Phenylbutyrate for Monogenetic Developmental and Epileptic Encephalopathy

Children's Hospital Colorado, SLC6A1 Connect, STXBP1 Foundation, Clara Inspired, University of Pennsylvania Orphan Disease Center, Horizon Therapeutics

This study is to evaluate the use of glycerol phenylbutyrate for monogenetic developmental epileptic encephalopathies (DEEs). DEEs are characterized by epilepsy and developmental delay in early life. Two examples of DEEs are STXBP1 and SLC6A1, though there are dozens of others. STXBP1 Encephalopathy is a severe disease that can cause seizures and developmental delays in infants and children. SLC6A1 neurodevelopmental disorder is characterized by developmental delay and often epilepsy. Both STXBP1 encephalopathy and SLC6A1 neurodevelopmental disorder cause symptoms 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 for STXBP1, SLC6A1, and/or other similar DEEs caused by single genes (i.e. "monogenetic"). This study is to test if glycerol phenylbutyrate is safe and well tolerated in children with monogenetic DEE.

STXBP1 encephalopathy (STXBP1-E) is a devastating neurodevelopmental disorder that often begins in infancy. Intellectual disability is a core feature, often severe to profound. Nearly all have epilepsy (95% in the largest series). The epilepsy is clinically heterogeneous, and may present as a well-defined epilepsy syndrome (e.g., early infantile epileptic encephalopathy, infantile spasms, epilepsy of infancy migrating focal seizure, or Dravet syndrome) or as non-syndromic epilepsy. Seizures are refractory to medications in one third. Affected individuals may have autistic features (1 in 5), low tone, movement disorders (including ataxia and bruxism), abnormal EEGs (> 60% with focal or multifocal epileptiform discharges), and/or abnormal MRI brain imaging (atrophy, thin corpus callosum, delayed myelination). The clinical spectrum is broad -- some individuals are profoundly impaired with seizures that begin in the first days of life; whereas others may have a few seizures in late infancy and mild learning difficulties. STXBP1 knockout mice show normal early brain assembly with subsequent degeneration, decreased neurite outgrowth, and completely abolished neurotransmitter release These mice die shortly after birth. Heterozygous STXBP1 mice are similar to wild-type, except they have abnormal behaviors during sleep (twitches and jumps) and EEG abnormalities. Thus, heterozygous STXBP1 mice recapitulate some aspects of the human disease, though they have neither seizures nor overt behavioral abnormalities. Human embryonic stem cell-derived neurons engineered for STXBP1 loss of function exhibit normal initial synaptogenesis, synapse size, and soma size; however, heterozygotes show decreased neurotransmitter release corresponding to decreased STXBP1 levels, while homozygous loss of function causes significant neural degeneration. Published experiments on neuronal lines derived from affected patients show decreased STXBP1 protein, STXBP1 protein mislocalization, and decreased neurite outgrowth. Early work in heterologous cell lines demonstrated STXBP1 mutations cause protein misfolding that leads to aggregation of the mutant protein with wild-type STXBP1. In laboratory settings, stabilizing protein folding of the STXBP1 protein product with chemical chaperones rescued molecular and functional deficits in all tested models, using any of three chemical chaperones: sorbitol, trehalose, and 4-phenylbutyrate. Sorbitol and trehalose are sugars, and would be metabolized in the gut. 4-phenylbutyrate, however, is available as an FDA approved medication, either via sodium phenylbutyrate or glycerol phenylbutyrate. The glycerol formulation is better tolerated, thus this trial. SLC6A1-related neurodevelopmental disorder (SLC6A1-NDD) begins in early childhood and is characterized by epilepsy (~91%, typically generalized) and developmental delay (~82%). The epilepsy is typically generalized (absence, atonic, myoclonic, generalized tonic-clonic) though is sometimes focal. Substantial minorities have an autism spectrum disorder, movement disorder, or problems with attention or aggression. The protein product of SLC6A1 is GABA transporter protein type 1 (GAT-1), which is important for GABA homeostasis in the brain. Pathogenic mutations in SLC6A1 lead to loss of function and haploinsufficiency. Preliminary data suggests a dramatic impairment in GABA uptake in cells with homozygous variants in the GAT-1 protein, which improves with administration of phenylbutyrate. The investigators began studying phenylbutyrate for STXBP1-E and SLC6A1-NDD with a pilot study (i.e. Phase 1 study) in order to (a) understand safety and tolerability of the medication in children with STXBP1-E and SLC6A1-NDD, (b) understand the peak plasma concentrations in order to estimate CSF levels, and (c) generate exploratory information about clinical outcomes as a means to estimate effect sizes and pilot a battery of clinical testing for STXBP1-E and SLC6A1-NDD for future trials. Based on additional publications and ongoing research, the study the study has expanded in scope to (a) follow enrolled children for a longer time and (b) broaden the enrollment criteria to include monogenetic DEEs.

STXBP1 Encephalopathy With Epilepsy, SLC6A1 Neurodevelopmental Disorder, Developmental and Epileptic Encephalopathy

This is a pilot, single treatment, multiple-dose, open label, study to be conducted in up to 10 children with STXBP1-E, and 10 with SLC6A1-NDD, and 30 children with monogenetic developmental and epileptic encephalopathy.

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.

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.

Glycerol phenylbutyrate (trade name "Ravicti") is an FDA-approved medication used for urea cycle disorders in children and adults. We will titrate to a goal dose of 1.2 mL/m2 (12.4 g/m2) in three equally divided doses given enterally (i.e., by mouth or by g-tube). The dosing is consistent with the dosing guidelines in the FDA approved Medication Guide (https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/203284s005lbl.pdf).

The qualitative safety endpoint will describe any adverse events. It will include a description of the incidence, frequency, and severity of adverse events (including known side effects of the medication, changes in vital signs, EKG changes, EEG changes, increase in seizures, changes in clinical laboratory results, and/or changes in physical examination). We will monitor for these adverse events throughout the study, and measure them definitely at the time of the second admission.

The long term qualitative safety endpoint will describe any adverse events. It will include a description of the incidence, frequency, and severity of adverse events (including known side effects of the medication, changes in vital signs, EKG changes, EEG changes, increase in seizures, changes in clinical laboratory results, and/or changes in physical examination). We will monitor for these adverse events throughout the study, and measure them yearly until December 2025.

The tolerability endpoint is quantitative and will measure medication compliance (i.e. what percentage of the doses are taken).

###### 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

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