On 30 June, at the tenth Congress of the European Academy of Neurology (EAN), two investigator-led e-presentation sessions on epilepsy outlined the effectiveness of a combination of a new anti-seizure medication (ASM), Xcopri (cenobamate) and vagus nerve stimulation (VNS), on the management of drug-resistant epilepsy (DRE).

Cenobamate and VNS was shown to be a safe and effective combination therapy for DRE.

This supports insights from key opinion leaders (KOLs) previously interviewed by leading data and analytics company GlobalData who have highlighted the high level of efficacy of cenobamate in clinical trials involving patients living with DRE.  

Epilepsy is a neurological disorder characterised by recurrent, unprovoked seizures.

Its pathophysiology involves an imbalance between excitatory and inhibitory neurotransmission in the brain, leading to abnormal electrical activity.

Understanding the underlying pathophysiology and mechanisms is crucial for developing targeted therapies to prevent or control seizures in individuals with epilepsy.

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Epilepsy is often treated in combination therapy as many patients do not achieve complete seizure control through monotherapy.

Sodium channel blockers, such as carbamazepine and lamotrigine, are commonly used monotherapies for epilepsy.

On the other hand, combination therapy targets multiple pathways involved in seizure generation as ASMs have diverse mechanisms of action.

Drugs commonly used in combination therapy include sodium channel blockers as aforementioned, alongside GABAergic drugs such as valproate, calcium channel blockers such as gabapentin, and SV2A protein ligands such as Keppra and Briviact.

Combination therapies are beneficial as they result in fewer side effects in comparison to using a single drug at a high dose.

Combination therapy may also prevent drug resistance, as using multiple ASMs may prevent the patient from developing resistance to any single drug.

DRE is defined as the persistence of seizures despite two trials with properly dosed ASMs.

Cenobamate is an ASM whose mechanism of action involves multiple pathways.

It has been found to inhibit persistent voltage-gated sodium channels, which helps stabilise the neuronal membrane and prevents the repetitive firing of neurons.

It has also been found to enhance the activity of γ-Aminobutyric acid (GABA) receptors, which are the primary inhibitory neurotransmitter receptors in the brain.

By increasing GABAergic inhibition, cenobamate helps to counterbalance the excessive excitatory activity that contributes to seizures.

On the other hand, VNS appears to exert its effects through a combination of neurochemical, neuroanatomical, and neurophysiological changes that collectively contribute to its efficacy in treating epilepsy.

Across two e-presentations, the reduction in seizure frequency achieved with combination therapy of cenobamate and VNS was demonstrated.

Research conducted by Hogeveen and colleagues at the University of Ghent noted that the addition of cenobamate to VNS treatment resulted in a worthwhile improvement in patients with DRE.

The study involved 447 patients who were already receiving VNS treatment.

The mean treatment duration of VNS was 11.6 years among patients involved in the study, and out of the 447 patients receiving VNS, 30 who had received at least six months of VNS treatment were elected to receive cenobamate as an add-on to their existing treatment regimen.

Monthly seizure frequency was measured before VNS treatment, after one year of VNS-only treatment, and after at least one month of VNS and cenobamate combination treatment.

The study found that after the addition of cenobamate to VNS treatment, the mean seizure reduction was 63%. This was after a mean follow-up period of eight months.

The findings were supported by a case study presented by Pardeo and colleagues from the University of Messina, Italy, on the same day.

In a session titled ‘VNS and Cenobamate: A potential new run against Ultra-refractory focal lesional epilepsy?’, Pardeo presented the case of a patient with DRE who was experiencing up to 60 focal seizures per month.

In February 2021, the patient was implanted with VNS, and daily vagus nerve stimulation over two years resulted in a meaningful reduction in seizure frequency, with the patient experiencing less than 30 per month.

Upon the introduction of cenobamate in January 2023 at a daily dose of 200mg, the patient completely ceased experiencing drop attacks and seizure frequency and currently experiences less than three seizures a month.

The efficacy data presented at EAN instils confidence in the combination of cenobamate and VNS for the treatment of DRE and points towards a potential roadmap of seizure control for patients living with DRE.

Furthermore, the data presented by Hogeveen and colleagues and Pardeo and colleagues may signify cenobamate’s candidacy as a monotherapy for epilepsy.

According to GlobalData’s Pharma Intelligence Center database, there is a Phase IV open-label study currently being planned in the US, which aims to assess the efficacy and safety of cenobamate monotherapy in adult subjects with newly diagnosed or recurrent partial-onset epilepsy.

This is a testament that cenobamate’s potential as a monotherapy is being recognised.

Furthermore, KOLs previously interviewed by GlobalData have stated that drug regulatory bodies, including the US Food and Drug Administration and the European Medicines Agency, are considering changing the approval patterns of ASMs to allow for additional monotherapies to treat epilepsy.

This is provided that the treatment has displayed efficacy in combination therapy.

Given cenobamate’s success when used in combination with VNS, it is not difficult to envision a future for cenobamate as a monotherapy for epilepsy.

However, further research into the combination of cenobamate and VNS is warranted to optimise treatment protocols and confirm its benefit and reliability.

Cenobamate’s potential as a monotherapy for epilepsy can then be further evaluated.