Authors :
Presenting Author: Millie Stone, BA – Weill Cornell Medicine
Kelly Knupp, MD, MSCS, FAES – University of Colorado, Anschutz Medical Campus
Scott Demarest, MD – Children's Hospital Colorado
Jennifer Cross, MD – Weill Cornell
Andrea Miele, PhD – Children's Hospital Colorado
Maria Abila, BS – Childrens Hospital Colorado
Carla Cobos-Hernandez, BS – Children's Hospital Colorado
Natasha Basma, MPH – Weill Cornell Medicine
Natalie Wayland, BS – Weill Cornell Medicine
Zachary Grinspan, MD, MS – Cornell Weill Medicine
Rationale: Children with monogenic developmental and epileptic encephalopathies often have seizures that are refractory to antiseizure medications. Early clinical reports have found that phenylbutyrate, an FDA-approved drug for urea cycle disorders, improves seizure control for children with SLC6A1- and STXBP1-related epilepsy. Unpublished pre-clinical data suggests phenylbutyrate may improve seizures for children with SCN1A mutations. We hypothesized that phenylbutyrate would also improve clinical outcomes in children with Dravet Syndrome attributed to variants in SCN1A.
Methods: We enrolled children with Dravet Syndrome due to SCN1A variants in an open-label, multiple-dose study to test the safety and preliminary effectiveness of glycerol phenylbutyrate as part of an ongoing study (NCT04937062). After 5 weeks of baseline seizure frequency assessment, each child received an initial dose of glycerol phenylbutyrate during an inpatient EEG admission for 3 days and 2 nights. The children then titrated up to the goal dose of 11.2 mL/m2/day in the outpatient setting. After 12 weeks of taking glycerol phenylbutyrate, each child returned for a 24-hour video EEG. Here we report preliminary assessments of the clinical effect of glycerol phenylbutyrate on seizure frequency.
Results:
Six children with Dravet Syndrome, three female, aged 4 to 13 years were enrolled. One participant had a dramatic reduction in seizures ( >80%). Five participants had a transient response or no response. Two patients were hospitalized for metabolic acidosis. Other common, less serious side effects included a honey-like body odor, fatigue, and loss of appetite.
Conclusions: Glycerol phenylbutyrate is well-tolerated, but acidosis can lead to hospitalization in vulnerable children. The drug was associated with seizure frequency improvement (80% reduction) for one of six (17%) treated children with Dravet Syndrome due to SCN1A. This response rate is lower than observed for children with SLC6A1 (70%) and STXBP1 (60%). Analysis of effects on development is ongoing.
Funding: This study is funded by Weill Cornell Medicine and Amgen.