Novel therapeutic options for Dravet and Lennox-Gastaut syndrome

KEYWORDS:

• Cannabidiol
• fenfluramine
• epilepsy
• Dravet syndrome
• Lennox-Gastaut syndrome
• antiseizure medications

1. Introduction

Epileptic encephalopathies affect around one in 2000 children and often receive supportive treatment.Therefore, novel strategies to improve their overall neurological outcome are needed. Dravet syndrome (DS) is a genetic condition that is primarily associated with loss-of-function mutations in SCN1A, encoding for voltage-gated sodium channels and resulting in loss of action firing in gamma-aminobutyric acid (GABA)-ergic interneurons [1]. By contrast, Lennox-Gastaut syndrome (LGS) has a relatively heterogeneous etiology: in 65–75% of patients, the cause is identifiable (genetic, structural, or metabolic) but unknown in others [1].Patients withthese syndromes are typically refractory to treatment except occasional, short remission periods.

Data deriving from new studies have suggested the use as an antiepileptic drug of an old drug like fenfluramine (FFA) which was previously used as an appetite suppressant [2].Moreover, cannabidiol (CBD) has some evidence of efficacy and an adequate safety profile when used as adjunctive therapy in children and young adults with treatment-resistant epilepsies, including LGS and DS [3,4].We herein focuson available data about the use of FFA and CBD, discussing the most solid clinical evidence supporting their use as medications in LGS and DS.

2. Two novel options: fenfluramine and cannabidiol

2.1. Fenfluramine

FFA is a derivative of amphetamine and exerts pro-serotoninergic activity by disrupting the vesicle storage of serotonin (5-HT) and by inhibiting its reuptake from the synapse.Pre-clinical studies show a mechanism of action in that goes beyond the pro-serotoninergic activity, at the intersection between several pathways involved in excitation/inhibition balanceby multiple mechanisms including a positive modulation of sigma-1 receptors [5].

Following robust experimental studies carried out in theSCN1A-mutated zebrafish and rodent models [6], a retrospective study by Ceulemans et al [7] showed seizure freedom in 70% of the 12 patients receiving FFA add-on treatment (mean dose: 0.34 mg/kg/day) for a mean follow-up of 11 years and 4 months. Moreover, seizure recurred in 3 patients who withdrawn treatment. Likewise, in a prospective study by Schoonjans et al [8]on 9 DS patients treated with FFA at the mean dose of 0.35 (range: 0.16–0.69) mg/kg/day for a median period of 1.5 years, it was observed a median seizure reduction of 75% (range, 28–100%), including major motor seizures. The AEs reported were mild and transient [8].Two multicenter double-blind, placebo-controlled, parallel-group randomized clinical trials conducted in children and adults with Dravet syndrome receiving stable, stiripentol-inclusive antiepileptic drug regimens multiple centershave been published in 2020 [9,10].In both studies, FFA add-on provided significantly greater reduction in convulsive seizure frequency compared with placebo and was generally well-tolerated, with no observed valvular heart disease or pulmonary arterial hypertension.

2.2. Cannabidiol

Cannabis has been used to treat epilepsy since antiquity but the interest in cannabis-based therapies has recently raiseddue to the availability of a plant-derived formulation of purified CBD oral solution (Epidiolex®) approved as adjunctive therapy with clobazam (CLB) in DS and LGS patients from age 2 years.A first phase II, randomized, double-blind, placebo-controlled trial of CBD was performed on 120 DS subjects aged 2–18 years with ≥4 convulsive seizures per month (GWPCARE1 part B) [11]. The trial consisted ofa 4-week baseline period, followed by 2-week titration, 12-week maintenance and 10-day tapering. Patients were randomized to either CBD 20 mg/kg/day BID or placebo. The maximal dose of 20 mg/kg/day was recommended based on the safety and PK data from GWPCARE 1 part A study [12]. In this study, the CBD-treated group showed a median change in convulsive seizure frequency of −38.9% (from a median of 12.4 seizures/month at baseline to 5.9) compared with −13.3% (from 14.9 to 14.1) in the placebo group, resulting in the adjusted median difference of −22.8%. Moreover, the number of total seizuresper month decreased by 28.6% in patients on CBD compared with 9% in those receiving placebo, with an adjusted median difference of around 19%. However, the responder rate (43% vs 27% in CBD and placebo group) did not support the superiority of the active drug over placebo, neither did the reduction in nonconvulsive seizures alone (p = 0.88). These data suggest that CBD is effective in some convulsive seizures and not in all types of seizures presented by DS patients.

