment started before seizure onset prevents the ure outcome in patients resistant to older agents justifies occurrence of seizures in patients still receiving that continuing efforts to develop newer and potentially more treatment does not prove epilepsy prevention, because effective treatments (Table 3). Drug development is cur- any ASM having a purely symptomatic effect could also rently benefiting from many advances, including deeper produce such an outcome. Likewise, some comorbidities, knowledge of the mechanisms of epileptogenesis and such as progression of cognitive disability, may be pre- seizure generation in relation to specific etiologies, vented solely as a result of seizure suppression. Truly in- improved understanding of mechanisms of pharmacore- novative trial designs will be required to generate sistance, and availability of disease-specific models as unequivocal evidence that a drug is effective in prevent- well as models of pharmacoresistance [53, 60]. These ad- ing epilepsy, or has a direct disease modifying effect [78]. vances are changing the paradigms used to discover and develop new drugs. Conclusions An important paradigm change is a switch from a Despite the fact that second-generation ASMs have not focus on medications aimed at suppressing seizures to a reduced substantially the burden of pharmacoresistance, focus on treatments targeting the underlying disease, i.e. advances in the drug treatment of epilepsy continue to specific etiologies and the molecular mechanisms associ- be made. These advances result mostly from improved ated with such etiologies [51, 61]. Future precision treat- understanding of the comparative efficacy and safety of ments emerging from this approach will include existing ASMs and from the introduction of newer med- repurposed drugs [50, 62], novel small molecules, and icines and innovative formulations. Further advances can other treatments based on innovative technologies such be ascribed to technological tools for distant education, as antisense oligonucleotides [63, 64] and gene therapy telemedicine, and patient empowerment made possible [65]. Some of these therapies require invasive routes of by self-management smartphone-based apps. administration, which are also being explored for in- It likely that further important therapeutic advances novative uses of already established medications [66]. will occur in the coming years. Thanks to ongoing A closely related paradigm change consists in targeting multidisciplinary efforts, clinical outcome for people specifically epileptogenesis and other manifestations of the with epilepsy is likely to improve due to advances in IT disease [60, 62, 67]. Such treatment could potentially be used technology, development of novel precision therapies, to prevent epilepsy, to inhibit its progression (in those syn- identification of biomarkers to guide drug development dromes showing a progressive course), or to alter the appear- as well as routine clinical management, and, ultimately, ance or progression of comorbidities such as intellectual introduction of truly innovative disease modifying disability and other disorders. 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The pharmacological treatment of epilepsy: recent advances and future perspectives

Perucca, Emilio
Acta Epileptologica , Volume 3 (1) – Sep 17, 2021
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Abstract

The pharmacological armamentarium against epilepsy has expanded considerably over the last three decades, and currently includes over 30 different antiseizure medications. Despite this large armamentarium, about one third of people with epilepsy fail to achieve sustained seizure freedom with currently available medications. This sobering fact, however, is mitigated by evidence that clinical outcomes for many people with epilepsy have improved over the years. In particular, physicians now have unprecedented opportunities to tailor treatment choices to the characteristics of the individual, in order to maximize efficacy and tolerability. The present article discusses advances in the drug treatment of epilepsy in the last 5 years, focusing in particular on comparative effectiveness trials of second-generation drugs, the introduction of new pharmaceutical formulations for emergency use, and the results achieved with the newest medications. The article also includes a discussion of potential future developments, including those derived from advances in information technology, the development of novel precision treatments, the introduction of disease modifying agents, and the discovery of biomarkers to facilitate conduction of clinical trials as well as routine clinical management. Keywords: Epilepsy, Seizures, Drug therapy, Antiepileptic drugs, Antiseizure medications, Advances, Review Background the ASMs introduced after 1985, usually referred to as The modern treatment of epilepsy started with the intro- second-generation drugs, have some safety advantages duction of phenobarbital in 1912. The advent of pheny- over older generation agents, but have not increased toin in the late thirties marked another milestone, substantially the proportion of patients who achieve because it was made possible by the introduction of ani- complete freedom from seizures [3]. For many of these mal models of antiseizure activity [1]. Similar models patients, the feasibility of epilepsy surgery, or alternative also played a key role in the subsequent development of therapies, should be given early consideration [4, 5]. many other antiseizure