Phenylbutyrate for STXBP1 Encephalopathy and SLC6A1 Neurodevelopmental Disorder

• Status: Recruiting
• Trial end date: 2023-07-31
• Target enrollment: 0
• Participant gender: All

Summary

STXBP1 Encephalopathy is a severe disease that can cause seizures and developmental delays in infants and children. It occurs when one copy of the STXBP1 gene has a mutation that causes the gene's protein to not work properly.

SLC6A1 neurodevelopmental disorder is characterized by developmental delay and often epilepsy. It occurs when one copy of the SLC6A1 gene has a mutation that causes the gene's protein to not work properly.

Both STXBP1 encephalopathy and SLC6A1 neurodevelopmental disorder cause symptom because there are not enough working proteins made by these genes. It is possible that a medication called phenylbutyrate may help the the remaining proteins work better. This study is to test if phenylbutyrate is safe and well tolerated in children with STXBP1 encephalopathy and SLC6A1 neurodevelopmental disorder.

• Phase: Early Phase 1
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Weill Medical College of Cornell University
• Treatments: 4-phenylbutyric acid; Glycerol

Criteria

Inclusion Criteria:

• Diagnosed with STXBP1-E or SLC6A1-NDD; confirmed by laboratory report (i.e., a genetic test with a pathogenic or likely pathogenic mutation of STXBP1 or SLC6A1-NDD and a clinical picture consistent with the disorder, as determined by the Investigator). Patients with the appropriate clinical picture, a de novo variant of uncertain significance in STXBP1 or SLC6A1-NDD will also be eligible for enrollment, at the discretion of the Investigator.

• Is between 2 months and 17 years of age, inclusive.

• For children with STXBP1-E, the child must have had at least one seizure in the past 30 days prior to enrollment. If there is high demand for the study and we have several subjects to choose, we will prefer to enroll children with a high number of seizures in the past month.

• For SLC6A1-NDD, seizures occur later in the course (typically middle of 1st decade) and so seizures will not be an entry criteria.

• Is in general good health, aside from neurological consequences of STXBP1-E or SLC6A1-NDD, as determined by having no concurrent medical illness, in the opinion of the site investigator, that places the subject at increased risk of adverse drug reactions or that will interfere with study follow-up.

• Has normal laboratory test results (≤ 1.5 × upper limit of normal [ULN]) for serum aminotransferase (aspartate aminotransferas [AST] and alanine aminotransferase [ALT]) concentrations and ammonia at Screening.

• Has normal renal function, with estimated glomerular filtration rate > 90 mL/minute/1.73 m2 at Screening (using the Chronic Kidney Disease Epidemiology Collaboration equation).

• Has a platelet count > 150 × 103/μL at Screening.

• Has a QT interval corrected with Fridericia's formula (QTcF) < 450 msec on the Screening EKG.

• Parent or guardian is able to comprehend and willing to sign an informed consent form (ICF).

Exclusion Criteria:

• Has participated in another investigational study within 30 days or 5 half-lives of the test drug's biologic activity (whichever is longer) before the first study drug dose.

• Has a QT interval corrected with Fridericia's formula (QTcF) ≥ 450 msec on the Screening EKG.

• Has an active medical illness that would preclude participation in the study (as determined by the Investigator).

• Has a clinical laboratory evaluation outside of the test laboratory reference range, unless deemed not clinically significant by the Investigator and the Sponsor.

• Is unable to comply with the study protocol.

• Has poor venous access and/or cannot tolerate venipuncture.

• Is pregnant

• Is a female of child-bearing age (12 years old or older) and known to be sexually active (for example, as determined through a confidential HEADDSSS history), and not taking medication for contraception. This will be assessed confidentially as per good general pediatrics practice

• Known hypersensitivity to phenylbutyrate. Signs of hypersensitivity include wheezing, dyspnea, coughing, hypotension, flushing, nausea, and rash.

• Taking alfentanil, quinidine, cyclosporine, valproic acid or probenecid (known interactions with phenylbutyrate). For subjects who had taken any of these medications in the past, the last dose must have been taken at least 1 week prior to enrollment into the study.

• Inborn errors of beta oxidation.

• Pancreatic insufficiency or intestinal malabsorption