CBD is alsoindicated for the treatment of LGS.Twophase III, randomized, double-blind, placebo-controlled trials demonstrated CBD effectiveness and safety as an adjunctive drug in pediatric and adult patients [13,14].Overall, 396 patients, aged 2–55 years, with at least two generalized seizure types over the last 6 months and 2 drop seizures over the 4-week baseline period, were enrolled. A first study (GWPCARE3) compared CBD 10 mg/kg/day, CBD 20 mg/kg/day, and placebowhereas in the GWPCARE4 trial CBDwas administered only at 20 mg/kg dose.

Both the studies mainly focused on CBD effectiveness on drop seizures, whose median monthly frequency at baseline was 85 and 73.8. In the GWPCARE3 trial, the percentage change in 28-day frequency of drop seizures was significantly higher in both treatment arms (−37.2% in CBD 10 and −41.9% in CBD 20) in comparison with placebo-treated patients (−17.2%). These data were confirmed by the GWPCARE4 study, where the reduction in drop seizure frequency was significantly superior in the treated patients than in those receiving placebo (−43.9% vs −21.8%, with an estimated median difference of −17.21%). Likewise, significant responder rates for drop seizures were also found, regardless of dose (GWPCARE3: 36% in CBD 10, 39% in CBD 20, 14% in placebo; GWPCARE4: 43.9% in CBD group vs 21.8% in placebo). The clinical benefit on drop seizures appeared to be persistent over the entire 12-week maintenance period.

In a recent meta-analysis gathering data from both RCTs on LGS [15], no dose-response correlation was found in the data of the literature.Most patients participating in the above-illustrated RCTs were enrolled in an open-label extension (OLE) study (GWPCARE5), including overall 630 subjects (264 with DS and 366 with LGS) treated with adjunctive CBD (maximal dose 30 mg/kg/day) for 1–3 years, with 12-week follow-up period [16,17]. Many patients discontinued the treatment, mainly due to adverse events but, overall, these data confirm the usefulness of CBD on seizure control.Finally, a recent double-blind, placebo-controlled, randomized clinical trial (GWPCARE2) on nearly 200 DS patients from 38 centers in the United States, Spain, Poland, the Netherlands, Australia, and Israel showed that adjunctive cannabidiol at doses of 10 and 20 mg/kg/d led to similar clinically relevant reductions in convulsive seizure frequency with a better safety and tolerability profile for the 10-mg/kg/d dose [18].

3. Expert opinion

In the last few years, several anti-seizure medications have been discovered, relieving the burden of seizures for a significant number of patients. However, some conditions remain a challenge for epileptologists, including DS and LGS [1,2].With LGS accounting for an estimated 1–10% of childhood epilepsies, and a reported incidence of DS between 1 in 15,700 and 1 in 40,000 live births, these are rare diseases.

Treatment of DS and LGS traditionally focuses on alleviation of seizure burden, but in addition to treatment-resistant seizures, DS and LGS are associated with multiple comorbidities, which present further management challenges [1,2].However, the morbidity associated with DEEs such as LGS and DS leads to disproportionately large costs to the healthcare system and society in general.

Standard of care treatment for these conditions usually includes valproate and clobazam often in combination with stiripentolor topiramate in DS and rufinamide or felbamate in LGS [19,20].However, the development of novel antiseizure medications has been recently implemented; among these medications, FFA and CBD seem to be effective as adjunctive therapy for reducing the frequency and duration of the various types of seizures in both syndromes. Moreover, safety data are encouraging and suggest a good safety.

Fenfluramineemerged as a treatment for in a somehow unusual way. This drug, which was previously approved as a weight-loss drug, was withdrawn in 1997 when reports of cardiac valvulopathy emerged [21]. Such a severe side-effect would theoretically exclude any further use of this drug but the experience of child neurologists in Belgium encouraged them to continue, and a Royal Decree was issued in Belgium that permitted ongoing testing.Indeed, its anti-serotonergic effects provide some theoretical basis for its use in epilepsy, and a few case studies and case series have suggested it might be effective.

