It is a well-known fact that at least 25% of people with epilepsy are drug-resistant. The aim is to achieve greater efficacy and fewer side effects. In this context, recent real-world evidence comparing newer antiseizure medications shows cenobamate efficacy compared to brivaracetam, lacosamide, and perampanel in drug-resistant focal epilepsy, with approximately 84% responder rate and 32% achieving seizure freedom at 12 months (1). However, cenobamate was associated with the highest rate of adverse effects during follow-up, while lacosamide was associated with the lowest.
Furthermore, as standard anti-seizure medications are symptomatic, there is an increasing focus on developing curative treatments that target the underlying disease. Numerous new treatments are currently being developed to address this issue. The objectives of pharmacological research are increasingly oriented towards treatments that target etiology and that present disease-modifying effects. These extend beyond seizure control, also aiming to improve neurodevelopment and comorbidities.
Perrucca et al. (2) provided an overview of the progress made in the development of new treatments for epilepsy, focusing on drugs currently in clinical development, with a emphasis on precision medicine, gene therapies and syndrome-specific treatments, rather than on broad-spectrum antiepileptic drugs.
The novel major therapeutic interventions in the epilepsy field can be broadly divided into three categories: new small-molecule chemical entities; gene-targeted therapies; and therapeutic devices.
Regarding new small-molecules, the compound that showed the most promising evidence of efficacy was Azetukalner. Azetukalner (XEN1101), a Kv7.2/7.3 potassium channel activator, has in fact demonstrated reasonable efficacy in randomized controlled trials for both focal seizures and generalized tonic-clonic seizures. This agent may be considered for potential FDA approval, after successful placebo-controlled trials.
Among gene-target therapies, relevant data on efficacy were reported to Zorevunersen. Zorevunersen (STK-001), an Antisense Oligonucleotides (ASO) designed to increase the expression of the Nav1.1 protein in SCN1A mRNA, showed a good seizure reduction rate in patients with Dravet syndrome.
Regarding neuromodulation, Responsive Neurostimulation (RNS) and Deep brain stimulation (DBS) are highlighted (3). Both modalities can target the thalamus, but with different approaches. RNS uses adaptive, on-demand stimulation triggered by detected abnormalities, with the ability to adjust stimulation parameters based on ictal recorded EEG patterns. RNS traditionally targets the epileptogenic zones, but demonstrated encouraging effects using thalamic nuclei as targets in drug-resistant epilepsy patients, specifically idiopathic generalized epilepsy.
Deep brain stimulation (DBS) uses fixed, continuous cycling stimulation parameters on the centromedial thalamic nucleus and it shows efficacy comparable to RNS, particularly for Lennox-Gastaut syndrome and generalised epilepsy. The key mechanistic difference is that RNS efficacy appears to depend more on long-term neuromodulation of seizure networks rather than immediate seizure termination, despite its closed-loop design, however with comparable efficacy to DBS.
In conclusion, these therapeutic interventions expand treatment options in patients with pharmacoresistant epilepsy, tailoring treatment to each patient's epilepsy characteristics, comorbidities, and preferences, moving toward truly personalized epilepsy care.
Key Points:
- Cenobamate demonstrates superior efficacy among newer antiseizure medications
- Azetukalner shows promising efficacy for both focal and generalized seizures
- Zorevunersen showed a good seizure reduction rate in patients with Dravet syndrome
- Neurostimulation modalities are an effective treatment option for drug-resistant epilepsy
References:
- Cerulli Irelli E, Roberti R, Borioni MS, et al. Comparative Effectiveness of Brivaracetam, Cenobamate, Lacosamide, and Perampanel in Focal Epilepsy. JAMA Neurol. Published online February 09, 2026. doi:10.1001/jamaneurol.2025.5625
- Perucca P, Perucca E. Novel pharmacological therapies in development. Curr Opin Neurol. 2026 Apr 1;39(2):138-149. doi: 10.1097/WCO.0000000000001456. Epub 2026 Jan 29. PMID:41623087.
- Premaratne S, Zoghi M, Antonic-Baker A, Chen Z, Chen L, Hamer R, Major B, Thomas EHX, Kwan P, O'Brien TJ, Lundstrom BN, Simpson HD. Non-invasive neurostimulation for drug-resistant epilepsy: systematic review and meta-analysis of effectiveness, safety, and optimal stimulation parameters. J Neurol. 2025 Dec 6;273(1):7. doi: 10.1007/s00415-025-13522-1. PMID: 41351627.
Publish on behalf of the Scientific Panel Epilepsy