medications (ASMs). Today, the Despite the fact that pharmacoresistance has been pharmacological armamentarium against epilepsy little affected by the introduction of newer medications, includes more than 30 drugs (Table 1). These drugs dif- the drug treatment of epilepsy has made major advances fer in their pharmacokinetics, efficacy, and adverse effect in the last 50 years. In particular, we learnt how to profile, thereby offering unprecedented opportunities to individualize drug selection based on specific patient tailor treatment choices to individual needs [2]. Some of characteristics such as age, gender, epilepsy syndrome, seizure type, comorbidities, comedications, and other factors affecting clinical response [6]. We also learnt Correspondence: perucca@unipv.it This article is dedicated to the memory of Professor Alan Richens (1938–2021), how to optimize response by careful titration and adjust- my mentor and dear friend, in recognition of his outstanding contribution to ment of dosage, and use of serum drug levels whenever advancing the pharmacological treatment of epilepsy. indicated [7]. We made major progress in understanding Department of Internal Medicine and Therapeutics, Division of Clinical and Experimental Pharmacology, University of Pavia, Via Ferrata 9, 27100 Pavia, drug interactions, and recognizing the relative merits Italy and indications of monotherapy and polytherapy [8, 9]. Department of Neuroscience, Central Clinical School, Monash University, Likewise, we improved our knowledge of the natural Melbourne, Victoria 3004, Australia © The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Perucca Acta Epileptologica (2021) 3:22 Page 2 of 11 Table 1 Years of introduction in the market of currently available antiseizure medications. For all drugs, year of introduction refers to either Europe or the United States of America. The table does not include a number of drugs approved before 1970, but rarely used today 1900–1950 1951–1985 1986–2000 2001–2015 2015–2021 Phenobarbital Carbamazepine Felbamate Eslicarbazepine acetate Brivaracetam Phenytoin Clobazam Fosphenytoin Lacosamide Cannabidiol Clonazepam Gabapentin Perampanel Cenobamate Diazepam Lamotrigine Pregabalin Everolimus Ethosuximide Levetiracetam Rufinamide Fenfluramine Midazolam Lorazepam Stiripentol Primidone Oxcarbazepine Valproic acid Tiagabine Topiramate Vigabatrin Zonisamide history of epilepsy syndromes, and characterized prog- efficacious, generally devoid of adverse effects on mood and nostic factors for seizure recurrence for patients in cognitive function, and with a low potential to cause adverse whom discontinuation of ASMs can be considered after drug interactions, even though lamotrigine metabolisn can an adequate period of freedom from seizures [10]. be affected by a variety of concurrently administered drugs The purpose of the present article is to provide a [6]. One drawback of lamotrigine is the need for gradual ti- concise overview of some advances in research on the tration in order to minimize the risk of serious skin rashes, drug treatment of epilepsy made in the last 5 years, and and therefore it may not be the most appropriate drug for to discuss currently unmet needs as well as develop- use in patients with frequent severe seizures requiring a ments which are likely to occur in the foreseeable future. prompt onset of antiseizure activity. The findings from the SANAD studies that valproate Advances in characterizing the comparative is superior to lamotrigine, topiramate and levetiracetam effectiveness and safety of ASMs in the treatment of patients with generalized epilepsy A number of recent clinical trials and observational are consistent with other lines of evidence. In particu- studies have provided valuable information which can lar, a recent study from Denmark found that failure to assist physicians in making rational treatment selections. achieve seizure freedom with valproate was the single As a follow-up to the initial Standard and New Antiepileptic most important predictor of pharmacoresistance in a Drugs (SANAD) trials, which found lamotrigine to be super- cohort of 137 adults with idiopathic (genetic) general- ior to carbamazepine, oxcarbazepine, topiramate and gaba- ized epilepsy [15]. The superior efficacy of valproate in pentin in time to treatment failure in patients with mostly controlling seizures associated with generalized epi- focal epilepsy [11], and valproate to be superior to lamotri- lepsy, however, creates a dilemma in the treatment of gine and topiramate in patients with mostly generalized and females of childbearing potential. In fact, valproate is unclassified epilepsy [12], two more recent SANAD trials regarded by theEuropeanMedicineAgencyascontra- have been completed. In the first of these trials, 990 adults indicated for use as first-line treatment in these women and children with newly diagnosed focal epilepsy were ran- (unless the conditions of a rigorous pregnancy preven- domized to receive lamotrigine, levetiracetam or zonisamide, tion programme are fulfilled), due to the higher risk of and followed-up for 2 years [13]. In the per-protocol analysis, inducing teratogenic effects as well as impaired postna- lamotrigine was associated with a better 12-month remission tal cognitive development in the offspring [16, 17]. from seizures compared with both levetiracetam and zonisa- With respect to teratogenic potential of ASMs, prospective mide. In the second SANAD-II trial, which used a similar pregnancy registries have contributed greatly to characterize