Introduction
There is a urgent need for novel anti-seizure drugs that are both efficacious, safe and absent undesirable side effects. In particular, the number of epilepsy patients who are drug resistant remains at an unacceptably high rate of 30%. Untreated epilepsy has dire consequences including injury and death. Additionally, those who are seizure free with drug therapy are not free from unwanted neurological side effects such as headaches, somnolence, and memory impairment. Therefore, research for novel anti-seizure drugs that prevent seizures at doses absent of side effects is desperately needed but incredibly challenging (see Blog 15 for overview). This blog discusses some of the novel anti-seizure drugs – ongoing research.
Specifically, this blog reviews three of 5 novel anti-seizure drugs that have met their goals in early clinical trials with positive data on anti-seizure efficacy (1). Novel anti-seizure drugs introduced here are A) azetukalner (XEN1101), B) bexicaserin (LP352), and C) soticletstat (TAK-935).
A) Azetukalner – Novel Anti-Seizure Drug Candidate
Azetukalner is a potassium channel opener that selectively acts on specific channels designated Kv7.2/7.3. Importantly, azetukalner, by opening potassium channels, accelerates the movement of potassium ions through Kv7.2/7.3 channels across the nerve membrane. This is an critical action because it lowers the membrane potential and essentially dampens excitable (seizure) nerve activity that promotes a seizure. Thus, the rational is that the selectivity of azetukalner allows it to bypass all the other ion channels, potassium or otherwise, and focus only on excitable nerves where Kv7.2/7.3 channels need assistance.
Selectivity
Based on in vitro findings, azetukalner is 4 fold more selective for potassium Kv7.2/7.3 channels compared to closely related potassium (Kv) channels. Additionally, oral dosing in classic seizure rodent models (electrical and chemical) reduced seizures to a greater extent than a current standard drug, retigabine, a nonselective Kv7 potassium opener (2), used now only experimentally.
Clinical Results
Two clinical trials evaluated azetukalner for efficacy and safety. The first was a randomized double-blind trial of 8 weeks with escalating doses (10, 20, and 25 mg) in adults with focal onset seizures, baseline median number of 13.5 seizures per month (3). Most importantly, a reduction in monthly seizure frequency was slightly over 50% with the highest dose compared to an 18% reduction of seizure frequency in the control group.
The second trial was an open-label trial that allowed participants in the first trial to continue with the medication (20 mg dose). Data after one year for those who chose to continue show that nearly 15% were seizure free. After 2 years, nearly 24% were seizure free (4). This trial had no control group. The dropout rate was approximately 25%. Nevertheless, the results are considered good in light of the difficult to treat seizures in this group of patients (4).
Treatment Related Adverse Effects
Adverse effects from this long term trial were considered mild to moderate. They ranged from dizziness, headache, coronavirus infection, somnolence, falls and memory impairment at rates of 12.7-21.8% (4).
B) Bexicaserin – Novel Anti-Seizure Drug Candidate
Bexicaserin is a 5HT2C serotonin receptor stimulant (agonist). Importantly, 5HT2C is one of three serotonin receptors. Specifically, it is the one that plays a major role in seizure activity such that activation damps seizures.
Selectivity
Bexicaserin is “super” selective (more than 1000 fold) for the 5HT2C receptor compared to the other serotonin receptors as demonstrated in vitro studies. In this regard it’s selectivity stands out against current drugs in this category e.g. fenfluramine (5) and lorcaserin (6). Furthermore, bexicaserin also had no effect on an extensive battery of other known brain receptors (7). In animal models of genetically or drug-induced seizure activity (zebra fish, see blog 18; mice), bexicaserin reduced seizure activity.
Clinical Results
A phase 1b/2a randomized clinical trial tested 41 patients with developmental epileptic encephalopathies (serious epilepsy affecting brain development). Patients receiving 6 month treatment with increasing doses of bexicaserin (6-12 mg/day) exhibited reduced median motor seizure activity by slightly more than 50% compared to start of the study (8). Noteably, a Phase 3 trial (NCT06660394) with bexicaserin is currently recruiting children and adults with Dravet Syndrome, a developmental epileptic encephalopathy.
Treatment Related Adverse Effects
The two main adverse reactions affecting 20% or more of participants were somnolence and decreased appetite (8).
C. Soticlestat – Novel Anit-Seizure Drug Candidate
Soticlestat inhibits the metabolism of cholesterol in the brain (9). Drug action prevents the formation of cholesterol-24 hydroxylase (24HC). 24HC is a known facilitator of nerve excitability. Specifically, 24HC increases the concentration of glutamate, a pro-excitability transmitter. Additionally, it modulates NMDA (N-methyl-D-aspartate) “excitable” receptors and enhances inflammation, three actions that support abnormal brain excitability (10). Therefore, reducing 24HC would diminish these activities.
Preclnical Results
Results in mouse models of epilepsy showed soticlestat as an efficacious antiseizure chemical entity worthy of clinical evaluation.
Clinical Results
The most recent trial (ELEKTRA) was a phase 2 randomized double-blind trial of 126 patients for 12 weeks (up to 300 mg/d). It reported significant (median 50%) seizure frequency reduction in children and adolescents with Dravet Syndrome. However, it did not significantly reduce seizure frequency in patients with Lennox–Gastaut syndrome, another difficult to treat epilepsy (11). An interesting asset of this drug is that efficacy can be followed by measuring the concentration of 24HC in the blood. Thus, as 24HC declines with soticlestat use, seizure frequency also declines.
