Clinical Responses to Off-Label Use of Phenylbutyrate for STXBP1 and SLC6A1
Clinical Genetics and Therapeutics
-
Primary Categories:
- Clinical- Pediatric
-
Secondary Categories:
- Clinical- Pediatric
Introduction:
Epileptic encephalopathies are associated with early onset epilepsy and intellectual disability. Data from preclinical models suggests a repurposed therapeutic, phenylbutyrate, may treat seizures in STXBP1 and SLC6A1 related encephalopathies (Lewis Guiberson et al., 2018; Nat Commun; Nwosu et al., 2022; Brain Commun). Phenylbutyrate is a chemical chaperone that is thought to work by improving cell membrane trafficking, protein function and stability, and GABA uptake in the brain. Subsequent preclinical research suggests phenylbutyrate may be used for a broader group of genetic epileptic encephalopathies (Shen et al., 2024; Epilepsia).
The first study in humans was recently published and demonstrated safety and improved seizure control in children with STXBP1 and SLC6A1 (Grinspan et al., Nov 8, 2024; medRxiv preprint). Phenylbutyrate is currently approved for the treatment of urea cycle disorders and clinicians have started prescribing it off-label for STXBP1 and SLC6A1. Little is known about these experiences. The purpose of the current study is to understand real-world experiences using phenylbutyrate for genetic encephalopathies.
Methods:
Children (age 0-17 years) treated with phenylbutyrate for STXBP1 or SLC6A1 were enrolled in an observational study to understand their experiences using phenylbutyrate. Parents participated in a phone interview with a child neurologist and described their child’s clinical responses and adverse effects.
Results:
Fifteen children (7 males) participated in the study with a median age when starting phenylbutyrate of 5.8 years (interquartile range = 3.7-7.4). Ten (67%) had STXBP1 and 5 (33%) had SLC6A1. All had developmental delays and 13 (87%) had epilepsy.
Of the 13 children with epilepsy, 8 (62%) had improved seizure control and 4 (31%) were able to stop or decrease at least one antiseizure medication. All families noticed improved development after starting phenylbutyrate, including improvements in social behaviors (13/15), gross motor (7/15), fine motor (6/15), expressive language (7/15), and receptive language (8/15). In addition, families noted improvements in attention/ engagement in therapies (12/15), sleep (6/15), and mood (6/15). Clinical improvements were noticed in the first 1-3 weeks after starting phenylbutyrate.
Adverse effects included odor (11/15), somnolence (8/15), decreased appetite (7/15), nausea (6/15), constipation (3/15), diarrhea (1/15), rash (1/15), ataxia (1/15), metabolic acidosis (1/15), and increased seizures (1/15). Phenylbutyrate was stopped for 3/15 children due to adverse effects - one because of hospitalization for metabolic acidosis, another due to increase in seizures, and a third due to constipation. Of the 12 who continued phenylbutyrate, nearly all (11/12) had resolution of adverse effects after an initial adjustment period around 2-10 days. One had constipation that persisted and was well controlled with a laxative.
Clinicians gradually uptitrated doses in 1 week or longer intervals to reach a maximum goal dose of 11.2 mL/m2/day. Some reached their goal dose in 1 month and others more gradually over several months. Many preferred 3 times a day dosing but this varied from 2-6 times per day.
Conclusion:
The current study evaluates the off-label use of phenylbutyrate for STXBP1 and SLC6A1. Early clinical experiences suggest improved seizure control and a well-tolerated side effect profile consistent with data from a recently published clinical trial (Grinspan et al., Nov 8, 2024; medRxiv preprint). Most noticed improved seizure control and a sizable minority were able to stop or decrease other antiseizure medications. Most adverse effects were mild (odor, sedation, decreased appetite) and resolved after an initial adjustment period. Three stopped phenylbutyrate due to more serious adverse effects (metabolic acidosis, increased seizures, constipation).
All families noticed improved development, including improved engagement in therapies, social behaviors, and language. The developmental improvements are promising but need confirmation. Outcomes are limited since they relied on subjective recollections. Further research is needed with objective measurements, such as neuropsychology testing and EEG.