protocol and enrolled 520 newly diagnosed adults and chil- risks associated with individual medications. A particularly dren, valproate was found to be more effective than levetirac- important advance was the 2018 publication of data from etam in controlling seizures in a pooled cohort of patients the international EURAP registry [18]. This study, based on with generalized or unclassified epilepsy [14]. These trials analysis of 7355 prospective pregnancies exposed to 8 differ- used a pragmatic design mimicking routine clinical practice, ent ASM monotherapies provides risk estimates non only even though the possibility of assessment bias due to the for specific ASMs, but also for different doses of the most open-label, unblinded design cannot be excluded. When commonly used drugs. Overall, the lowest prevalence of considered together with other available lines of evidence, major congenital malformations (MCMs) in the offspring these findings confirm that lamotrigine should be regarded was associated with exposure to levetiracetam (2.8% preva- as one of the treatments of first choice for patients with focal lence), lamotrigine (2.9%) and oxcarbazepine (3.0%). Preva- seizures. Lamotrigine offers the advantage of being lence estimates were intermediate for topiramate (3.9%), Perucca Acta Epileptologica (2021) 3:22 Page 3 of 11 carbamazepine (5.5%), phenytoin (6.4%) and phenobarbital have been introduced into the market. Key features of (6.5%), and highest for valproate (10.3%). An increased risk each of these medications are summarized in Table 2. with increasing dose was identified for lamotrigine and The history of these drugs is illustrative of different carbamazepine, and was most prominent for phenobarbital strategies being used in developing novel ASMs. and valproate. In particular, the prevalence of MCMs (with The development of brivaracetam followed a paradigm 95% confidence intervals) associated with phenobarbital ex- which has been in place for a very long time, i.e. the posure was 2.7% (0.3–9.5%) at doses < 80 mg/day, 6.2% (3.0– structural modification of an already existing medication 11.1%) at doses > 80 to < 130 mg/day and 11.7% (4.8–22.6%) with the aim of improving its pharmacological profile. at doses > 130 mg/day. For valproate, the prevalence of Examples of other ASMs developed with this strategy in- MCMs was 6.3% (4.5–8.6%) at doses < 650 mg/day, 11.3% clude methylphenobarbital and primidone (both struc- (9.0–13.9%) at doses > 650 to ≤ 1450 mg/day and 25.2% turally related to phenobarbital), the phenytoin (17.6–34.2%) at doses > 1450 mg/day. These findings are im- derivative fosphenytoin, and oxcarbazepine and eslicar- portant because they alert physicians about the need to con- bazepine acetate, which represent successive modifica- sider teratogenic risks not only in relation to type of ASM tions of the carbamazepine structure. In fact, prescribed, but also in relation to dose. A subsequent levetiracetam itself was originally developed with the EURAP investigation documented a clear-cut decrease in the aim of improving the pharmacological profile of pirace- prevalence of MCMs over the period from 2000 to 2013 tam, and its antiseizure activity was discovered by [19]. Specifically, there was a 27% decrease in prevalence of chance. Brivaracetam was selected for development after MCMs between pregnancies enrolled in the period 2010– extensive preclinical screening of a large numbers of le- 2013 compared with those enrolled in the period 2000–2005 vetiracetam derivatives. Compared with levetiracetam, (Fig. 1). Further analysis of these data provided a strong indi- brivaracetam has higher affinity for the synaptic vesicle cation that the improvement in pregnancy outcomes over 2A (SV2A), and a similar pharmacological profile [20]. time was related to changes in ASM prescription patterns, Brivaracetam has been found to be superior to placebo including a major decline in the proportion of pregnancies in adjunctive-therapy trials in focal epilepsy, but its exposed to valproate. In fact, a reduction in teratogenic risk activity profile in other seizure types has not yet been is one of the important advances associated with the intro- definedinwell designedcontrolledtrials. Onelimita- duction of second-generation ASMs [3]. tion of brivaracetam is its lack of efficacy when added-on to levetiracetam, presumably due to compe- Introduction of novel ASMs tition between the two drugs for the SV2A binding During the last 5 years, five novel ASMs (brivaracetam, site. The still unanswered question about brivarace- cannabidiol, cenobamate, everolimus and fenfluramine) tam is whether, and to what extent, its efficacy and Fig. 1 Prevalence of major congenital malformations (MCMs) following prenatal exposure to monotherapy with antiseizure medications (ASMs) among cases enrolled in the EURAP international registry during three different periods. Number of exposures during each period (listed in brackets) refer to the eight most common monotherapies, which accounted for 96.7 to 98.1% of all monotherapy exposures. Based on data from Tomson et al [19]. Perucca Acta Epileptologica (2021) 3:22 Page 4 of 11 Table 2 Summary of the pharmacological and clinical profile of antiseizure medications (ASMs) introduced in the market after 2015 Brivaracetam Cannabidiol Cenobamate Everolimus Fenfluramine Chemical Levetiracetam derivative Cannabinoid Carbamate derivative Rapamycin derivative Amphetamine derivative structure Approved Treatment of focal Treatment of seizures Treatment of focal Add-on treatment