New Epilepsy Drugs: Emerging Therapeutic Possibilities

Epilepsy treatment has advanced, yet many patients still struggle with drug-resistant seizures or intolerable side effects. The search for more effective therapies continues, with new drugs offering hope for better seizure control and quality of life.

Recent advancements target diverse mechanisms beyond traditional approaches, expanding treatment possibilities.

Ion Channel-Focused Medications

Ion channels regulate neuronal excitability, making them key targets for epilepsy treatment. These membrane proteins control ion flow, influencing seizure activity. Many established antiepileptic drugs (AEDs) modulate ion channels, but newer compounds refine this approach with greater specificity and fewer side effects.

Selective sodium channel inhibitors are a promising development, designed to target hyperactive neurons while sparing normal function. Cenobamate, approved in 2019, exemplifies this strategy by enhancing sodium channel inactivation and modulating GABAergic activity. Clinical trials show it reduces seizure frequency by over 50% in many patients with focal epilepsy, even those resistant to prior treatments (Krauss et al., 2020). Unlike older sodium channel blockers, cenobamate’s dual mechanism may contribute to its superior efficacy.

Potassium channels are also gaining attention due to their role in stabilizing neuronal resting potential. XEN1101, a potassium channel opener, enhances KCNQ2/3 channel activity to reduce excitability. A Phase 2b study in The Lancet Neurology (French et al., 2021) reported a median seizure reduction of 52.8% in drug-resistant focal epilepsy patients. Unlike ezogabine, withdrawn due to retinal toxicity, XEN1101 appears safer, with dizziness and somnolence as the most common side effects.

Calcium channel modulation is another approach, particularly for absence epilepsy. T-type calcium channels contribute to pathological thalamocortical oscillations in this seizure type. Z944, a selective T-type calcium channel blocker, has shown anticonvulsant effects in preclinical and early human trials. Unlike ethosuximide, the standard treatment for absence seizures, Z944 offers a more targeted approach with potentially fewer gastrointestinal side effects.

GABA System-Enhancing Agents

Gamma-aminobutyric acid (GABA), the brain’s primary inhibitory neurotransmitter, plays a central role in controlling neuronal excitability. Many antiseizure medications (ASMs) enhance GABAergic signaling, counteracting hyperexcitability. While benzodiazepines and barbiturates have long been used, newer strategies refine this approach for improved efficacy and tolerability.

Positive allosteric modulators of GABA-A receptors enhance endogenous inhibitory signaling without directly activating the receptor. Staccato alprazolam, an investigational inhaled benzodiazepine, delivers rapid seizure suppression. Unlike oral formulations requiring systemic absorption, this inhaled system achieves peak plasma concentrations within minutes, making it ideal for acute seizure clusters. A Phase 3 trial (Jagoda et al., 2022) found it terminated seizures within 2 minutes in 65% of treated patients, offering an alternative to rectal or intranasal benzodiazepines.

Some novel therapies enhance GABA synthesis or reduce its degradation. Padsevonil was developed to modulate synaptic and extrasynaptic GABA-A receptors while inhibiting synaptic vesicle protein 2A (SV2A), a target of levetiracetam. However, a Phase 3 trial (Krauss et al., 2021) failed to show superior efficacy, leading to its discontinuation. Despite this, multi-target strategies remain an active research area.

Inhibiting GABA transaminase, the enzyme responsible for GABA degradation, is another approach. Vigabatrin, an irreversible inhibitor of this enzyme, is effective for infantile spasms and refractory focal seizures but has a risk of irreversible retinal toxicity. OV329 aims to achieve similar effects while minimizing ocular side effects. Preclinical studies suggest OV329 selectively targets peripheral GABA metabolism, reducing central nervous system exposure. If clinical trials confirm its efficacy and improved safety, OV329 could be a safer alternative for GABAergic augmentation.

Monoclonal Antibody Strategies

Monoclonal antibodies (mAbs) offer a precision-targeted approach to epilepsy treatment, minimizing systemic side effects. Unlike small-molecule drugs, which interact with multiple pathways, mAbs selectively bind to specific proteins involved in seizure generation. This specificity allows for longer-lasting effects, reducing dosing frequency and improving adherence.