Epileptic encephalopathies are associated with early onset epilepsy and intellectual disability. Data from preclinical models suggests a repurposed therapeutic, phenylbutyrate, may treat seizures in STXBP1 and SLC6A1 related encephalopathies (Lewis Guiberson et al., 2018; Nat Commun; Nwosu et al., 2022; Brain Commun). Phenylbutyrate is a chemical chaperone that is thought to work by improving cell membrane trafficking, protein function and stability, and GABA uptake in the brain. Subsequent preclinical research suggests phenylbutyrate may be used for a broader group of genetic epileptic encephalopathies (Shen et al., 2024; Epilepsia).
The first study in humans was recently published and demonstrated safety and improved seizure control in children with STXBP1 and SLC6A1 (Grinspan et al., Nov 8, 2024; medRxiv preprint). Phenylbutyrate is currently approved for the treatment of urea cycle disorders and clinicians have started prescribing it off-label for STXBP1 and SLC6A1. Little is known about these experiences. The purpose of the current study is to understand real-world experiences using phenylbutyrate for genetic encephalopathies.
Methods:
Children (age 0-17 years) treated with phenylbutyrate for STXBP1 or SLC6A1 were enrolled in an observational study to understand their experiences using phenylbutyrate. Parents participated in a phone interview with a child neurologist and described their child’s clinical responses and adverse effects.
Results:
Fifteen children (7 males) participated in the study with a median age when starting phenylbutyrate of 5.8 years (interquartile range = 3.7-7.4). Ten (67%) had STXBP1 and 5 (33%) had SLC6A1. All had developmental delays and 13 (87%) had epilepsy.
Of the 13 children with epilepsy, 8 (62%) had improved seizure control and 4 (31%) were able to stop or decrease at least one antiseizure medication. All families noticed improved development after starting phenylbutyrate, including improvements in social behaviors (13/15), gross motor (7/15), fine motor (6/15), expressive language (7/15), and receptive language (8/15). In addition, families noted improvements in attention/ engagement in therapies (12/15), sleep (6/15), and mood (6/15). Clinical improvements were noticed in the first 1-3 weeks after starting phenylbutyrate.
Adverse effects included odor (11/15), somnolence (8/15), decreased appetite (7/15), nausea (6/15), constipation (3/15), diarrhea (1/15), rash (1/15), ataxia (1/15), metabolic acidosis (1/15), and increased seizures (1/15). Phenylbutyrate was stopped for 3/15 children due to adverse effects - one because of hospitalization for metabolic acidosis, another due to increase in seizures, and a third due to constipation. Of the 12 who continued phenylbutyrate, nearly all (11/12) had resolution of adverse effects after an initial adjustment period around 2-10 days. One had constipation that persisted and was well controlled with a laxative.
Clinicians gradually uptitrated doses in 1 week or longer intervals to reach a maximum goal dose of 11.2 mL/m2/day. Some reached their goal dose in 1 month and others more gradually over several months. Many preferred 3 times a day dosing but this varied from 2-6 times per day.
Conclusion:
The current study evaluates the off-label use of phenylbutyrate for STXBP1 and SLC6A1. Early clinical experiences suggest improved seizure control and a well-tolerated side effect profile consistent with data from a recently published clinical trial (Grinspan et al., Nov 8, 2024; medRxiv preprint). Most noticed improved seizure control and a sizable minority were able to stop or decrease other antiseizure medications. Most adverse effects were mild (odor, sedation, decreased appetite) and resolved after an initial adjustment period. Three stopped phenylbutyrate due to more serious adverse effects (metabolic acidosis, increased seizures, constipation).
All families noticed improved development, including improved engagement in therapies, social behaviors, and language. The developmental improvements are promising but need confirmation. Outcomes are limited since they relied on subjective recollections. Further research is needed with objective measurements, such as neuropsychology testing and EEG.
)
){kind=logo}
){kind=logo}
){kind=logo}
){kind=logo}
){kind=logo}
){kind=logo}
)
){kind=logo}
)
)
)
)
)
)
){kind=logo}
){kind=logo}
){kind=logo}