Phase 3 trial (NCT05163314) is in progress (ClinicalTrials.gov). The clinical trial goal is the determination of safety and tolerability. This is a trial of projected 400 patients with Dravet syndrome or Lennox-Gastaut Syndrome worldwide taking solticlestat (100mg/d) for 4 years.
Treatment Related Adverse Events
Adverse effects of soticlestat were comparable to placebo with 5% experiencing lethargy and constipation to a greater degree than placebo.
Critique
The three novell anti-seizure drugs, working toward FDA approval, each act by a different mechanism. Azetukalner opens a potassium channel subtype, bexicaserin stimulates a serotonin receptor subtype and soticlestat blocks cholesterol metabolism in the brain. The variety of targets speaks to the complexity of seizures and the lack of clear knowledge about epilepsy. All three drugs have completed phase 2 trials with evidence of efficacy and safety.
Despite the fact that these drugs reduce seizure frequency up to 50% in different epilepsies, these drugs are far from ideal. Selectivity of azetukalner for the Kv7,2/7.3 channels is only 4 time greater than it is for other Kv channels. This modest selectivity most likely disappears in human, leading to general suppression of neuronal activity supporting side effects of somnolence and memory impairment. Bexicaserin exhibits a 1000 fold selectivity for the 5HT2C receptors compared to same class subtypes. This impressive selectivity will most likely be maintained in humans. However, stimulation of 5HT2C does more than dampen seizures and affects multiple functions such as appetite and mood. The multiple functionality of this serotonin receptor would brings in undesired side effects.
Soticlestat is a truly novel drug that targets the destructive brain metabolite of cholesterol. Its unique effect knocks out three potential mechanisms supporting seizures and has the greatest chance of reducing seizures with the least induction of side effects. Furthermore, its effects can be track with measurement of 24HC in blood.
Patients with epilepsy deserve medications that prevent seizure without blocking other vital brain activities. Patients with epilepsy eagerly await the results of Phase 3 clinical trials for these compounds.
References
1. Bailer M, Johannessen SI, Koepp MJ, Perucca E, Perucca P et al. Progress report on new medications for seizures and epilepsy: A summary of the 17th Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XVII). II. Drugs in more advanced clinical development Epilepsia . 2024 Oct;65(10):2858-2882. doi: 10.1111/epi.18075.
2. Gunthorpe MJ, Large CH, Sankar R. The mechanism of action of retigabine (ezogabine), a first-in-class K+ channel opener for the treatment of epilepsy Epilepsia . 2012 Mar;53(3):412-24. doi: 10.1111/j.1528-1167.2011.03365.x.
3. French JA, Porter RJ, Perucca E, Brodie MJ, Rogawski MA, Pimstone S, et al. Efficacy and safety of XEN1101, a novel potassium channel opener, in adults with focal epilepsy: a phase 2b randomized clinical trial. JAMA Neurol. 2023;80(11):1145–54.
4. French JAm Porter RJ, Perucca E, Brodie MJ Rogawski MA et al. Interim analysis of the long-term efficacy and safety of azetukalner in an ongoing open-label extension study following a phase 2b clinical trial (X-TOLE) in adults with focal epilepsy Epilepsia Open. 2025 Apr;10(2):539-548. doi: 10.1002/epi4.70015.
5. Sourbron J, Lagae L. Fenfluramine: a plethora of mechanisms? Front Pharmacol. 2023 May 12;14:1192022. doi: 10.3389/fphar.2023.1192022
References
6. Gutafson A, King C, Rey JA. Lorcaserin (Belviq)A Selective Serotonin 5-HT2C Agonist In the Treatment of Obesity Pharmacy and Therapeutics. 2013 Sep;38(9):525-530, 534.
7. Ren A, Zhu Z, Lehmann J, Kasem M, Schrader TO, Dang H et al. Diazepine Agonists of the 5‑HT2C Receptor with Unprecedented Selectivity: Discovery of Bexicaserin (LP352). J. Med. Chem. 2025, 68, 10599−10618 https://doi.org/10.1021/acs.jmedchem.4c02923
8. Kaye R, Orevillo C, Dlugos DJ, Scheffer IE. Efficacy and safety of bexicaserin (LP352) in adolescents and adult participants with developmental and epileptic encephalopathies: Results of the phase 1B/2A pacific study. In 76th Annual Meeting of the American Academy of Neurology, April 13−18, 2024, Denver, CO, 2024
9. Nishi T, Kondo S, Miyamoto M, Watanabe S, Hasegawa S, Kondo S, et al. Soticlestat, a novel cholesterol 24-hydroxylase inhibitor shows a therapeutic potential for neural hyperexcitation in mice. Sci Rep. 2020;10(1):17081
10. Kondo S, Murthy V, Asgharnejad M, Benitez A, Nakashima K, Hawkins N, White HS. A review of the putative antiseizure and antiepileptogenic mechanisms of action for soticlestat. Epilepsia. 2025 May;66(5):1394-1405. doi: 10.1111/epi.18287.
11. Hahn CD, Jiang Y, Villanueva V, Zolonowska M, Arkilo D et al. A phase 2, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of soticlestat as adjunctive therapy in pediatric patients with Dravet syndrome or Lennox-Gastaut syndrome. (ELEKTRA) Epilepsia. 2022 Oct;63(10):2671-2683. doi: 10.1111/epi.17367.