4-Phenylbutyrate for STXBP1 and SLC6A1. Safety, tolerability, seizure, and EEG outcomes. A case series at 2 centers

ABSTRACT Introduction Pathogenic mutations in STXBP1 and SLC6A1 can cause developmental delay and epilepsy. 4-phenylbutyrate (4PB), a drug used for urea cycle disorders, rescues dysfunction in pre-clinical models for both genes, suggesting an opportunity for drug repurposing. Methods We conducted a single-treatment group, multiple-dose, open-label study of 4PB (as glycerol phenylbutyrate) in children with pathogenic STXBP1 and SLC6A1 mutations at two centers ( NCT04937062 ). Enrolled participants were monitored for 4 weeks (baseline) then received 4PB for 10 weeks, with an option for extended use. Endpoints were safety and tolerability (primary) as well as seizure burden, EEG abnormalities, quality of life, development, behavior, and sleep (exploratory). We report safety, tolerability, EEG, and seizure outcomes. Results We enrolled 20 children (10 STXBP1, 10 SLC6A1; median age 5 years, absolute range 4 months to 11 years; 14 males; all White, 2 Hispanic). There were six serious adverse events, one attributed to 4PB (hospitalization for metabolic acidosis). Other common adverse events included a honey-like odor, sedation, and anorexia. After one participant initially withdrew for metabolic acidosis (SLC6A1), 18 of the 19 remaining participants opted for extended use. Of these 18, 17 (94%) continued 4PB within 10% of the target dose (11.2 mL/m^2/day) at the last clinical visit (2-3 years). At baseline, every child had abnormal EEG findings (seizures, paroxysmal or generalized slowing, or epileptiform discharges). For STXBP1, EEG improvements after one year of 4PB include (1) six with EEG seizures before 4PB versus two after and (2) nine with epileptiform discharges on initial EEGs versus four after. For SLC6A1, there was no clear pattern of EEG evolution. After 10 weeks of 4PB, seizures (or spells) were reduced in STXBP1 for six (60%), and in SLC6A1 for seven (70%). Seizure outcomes at the last visit were as follows. For STXBP1, three children were seizure-free and six had seizures daily to monthly; for SLC6A1, eight had sustained reduction in seizures, typically with seizure freedom and brief relapses that resolved after weight adjustment of the 4PB dose. Conclusion This case series found 4PB was safe and well-tolerated and reduced seizures for STXBP1 and SLC6A1 disorders. KEY POINTS Question Is 4-phenylbutyrate (4PB; a drug used for urea cycle disorders) safe, tolerable, and effective for people with developmental delay and seizures due to mutations in STXBP1 or SLC6A1? Findings In a single-treatment group, multiple-dose, open-label study of 4PB at two centers, treatment of 20 children (10 STXBP1 and 10 SLC6A1) with 4PB (as glycerol phenylbutyrate) was safe (no new side effects) and well tolerated (19 enrolled in extended use). For both disorders, seizures improved in the short term (6 STXBP and 7 SLC6A1 with fewer seizures after 6 weeks) and long term (3 STXBP1 and 8 SLC6A1 with sustained seizure reduction after 2-3 years of use). Meaning 4PB is a safe and well-tolerated repurposed drug that may improve seizure control in STXBP1 and SLC6A1.