Phenylbutyrate for Neurodevelopmental Disorders

Not currently recruiting at 1 trial location

Overseen By Natasha Basma, MPH

Age: < 18

Sex: Any

Trial Phase: Phase < 1

Sponsor: Weill Medical College of Cornell University

Must not be taking: Alfentanil, Quinidine, Cyclosporine, Probenecid

Disqualifiers: Pregnancy, Beta oxidation errors, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 4

Duration: 8-12 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether a medication called phenylbutyrate (specifically, glycerol phenylbutyrate) can help children with certain genetic conditions that cause epilepsy and developmental delays. These conditions, such as STXBP1 and SLC6A1, occur because the body doesn't produce enough of certain proteins. The trial aims to determine if phenylbutyrate can enhance the function of the existing proteins. Children eligible for this trial must have a confirmed diagnosis of STXBP1 or SLC6A1 and have experienced at least one seizure in the past month. As an Early Phase 1 trial, this research focuses on understanding how the treatment works in children, providing an opportunity to explore its potential benefits.

Will I have to stop taking my current medications?

You may need to stop taking certain medications before joining the trial. Specifically, if you are taking alfentanil, quinidine, cyclosporine, or probenecid, you must stop at least one week before enrolling. For other medications, the trial protocol does not specify, so it's best to discuss with the study team.

Is there any evidence suggesting that glycerol phenylbutyrate is likely to be safe for humans?

Research has shown that the FDA has approved glycerol phenylbutyrate for treating urea cycle disorders, where it helps lower ammonia levels in the blood. This approval indicates the drug is considered reasonably safe for those conditions. The newer version of the drug is also easier for patients to tolerate.

However, limited information exists about using this drug for treating certain genetic forms of epilepsy known as developmental epileptic encephalopathies (DEEs). Since this treatment is still in the early testing stages for DEEs, researchers are studying its safety for these specific conditions. Early trials typically focus on finding the right dose and ensuring safety for patients.

So far, reports of serious side effects have not emerged, but a clearer understanding of its safety for DEEs will develop as ongoing studies collect more data. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for DEEs?

Glycerol Phenylbutyrate is unique because it offers a novel approach to treating neurodevelopmental disorders like monogenetic epileptic encephalopathy, SLC6A1, and STXBP1. Unlike traditional anti-seizure medications that primarily work by stabilizing electrical activity in the brain, Glycerol Phenylbutyrate targets metabolic pathways, potentially offering benefits for patients with specific genetic mutations. Researchers are especially excited because it may provide a more tailored treatment option, potentially reducing seizures and improving cognitive functions with fewer side effects. This focus on metabolic intervention could represent a significant shift from the typical neuro-centric treatments currently available.

What evidence suggests that glycerol phenylbutyrate might be an effective treatment for monogenetic developmental epileptic encephalopathies?

Research has shown that glycerol phenylbutyrate might help reduce seizures in some genetic epilepsy conditions. This trial will enroll participants in different arms to study its effects on specific disorders. Early studies suggest it could be effective for disorders like STXBP1 and SLC6A1, caused by gene changes that result in too few working proteins. Phenylbutyrate may enhance the function of the remaining working proteins. This approach is promising, especially for children with these gene changes, as it might lower or even stop their seizures. Although this research remains in the early stages, the initial results are encouraging. ^{1 2 4 5 6}

Who Is on the Research Team?

Zachary Grinspan, MD

Principal Investigator

Weill Medical College of Cornell University

Are You a Good Fit for This Trial?

This trial is for children aged 2 months to 17 years with specific genetic disorders causing epilepsy and developmental delays, such as STXBP1 Encephalopathy or SLC6A1 neurodevelopmental disorder. Participants need a confirmed diagnosis through genetic testing, normal heart rhythm on an EKG, and good kidney function. They should be in stable health apart from their neurological condition.

Inclusion Criteria

I have SLC6A1-NDD, but seizures are not a main concern for my condition.

Your heart's electrical activity measured on a test is less than 450 milliseconds.

I am between 2 months and 17 years old.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Baseline

Participants undergo baseline assessments before starting treatment

4-5 weeks

1 visit (in-person)

Treatment

Participants receive glycerol phenylbutyrate for drug exposure

8-12 weeks

2 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 weeks

1 visit (in-person)

Extended Use (optional)

Participants may continue to receive the study medication up to December 2025

Long-term

Quarterly video visits, yearly in-person visit

What Are the Treatments Tested in This Trial?

Interventions

• Glycerol Phenylbutyrate

Trial Overview The study tests the safety and tolerability of glycerol phenylbutyrate (Ravicti) in treating monogenetic developmental epileptic encephalopathies (DEEs). It aims to see if this medication can enhance the functioning of proteins affected by these genetic conditions.

How Is the Trial Designed?