of Treatment of seizures epilepsy seizures in patients aged associated with LGS, DS seizures in adults focal seizures associated with DS in indications 1 month and older or TSC in patients 1 year associated with TSC in patients 2 years of age (United of age and older patients aged 2 years and older. States) and older Main SV2A modulator Several, including Blockade of persistent mTOR inhibition Several, including indirect mechanisms GPR55 antagonism, sodium currents and stimulation of 5-HT and 2C of action desensitization of increase of phasic and 5-HT receptors as well 1D TRPV1channels, tonic GABA inhibition. as interactions with σ1- enhanced adenosine- receptors mediated signaling, and GABAergic effects. Oral Complete (100%) About 6% in the fasting About 90% Variable About 80% bioavailability state. About 25% when taken with a high-fat meal Main route CYP2C19-mediated CYP2C19 and CYP3A4- UGT2B7- and UGT2B4- CYP3A4-mediated CYP-mediated of hydroxylation and mediated oxidation, and mediated glucuronida- metabolism metabolism, involving elimination hydrolysis other metabolic tion and CYP-mediated conversion to the active pathways oxidation metabolite norfenfluramine Half-life About 9 h About 15 h after a single About 50–60 h About 30 h Fenfluramine = about 20 dose, and about 60 h h. Norfenfluramine = after multiple dosing about 24 to 48 h Most Sommnolence, fatigue, Somnolence, anorexia, Dizziness, fatigue, Stomatitis, pyrexia, Anorexia, decreased common dizziness, coordination diarrhea, fatigue, sleep somnolence, ataxia, pneumonia, diarrhea, weight, diarrhea, adverse disturbances, mood and disorders, behavioral dysarthria, visual hypercholesterolemia constipation, effects behavioural disturbances disturbances disturbances, somnolence, fatigue, gastrointestinal coordination disturbances disturbances, behavioral disturbances Other Hypersensitivity reactions Hypersensitivity reactions, Hypersensitivity reactions Hypersensitivity Cardiac valvulopathy, adverse increased liver enzymes, reactions, infections, pulmonary hypertension, effects of pneumonia renal failure, serotonin syndrome potential myelosuppression concern Main drug Serum brivaracetam levels Cannabidiol inhibits the Serum cenobamate Serum everolimus Serum fenfluramine levels interactions can be increased by metabolism of several levels are decreased by levels can be increased are increased by the cannabidiol, and drugs. In particular, it phenytoin. Cenobamate by inhibitors of P-gp combination of moderately reduced by increases markedly the increases serum and by CYP3A4 inhibi- stiripentol with clobazam. enzyme inducing ASMs. serum levels of phenytoin levels, and can tors, and decreased by Use together with other Brivaracetam increases norclobazam, the active modify the serum levels inducers of P-gp / serotoninergic drugs may serum levels of carbama- metabolite of clobazam of several other drugs CYP3A4 involve a risk of zepine-10,11-epoxide precipitating a serotonin syndrome Abbreviations: CYP cytochrome P450; DS Dravet syndrome; GABA gamma-aminobutyric acid, GPR55 G protein-coupled receptor 55, LGS Lennox-Gastaut syndrome; mTOR mechanistic target of rapamycin; P-gp P-glycoprotein, TRPV1 transient receptor potential vanilloid type 1, TSC tuberous sclerosis complex, UGT uridine 5′-diphospho-glucuronosyltransferase tolerability profile differs from that of levetiracetam. Another ASM recently approved for the treatment of It has been suggested that brivaracetam is less likely focal seizures is cenobamate, a carbamate derivative to cause irritability and other behavioral disturbances which is also structurally related to previously developed compared with levetiracetam [20]. However, evidence drugs [22]. During clinical development, three confirmed on this remains inconclusive, because to date there cases of DRESS (Drug Reaction with Eosinophilia and have been no randomized head-to-head trials compar- Systemic Symptoms), including one fatality, were ing these two drugs [21]. reported when cenobamate was titrated rapidly (weekly Perucca Acta Epileptologica (2021) 3:22 Page 5 of 11 or faster titration). Consequently, a revised dosing [26]. In these trials, many patients received concomitant scheme involving initiation at a small dose and slow ti- treatment with clobazam, and the improvement in tration at 2-week intervals has been implemented. In a seizure control observed after adding cannabidiol could safety study, no cases of DRESS were reported when be ascribed at least in part to a drug interaction. In fact, 1339 patients were titrated using the slow titration cannabidiol is a powerful inhibitor of cytochrome scheme, and the drug has since been approved in the CYP2C19 and by this mechanism increases more than U.S. and Europe [23]. In the pivotal adjunctive-therapy three-fold the serum concentration of norclobazam, randomized trial in patients with refractory focal sei- the active metabolite of clobazam. There is, however, zures that led to regulatory approval, the most remark- also evidence that cannabidiol retains independent able finding was the relatively high proportion of antiseizure activity, unrelated to its interaction with patients who achieved seizure freedom (21% in the 400 clobazam [27]. mg/day cenobamate group versus 1% in the placebo Another ASM recently introduced for the treatment of group) [24]. This contrasts with seizure freedom rates seizures associated with Dravet syndrome is fenflur- ranging from 0 to 6.5% in comparable trials with other amine, which was first marketed in the sixties and widely