Antiseizure medication safe across age groups in early LGS trial
Findings helped guide dose selection for ongoing Phase 3 study of Carisbamate
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A doctor sits at a desk across from a young patient and their parent. (Photo by iStock)
Carisbamate, an experimental oral therapy for the treatment of seizures in people with Lennox-Gastaut syndrome (LGS), was generally safe and well-tolerated in children, adolescents, and adults with the disease, according to data from a Phase 1 safety study.
The antiseizure medication also showed consistent pharmacokinetics, or how the drug is absorbed, distributed, and cleared by the body, across age groups. These findings helped guide dose selection for an ongoing Phase 3 trial, dubbed DISCOVER (NCT05219617), which is currently recruiting participants at several dozen sites worldwide.
DISCOVER is testing carisbamate’s long-term safety and ability to reduce the frequency of seizures in people ages 4 to 55 with the severe form of epilepsy.
“This phase 1 study provided the first characterization of the [pharmacokinetics], safety, and tolerability of carisbamate oral suspension in pediatric and adult patients 6 [to] 52 years old with LGS,” researchers wrote.
The study, “Carisbamate treatment of adult and pediatric patients with Lennox-Gastaut syndrome: A phase 1 pharmacokinetic, safety, and tolerability study,” was published in Epilepsy Research. It was funded by SK Life Science, a subsidiary of SK Biopharmaceuticals, which is developing the oral therapy.
Carisbamate helps control nerve cell firing that causes seizures
LGS is a severe form of epilepsy that usually begins in early childhood. It is marked by multiple types of seizures that are often difficult to control, along with a range of developmental issues. Although several antiseizure medications are approved for LGS, many patients continue to experience seizures despite taking multiple treatments, highlighting the need for safer and more effective options.
Carisbamate, formulated as an oral liquid, is designed to block certain sodium channels on the surface of nerve cells that help them generate electrical signals. By preventing sodium from entering the cells, carisbamate helps control excessive, synchronized nerve cell firing that causes seizures.
Earlier studies in healthy adults and older volunteers found that the therapy was rapidly absorbed and behaved predictably in the body. In adults with treatment-resistant focal epilepsy, or seizures that originate in one area of the brain, carisbamate also significantly reduced seizure frequency when given as an add-on therapy.
“Before undertaking large-scale efficacy trials in the LGS population, it was necessary to assess the pharmacokinetic (PK) profile of carisbamate across different age groups of patients with LGS,” the researchers wrote.
Oral therapy was rapidly absorbed in all participants
In this study, a team of researchers reports the results of a Phase 1 safety study (NCT03731715) involving 18 people with LGS, of whom eight were adults (18 years and older), three were adolescents (12-17), and seven were children (6-11). The main study’s goal was to evaluate carisbamate’s pharmacokinetics and assess its short-term safety and tolerability.
Participants received a single oral dose of carisbamate — 200 mg for adults, 140 mg for adolescents, and 60 mg for children — followed by 14 days of twice-daily treatment at half those doses. Afterward, doses could be adjusted based on each participant’s tolerance to the treatment.
Overall, 16 participants (88.9%) completed the study. Carisbamate was generally well tolerated, with about two-thirds of participants (66.7%) experiencing at least one treatment-emergent side effect, most of which were mild or moderate in severity.
Two participants discontinued treatment early: one because of treatment-related sedation, and another because of worsening behavioral problems.
No serious treatment-related adverse events or deaths were reported, and researchers found no clinically meaningful changes in laboratory tests, heart rhythm, or vital signs.
The drug’s pharmacokinetics appear linear and predictable across a broad age range, simplifying dose selection, and the safety profile observed in this small, short-term study suggests that carisbamate may be administered to LGS patients with acceptable tolerability.
After a single dose, blood samples from all 18 participants showed that carisbamate was rapidly absorbed, reaching peak levels in the bloodstream within 1.1 to 1.5 hours across all age groups. Drug exposure increased predictably with increasing doses, although children cleared the medicine somewhat faster than adolescents and adults.
After two weeks of twice-daily treatment, blood samples from the 16 participants who remained in the study showed that carisbamate had reached stable blood levels. Drug exposure remained proportional to the administered dose and, after accounting for dose differences, was similar among children, adolescents, and adults, indicating a consistent pharmacokinetic profile across age groups.
“The drug’s pharmacokinetics appear linear and predictable across a broad age range, simplifying dose selection, and the safety profile observed in this small, short-term study suggests that carisbamate may be administered to LGS patients with acceptable tolerability,” the researchers wrote, adding that such findings have directly informed the design of DISCOVER.
Participants in DISCOVER will be assigned to receive either carisbamate or a placebo as an add-on to their existing treatment regimen for a little over three months, after which all will be transitioned to carisbamate. The study’s main goal is to evaluate changes in the frequency of drop seizures, a seizure type that can cause falls.
