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Summary
Approximately 30% of people with epilepsy have drug-resistant seizures — seizures that persist despite trying two or more appropriate antiseizure medications (ASMs). For this population, and for children with severe genetic epilepsies like Dravet syndrome and tuberous sclerosis complex (TSC), 2026 clinical research is delivering targeted options: fenfluramine and cannabidiol for specific genetic syndromes, gene therapy approaches that address the underlying mutation, and closed-loop neurostimulation that can detect and abort seizures in real time.
Fenfluramine for Dravet Syndrome and Lennox-Gastaut
Dravet syndrome is a severe, treatment-resistant epilepsy caused primarily by SCN1A gene mutations that impair sodium channel function in inhibitory interneurons. Patients experience prolonged febrile seizures beginning in the first year of life, followed by a lifetime of multiple seizure types and developmental impairment.
Fenfluramine (Fintepla, UCB), originally known as a weight-loss drug withdrawn from the market in 1997 due to cardiac valvulopathy, has been reformulated at much lower doses for epilepsy. At the doses used (0.1–0.7 mg/kg/day), cardiac effects have not been observed in trials. The STUDIO Phase 3 trial in Dravet syndrome showed fenfluramine reduced monthly convulsive seizure frequency by 62.3% vs. 11.1% for placebo. It received FDA approval in 2020 for Dravet syndrome and in 2022 for Lennox-Gastaut syndrome (LGS). Current trials are evaluating combination strategies and long-term cardiac surveillance.
Cannabidiol (Epidiolex) Expansion
Pharmaceutical-grade cannabidiol (Epidiolex, Jazz Pharmaceuticals) is FDA-approved for seizures associated with Dravet syndrome, Lennox-Gastaut syndrome, and tuberous sclerosis complex (TSC). Unlike THC, CBD does not produce psychoactive effects. Its precise mechanism in epilepsy is not fully established but likely involves modulation of voltage-gated sodium channels, GPR55 antagonism, and effects on adenosine signaling.
The GWPCARE series of trials (GWPCARE1–6) demonstrated 40–50% median reduction in seizure frequency across these syndromes. A common interaction: CBD significantly increases serum levels of clobazam (a common co-medication) through CYP2C19 inhibition, contributing to some of its efficacy but also somnolence. Current research is investigating CBD formulations, dosing strategies, and whether efficacy extends to other genetic epilepsies including CDKL5 deficiency disorder and PCDH19 epilepsy.
Gene Therapy for Dravet Syndrome and TSC
Dravet syndrome's etiology — loss of function in one SCN1A allele — makes it a compelling gene therapy target. Multiple approaches are in development:
ETX101 (Encoded Therapeutics): An AAV9 gene therapy delivering an engineered transcription activator (EtCas9-VP64-p65-Rta) to upregulate transcription from the intact SCN1A allele, compensating for the haploinsufficiency. This "transcription factor" approach avoids the challenges of delivering a full-length SCN1A gene (too large for standard AAV vectors). Phase 1/2 ENDEAVOR trial results in young children with Dravet syndrome have shown promising seizure reduction with acceptable safety. FDA Breakthrough Therapy designation was granted.
Antisense oligonucleotides (ASOs) for TSC: Tuberous sclerosis complex is caused by TSC1 or TSC2 mutations leading to mTOR pathway hyperactivation in neurons. While mTOR inhibitors (everolimus) reduce subependymal giant cell astrocytomas and some seizure types, they don't address neurological symptoms fully. ASO approaches targeting mTOR pathway components are in preclinical and early clinical development.
Vigabatrin alternatives for TSC-related infantile spasms: Vigabatrin has been first-line for TSC-related infantile spasms but causes irreversible visual field defects. Trials of mTOR inhibitor + ACTH combinations are seeking to reduce vigabatrin exposure.
Closed-Loop Neurostimulation
For drug-resistant focal epilepsy, neurostimulation devices offer a non-pharmacologic option. The RNS System (NeuroPace) is unique in being a closed-loop device: electrodes implanted directly at seizure foci continuously record EEG and, when they detect characteristic pre-seizure patterns, deliver responsive electrical stimulation to abort the ictal event before it propagates.
Long-term follow-up data from the RNS pivotal trial (now 9+ years) shows a median 75% seizure reduction — and responder rates (>50% reduction) continue improving over time, suggesting ongoing neuroplastic changes. The device also continuously records intracranial EEG, providing unprecedented data on seizure patterns. Trials are evaluating RNS for primary generalized epilepsies (previously contraindicated), pediatric patients, and using machine learning algorithms to improve detection sensitivity and specificity.
Deep brain stimulation (DBS) targeting the anterior nucleus of the thalamus (ANT-DBS, Medtronic Percept PC) received FDA approval in 2018. The SANTE trial showed 69% median seizure reduction at 5 years. Updated closed-loop DBS systems using on-device sensing are in active Phase 2 trials.
Key Takeaways
- Fenfluramine (at low doses) reduces Dravet syndrome convulsive seizures by ~62% in trials; it's also approved for Lennox-Gastaut syndrome.
- Cannabidiol (Epidiolex) is approved for three severe childhood epilepsies and is being studied in additional genetic epilepsy syndromes.
- ETX101 gene therapy upregulates the intact SCN1A allele in Dravet syndrome — Phase 1/2 ENDEAVOR trial is yielding promising early results.
- Closed-loop responsive neurostimulation (RNS) achieves 75% median seizure reduction at 9 years with continuous improvement over time.
- ANT-DBS and machine-learning-enhanced closed-loop DBS systems are expanding options for drug-resistant focal and generalized epilepsies.