Group I: SLC6A1 and STXBP1 Experimental Treatment 1 Intervention

Each participant will be enrolled for 14 weeks (4 weeks baseline, 8 weeks of drug exposure, and 2 weeks follow-up). After clinical assessment by the investigator if deemed safe and appropriate, and requested by the caregiver, participants may continue to receive the study medication ("extended use"), up to December 2025. Participants who remain on phenylbutyrate therapy will be followed quarterly through video visits, and yearly in-person visit. Participants who do not opt to remain on phenylbutyrate therapy will be weaned off the medication during the 2 week follow-up period.

Group II: Monogenetic Epileptic Encephalopathy Experimental Treatment 1 Intervention

Each participant will be enrolled for 20 weeks (5 weeks baseline, 12 weeks of drug exposure, and 2 weeks follow-up) . After clinical assessment by the investigator if deemed safe and appropriate, and requested by the caregiver, participants may continue to receive the study medication ("extended use"), up to December 2025. Participants who remain on phenylbutyrate therapy will be followed quarterly through video visits, and yearly in-person visit. Participants who do not opt to remain on phenylbutyrate therapy will be weaned off the medication during the 2 week follow-up period.

Who Is Running the Clinical Trial?

Weill Medical College of Cornell University

Lead Sponsor

Trials

1,103

Recruited

1,157,000+

University of Pennsylvania Orphan Disease Center

Collaborator

Trials

1

Recruited

50+

Horizon Therapeutics

Collaborator

Trials

1

Recruited

50+

Clara Inspired

Collaborator

Trials

1

Recruited

50+

Children's Hospital Colorado

Collaborator

Trials

121

Recruited

5,135,000+

SLC6A1 Connect

Collaborator

Trials

1

Recruited

50+

STXBP1 Foundation

Collaborator

Trials

2

Recruited

450+

Published Research Related to This Trial

A report on 5 patients in California revealed that illicitly marketed gamma-hydroxybutyrate (GHB) can cause adverse reactions such as drowsiness, dizziness, and nausea, but no deaths were reported, and all patients fully recovered without long-term effects.

Despite being banned by the FDA, GHB remains available in the underground market, particularly among athletes seeking performance enhancement, highlighting the need for physicians to recognize signs of GHB poisoning in patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acute poisoning from gamma-hydroxybutyrate in California. Chin, MY., Kreutzer, RA., Dyer, JE.[2018]

Sodium phenylbutyrate and taurursodiol (SP + T) have been shown to slow the progression of amyotrophic lateral sclerosis (ALS), with a significant reduction in the rate of decline in functional ability compared to placebo, as evidenced by a phase II trial involving an open-label extension phase.

Patients receiving SP + T experienced a median survival benefit of 4.8 months compared to those on placebo, highlighting its potential as a new treatment option for ALS, although further phase III trials are needed to confirm its long-term safety and efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sodium Phenylbutyrate and Taurursodiol: A New Therapeutic Option for the Treatment of Amyotrophic Lateral Sclerosis. Alqallaf, A., Cates, DW., Render, KP., et al.[2023]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04937062

Study Details | NCT04937062 | Phenylbutyrate for ... This study is to evaluate the use of glycerol phenylbutyrate for monogenetic developmental epileptic encephalopathies (DEEs).

2. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0920121125001226

Phenylbutyrate for monogenetic epilepsy: Literature review Preclinical data suggests that 4-phenylbutyrate (PBA) may produce an anti-seizure effect in individuals with genetic epilepsies.

3. stxbp1disorders.org stxbp1disorders.org/clinicaltrialsandresearch

Clinical Trials and Observational Studies Below is a list of current or planned clinical trials involving STXBP1 disorders. For a general overview of clinical trials click here.

4. aesnet.org aesnet.org/abstractslisting/4-phenylbutyrate-for-children-with-stxbp1-and-slc6a1-mutations---a-pilot-clinical-trial

4-phenylbutyrate-for-Children-with-STXBP1-and-SLC6A1 ... 4-phenylbutyrate is a promising approach to reduce or eliminate seizures in children with pathogenic mutations of STXBP1 or SLC6A1.

5. centerwatch.com centerwatch.com/clinical-trials/listings/NCT04937062/phenylbutyrate-for-monogenetic-developmental-and-epileptic-encephalopathy

Phenylbutyrate for Monogenetic Developmental and ... This study is to evaluate the use of glycerol phenylbutyrate for monogenetic developmental epileptic encephalopathies (DEEs).

6. medrxiv.org medrxiv.org/content/10.1101/2024.11.06.24316676v2.full.pdf

4-Phenylbutyrate for STXBP1 and SLC6A1. Safety, ... Pathogenic mutations in STXBP1 and SLC6A1 can cause developmental delay and epilepsy. 4- phenylbutyrate (4PB), a drug used for urea cycle ...