Cenobamate & Newer ASMs
The past decade has witnessed the introduction of several novel antiseizure medications (ASMs) with unique mechanisms of action and specialized indications. Cenobamate, marketed in 2020, has generated particular excitement due to its exceptional seizure-free rates in drug-resistant focal epilepsy—higher than any other ASM in the past 30 years. Other newer agents—brivaracetam, cannabidiol, fenfluramine, and ganaxolone—have filled critical therapeutic niches in developmental and epileptic encephalopathies (DEEs) and specific genetic epilepsy syndromes. Understanding these agents is essential for the modern epileptologist, as they have redefined treatment expectations for some of the most challenging epilepsy populations.
Bottom Line
- Cenobamate: Dual mechanism (sodium channel blockade of persistent current + GABA-A positive allosteric modulation); exceptional seizure-free rates (21% in phase 3 trials—unprecedented for adjunctive therapy); requires very slow titration (12.5 mg → 200 mg over 10+ weeks) to avoid DRESS syndrome; strong CYP2C19 inhibitor and CYP3A4 inducer; may be considered before surgery in drug-resistant focal epilepsy
- Brivaracetam: SV2A ligand with 20× higher affinity than levetiracetam; fewer behavioral side effects; useful as levetiracetam replacement; not effective when added to levetiracetam
- Cannabidiol (Epidiolex): FDA-approved for Lennox-Gastaut syndrome, Dravet syndrome, and tuberous sclerosis complex; important interaction with clobazam (increases active metabolite); monitor liver enzymes, especially with concurrent valproate
- Fenfluramine: Serotonergic mechanism; repurposed for Dravet syndrome and LGS; lower doses than obesity treatment—no cardiac valvulopathy observed; REMS program with echocardiography monitoring
- Ganaxolone: Neurosteroid GABA-A modulator at a unique binding site; FDA-approved for CDKL5 deficiency disorder only
Cenobamate
Mechanism of Action
Cenobamate is an alkyl-carbamate with a dual mechanism of action that distinguishes it from other ASMs:
- Sodium channel blockade: Preferentially attenuates the persistent sodium current (rather than the transient current targeted by traditional sodium channel blockers), which may contribute to its superior efficacy and distinct mechanism
- GABA-A positive allosteric modulation: Enhances GABA activity through a mechanism similar to but distinct from benzodiazepines
This dual mechanism—combining sodium channel and GABAergic effects—may explain cenobamate's exceptional clinical efficacy and is the basis for potentially synergistic combinations with other ASMs.
Pharmacokinetics
- Bioavailability: Very good (~88%)
- Protein binding: 60% (not clinically relevant)
- Metabolism: Extensive hepatic glucuronidation and oxidation; predominantly inactive urinary metabolites
- Half-life: 50–60 hours—justifies once-daily dosing
- Interactions: Multiple and clinically important:
- CYP2C19 inhibitor: Reduces clearance of phenytoin, phenobarbital, and the active metabolite of clobazam (N-desmethylclobazam)—dose adjustments often necessary
- CYP3A4 inducer: May reduce efficacy of oral contraceptives
- May reduce lamotrigine concentration
- Concentration is reduced by enzyme inducers (carbamazepine, phenytoin)
Clinical Trial Results
| Trial | Design | Key Results |
|---|---|---|
| Phase 2 (C013) | Double-blind, placebo-controlled; adjunctive in drug-resistant focal epilepsy | Dose-dependent seizure reduction; established 100 mg as minimum effective dose |
| Phase 3 (C017) | Double-blind, placebo-controlled; adjunctive in drug-resistant focal epilepsy; doses of 100, 200, 400 mg/d | ≥50% responder rate: 40% (100 mg), 56% (200 mg), 64% (400 mg) vs. 25% placebo; seizure-free rate: 4% (100 mg), 11% (200 mg), 21% (400 mg) vs. 1% placebo—the highest seizure-free rates ever reported in an adjunctive therapy trial |
| Open-label safety study | Large safety study with slowed titration | DRESS (drug rash with eosinophilia and systemic symptoms) did not recur with the current slow titration protocol; confirmed long-term tolerability |
Dosing and Titration
Cenobamate: Mandatory Slow Titration (REMS)
- Cenobamate requires a very slow titration to avoid the risk of DRESS syndrome (drug rash with eosinophilia and systemic symptoms), which occurred in early studies with faster titration
- Titration protocol:
- Weeks 1–2: 12.5 mg/d
- Weeks 3–4: 25 mg/d
- Weeks 5–6: 50 mg/d
- Weeks 7–8: 100 mg/d (minimum effective dose)
- Then increase by 50 mg every 2 weeks as needed, up to 400 mg/d
- Total time to target dose: approximately 10–14 weeks (minimum)
- Cenobamate is available through a Risk Evaluation and Mitigation Strategy (REMS) program requiring prescriber certification
- With this titration, DRESS has not recurred in the large safety study
- Cenobamate is a controlled substance (DEA Schedule V)
Adverse Effects
The most common adverse effects are somnolence, dizziness, and fatigue. Importantly, cenobamate did not seem to adversely affect cognition, affect, or quality of life in clinical studies—a notable advantage over topiramate and other multi-mechanism ASMs.
