Received: 21 December 2020 | Revised: 11 January 2021 | Accepted: 13 January 2021 DOI: 10.1111/epi.16832 CRITICAL REVIEW – INVITED COMMENTARY The ups and downs of alkyl- carbamates in epilepsy therapy: How does cenobamate differ? Wolfgang Löscher1,2 | Graeme J. Sills3 | H. Steve White4 1Department of Pharmacology, Toxicology, and Pharmacy, University Abstract of Veterinary Medicine Hannover, Since 1955, several alkyl- carbamates have been developed for the treatment of anxiety Hannover, Germany and epilepsy, including meprobamate, flupirtine, felbamate, retigabine, carisbamate, 2Center for Systems Neuroscience Hannover, Hannover, Germany and cenobamate. They have each enjoyed varying levels of success as antiseizure 3School of Life Sciences, University of drugs; however, they have all been plagued by the emergence of serious and some- Glasgow, Glasgow, UK times life- threatening adverse events. In this review, we compare and contrast their 4 Department of Pharmacy, School of predominant molecular mechanisms of action, their antiseizure profile, and where Pharmacy, University of Washington, possible, their clinical efficacy. The preclinical, clinical, and mechanistic profile of Seattle, Washington, USA the prototypical γ- aminobutyric acidergic (GABAergic) modulator phenobarbital is Correspondence included for comparison. Like phenobarbital, all of the clinically approved alkyl- Wolfgang Löscher, Department of Pharmacology, Toxicology, and carbamates share an ability to enhance inhibitory neurotransmission through modula- Pharmacy, University of Veterinary tion of the GABAA receptor, although the specific mechanism of interaction differs Medicine, Bünteweg 17, D- 30559 among the different drugs discussed. In addition, several alkyl-carbamates have been Hannover, Germany. Email: wolfgang.loescher@tiho- shown to interact with voltage- gated ion channels. Flupirtine and retigabine share an hannover.de ability to activate K+ currents mediated by KCNQ (Kv7) K+ channels, and felbamate, carisbamate, and cenobamate have been shown to block Na+ channels. In contrast to other alkyl- carbamates, cenobamate seems to be unique in its ability to preferentially attenuate the persistent rather than transient Na+ current. Results from recent rand- omized controlled clinical trials with cenobamate suggest that this newest antiseizure alkyl- carbamate possesses a degree of efficacy not witnessed since felbamate was approved in 1993. Given that ceno-bamate's mechanistic profile is unique among the alkyl- carbamates, it is not clear whether this impressive efficacy reflects an as yet undescribed mechanism of action or whether it possesses a unique synergy between + its actions at the GABAA receptor and on persistent Na currents. The high efficacy of cenobamate is, however, tempered by the risk of serious rash and low tolerability at higher doses, meaning that further safety studies and clinical experience are needed to determine the true clinical value of cenobamate. KEYWORDS antiseizure drugs, carisbamate, felbamate, flupirtine, GABAA receptor, meprobamate, retigabine, voltage- gated Na+ channels This is an open access article under the terms of the Creative Commons Attribution- NonCommercial- NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non- commercial and no modifications or adaptations are made. © 2021 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy. 596 | wileyonlinelibrary.com/journal/epi Epilepsia. 2021;62:596–614. LÖSCHER ET AL. | 597 1 | INTRODUCTION Key Points The discovery in 1951 of the dicarbamate meprobamate as 1 • Alkyl- carbamate drugs have efficacy in experi- a new anxiolytic that also possessed antiseizure activity mental models of seizures and epilepsy and in the triggered the search for new central nervous system (CNS)- 2- 6 clinical management of seizure disorders active carbamate compounds, finally resulting in the dis- 6 • Two classes of alkyl- carbamates exist; dicarba- covery of the dicarbamate felbamate in 1969. Since then, mates (e.g., felbamate) and monocarbamates (e.g., a total of three alkyl-carbamates (i.e., felbamate, retigabine, retigabine, carisbamate, cenobamate) and cenobamate) have been approved for treatment of epi- • Most alkyl- carbamates act as positive allosteric lepsy (Figure 1), making alkyl- carbamates one of the most modulators of the GABA receptor and enhance successful chemical classes in the history of antiseizure drug A inhibitory neurotransmission (ASD) development. Another alkyl-carbamate, carisbamate, • Most also possess additional modes of action, received provisional approval from the US Food and Drug including effects on voltage-gated Na+ and K+ Administration (FDA) in 2008, but this was withdrawn in