P4A039: 4-phenylbutyrate for Children with STXBP1 and SLC6A1 Mutations - A Pilot Clinical Trial

Background: Mutations in STXBP1 and SLC6A1 are both highly associated with developmental delay and epilepsy. Preclinical data for both STXBP1 and SLC6A1 indicate that 4-phenylbutyrate can stabilize protein function. We launched a pilot clinical trial (NCT04937062) to administer glycerol phenylbutyrate to 20 children (10 with each disorder).

Methods: This was a single treatment group, multiple-dose, open-label, pilot study to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of glycerol phenylbutyrate in children with STXBP1 encephalopathy and SLC6A1 neurodevelopmental disorder at two centers: Weill Cornell Medicine and Children's Hospital Colorado. Each participant was enrolled for 14 weeks (4 weeks baseline, 10 weeks of drug exposure), with an option for ongoing extended use. The primary endpoints were safety and tolerability. Exploratory clinical outcomes include seizure burden, EEG abnormalities, abnormal movements, quality of life, development, behavior, sleep, and caregivers’ qualitative experiences. Here we report initial impressions of 6-week developmental outcomes. Developmental profiles of each child pre- and post- treatment with glycerol phenylbutyrate were measured using the Vineland Adaptive Behavior Scales 3rd Edition Parent/Caregiver report and direct evaluation by a developmental pediatrician or neuropsychologist using developmental assessment tools tailored to the age and developmental level of the patient.

Results: Twenty children were enrolled (10 STXBP1, 10 SLC6A1), aged 4 months to 11 years, 14 boys and 6 girls, 18 White and 2 Hispanic. Most of the children with STXBP1 related disorder were severely to profoundly cognitively delayed and so standardized testing with age appropriate measures was not possible. While they were able to complete measures meant for children at their developmental level, only raw scores, age equivalents and growth scale values are available for analysis. Children with STXBP1 related disorder were largely nonverbal with limited language comprehension, though in some eye contact was strong and they made their wants known with noises or physical contact. Motor skills varied from non-ambulatory to very active. In contrast all children with the SLC6A1- related disorder were verbal, ambulatory and able to complete IQ testing and often academic and fine motor measures as well. Qualitatively, most parents saw improvement in seizure frequency and an improvement in level of alertness and awareness. There was no reported developmental regression. Ongoing analysis will include quantitative assessments, including six week and 1-year outcomes.

Conclusion: Early clinical experience suggests 4-phenylbutyrate has no negative effects on development in children with STXBP1 and SLC6A1, though quantitative analysis is ongoing. Our experience highlights that future drug repurposing trials of interventions for developmental encephalopathies will benefit from instruments that measure a wide range of abilities. Full results are pending trial completion.