Phenylbutyrate for Monogenetic Developmental and Epileptic Encephalopathy

Launched by WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY · Jun 21, 2021

Keywords

ClinConnect Summary

This is an early, two-arm pilot study testing a medicine called glycerol phenylbutyrate (Ravicti) for children and teens with single-gene brain disorders that cause epilepsy and developmental problems—specifically STXBP1 encephalopathy (STXBP1-E), SLC6A1 neurodevelopmental disorder (SLC6A1-NDD), and other monogenetic developmental epileptic encephalopathies. The study is non-randomized and open-label, meaning all participants receive the drug and there is no placebo. It aims to see if the drug is safe and tolerable and to gather early data that could help with future trials. Up to about 50 children are planned: roughly 10 with STXBP1-E, 10 with SLC6A1-NDD, and 30 with other monogenetic DEEs, at sites in Colorado and New York.

Who can join and what to expect: eligibility depends on the specific group. Children up to 17 years old (and in some groups from infancy) with a confirmed single-gene cause of their developmental epileptic encephalopathy may be considered, provided they meet safety checks (for example, normal liver and kidney labs, a normal heart rhythm, and the ability to have informed consent). For the STXBP1-E group, seizures in the past 30 days are typical entry criteria; for SLC6A1-NDD and other monogenetic DEEs, the seizure pattern can be different. Each participant receives glycerol phenylbutyrate for a set period (about 14 weeks for the two gene groups or 20 weeks for the broader monogenic group) with a dosing plan given three times daily by mouth or via a feeding tube, and there’s a follow-up period after stopping the drug. The study will monitor safety (any adverse events, vital signs, labs, EEG changes, and seizures), how well participants stick with the treatment, and the drug’s blood level. If safety and care teams agree, families may choose to extend use of the medicine through 2025 with periodic check-ins. Results are not yet available, as this is an ongoing trial.

Gender

ALL

Eligibility criteria

• • ###### STXBP1 / SLC6A1 ARM
• 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, 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
• • ###### MONOGENETIC DEE ARM Inclusion Criteria
• • Diagnosed with a monogenic developmental and epileptic encephalopathy; confirmed by laboratory report (i.e., a genetic test with a pathogenic or likely pathogenic mutation of a monogenic developmental and epileptic encephalopathy and a clinical picture consistent with the disorder, as determined by the Investigator). Children with the appropriate clinical picture, a de novo variant of uncertain significance in a monogenic developmental and epileptic encephalopathy will also be eligible for enrollment, at the discretion of the Investigator. If the mutant is classified as definitively non-pathogenic, we would not enroll the child. "Appropriate clinical picture" is at the discretion of the Investigator.
• • Is between 0 months and 15 years of age, inclusive.
• • 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.)
• • Is in general good health, aside from neurological consequences of their monogenic developmental and epileptic encephalopathy, 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.
• • 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, 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