second-generation ASMs [25]. Comparisons of outcome used in Europe and the U.S. for over 30 years as an ap- data across trials, however, should be interpreted cau- petite suppressant, either as racemic fenfluramine or as tiously, because of differences in clinical settings and its d-enantiomer dexfenfluramine. In 1997, fenfluramine characteristics of the patients. Moreover, seizure free- and dexfenfluramine were withdrawn from the market dom data in randomized clinical trials refer to limited following the discovery of their association with cardiac assessment periods (typically, a 12-week maintenance valvulopathy and pulmonary hypertension. Prior to its period) and can be inflated by the last-observation- withdrawal from the market, however, fenfluramine had carried-forward (LOCF) analysis, whereby patients who been found to improve seizure control in a small cohort did not experience seizures but exited the trial prema- of patients with Dravet syndrome, who were allowed to turely are still counted as seizure-free in the final ana- continue treatment with the drug [28]. These observa- lysis. In the pivotal cenobamate trial, the proportion of tions led to recent conduction of randomized placebo- randomized patients who were seizure-free during the controlled adjunctive therapy trials, which demonstrated entire 12-week maintenance period and did not exit the a robust seizure-suppressing effect in patients with Dra- trial prematurely was 14%, which is still a relatively high vet syndrome, and subsequent regulatory approval for proportion [24]. this indication both in Europe and the United States All three remaining ASMs introduced in the last [29]. Recent data suggest that fenfluramine may also be 5 years share a common feature, i.e. they were approved useful for the treatment of seizures associated with for orphan indications. Specifically, cannabidiol was ap- Lennox-Gastaut syndrome [30]. To date, no evidence of proved for the treatment of seizures associated with Dra- cardiovascular toxicity has been found in patients with vet syndrome, Lennox-Gastaut syndrome and tuberous epilepsy treated with fenfluramine, possibly because the sclerosis complex, fenfluramine was approved for the doses used for seizure protection are generally lower treatment of seizures associated with Dravet syndrome, than those used originally for appetite suppression. Yet, and everolimus was approved for the add-on treat- there are still many unanswered questions concerning ment of focal seizures in patients with tuberous scler- fenfluramine, including the serum levels of parent drug osis complex (Table 2). Introduction of ASMs for and its active de-ethylated metabolite norfenfluramine orphan indications is a novel development, made pos- required for seizure suppression in children in compari- sible by increased awareness of the unmet needs asso- son with those known to be associated with cardiovascu- ciated with many rare epilepsies and by regulatory lar toxicity in adults [29]. The potential efficacy and incentives to develop drugs for these indications, par- safety advantages of developing individual enantiomers ticularly for children. In fact, only 2 of the 25 ASMs of fenfluramine and norfenfluramine should also be con- developed prior to 2015 were developed for orphan sidered [29]. indications, compared with 3 out of 5 ASMs devel- The last medication discussion in this section, everoli- oped in the last 5 years. mus, is an inhibitor of mTOR (mammalian Target Of Cannabidiol is one of the many active principles con- Rapamycin). Its use in the treatment of focal seizures as- tained in the Cannabis plant, which has been used as an sociated with tuberous sclerosis complex (TSC) has been herbal remedy in China as early as 2000 BC. Unlike prompted by evidence linking the pathogenesis of TSC tetrahydrocannabidol (THC), cannabidiol lacks unwar- to mTOR overactivation [31]. Accordingly, everolimus is ranted psychoactive effects. Its antiseizure efficacy in its an example of a novel strategy in drug development, i.e. approved indications has been demonstrated in several a precision treatment targeting the etiology of the dis- adjunctive-therapy randomized placebo-controlled trials ease. Everolimus has been found to be effective in Perucca Acta Epileptologica (2021) 3:22 Page 6 of 11 reducing tumor growth as well as drug-resistant seizures used at times as a rescue treatment, but they can be in TSC patients. Up to 40% of TSC patients show a sig- associated with drawbacks in this setting, such as nificant improvement in seizure control when given ad- slower or suboptimal absorption, need for patient co- junctive treatment with everolimus. In the pivotal trial operation (which is not always feasible) and risk of that led to its regulatory approval for use as ASM, seiz- aspiration [36]. ure frequency decreased progressively over time during treatment, suggesting a possible disease modifying effect Future perspectives [32]. However, a clinically relevant antiepileptogenic or Extensive research is ongoing in many areas, and im- disease-modifying effect has not yet been clearly demon- portant advances leading to improved epilepsy outcomes strated. The age at which treatment is initiated may be are likely to occur in a not too distant future. A few rele- important for the final outcome, but controlled trials in vant examples will be discussed below. children below 2 years of age have not yet been com- pleted [31]. Increased application of technological tools to epilepsy Cannabidiol, fenfluramine and everolimus are also ex- management