Repurposed urea drug shows promise controlling seizures in rare childhood brain disorders
A small study of children with genetic epilepsies found that phenylbutyrate, an existing medication for metabolic disorders, reduced seizures by at least 50% in 73% of cases and may improve development. The findings could accelerate treatment options for rare genetic encephalopathies and demonstrate how existing drugs can be repositioned to address unmet pediatric neurological needs.
Originaltitel: Parent-Reported Improvement in Seizure Control and Development After Phenylbutyrate Treatment in Children With STXBP1 and SLC6A1.
Fenylbutyratkandidaten växer från sällsynta epilepsiformer — en befintlig urinvägsläkemedel visar lovande resultat vid två genetiska utvecklingsencefalopatier. I en observationsstudie av 18 barn med STXBP1- och SLC6A1-mutationer rapporterade 73 procent av patienterna med okontrollerade anfalls minst 50 procent reduktion under en median behandlingstid på sex månader. Nästan alla familjer (17 av 18) observerade utvecklingsmässiga förbättringar. Mild toxicitet — sedation, minskad aptit, illamående — var vanlig initialt men löste sig inom två till tio dagar. En patient utvecklade allvarlig metabolisk acidosis och aspirationspneumoni som krävde intensivvård. Scripps Research och Karolinska institutet ledde arbetet. För bioteknikbolag och investerare är detta en möjlig väg till ny indikation för ett redan godkänt läkemedel — vilket förkortar utvecklingstiden betydligt — men säkerhetsprofilen kräver noggrann dosövervakning.
BACKGROUND: Preclinical studies and early clinical trials suggest phenylbutyrate (an FDA and European Medicines Agency-approved medication for urea cycle disorders) may improve seizure control in certain developmental and epileptic encephalopathies (DEEs). Its effect on development is unknown, and comorbidities like hypotonia may raise toxicity risks. This study examines early clinical experiences with phenylbutyrate in children with DEEs, outside the context of a clinical trial. METHODS: We conducted semistructured phone interviews with parents of children with STXBP1- and SLC6A1-encephalopathy treated with phenylbutyrate. We evaluated seizure and developmental outcomes, side effects, and toxicity. Among children with uncontrolled seizures before treatment, we defined seizure response as having a ≥50% reduction in seizures. We assessed the proportion of children experiencing clinical changes and provided narrative descriptions of these changes. RESULTS: Eighteen children (median age 6 years) were included, with a median treatment duration of 6 months. Among 11 children with uncontrolled seizures, 8 showed improvement (all with ≥50% seizure reduction), resulting in a 73% seizure response rate. Nearly all families (17/18) reported improvements in development. Mild toxicity (sedation, decreased appetite, and/or nausea) was common (14/18) at the start of phenylbutyrate treatment but typically resolved within 2-10 days. One child (1/18) had severe toxicity, with metabolic acidosis and aspiration pneumonia requiring intubation. CONCLUSIONS: Phenylbutyrate was generally well tolerated with improved seizure control and development in children with STXBP1- and SLC6A1-encephalopathy, although we observed 1 intensive care unit-level hospitalization from dose-related toxicity. These results support the use of phenylbutyrate treatment for DEEs and highlight safety considerations.