4-phenylbutyrate for Children with STXBP1 and SLC6A1 Mutations - A Pilot Clinical Trial
Abstract number :
1.287
Submission category :
7. Anti-seizure Medications / 7B. Clinical Trials
Year :
2022
Submission ID :
2204919
Source :
www.aesnet.org
Presentation date :
12/3/2022 12:00:00 PM
Published date :
Nov 22, 2022, 05:27 AM
Authors :
Zachary Grinspan, MD, MS – Weill Cornell Medicine; Maria Abila, NA – Children's Colorado; Natasha Basma, MPH – Research Coordinator, Weill Cornell Medicine; Jacqueline Burré, PhD – Weill Cornell Medicine; Jennifer Cross, MD – Weill Cornell Medicine; Scott Demarest, MD – Children's Hospital Colorado; Margaret Elizabeth Ross, MD – Weill Cornell Medicine; Kerry Gao, NA – Clinical Research Assistant, Weill Cornell Medicine; Alexandra Mackie, NA – Childrens Hospital Colorado; Elizabeth Dubow, MD – Children's Colorado
Rationale: Mutations in STXBP1 and SLC6A1 each can lead to developmental delay and epilepsy. Preclinical data for both STXBP1 and SLC6A1 indicate that 4-phenylbutyrate can increase protein function. 4-phenylbutyrate crosses the blood-brain barrier and may act as a chemical chaperone (i.e., by modulating the toxic effects of the unfolded protein response, reducing aberrant protein aggregation, or improving protein trafficking). Glycerol phenylbutyrate is an FDA-approved medication indicated to reduce blood ammonia levels in people with urea cycle disorders. 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, and pharmacodynamics 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 1 year of extended use. The primary endpoints were safety and tolerability. Exploratory clinical outcomes included seizure burden, EEG abnormalities, abnormal movements, quality of life, development, behavior, sleep, and caregivers’ qualitative experiences. We report interim safety outcomes for all enrolled children, and interim seizure frequency outcomes for children with seizures at enrollment and at least 10 weeks of exposure. We classified a child with 50% or more seizure reduction clinically attributable to the study drug as a “responder.” If a child’s seizures improved, but the improvement was less than 50% or more likely due to a different intervention, we classified the response as “indeterminate.” If seizures worsened or stayed the same, we classified the child as a “non-responder.”
Results: Twenty children were enrolled (10 STXBP1, 10 SLC6A1), aged 4 months to 11 years, 14 boys and 6 girls, 20 White and 2 Hispanic. Common side effects include somnolence, loss of appetite, and a honey-like body odor. One serious adverse event was probably related to the study drug: a child was admitted to the hospital for metabolic acidosis, a known side effect of glycerol phenylbutyrate, which resolved upon discontinuation of the medication. Ten children had seizures and at least 10 weeks of exposure. Of these 10, 6 were responders, 2 indeterminate, and 2 non-responders (Table).
Conclusions: Early clinical experience suggests that 4-phenylbutyrate is a promising approach to reduce or eliminate seizures in children with pathogenic mutations of STXBP1 or SLC6A1. Full results are pending trial completion.
Funding: Orphan Disease Center at the University of Pennsylvania, SCL6A1 Connect, STXBP1 Foundation, Clara Inspired
Anti-seizure Medications