Phenylbutyrate for Neurodevelopmental Disorders

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

50 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is testing glycerol phenylbutyrate, a medication that helps brain proteins work better, in children with severe genetic epilepsy and developmental delays. The goal is to see if it is safe and effective for these children.

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.

What data supports the effectiveness of the drug Glycerol Phenylbutyrate for neurodevelopmental disorders?

Glycerol phenylbutyrate has been shown to effectively control ammonia levels in children with urea cycle disorders, which suggests it may help manage conditions related to ammonia imbalance. ^{1 2 3 4 5}

Is glycerol phenylbutyrate safe for humans?

Glycerol phenylbutyrate (GPB) has been studied for safety in both healthy adults and those with liver conditions, showing satisfactory safety results. However, some side effects have been reported, including loss of appetite, nausea, and abdominal pain, which may require discontinuation of the treatment in certain cases. ^{3 4 5 6 7}

How is the drug glycerol phenylbutyrate unique for neurodevelopmental disorders?

Glycerol phenylbutyrate is unique because it is a liquid triglyceride pro-drug that is converted in the body to phenylbutyric acid, which helps remove waste nitrogen by forming a compound that is excreted in urine. Unlike other treatments, it does not contain sodium, making it potentially more palatable and safer for long-term use. ^{2 4 6 8 9}

Research Team

Zachary Grinspan, MD

Principal Investigator

Weill Medical College of Cornell University

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

References

1. United States pubmed.ncbi.nlm.nih.gov

Sodium Phenylbutyrate and Taurursodiol: A New Therapeutic Option for the Treatment of Amyotrophic Lateral Sclerosis. [2023]

2. United States pubmed.ncbi.nlm.nih.gov

Glycerol phenylbutyrate treatment in children with urea cycle disorders: pooled analysis of short and long-term ammonia control and outcomes. [2022]

3. China pubmed.ncbi.nlm.nih.gov

[Preliminary study of glyceryl phenylbutyrate therapy for Ornithine transcarbamylase deficiency and a literature review]. [2023]

4. United States pubmed.ncbi.nlm.nih.gov

Ammonia control in children ages 2 months through 5 years with urea cycle disorders: comparison of sodium phenylbutyrate and glycerol phenylbutyrate. [2021]

5. United States pubmed.ncbi.nlm.nih.gov

Severe loss of appetite and refusal to eat as severe side effect of glycerol phenylbutyrate. [2022]

6. United States pubmed.ncbi.nlm.nih.gov

Pharmacology and safety of glycerol phenylbutyrate in healthy adults and adults with cirrhosis. [2021]

7. United States pubmed.ncbi.nlm.nih.gov

Acute poisoning from gamma-hydroxybutyrate in California. [2018]

8. United States pubmed.ncbi.nlm.nih.gov

Pharmacokinetics of glycerol phenylbutyrate in pediatric patients 2 months to 2 years of age with urea cycle disorders. [2019]

9. United States pubmed.ncbi.nlm.nih.gov

Ammonia control and neurocognitive outcome among urea cycle disorder patients treated with glycerol phenylbutyrate. [2021]