amples of drugs approved initially for other indications. In recent years, information technology (IT)-based appli- In fact, cannabidiol was first marketed in a fixed com- cations have been increasingly utilized in epilepsy bination product with THC as a nasal spray for the management, as shown by the widespread use of smart- treatment of spasticity associated with multiple sclerosis, phones to record seizures in the out-hospital setting, fenfluramine was used initially as an appetite suppres- and the expanding opportunities offered by Internet- sant, and everolimus was first approved for the treat- based services in areas such as distant education and ment of advanced kidney cancer, subependymal giant telemedicine [37]. Smartphone applications (apps) are cell astrocytoma (SEGA) associated with TSC, pancreatic also being increasingly used to assist people with epi- neuroendocrine tumors, and other tumors. The repur- lepsy to manage and cope with their disease. Most of posing for use in epilepsy of drugs initially approved for these apps focus on issues such as treatment manage- other indications is one of the options being pursued in ment, medication adherence, health care communica- the effort to develop precision treatments (see below). tion, and seizure tracking [38]. Other apps are aimed at assisting healthcare professionals (HCPs), on example Introduction of novel formulations being tools to improve epilepsy diagnosis in non- Advances in epilepsy treatment can be achieved not only specialist settings [39, 40]. We recently designed a by developing novel drugs, but also by improving the smartphone app to help HCPs in selecting ASM selec- pharmaceutical formulation of already available medica- tion for patients with seizure onset at age 10 years or tions. One area where particularly significant advances above, particularly in settings where no specialized ex- have been made in the last 5 years is the development of pertise is available [41, 42]. This app is freely available novel formulations of ASMs for the treatment of seizure on the Internet (www.epipick.org). In a recent validation clusters and acute repetitive seizures in the out-of-hospital study, selection of ASMs recommended by the app setting [33]. Until 2018, the only FDA-approved rescue based on individual patient characteristics was found to ASM for out-of-hospital use was diazepam rectal gel. In be associated with improved seizure outcomes and fewer 2019, the FDA approved two additional products for this adverse effects compared with use of ASMs not recom- indication, namely intranasal midazolam [34] and intrana- mended by the app [43]. In the future, individualized sal diazepam [35]. Use of these medications is associated ASM selection is likely to empowered by more sophisti- with a rapid onset of antiseizure effect, thereby stopping cated technology, including artificial intelligence (ma- seizures before they progress to established status epilepti- chine learning)-based approaches. In a recent study, a cus. The intranasal route is generally well accepted by machine learning approach combining clinical, genetic patients and caregivers, as it avoids the social embarrass- and clinical trial data derived from individual patients ment associated with use of the rectal route. permitted to construct a computerized model that pre- Alternative non-rectal rescue formulations of benzo- dicted response to a specific ASM [44]. diazepines for out-of-hospital use have been available In addition to facilitating treatment selection, technol- in other countries for a number of years. In particu- ogy will increasingly assist patients and physicians in lar, a rapidly absorbed buccal formulation of midazo- monitoring response to treatment through a variety of lam has been available in Europe since 2011 [36]. tools, including seizure detection devices [45]. Efforts Innovative formulations of ASMs under development are also ongoing into development of sophisticated tech- as potential rescue therapy for emergency use include nology, including artificial intelligence, for the prediction a diazepam buccal film, and an inhaled formulation of epileptic seizures [46]. This could pave the way to in- of alprazolam [33]. Oral formulations can also be novative treatment strategies, such as the intermittent Perucca Acta Epileptologica (2021) 3:22 Page 7 of 11 use of ASMs prior to the time at which a seizure is pre- and electrophysiological measures, other clinical or dicted to occur. laboratory data, or a combination of these [56, 57]. Bio- markers could potentially be used for different purposes, Precision therapies for example to improve diagnostic accuracy, to identify In recent years, our understanding of the molecular ongoing epileptogenesis and its mechanisms, to pre- mechanisms involved in the pathogenesis of epilepsies dict seizure response (or lack of response) to specific has improved considerably. One area where advances treatments, to assess the probability of seizure recur- have been greatest is the genetics of the epilepsies, and rence after treatment withdrawal, or to evaluate sus- in particular the discovery of gene mutations responsible ceptibility to adverse drug effects. Some biomarkers, for a large proportion of patients with developmental such as the HLA-B*15:02 antigen to identify individ- and epileptic encephalopathies (DEEs) [47]. The elucida- uals at high risk of carbamazepine-induced serious tion of an epileptogenic mutation permits to establish cutaneous adverse reactions among Han Chinese and the functional