One promising target is neuropeptide signaling, particularly corticotropin-releasing factor (CRF) and its receptors, which are linked to seizure susceptibility. Elevated CRF levels increase excitability in animal models, suggesting that blocking this pathway could reduce seizures. Monoclonal antibodies neutralizing CRF or its receptors have shown early preclinical success in reducing seizure duration and severity. While human trials are in early stages, this approach offers a novel way to modulate brain excitability without affecting ion channels or neurotransmitter systems.

Another focus is targeting pro-epileptic proteins that contribute to hyperexcitability. LGI1, a neuronal protein involved in synaptic transmission, is a key candidate. Autoantibodies against LGI1 are linked to limbic encephalitis, a condition often presenting with seizures. Researchers hypothesize that restoring LGI1 function through recombinant monoclonal antibodies could benefit epilepsy patients with LGI1 dysfunction. Animal models show improved seizure control following administration of engineered LGI1-targeting antibodies.

Glutamate Receptor Modulators

Glutamate, the brain’s primary excitatory neurotransmitter, plays a significant role in seizure generation. Excessive glutamatergic activity leads to hyperexcitability, increasing seizure risk. Targeting glutamate receptors, particularly AMPA and NMDA subtypes, is a promising strategy for seizure control while minimizing cognitive side effects.

AMPA receptors mediate fast excitatory transmission, making them a logical target for seizure suppression. Perampanel, an FDA-approved AMPA receptor antagonist, reduces seizure frequency in focal and generalized epilepsy. However, its dose-dependent neuropsychiatric side effects, including aggression and dizziness, have prompted research into next-generation AMPA modulators. Selurampanel, a selective AMPA antagonist with a shorter half-life, may reduce long-term adverse effects. Early trials suggest selurampanel provides comparable seizure reduction with improved tolerability.

NMDA receptors have also been investigated, but broad NMDA antagonists can impair cognition and cause dissociative effects. Researchers now focus on partial NMDA modulation, fine-tuning receptor activity without widespread inhibition. Targeting specific NMDA subunits, such as GluN2B, offers a promising approach. Experimental compounds selectively inhibiting GluN2B-containing NMDA receptors show anticonvulsant effects in preclinical models while preserving normal function.

Neuroinflammation-Targeted Compounds

Neuroinflammation contributes to seizure development, particularly in drug-resistant epilepsy. Inflammatory processes alter neuronal excitability, disrupt the blood-brain barrier, and promote gliosis, exacerbating seizures. While corticosteroids and immunosuppressants have been explored, newer compounds aim for more precise modulation without broad immune suppression.

Interleukin-1β (IL-1β), a proinflammatory cytokine, is a promising target. Canakinumab, a monoclonal antibody neutralizing IL-1β, has been investigated for seizure reduction in epilepsy linked to neuroinflammation. Preclinical studies and small-scale trials suggest IL-1β inhibition may lower seizure frequency, particularly in autoimmune or febrile seizures. Another approach targets the IL-1 receptor with anakinra, an FDA-approved drug for rheumatoid arthritis, which has shown anticonvulsant effects in experimental models.

Cyclooxygenase-2 (COX-2) inhibition is another potential strategy. Traditional NSAIDs like celecoxib selectively inhibit COX-2 and have anticonvulsant properties in animal studies. However, long-term NSAID use carries cardiovascular risks, prompting research into COX-2 inhibitors with better brain penetration and fewer systemic side effects. These compounds could benefit patients whose seizures are aggravated by inflammation, such as those with Rasmussen’s encephalitis or post-traumatic epilepsy.

Non-Oral Delivery Methods

While oral medications remain standard, alternative delivery methods address issues like delayed absorption, gastrointestinal side effects, and poor adherence. Innovations in drug formulation and administration enhance bioavailability, provide rapid seizure relief, and improve compliance.

Transdermal drug delivery is a significant advancement. Cannabidiol (CBD) transdermal patches offer steady-state drug release, avoiding fluctuations seen with oral dosing. Unlike ingested formulations, which undergo liver metabolism, transdermal CBD bypasses this process, leading to more consistent plasma concentrations. This could benefit refractory epilepsy patients needing stable drug levels for seizure control.

Intranasal administration is another emerging strategy, offering rapid absorption through the nasal mucosa. Diazepam nasal spray, FDA-approved for acute seizure clusters, provides a non-invasive alternative to rectal diazepam. This formulation allows faster onset of action, making it valuable for immediate seizure intervention. Researchers are also exploring intranasal delivery of other antiseizure medications, including midazolam and brivaracetam, to expand treatment options.