In a recent study conducted to characterize the cardiovascular safety profile of low-dose fenfluramine when used in a pediatric population to reduce seizure frequency in DS patients, longitudinal echocardiography over a median 8.4 months of treatment confirms a low risk of developing cardiac effects and PAH when used to treat pediatric DS patients. These findings support the view that the low incidence of valvular changes results of the low doses (>20 mg/day) used to treat epilepsy patients compared with weight loss patients who developed valvulopathy treated at a dose >60 mg/day [22].

In the last few years, a broad spectrum of products containing CBD has emerged on the market although their effects are largely dependent on the purity, the preparation, and the concentration of CBD and other components. CBD lacks psychoactive effects and, compared with conventional drugs, it has a distinctive chemical structure and mechanism of action due to a negligible affinity or activity at the cannabinoid receptors at clinically meaningful concentrations and eliciting its anti-seizure properties by acting on multiple molecular targets, including the antagonism of G protein-coupled receptor 55 (GPR55), desensitization of transient receptor potential of vanilloid type 1 (TRPV1) channels, and positive allosteric modulation of GABAA receptors [23,24]. Accordingly, evidence suggests that Epidiolex® significantly affects levels of clobazam/N-desmethylclobazam, rufinamide, topiramate, zonisamide, and eslicarbazepine [25]. However, robust data also indicate CBD is efficacious with and without concomitant treatment with clobazam, even if it cannot be excluded a synergistic effect associated with the combination of these two agents [26–28].

The authorization of CBD for the treatment of childhood epilepsy is a milestone in the history of medical use of cannabinoids to treat epileptic disorders. So far, Epidiolex® is the only pharmaceutical product deriving directly from the cannabis plant rather than produced synthetically that has undergone review through the approval processes and represents the first in a new class of drugs. Five multicenter, randomized, double-blind, placebo-controlled trials have shown the efficacy and safety of adjunctive CBD resulting in a reduction of the seizure frequency and generally well tolerability. Moreover, the open-label extension and expanded access program results provided further supporting evidence about the long-term effectiveness of add-on CBD in patients with drug-resistant epilepsy. Besides, controlled studies in other types of epilepsy, including refractory focal epilepsy, are warranted to further explore and fully understand the therapeutic potentialsof CBD [29].

4. Five-year perspective

It is likely that in the next 5 years, we will observe a great increase in data about the physiopathological mechanisms of DS and LGS. These data will eventually contribute to understanding better how to treat these epileptic syndromes. Moreover, more reliable dataobtained from large studies about the efficacy and safety of these new compounds for the treatment of DS and LGS will be available. Due to these data, we will confirm or not the real usefulness of FFA and CBD. Probably, both FFA and CBD will be used in other severe types of epilepsies where classical antiepileptic drugs do not control seizures. It is also likely that new other drugs will be added for the treatment of these two severe epileptic encephalopathies.

In conclusion, FFA and CBD will probably have an important role in the treatment of these pharmacoresistant encephalopathies. In addition to these therapeutic advances, other more innovative approaches are currently under investigation and perhaps the most exciting is the promise of antisense oligonucleotides that directly target mRNA related to the genetic abnormalities, generating a wave of excitement between clinicians and the patients’ families [30]. In the meanwhile, a thorough and accurate early assessment and diagnosis, which requires careful assessment of clinical and electroencephalography features, is important to ensure that patients receive the most appropriate treatment and necessary support systems as soon as possible, potentially helping to optimize long-term neurodevelopmental outcome.

Key points

• Dravet syndrome (DS) and Lennox-Gastaut Syndrome (LGS) are two pharmacoresistantdevelopmental epileptic encephalopathies still in need for an effective treatment.

• Fenfluramine (FFA) and cannabidiol (CBD) are promising drugs for the add-on treatment of DS and LGS as supported by animal and clinical studies.

• FFAand CBD are well tolerated at the therapeutic dose and exhibita favourable benefit-risk profile for the treatment of DS and LGS.

Declaration of interests

A Verrotti has received speaker fees and participated at advisory boards for Eisai, Zogenyx, and GW Pharmaceuticals. P Striano has received speaker fees and participated at advisory boards for Biomarin, Zogenyx, GW Pharmaceuticals, and has received research funding from ENECTA Srl, GW Pharmaceuticals, KolfarmaSrl., Eisai. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or conflict with the subject matter or materials discussed in this manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Acknowledgments

The authors developed this work within the framework of the DINOGMI Department of Excellence of MIUR 2018-2022 (legge 232 del 2016).

Additional information

Funding

This paper was not funded.