Cenobamate: Place in Therapy
- FDA-approved for focal-onset seizures in adults (November 2019; marketed May 2020)
- Its exceptional efficacy supports early use in patients with drug-resistant focal epilepsy, particularly before invasive surgical evaluation in patients who are not ideal surgical candidates
- The combination of cenobamate + clobazam has shown potentially synergistic efficacy
- When adding cenobamate to existing sodium channel blockers, reduce the co-medication dose if adverse effects emerge (pharmacodynamic interaction)
- Monitor phenytoin and phenobarbital levels when adding cenobamate (CYP2C19 inhibition raises their concentrations)
Brivaracetam
Brivaracetam is structurally related to levetiracetam and binds the same target (SV2A) with approximately 20-fold higher affinity and greater selectivity. It also has higher brain permeability. FDA-approved for focal seizures in patients ≥4 years.
| Feature | Levetiracetam | Brivaracetam |
|---|---|---|
| SV2A binding affinity | Baseline | ~20× higher, more selective |
| Brain permeability | Good | Higher |
| Metabolism | None (66% unchanged renal) | Hepatic hydrolysis + CYP2C19 hydroxylation |
| Drug interactions | None | Moderate (increased by inducers; may raise CBZ-epoxide and phenytoin by ~20%) |
| Half-life | 6–8 hours | ~7–8 hours |
| Behavioral side effects | Irritability/hostility in ~10–15% | Irritability in 3.2% (vs. 1.1% placebo)—significantly lower |
| Starting dose | 500 mg/d | 50 mg twice daily (or 25 mg BID in elderly) |
| Dose range | 1000–4000 mg/d | 50–200 mg/d |
| IV formulation | Yes (status epilepticus) | Yes (explored for SE due to superior brain permeability) |
| Controlled substance | No | Yes (Schedule V) |
Key clinical points:
- Brivaracetam is NOT effective when added to levetiracetam (both compete for SV2A binding)—should be used as a replacement, not add-on
- Improvement or resolution of behavioral side effects reported in the majority of patients switching from levetiracetam to brivaracetam
- Post hoc analysis: 75–100% of responders responded from the time of treatment initiation
- Open-label data support efficacy for generalized seizure types, particularly juvenile myoclonic epilepsy
Cannabidiol (Epidiolex)
Mechanism of Action
Cannabidiol (CBD) is a cannabinoid that does not interact with the CB1 receptor and does not share the psychoactive properties of tetrahydrocannabinol (THC). Its mechanisms include enhancement of GABA activity through allosteric modulation of the GABA-A receptor and modulation of intracellular calcium. Bioavailability is increased with a high-fat meal. It is highly protein-bound (>94%) and extensively metabolized by CYP2C19 and CYP3A4.
FDA-Approved Indications
- Lennox-Gastaut syndrome (ages ≥1 year)
- Dravet syndrome (ages ≥1 year)
- Tuberous sclerosis complex (ages ≥1 year)
Dosing
- Starting dose: 5 mg/kg/d in 2 divided doses for 1 week
- Target dose: 10 mg/kg/d
- Maximum dose: 20 mg/kg/d
- Available as oral solution only
Cannabidiol: Drug Interactions and Hepatotoxicity
- Clobazam interaction: Cannabidiol increases the concentration of N-desmethylclobazam (active metabolite of clobazam) by inhibiting CYP2C19—requires clobazam dose reduction (typically by 50%); much of CBD's clinical benefit in LGS and Dravet may be mediated through this interaction
- Hepatotoxicity: Elevation of liver enzymes, particularly with concurrent valproate and/or clobazam; obtain liver enzymes and total bilirubin at baseline, 1, 3, and 6 months after initiation
- Valproate interaction: Increased risk of hepatotoxicity when combined with valproate
- Clearance increased by enzyme inducers (carbamazepine, phenytoin) and decreased by CYP2C19/3A4 inhibitors
- Artisanal cannabidiol formulations are NOT equivalent to pharmaceutical-grade Epidiolex and have not been evaluated in controlled trials
Fenfluramine
Mechanism of Action
Fenfluramine is a repurposed medication, originally marketed as an appetite suppressant in the 1970s (withdrawn due to cardiac valvulopathy and pulmonary hypertension at obesity-treatment doses). Its antiseizure mechanism involves increasing serotonin by disrupting vesicular storage and reversing serotonin transporter function. The active metabolite norfenfluramine binds and activates serotonin receptors.