abnormality responsible for the epilepsy other South Asian ethnic groups, are already in rou- in the affected individual, and to identify (or develop) tine clinical use [58]. precision-therapy medications that may be able to cor- With respect to potential therapeutic advances, identi- rect such abnormality. One example of a precision ther- fication and validation of biomarkers could improve apy is the utilization of the ketogenic diet to control treatment outcomes in many ways [56, 57, 59]. First, seizures associated with Glucose Transporter Type 1 biomarkers could be used to identify individuals at high (GLUT1) deficiency syndrome. In this condition, GLUT1 risk of developing epilepsy after an epileptogenic insult, deficiency results in impaired brain uptake of glucose thereby permitting selection of these individuals for clin- and consequent neuronal dysfunction, which can be ical trials of potential antiepileptogenic therapies. Sec- overcome by supplying the brain with an alternative ond, identification of biomarkers predictive of seizure source of energy [48]. As discussed in recent reviews recurrence could facilitate decision on whether to start [49–51], precision treatments targeting the mechanisms or withhold ASM therapy in patients who experienced a responsible for epilepsy in individuals with specific gene single seizure. Third, biomarkers predictive of a favor- mutations may involve use of drugs previously approved able response to a specific medication would be valuable for other indications, a process known as drug repurpos- to select patients to be enrolled in clinical trials of that ing. One example of repurposed drug is the mTOR in- medication, thereby increasing responder rate and spar- hibitor everolimus for the treatment of seizures ing non-responders the burden of receiving placebo or associated with TSC, as discussed above in this article. an ineffective treatment. Fourth, biomarkers could the- Approaches to identify repurposed drugs for specific oretically be used to monitor response to treatment, by monogenic epilepsies have been described [52]. In some informing physicians at an early stage on whether the cases, improved outcomes can be achieved not by ad- prescribed medication has the required efficacy and ministering additional drugs, but by removing medica- safety in a specific individual. Lastly, and most im- tions that can paradoxically aggravate seizures in these portantly, biomarkers could in the future inform phy- patients [49]. Importantly, precision therapies are applic- sicians on which ASM is most likely to control able not only to genetic epilepsies, but also to epilepsies seizures effectively and with fewest adverse effects. due to other etiologies, such metabolic, inflammatory or This may change radically treatment paradigms: for immune-mediated causes [53]. example, the value of a drug which is effective in At present, application of precision therapies in the achieving complete seizure control in 5% of patients management of epilepsy is still in its early days, and with pharmacoresistant epilepsy would be greatly en- will likely expand as further knowledge accrues and hanced if we had a biomarker that can identify be- newer and more effective targeted treatments are in- forehand thosepatientswho areresponsivetothat troduced. For genetic epilepsies, targeted (precision) drug. In that scenario, we would use that drug only treatments have been reported to improve outcomes in responsive patients, thereby increasing the success in a considerable proportion patients with identified rate to 100%. gene mutations [54], although a more recent survey In practice, in most situations it is unlikely that a gave a more sober assessment of the current impact single biomarker will provide optimal information for of these treatments [55]. any intended purpose. More realistically, break- throughs are likely to come from algorithms that Biomarker-guided therapies utilize a combination of biomarkers and other clin- The search for biomarkers continues to be a hot topic in ical information. The development of artificial epilepsy research. Biomarkers can be based on a variety intelligence-based tools can facilitate greatly these of measures such as genetic, molecular, cellular, imaging, approaches [44]. Perucca Acta Epileptologica (2021) 3:22 Page 8 of 11 Table 3 A list of investigational drugs currently in clinical melatonin, erythropoietin, vitamins and other dietary constit- development as potential treatments for epilepsy. The list is not uents [68, 70, 72–74], as well as medications already ap- exhaustive and does not include medications approved for proved for other indications, such as metformin [75], other indications and currently being tested for potential montelukast [76], atorvastatin, ceftriaxone, and losartan [62]. repurposing in epilepsy Whether these properties documented in animal models Anavex 2–73 Omaveloxolone (RTA 408) translate into benefit in the clinical setting remains to be Ataluren OV 329 demonstrated. Of note, a number of precision treatments di- rected at specific etiologies of epilepsy could exhibit disease- Carisbamate Sec-butylpropylacetamide modifying effects, although it is possible that any medication CVL 865 (PF-03672865) Soticlestat (TAK 935, OV935) acting on a single molecular pathway may not address all the CX8998 Vatiquinone (EPI-743) complex comorbidities associated with aberrant neural net- Ganaxolone Vixotrigine (CNV 1014802) works [61]. Huperzyne A XEN 496 As discussed above, clinical trials of investigational JJ 40411813 XEN 