channels and on ionotropic glutamate receptors 2010 because of inconsistent efficacy across different clini- 7 • In addition to their recognized clinical efficacy, cal trials in patients with drug-resistant focal epilepsy. alkyl- carbamates have often been associated with Nonetheless, in 2012, carisbamate received an orphan drug serious adverse reactions designation for the management of infantile spasms and is currently in clinical development for therapy of Lennox– Gastaut syndrome.8 Cenobamate, the most recent drug of the series of alkyl- and safety; and finally, discuss additional alkyl- carbamates in carbamates developed for epilepsy therapy, showed remark- the preclinical pipeline. able antiseizure efficacy in clinical trials, suggesting that this novel ASD brings substantial promise for patients with focal seizures that have been difficult to control with other 2 | ALKYL- CARBAMATES WITH medications, and with the potential for freedom from sei- PRECLINICAL AND CLINICAL zures.9 However, impressive clinical efficacy was also de- ANTISEIZURE EFFECTS scribed for felbamate shortly after its approval in 1993 for the management of focal seizures and Lennox– Gastaut syn- 2.1 | Meprobamate drome.10 Within 1 year, ~120,000 people had been exposed to felbamate. Unfortunately, this extensive postapproval use Meprobamate, a carbamylated derivative of propanediol (2-m revealed a previously unknown risk of life- threatening idio- ethyl- 2- propyl- 1,3- propanediol dicarbamate; Figure 1), was syncratic adverse events (aplastic anemia and hepatic failure) introduced as an antianxiety drug in 1955. It was the first drug not seen in preapproval studies,11 which led to a dramatic to be used as an anxiolytic agent; it was also used as a sedative– reduction in its use. For experienced pharmacologists and hypnotic and, less frequently, as an ASD. Meprobamate was toxicologists, these idiosyncratic adverse events of felbamate developed by Frank Berger at Wallace Laboratories, a di- were not entirely surprising, because induction of aplastic vision of Carter Products (later Carter- Wallace; Cranbury, anemia was previously reported for the structurally similar New Jersey) in the early 1950s, based on previous experience alkyl- dicarbamate meprobamate.11,12 In a later development, with the sedating or “tranquilizing” effect of mephenesin in a new type of adverse effect (i.e., blue skin discoloration and rodents.14 The report of Berger14 marked the beginning of pigment changes in the retina) was reported for retigabine, investigations of modern sedatives with useful antianxiety leading to its withdrawal in 2017.13 and minor tranquilizing properties. After its approval, me- The aim of this review is to critically discuss the “ups and probamate rapidly became the first blockbuster psychotropic downs” of alkyl-carbamates in epilepsy therapy. Are they drug in American history,15 but it was later largely replaced all the same, or do they differ in their pharmacology, toxi- by the benzodiazepines (BDZs) due to their wider therapeu- cology, and clinical efficacy? Is cenobamate really a “game tic index. In addition to its anxiolytic and sedative effects, changer,”9 or is it too early to assess its efficacy, tolerability, meprobamate exerts antiseizure activity in animal models and safety? Finally, with the evolving era of precision med- (see below) and epilepsy patients. Meprobamate appears to icine for rare monogenetic epilepsies, will alkyl- carbamates act by modulating the γ- aminobutyric acid type A (GABAA) such as retigabine and carisbamate attract renewed interest? receptor via a barbiturate- like action,16 but other mechanisms We briefly review each of the alkyl-carbamates shown in may contribute to its pharmacology (see below for more Figure 1; compare their preclinical efficacy in animal seizure detailed discussion). Based on its GABAergic effect, me- and epilepsy models, mechanisms of action, clinical efficacy, probamate has abuse potential and may induce dependence 598 | LÖSCHER ET AL. FIGURE 1 Alkyl- carbamates with antiseizure activity. Note that meprobamate and felbamate are dicarbamates, whereas the other drugs are monocarbamates with continued use; it is a Drug Enforcement Administration voltage- dependent Na+ channels.19 In contrast to meproba- (DEA) Schedule IV controlled drug in the United States (as is mate (and phenobarbital), felbamate is not listed in the DEA the anticonvulsant and sedative/hypnotic drug phenobarbital, Schedules, possibly as a result of its lower potency in mod- which also mainly acts via the GABAA receptor). The major ulating the GABAA receptor (see more detailed discussion unwanted effects of the usual sedative doses of meprobamate below).