FDA-Approved Indications
- Dravet syndrome (ages ≥2 years)
- Lennox-Gastaut syndrome (ages ≥2 years)
Dosing and Monitoring
- Starting dose: 0.1 mg/kg twice daily
- Maximum dose: 0.7 mg/kg/d (max 26 mg/d); lower maximum of 0.4 mg/kg/d (max 17 mg/d) when co-administered with stiripentol and clobazam
- Half-life: ~20 hours
Fenfluramine: Cardiac Monitoring (REMS)
- Valvular heart disease and pulmonary hypertension have not been observed in pediatric epilepsy studies, possibly due to lower doses than obesity treatment and younger patient age
- Nevertheless, fenfluramine is available only through a REMS program requiring:
- Echocardiography before treatment, every 6 months during treatment, and 3–6 months after discontinuation
- Prescriber certification and patient enrollment
- Most common adverse effects: decreased appetite, fatigue, somnolence, weight decrease
- Important interaction: stiripentol + clobazam co-administration increases fenfluramine plasma concentration
- Fenfluramine is a controlled substance (DEA Schedule V)
Ganaxolone
Mechanism of Action
Ganaxolone is a neuroactive steroid that is a positive allosteric modulator of GABA-A receptors, targeting a unique binding site distinct from benzodiazepines and barbiturates. This mechanism means it should not exhibit cross-tolerance with benzodiazepines.
Pharmacokinetics
- Bioavailability: Low but markedly enhanced with a high-fat meal
- Protein binding: ~99% (highly bound)
- Metabolism: Extensive hepatic via CYP3A4/5, CYP2B6, CYP2C19, CYP2D6
- Half-life: ~34 hours
- Interactions: Not an enzyme inducer or inhibitor; however, clearance is increased by enzyme inducers
Indication and Dosing
- FDA-approved for seizures associated with CDKL5 deficiency disorder (cyclin-dependent kinase-like 5) in patients ≥2 years—a very narrow indication
- Starting dose: 18 mg/kg/d (pediatric) or 450 mg/d (adult)
- Titration: Increase by 5 mg/kg/d weekly (pediatric) or 450 mg/wk (adult)
- Target dose: 63 mg/kg/d (pediatric) or 1800 mg/d (adult)
- Most common adverse effect: somnolence/sedation
Comparative Overview of Newer ASMs
| Agent | Mechanism | FDA Indication | Key Interaction | Monitoring |
|---|---|---|---|---|
| Cenobamate | Na+ channel (persistent current) + GABA-A PAM | Focal seizures (adults) | CYP2C19 inhibitor; CYP3A4 inducer | Slow titration per REMS; co-medication levels |
| Brivaracetam | SV2A (20× affinity vs. LEV) | Focal seizures (≥4 years) | Raises CBZ-epoxide, phenytoin | None specific |
| Cannabidiol | GABA-A allosteric modulation, Ca2+ modulation | LGS, Dravet, TSC (≥1 year) | Increases N-desmethylclobazam; hepatotoxicity with VPA | LFTs at baseline, 1, 3, 6 months |
| Fenfluramine | Serotonin release and receptor activation | Dravet, LGS (≥2 years) | Stiripentol + clobazam increase levels | Echocardiogram q6mo (REMS) |
| Ganaxolone | Neurosteroid GABA-A PAM (unique site) | CDKL5 deficiency (≥2 years) | Clearance increased by inducers | None specific |
Pipeline ASMs and Emerging Targets
The epilepsy therapeutic pipeline continues to expand with agents targeting novel pathways:
- Precision medicine approaches: Growing understanding of genetic etiologies (SCN1A in Dravet, TSC1/TSC2 in tuberous sclerosis, CDKL5 deficiency) is driving development of mechanism-specific therapies. The success of cannabidiol, fenfluramine, and ganaxolone in specific genetic syndromes validates this approach
- Antisense oligonucleotides (ASOs): Under investigation for genetic epilepsies such as Dravet syndrome (targeting SCN1A upregulation)
- Gene therapy: Early-phase trials for monogenic epilepsies
- Autoimmune epilepsy recognition: Increasing awareness that some epilepsies have autoimmune pathophysiology requiring immunotherapy rather than (or in addition to) traditional ASMs—a paradigm shift in treatment approach
- Multi-mechanism ASMs: The success of cenobamate (dual sodium channel + GABA mechanism) has reinforced interest in ASMs with complementary mechanisms of action in a single molecule
Selecting Among Newer ASMs: Clinical Decision Points
- Drug-resistant focal epilepsy: Cenobamate should be considered early (21% seizure-free rate in clinical trials); may be tried before proceeding to surgical evaluation in non-ideal surgical candidates
- Levetiracetam intolerance (behavioral): Brivaracetam is the logical replacement—majority improve behaviorally after switching
- Dravet syndrome: Cannabidiol, fenfluramine, stiripentol (+ clobazam), and valproate are the mainstay agents; avoid sodium channel blockers (carbamazepine, phenytoin, lamotrigine), which worsen seizures
- Lennox-Gastaut syndrome: Cannabidiol, fenfluramine, clobazam, lamotrigine, rufinamide, and felbamate all have evidence; individualize based on current medications and side effect profile
- CDKL5 deficiency disorder: Ganaxolone is the only specifically approved agent
References
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