1101 new drugs could be facilitated by development of bio- markers to detect the occurrence of epileptogenesis at NBI 921352 (XEN 901) an early stage, to identify drug responsive patients and to monitor response to treatment. Despite claims to the Novel drugs and the search for disease-modifying therapies contrary [77], demonstrating that a chronically adminis- The modest impact of second-generation ASMs on seiz- tered treatment started before seizure onset prevents the ure outcome in patients resistant to older agents justifies occurrence of seizures in patients still receiving that continuing efforts to develop newer and potentially more treatment does not prove epilepsy prevention, because effective treatments (Table 3). Drug development is cur- any ASM having a purely symptomatic effect could also rently benefiting from many advances, including deeper produce such an outcome. Likewise, some comorbidities, knowledge of the mechanisms of epileptogenesis and such as progression of cognitive disability, may be pre- seizure generation in relation to specific etiologies, vented solely as a result of seizure suppression. Truly in- improved understanding of mechanisms of pharmacore- novative trial designs will be required to generate sistance, and availability of disease-specific models as unequivocal evidence that a drug is effective in prevent- well as models of pharmacoresistance [53, 60]. These ad- ing epilepsy, or has a direct disease modifying effect [78]. vances are changing the paradigms used to discover and develop new drugs. Conclusions An important paradigm change is a switch from a Despite the fact that second-generation ASMs have not focus on medications aimed at suppressing seizures to a reduced substantially the burden of pharmacoresistance, focus on treatments targeting the underlying disease, i.e. advances in the drug treatment of epilepsy continue to specific etiologies and the molecular mechanisms associ- be made. These advances result mostly from improved ated with such etiologies [51, 61]. Future precision treat- understanding of the comparative efficacy and safety of ments emerging from this approach will include existing ASMs and from the introduction of newer med- repurposed drugs [50, 62], novel small molecules, and icines and innovative formulations. Further advances can other treatments based on innovative technologies such be ascribed to technological tools for distant education, as antisense oligonucleotides [63, 64] and gene therapy telemedicine, and patient empowerment made possible [65]. Some of these therapies require invasive routes of by self-management smartphone-based apps. administration, which are also being explored for in- It likely that further important therapeutic advances novative uses of already established medications [66]. will occur in the coming years. Thanks to ongoing A closely related paradigm change consists in targeting multidisciplinary efforts, clinical outcome for people specifically epileptogenesis and other manifestations of the with epilepsy is likely to improve due to advances in IT disease [60, 62, 67]. Such treatment could potentially be used technology, development of novel precision therapies, to prevent epilepsy, to inhibit its progression (in those syn- identification of biomarkers to guide drug development dromes showing a progressive course), or to alter the appear- as well as routine clinical management, and, ultimately, ance or progression of comorbidities such as intellectual introduction of truly innovative disease modifying disability and other disorders. A wide variety of compounds therapies. have been found to possess antiepileptogenic and/or neuro- protective activity in preclinical models through antiinflam- Abbreviations ASM: Antiseizure medication; DEE: Developmental and epileptic matory, antioxidant and other mechanisms [68–71]. In encephalopathy; CSF: Cerebrospinal fluid; DRESS: Drug Reaction with addition to novel molecules, these compounds includes nat- Eosinophilia and Systemic Symptoms; DS: Dravet syndrome; urally occurring substances such as phytocannabinnoids, CYP: Cytochrome P450; EEG: Electroencephalography; EURAP: International Perucca Acta Epileptologica (2021) 3:22 Page 9 of 11 Registry of Antiepileptic Drugs and Pregnancy; FDA: Food and Drug systematic review and individual participant data meta-analysis. Lancet Administration (United States); HCP: Healthcare professional; GABA: Gamma- Neurol. 2017;16(7):523–31. https://doi.org/10.1016/S1474-4422(17)30114-X. aminobutyric acid; GPR55: G protein-coupled receptor 55; IT: Information 11. Marson AG, Al-Kharusi AM, Alwaidh M, Appleton R, Baker GA, Chadwick DW, technology; LGS: Lennox-Gastaut syndrome; MCM: Major congenital et al. The SANAD study of effectiveness of carbamazepine, gabapentin, malformation; LOCF: Last-observation-carried-forward; mTOR: Mammalian lamotrigine, oxcarbazepine, or topiramate for treatment of partial epilepsy: Target Of Rapamycin; P-gp: P-glycoprotein; SANAD: Standard and New an unblinded randomised controlled trial. Lancet. 2007;369(9566):1000–15. Antiepileptic Drugs; SEGA: Subependymal giant cell astrocytoma; https://doi.org/10.1016/S0140-6736(07)60460-7. SV2A: Synaptic vesicle 2A; TRPV1: Transient receptor potential vanilloid type 12. 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Journal

Acta Epileptologica – Springer Journals

Published: Sep 17, 2021

Keywords: Epilepsy; Seizures; Drug therapy; Antiepileptic drugs; Antiseizure medications; Advances; Review

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